https://www.dolcera.com/wiki/api.php?action=feedcontributions&user=Vishal.jaiswal&feedformat=atomDolceraWiki - User contributions [en]2024-03-28T15:59:43ZUser contributionsMediaWiki 1.24wmf12https://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11085Alopecia - Hair Loss2014-12-04T11:04:05Z<p>Vishal.jaiswal: /* Structure-Activity Relationships(SARs) */</p>
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<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.gif|center|720 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|720px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
<br />
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! style="background:lightgrey" | Contact Dolcera<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
|-<br />
| '''Phone''': +1-650-269-7952<br />
|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11084Alopecia - Hair Loss2014-12-04T11:03:15Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.gif|center|720 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
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|-<br />
| '''Phone''': +1-650-269-7952<br />
|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11083Alopecia - Hair Loss2014-12-04T11:02:26Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.gif|center|600 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
<br />
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! style="background:lightgrey" | Contact Dolcera<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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| '''Phone''': +1-650-269-7952<br />
|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11082Alopecia - Hair Loss2014-12-04T11:01:47Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.gif|thumb|center|400 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11081Alopecia - Hair Loss2014-12-04T11:01:05Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[File:Slide3.gif|thumb|right|200 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11080Alopecia - Hair Loss2014-12-04T10:58:49Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[File:Slide3.jpg|700 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11079Alopecia - Hair Loss2014-12-04T10:56:50Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.jpg|700 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Slide3.gif&diff=11078File:Slide3.gif2014-12-04T10:55:42Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11077Alopecia - Hair Loss2014-12-04T10:54:49Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide3.gif|700 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11076Alopecia - Hair Loss2014-12-04T10:53:12Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide2.gif|700 px|Alopecia pathways]]<br />
<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11075Alopecia - Hair Loss2014-12-04T10:50:40Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide2.gif|500 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11074Alopecia - Hair Loss2014-12-04T10:50:21Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide2.gif|700 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br><br />
<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Slide2.gif&diff=11073File:Slide2.gif2014-12-04T10:49:39Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11072Alopecia - Hair Loss2014-12-04T10:48:27Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide2.gif|thumb|right|700 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11071Alopecia - Hair Loss2014-12-04T10:47:32Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide1.gif|thumb|right|700 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
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<br><br />
<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Slide1.gif&diff=11070File:Slide1.gif2014-12-04T10:45:55Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11069Alopecia - Hair Loss2014-12-04T10:44:53Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide1.gif|700 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
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<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
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| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
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|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Alopecia_-_Hair_Loss&diff=11068Alopecia - Hair Loss2014-12-04T10:41:59Z<p>Vishal.jaiswal: /* Pathways associated with Anti Androgen */</p>
<hr />
<div>{{TOCrightEx}}<br />
== Rationale ==<br />
* "Medication for men plagued by hair loss has become a topic of interest in Japan since a drug company began marketing it at the end of last year." March 5th, 2006 – [http://stophair.setupmyblog.com/?p=55 Source]<br />
* "An increasing number of companies are apparently turning the Chinese fear of a bald spot into big bucks with some doing so well they are branching out into other countries." February 16, 2006 – [http://stophair.setupmyblog.com/ Source]<br />
* "There is something in the air, or should we say in the hair, these days. Scientific research into hair loss remedies has never been more active or more exciting." June 7, 2006 - [http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-07-2005/0003821470&EDATE= Source]<br><br><br />
<br><br />
<br />
== Introduction ==<br />
<br />
=== Hair basics ===<br />
* Hair is a complex and delicate part of the body.<br />
* Keeping it healthy and beautiful is a challenge.<br />
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.<br />
* Hair is basically a form of skin. <br />
* Hair is made up of a protein called keratin.<br />
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin. <br />
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]<br />
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]<br />
<br />
[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]<br />
<br />
=== What causes hair loss? === <br />
* Decrease in growth of hair <br />
* Increase in shedding of hair <br />
* Breakage of hair <br />
* Conversion of thick terminal hairs to thin vellus hairs <br />
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]<br />
Both men and women lose hair for similar reasons. Hair loss in men is often more dramatic, and follows a specific pattern of loss, one of which has been termed “Male Pattern Baldness" or "Androgenetic Alopecia".<br />
<br />
<br />
=== Types of alopecia===<br />
<br />
* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.<br />
* Alopecia Totalis (AT): Total loss of the hair on the scalp.<br />
* Alopecia Universalis (AU): Total loss of all hair on the body.<br />
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.<br />
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.<br />
* Androgenetic Alopecia (AGA): Also known as male pattern baldness. It is a thinning of the hair to an almost transparent state, in both men or women. It is thought to be a hereditary form of hair loss.<br />
* Traction Alopecia: Traction alopecia is usually due to excessive pulling or tension on hair shafts as a result of certain hair styles. It is seen more often in women, particularly those of East Indian and Afro-Caribbean origin. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles from developing and leads to permanent hair loss.<br />
* Anagen Effluvium: This hair loss is generally caused by chemicals such as those used to treat cancer. Initially it causes patchy hair loss, which often then leads to total hair loss. The good news is that when you stop using these chemicals the hair normally grows back (usually about 6 months later). Other drugs also can cause hair loss. Many medicines used to treat even common diseases can cause hair loss.<br />
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.<br />
* Telogen Effluvium: A form of hair loss where more than normal numbers of hair fall out. There is a general 'thinning' of the hair. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. ([http://www.alopeciaonline.org.uk/about/types.asp Source])<br />
<br />
=== Androgenetic alopecia ===<br />
* Gradual onset<br />
* Transition from large, thick, pigmented terminal hairs to thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented vellus hairs in the involved areas<br />
* Characterized by a receding hairline and/or hair loss on the top of the head<br />
<br />
'''Main causes'''<br />
* Genetic predisposition<br />
* Hormonal effect of androgen <br />
* Reduction of blood circulation around hair follicle<br />
* Deactivation of hair matrix cells<br />
<br />
'''Some facts from Japan''' <br />
<br />
* Market size: ¥ 30 Billion<br />
* Number of products: more than 100<br />
<br />
(JICST-EPlus - Japanese Science & Technology)<br />
<br />
== IP activity over the years ==<br />
The graph indicates:<br />
* Number of patents filed every 5 years (except for first 7 years).<br />
* First solution proposed in 1973<br />
* Filing trend indicates steep rise in activity recently.<br />
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]<br />
<br />
== Major players ==<br />
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]<br />
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]]<br><br />
<br />
* '''Active assignees'''<br />
Assignees currently active with more than 5 patents to their credit during 2000-2005. <br />
* Warner with 9 patents,<br />
* Bristol with 6 and<br />
* Abbott with 5.<br />
<br />
[[Image:Active.jpg|thumb|center|500px|Active Assignees]]<br />
<br />
== Taxonomy ==<br />
<br />
[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]<br />
<br />
== Interactive Taxonomy ==<br />
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' <br><br />
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard'' <br />
<br />
<mm>[[Map12.mm]]</mm><br />
<br />
== Treatment Approaches==<br />
Composition of treatment for causes are identified and categorized as follows:<br />
<br />
* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]<br />
* Double action (Anti-androgen + Vasodilator)<br />
* Hair matrix cells activator<br />
<br />
{|border="1" cellpadding="2", style="#008080" align="center"<br />
|- style="font-weight:bold" valign="top"<br />
! Cause !! Treatment approach !! Pathways affected<br />
<br />
|- valign="top"<br />
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway<br />
<br />
|- valign="top"<br />
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway<br />
<br />
|- valign="top"<br />
| Deactivation of hair matrix cells || Hair matrix cells activator<br />
| <br />
* Wnt pathway<br />
* STAT pathway<br />
* TGF beta/BMP Pathway<br />
* FGF Pathway<br />
* MAPK Pathway<br />
* NOTCH Pathway<br />
* Hedgehog Pathway<br />
|}<br />
<br />
=== Anti-androgens ===<br />
* Anti-androgens are used in hormone therapy.<br />
* Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect leading to hair loss.<br />
<br />
'''What causes hair loss?'''<br />
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.<br />
* DHT attaches to androgen receptor sites at the hair follicle. <br />
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.<br />
<br />
'''How do anti-androgens treat hair loss?'''<br />
* Anti-androgens compete with DHT to bind to the androgen receptor.<br />
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.<br />
<br />
==== Functions of Anti-androgen ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen]<br />
<br />
[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]<br />
<br />
==== IP Map for anti-androgen ====<br />
<br />
{| border="1" cellpadding="0", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="450" bgcolor=DodgerBlue|'''Composition''' <br />
!width="400" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[[US20060009430]] <br />
BLOTECH (2004)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Palmetto berry extract (fatty acids & sterols), Pumpkin seed extract (Vitamins-B, alpha-linolenic acid, amino acids and phytosterols), Quercetin (Flavonoids) and Beta-sitosterol (Rice bran, wheat germ, corn oils and soybeans)<br />
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone<br />
Sterols - Mechanism of action unknown.<br />
<br />
Quercetin results in cell growth cycle.<br />
<br />
Beta-sitosterol reduce inflammation on scalp<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts<br />
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
WARNER LAMBERT(2004)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.<br />
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
APHIOS Corp (2003)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.<br />
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
Fundacion Pablo Cassara (2003)<br />
|bgcolor=LightCyan|Nucleotide<br />
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)<br />
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
PFIZER INC (2001)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate <br />
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
N/A (1995)<br />
|bgcolor=LightCyan|Peptides/nucleic acid<br />
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)<br />
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor<br />
|- style="height:20px" <br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
KAO Corp (1987)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent<br />
|bgcolor=LightCyan|Blocks formation of DHT<br />
|}<br />
<br />
=== Minoxidil (Vasodilators) ===<br />
* Minoxidil is a "potassium channel opener" that leads to vasodilation.<br />
* The drug is available in two forms. Oral minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness.<br />
<br />
'''What causes hair loss?'''<br />
* A thick network of tiny veins and arteries line the outer wall of the follicle. Blood pumps through the bulb and hair via this network.<br />
* DHT accumulates in the hair follicles and roots, constricting the blood supply of oxygen and nutrients to the hair roots; which is also seen to possibly contribute towards hair loss.<br />
<br />
'''How does Minoxidil treat hair loss?'''<br />
* Minoxidil is applied to the scalp topically, where it dilates blood vessels in the scalp and sustains the hair follicles for longer period of time.<br />
* Minoxidil is thought to have a direct mitogenic effect on epidermal cells, as has been observed both in vitro and in vivo. Though the mechanism of its action for causing cell proliferation is not very clear, minoxidil is thought to prevent intracellular calcium entry. Calcium normally enhances epidermal growth factors to inhibit hair growth, and Minoxidil by getting converted to minoxidil sulfate acts as a potassium channel agonist and enhances potassium ion permeability to prevent calcium ions from entering into cells. ([http://www.hairtransplantadvice.com/medical-hair-restoration.php Source])<br />
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.<br />
<br />
==== Functions of Vasodilators ==== <br />
<br />
[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]<br />
<br />
==== IP Map for Vasodilators ====<br />
<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="600" bgcolor=DodgerBlue|'''Composition'''<br />
!width="300" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
WARNER LAMBERT(2002)<br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|Benzopyran compounds<br />
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
LG HOUSEHOLD & HEALTH CARE(2001)<br />
|bgcolor=LightCyan|Natural extracts<br />
|bgcolor=LightCyan|Sophora flavescens extract (alkaloids & flavonoids, luteolin-7-glucose and cytosine) Hinokitiol (Taiwan hinoki oil, Aomori, Western Red Cedar oil) and Nicotinamide (Vitamin B complex)<br />
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels<br />
|}<br />
<br />
=== Double action (Anti-androgen + Vasodilator) ===<br />
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.<br />
<br />
'''What is the problem with using only Anti-androgen therapy?'''<br />
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.<br />
* Anti-androgen only prevents binding of DHT to androgen receptors. However, the effects of improper oxygen and nutrient supply to the brain due to vasocontriction still remains and gradually causes hair loss.<br />
<br />
'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''<br />
* Vasodilator or Minoxidil-based products are generally not effective in stopping hair loss as vasodilators (or Minoxidil) do not block the harmful effects of DHT in the scalp and hair follicles. <br />
* Vasodilators or Minoxidil simply dilate blood vessels in the scalp. However, the harmful DHT still gets produced in the body, enters the scalp and hair follicles causing hair loss.<br />
<br />
'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''<br />
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.<br />
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.<br />
* Combination therapy therefore proves to be much more effective than individual therapy.<br />
<br />
==== Functions of (Anti-androgen + Vasodilators) ==== <br />
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]<br />
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]<br />
<br />
==== IP Map for (Anti-androgen + Vasodilators) ====<br />
{| border="1" cellpadding="3"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="75" bgcolor=DodgerBlue|'''Nature'''<br />
!width="500" bgcolor=DodgerBlue|'''Composition''' <br />
!width="500" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405] <br />
N/A(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Testosterone blocker or vascular toner (Flutamide, cyproterone acetate, spironolactone, progesterone, or analogs or derivatives) and minoxidil mixed along with non-retinoid penetration enhancer and sunscreen<br />
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577] <br />
L'OREAL(2000)<br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Prostaglandin (polyunsaturated fatty acids) EP-2, EP-3 EP-4 receptor agonist with Minoxidil, 2,4-diaminopyrimidine 3-oxide, and Aminexil, cyclic AMP<br />
|bgcolor=LightCyan|Minoxidil (designed to mimic nitric oxide's effects) grows hair via prostaglandin-H synthase stimulation. EP-3 and EP-4 are expressed in anagen hair follicles which induce a reduction in the level of cAMP<br />
|- style="height:100px" <br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762] <br />
COLOMER GROUP(1999)<br />
|bgcolor=LightCyan|Natural extract<br />
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)<br />
|bgcolor=LightCyan|Inhibits activity of 5-alpha-reductase, protects follicular cell membranes by neutralizing action of oxidation reaction in tissues, stimulates hair follicles and blood circulation to the hair root, supplies oxygen and nutrients to base of follicle, retains humidity, avoids dehydration of scalp<br />
|}<br />
<br />
=== Hair matrix cell activator ===<br />
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.<br />
<br />
'''What causes hair loss?'''<br />
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.<br />
* Stem cells migrate to hair matrix where they start to divide and differentiate, under the influence of substances produced by cells of the dermal papilla.<br />
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.<br />
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.<br />
<br />
<br />
'''How does hair cell matrix activator treat hair loss?'''<br />
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.<br />
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.<br />
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.<br />
<br />
==== Functions of Hair matrix cell activator ====<br />
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]<br />
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]<br />
<br />
==== IP Map for Hair matrix cell activator ====<br />
{| border="1" cellpadding="2"<br />
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''<br />
!width="100" bgcolor=DodgerBlue|'''Nature'''<br />
!width="200" bgcolor=DodgerBlue|'''Composition''' <br />
!width="600" bgcolor=DodgerBlue|'''Composition action'''<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
SHISEIDO(1999) <br />
|bgcolor=LightCyan|Organic compound<br />
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt<br />
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect<br />
|- style="height:50px" <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
L'OREAL(1998) <br />
|bgcolor=LightCyan|Peptides<br />
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions<br />
|bgcolor=LightCyan|Reducing the expression of MMPs (Metalloproteases) in the scalp - slows down or inhibits the degradation of the perifollicular matrix (extracellular matrix surrounding the hair follicle) <br />
|}<br />
<br />
== Technology mapping based on patents analyzed ==<br />
<br />
=== IPMap: Composition nature matrix ===<br />
<br />
{| border="1" cellpadding="11", style="#008080"<br />
!width="120" bgcolor=DodgerBlue|'''Year'''<br />
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extracts''' <br />
!width="200" bgcolor=DodgerBlue|'''Peptides'''<br />
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''<br />
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''<br />
|- style="height:10px"<br />
|bgcolor=LightCyan|2005 <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|- <br />
|bgcolor=LightCyan|2004 <br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|BLOTECH (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|- <br />
|bgcolor=LightCyan|2003<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|APHIOS (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|FUNDACION (1)<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2002<br />
|bgcolor=LightCyan|WARNER (1)<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2001<br />
|bgcolor=LightCyan |PFIZER (1)<br />
|bgcolor=LightCyan|LG HEALTH-CARE (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|2000<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1999<br />
|bgcolor=LightCyan|SHISEDIO (1)<br />
|bgcolor=LightCyan|COLOMER (1) <br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|- <br />
|bgcolor=LightCyan|1998<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|L’OREAL (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1995<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|bgcolor=LightCyan|N/A (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|.... <br />
|-<br />
|bgcolor=LightCyan|1987<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|KAO (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|-<br />
|bgcolor=LightCyan|1982<br />
|bgcolor=LightCyan|UNILEVER (1)<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|bgcolor=LightCyan|....<br />
|}<br />
=== Focus of patents ===<br />
<br />
{| border="1" cellpadding="17", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Synergic effect arising from the interaction of active ingredients, consisting of three plant extracts and a synthetic organosilicic compound for prevent hair loss and stimulate hair growth<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Method of decreasing sebum production and pore size<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277699%22.PGNR.&OS=DN/20050277699&RS=DN/20050277699 US20050277699 ]<br />
|bgcolor=LightCyan|16<br />
|- <br />
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4529587.PN.&OS=PN/4529587&RS=PN/4529587 US4529587]<br />
|bgcolor=LightCyan|17<br />
|}<br />
<br />
=== Technology focus===<br />
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]<br />
=== Distribution of patents ===<br />
<br />
==== By patent types ====<br />
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]<br />
<br />
<br />
==== By key ingredients ====<br />
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]<br />
<br />
==== By target disease ====<br />
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]<br />
<br />
<br />
==== Key ingredients vs. Target disease ====<br />
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]<br />
<br />
<br />
==== Target species ====<br />
[[Image:Species.jpg|thumb|center|700px|Target species]]<br />
<br />
<br />
<br />
==== Mode of administration ====<br />
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]<br />
<br />
<br />
==== Product type vs. Product form ====<br />
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]<br />
<br />
==== Patents by target diseases ====<br />
{| border="1" cellpadding="16", style="#008080"<br />
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220020052498%22.PGNR.&OS=DN/20020052498&RS=DN/20020052498 US20020052498]<br />
|bgcolor=LightCyan|1<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030007941%22.PGNR.&OS=DN/20030007941&RS=DN/20030007941 US20030007941]<br />
|bgcolor=LightCyan|2<br />
|- <br />
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009430%22.PGNR.&OS=DN/20060009430&RS=DN/20060009430 US20060009430]<br />
|bgcolor=LightCyan|3<br />
|- <br />
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009427%22.PGNR.&OS=DN/20060009427&RS=DN/20060009427 US20060009427]<br />
|bgcolor=LightCyan|4<br />
|- <br />
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050118282%22.PGNR.&OS=DN/20050118282&RS=DN/20050118282 US20050118282]<br />
|bgcolor=LightCyan|5<br />
|- <br />
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050085467%22.PGNR.&OS=DN/20050085467&RS=DN/20050085467 US20050085467]<br />
|bgcolor=LightCyan|6<br />
|- <br />
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders. <br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060009429%22.PGNR.&OS=DN/20060009429&RS=DN/20060009429 US20060009429]<br />
|bgcolor=LightCyan|7<br />
|- <br />
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220030073616%22.PGNR.&OS=DN/20030073616&RS=DN/20030073616 US20030073616]<br />
|bgcolor=LightCyan|8<br />
|- <br />
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]<br />
|bgcolor=LightCyan|9<br />
|- <br />
|bgcolor=LightCyan|Alopecia areata, female pattern hair loss, hair loss secondary to chemotherapy or radiation treatment, stress-related hair loss, self-induced hair loss, scarring alopecia, and alopecia in non-human mammal<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040157856%22.PGNR.&OS=DN/20040157856&RS=DN/20040157856 US20040157856]<br />
|bgcolor=LightCyan|10<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050053572%22.PGNR.&OS=DN/20050053572&RS=DN/20050053572 US20050053572]<br />
|bgcolor=LightCyan|11<br />
|- <br />
|bgcolor=LightCyan|Alopecia, androgenic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220060052405%22.PGNR.&OS=DN/20060052405&RS=DN/20060052405 US20060052405]<br />
|bgcolor=LightCyan|12<br />
|- <br />
|bgcolor=LightCyan|Hair loss<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050123577%22.PGNR.&OS=DN/20050123577&RS=DN/20050123577 US20050123577]<br />
|bgcolor=LightCyan|13<br />
|- <br />
|bgcolor=LightCyan|Male pattern alopecia<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6447762.PN.&OS=PN/6447762&RS=PN/6447762 US6447762]<br />
|bgcolor=LightCyan|14<br />
|- <br />
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040071647%22.PGNR.&OS=DN/20040071647&RS=DN/20040071647 US20040071647]<br />
|bgcolor=LightCyan|15<br />
|- <br />
|bgcolor=LightCyan|Curing other scalp related problems<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050244362%22.PGNR.&OS=DN/20050244362&RS=DN/20050244362 US20050244362]<br />
|bgcolor=LightCyan|16<br />
|}<br />
<br />
<br />
<br />
==== [[List of patents]] ====<br />
== Pathways and linkages ==<br />
<br />
=== Pathways associated with hair matrix cell activation===<br />
<br />
'''Molecular mediators of hair follicle embryogenesis:''' Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Homeobox (hox), hedgehog (hh), patched (ptc), wingless (wg}/wnt, disheveled (dsh), engrailed (en), Notch 1 and armadillo/B-catenin genes are all critical for hair follicle.<br />
<br />
* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.<br />
* '''Hedgehog pathway:''' Sonic hedgehog (SHH) signaling plays a critical role in hair follicle development. Sonic hedgehog gene. Sonic hedgehog, SHH for short, helps guide hair follicles from a resting stage into growth activity. SHH is particularly important in the embryonic formation of hair follicles.<br />
* '''STAT pathway'''<br />
* '''TGF beta/BMP Pathway:''' Bone morphogenetic protein (BMP) signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm, but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. Research results show that BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. Transforming growth factor beta (TGF-beta), inhibits mitogen - induced dermal papilla cell proliferation<br />
* '''FGF Pathway:''' Fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth.<br />
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.<br />
* '''NOTCH Pathway''': Notch-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and the follicle bulb, and in the suprabasal cells of the mature outer root sheath. Delta-1, one of the three ligands is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the pre-papilla located beneath the follicle placode, and appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the inner root sheath and hair shaft.<br />
<br />
=== Pathways associated with Anti Androgen===<br />
[[Image:Slide1.GIF|700 px|Alopecia pathways]]<br />
==== Players of WNT inhibition Pathway ==== <br />
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]<br />
{| border="1" cellpadding="15", style="#008080"<br />
!width="150" bgcolor=DodgerBlue|'''Patent no.'''<br />
!width="200" bgcolor=DodgerBlue|'''Key compound'''<br />
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''<br />
|- style="height:10px"<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6989385.PN.&OS=PN/6989385&RS=PN/6989385 US6989385]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|GSK3<br />
|-<br />
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]<br />
|bgcolor=lightyellow|Pyrazole compounds <br />
|bgcolor=lightyellow|CDK,GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6974819.PN.&OS=PN/6974819&RS=PN/6974819 US6974819]<br />
|bgcolor=LightCyan|Pyrimidine derivative<br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6743791.PN.&OS=PN/6743791&RS=PN/6743791 US6743791]<br />
|bgcolor=LightCyan|Heterocyclic compounds<br />
|bgcolor=LightCyan|AKT3, GSK-3, ERK2<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220050277773%22.PGNR.&OS=DN/20050277773&RS=DN/20050277773 US20050277773]<br />
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220040072836%22.PGNR.&OS=DN/20040072836&RS=DN/20040072836 US20040072836]<br />
|bgcolor=LightCyan|Aza-oxindole derivatives <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]<br />
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives <br />
|bgcolor=LightCyan|GSK3<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]<br />
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles <br />
|bgcolor=LightCyan|GSK3, AKT, PKC<br />
|-<br />
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]<br />
|bgcolor=LightCyan|Pyrazolon derivatives <br />
|bgcolor=LightCyan|GSK3, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6924141.PN.&OS=PN/6924141&RS=PN/6924141 US6924141]<br />
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7 <br />
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6706685.PN.&OS=PN/6706685&RS=PN/6706685 US6706685]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6683048.PN.&OS=PN/6683048&RS=PN/6683048 US6683048]<br />
|bgcolor=LightCyan|Peptide sequence <br />
|bgcolor=LightCyan|a-catenin, ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6677116.PN.&OS=PN/6677116&RS=PN/6677116 US6677116]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|-<br />
|bgcolor=LightCyan|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6303576.PN.&OS=PN/6303576&RS=PN/6303576 US6303576]<br />
|bgcolor=LightCyan|Peptide sequence LXXLL<br />
|bgcolor=LightCyan|ß-catenin<br />
|}<br />
<br />
==== Role of Pyrazole compounds in Wnt Pathway====<br />
'''Pyrazole'''<br />
* '''Pyrazole''' (C3H4N2) refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids although they are not known to occur in nature.<br />
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation <br />
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]<br />
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.<br />
* Structurally related compounds are pyrazoline and pyrazolidine.<br />
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]<br />
<br />
==== GSK3 inhibition by pyrazole compounds ====<br />
[[Image:bold3.jpg]]<br />
{| border="1" cellpadding="2", style="#008080"<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?TERM1=6989385+&Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=0&f=S&l=50 US6989385]<br />
[[Image:US6989385.jpg]]<br />
!width="350"|[http://patft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6664247.PN.&OS=PN/6664247&RS=PN/6664247 US6664247] <br />
[[Image:US6664247.jpg]]<br />
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256] <br />
[[Image:WO2005012256.jpg]]<br />
|- <br />
|bgcolor=lightcyan|R1=T-Ring D, wherein <br />
T is a valence bond and <br />
Ring D = 5-6 membered aryl or heteroaryl ring; <br />
<br />
R2 = hydrogen or C1-4 aliphatic and <br />
R2'= hydrogen; <br />
<br />
R3 = -R, -OR, or -N(R4)2, wherein <br />
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and <br />
L is -O-, -S-, or -NH-; and <br />
Ring D is substituted by up to three substituents selected from -halo, -CN, -NO2, -N(R4)2, optionally substituted C1-6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R<4>), -N(R4)COR, -N(R4)CO2R, -SO2N(R4)2, -N(R4)SO2R, -N(R6)COCH2N(R4)2, -N(R6)COCH2CH2N(R4)2, or -N(R6)COCH2CH2CH2N(R4)2, wherein R = hydrogen, C1-6 aliphatic, phenyl, 5-6 membered heteroaryl ring, or 5-6 membered heterocyclic ring<br />
<br />
|bgcolor=lightcyan|X = R1-A-NR4- or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, S02, C=O, NRg(C=O) or O(C=O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; <br />
<br />
R1 is hydrogen; carbocyclic or heterocyclic group having from 3 to 12 ring members; or C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from 0, S, NH, SO, S02; <br />
<br />
R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and <br />
<br />
R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).<br />
<br />
|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;<br />
A is a bond,SO2, C=O, NRg (C=O) or O(C=O) wherein Rg is hydrogen orC14 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy;Y is a bond or an alkylene chain of 1,2 or 3 carbon atoms in length;R'is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e. g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono-ordi-Cl 4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected fromO, S, NH, SO, SO2 ;R2 is hydrogen; halogen;C14 alkoxy (e. g. methoxy); or aC14 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl orC14 alkoxy (e. g. methoxy);R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; andR4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e. g. fluorine), hydroxyl or C1-4 alkoxy (e. g. methoxy).<br />
|}<br />
<br />
==== Inhibition by amine derivatives ====<br />
<br />
'''Patent Number''': US6989385<br />
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol1.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]<br />
<br />
'''Patent Number''': US7008948 <br />
'''Applicant''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure'''<br />
<br />
[[Image:pyrazol2.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]<br />
<br />
'''Patent Number''': US6977262<br />
'''Assignee''': Mitsubishi Pharma Corporation<br />
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof<br />
<br />
'''Basic Structure''':<br />
<br />
[[Image:pyrazol3.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]<br />
<br />
----<br />
'''Patent Number''': US6664247<br />
'''Assignee''': Vertex Pharmaceuticals Incorporated<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol4.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]<br />
<br />
----<br />
'''Patent Number''': US2004224944<br />
'''Assignee''': VERTEX PHARMACEUTICALS INC<br />
'''Title''': Pyrazole compounds useful as protein kinase inhibitors<br />
<br />
'''Basic Structure''': <br />
<br />
[[Image:pyrazol5.jpeg]]<br />
<br />
[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]<br />
<br />
[[Other derivates for alopecia]]<br />
<br />
==== GSK-3 Inhibition Mechanism - Phosphorylation====<br />
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]<br />
* In the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of beta-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of beta-catenin are the pivotal targets for the constitutively active serine kinase GSK3. GSK3 covalently modifies beta-catenin by attaching phosphate groups (from ATP) to serine, and threonine residues. In so doing, the functional properties of the protein kinase’s substrate (beta-catenin) are modified. <br />
<br />
* In the absence of Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate the N-terminal end of beta-catenin, thus promote degradation of beta-catenin and subsequent ubiquitination and proteasomal targeting.<br />
<br />
* Exposure of cells to Wnts leads to inactivation of GSK-3 through an as yet unclear mechanism.The phosphoprotein Dishevelled is required, after receptor-ligand interaction, to transduce the signal that results in the inactivation of GSK-3. As a result, beta-catenin is dephosphorylated and escapes the ubiqduitylation-dependent destruction machinery.<br />
<br />
* Unphosphorylated beta-catanin accumulates in the cytoplasm and translocates to the nucleus, where it can associate with the TCF/LEFs and become a transcriptional transactivator.<br />
<br />
'''[[More details on GSK-3]]'''<br />
<br />
'''Key points'''<br />
<br />
* Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation. [http://jb.oxfordjournals.org/cgi/content/abstract/132/5/697 source]<br />
* Regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. [http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=223838&ArtikelNr=66755&filename=66755.pdf source]<br />
* Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3.[http://lib.bioinfo.pl/auth:He,X source]<br />
* Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. [httSp://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2006/45/i16/abs/bi0601149.html source]<br />
<br />
'''GK3 Inhibition:''' <br />
<br />
* GSK3 is regulated by phosphorylation.<br />
* Phosphorylation of GSK3beta on Ser9 (Ser21 in GSK3alpha) by protein kinase B (PKB) causes its inactivation is the primary mechanism responsible for growth factor inhibition of this kinase. Activation of GSK3beta is dependent upon the phosphorylation of Tyr216 (Tyr279 in GSK3alpha). Upon activation, it has been shown to phosphorylate a number of different cellular proteins, including p53, c-Myc, c-Jun, heat shock factor-1 (HSF-1), beta-catenin and cyclin D1. [http://www.bioreagents.com/index.cfm/fuseaction/products.detail/CatNbr/OPA1-03082 source]<br />
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]<br />
* GSK3’s substrate specificity is unique in that phosphorylation of substrate only occurs if a phosphoserine or phosphotyrosine is present four residues C-terminal to the site of GSK phosphorylation. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430833&dopt=Abstract source]<br />
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]<br />
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.<br />
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP. <br />
<br />
[[image:GSK3_phosphorylation.jpg|400 px|center|thumb|Phosphorylation mechanism [http://images.google.com/images?q=tbn:DGnhgZ7y7pSejM:bass.bio.uci.edu/~hudel/bs99a/lecture26/phosphoaa.gif source]]]<br />
<br />
<br />
* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation. <br />
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation. <br />
* The two probable ways of blocking the oxygen atom are (a) As oxygen is a Lewis acid with strong electron donating capacity, so usually a strong electron pair acceptor can easily bind to oxygen atom and preventing phosphorylation or (b) breaking of the -OH bond with the carbon atom. <br />
<br />
'''Serine - pyrazole reaction'''<br />
<br />
[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]<br />
<br />
* The T-loop of GSK-3 is tyrosine phosphorylated at Y216 and Y279 in GSK-3b and GSK-3a, respectively, but not threonine phosphorylated. Y216/Y279 phosphorylation could play a role in forcing open the substrate (e.g, beta-catanin)-binding site.<br />
<br />
* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.<br />
<br />
* Stimulation of cells with pyrazole compounds cause inactivation of GSK-3 through phosphorylation (S9 of GSK-3 beta and S21 of GSK-3 alpha), which inhibits GSK-3 activity. Thus leading to dephosphorylation of substrates (e.g., beta-catanin) resulting in their functional activation and consequent increased hair follicle morphogenisis.<br />
<br />
* Phosphorylation of S9/S21 creates a primed pesudosubstrate that binds intramolecularly to the positively charged pocket of the GSK-3. This folding precludes phosphorylation of substrates (eg., beta-catanin) because the catalytic groove is occupied. The mechanism of inhibition is competitive. <br />
<br />
* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.<br />
<br />
* Thus, small molecule inhibitors modeled to fit in the positively charged pocket of the GSK-3 kinease domain could potentially be very effective for selective inhibition of primed substrates.<br />
<br />
'''Proposed mechanisms to regulate GSK-3''' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12615961 source]<br />
<br />
# inactivation of GSK-3 through serine phosphorylation<br />
# activation of GSK-3 through tyrosine phosphorylation<br />
# inactivation of GSK-3 through tyrosine dephosphorylation<br />
# Covalant modifications of substrates through priming phosphorylation<br />
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins<br />
# targeting of GSK-3 to different subcellular localizations<br />
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity<br />
# integration of parellel signals conveyed by a signal stimulus.<br />
<br />
'''Key Finding'''<br />
* '''Pyrazole compounds with inhibition constant (Ki) of <0.1 mM''' are a good starting point for developing molecules that can inhibit serine/threonine protein kinase (such as GSK-3) and the proteins they help to regulate. [http://www.chemistry.org/portal/a/c/s/1/acsdisplay.html?DOC=patentwatch%5Carchive%5C011204_patentwatch.html source]<br />
<br />
=== Pathway associated with anti-androgen ===<br />
<br />
* Dihydrotestosterone <br />
** Formed by peripheral conversion of testosterone by 5-alpha reductase<br />
** Binds to androgen receptor on susceptible hair follicles<br />
* Hormone-receptor complex activates genes responsible for gradual transformation of large terminal follicles to miniaturized (progressive diminution of hair shaft diameter and length in response to systemic androgens) follicles<br />
<br />
[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]<br />
<br />
==== Structure-Activity Relationships(SARs) ====<br />
[[Image:SAR_map.gif|center|600px]]<br />
<br />
=== Pathway associated with Minoxidil (vasodilators) ===<br />
Minoxidil is a well know drug used for the treatment of alopecia. A co-relation between Sesquiterpene lactone (Helenalin) produced from Arnica montana and Minoxidil is illustrated in the figure below. Arnica montana, a Vasodilator, acts on the NO/cGMP Pathway through T-cells, B-cells and epithelial cells & abrogates kappa B-driven gene expression.<br />
[[image:vasodiator-rev.jpg|800 px|center]]<br />
<br />
== Alopecia IPMap == <br />
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]<br />
<br />
<br />
<br />
<br />
<br />
== Patent activity in China ==<br />
===Treatment approaches===<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Priority year'''<br />
|align = "center"|'''Assignee/Inventor'''<br />
|-<br />
|rowspan = "7"|Vasodilators<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br />
|2005<br />
|叶明伟<br />
|-<br />
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]<br />
|2005<br />
|王亚杰<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br />
|2003<br />
|谈汝标<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br />
|2002<br />
|赵章光<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br />
|2001<br />
|范希田<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br />
|1996<br />
|殷国健<br />
|-<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br />
|1988<br />
|天津市轻工业化学研究所<br />
|-<br />
|Hair matrix activator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br />
|2002<br />
|朱静建<br />
|-<br />
|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br />
|1996<br />
|梅晓春<br />
|-<br />
|}<br />
<br />
=== Details of treatment approaches===<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"<br />
|align = "center"|'''Patent number'''<br />
|align = "center"|'''Patent title'''<br />
|align = "center"|'''Treatment approach'''<br />
|align = "center"|'''Composition nature'''<br />
|align = "center"|'''Composition'''<br />
|align = "center"|'''Composition action'''<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN200510107497.8&leixin=fmzl&title=治疗瘀血阻滞型脱发的中草药汤剂及制备方法&ipc=A61K36/804(2006.01)I CN1772105]<br>YE MINGWEI (CN)<br>叶明伟 (2005)<br />
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn<br>治疗瘀血阻滞型脱发的中草药汤剂及制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139<br>]WANG YAJIE (CN)<br>王亚杰 2005<br />
|align = "justify"|Alopecia areata treating medicine<br>一种治疗斑秃的药物<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc<br />
|align = "justify"|Promote blood circulation<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN03139861.8&leixin=fmzl&title=一种可用于治疗脱发、白发的天然中草药提取组合物及应用&ipc=A61K35/78 CN1569080]<br>TAN RUBIAO (CN)<br>谈汝标 2003<br />
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application<br>一种可用于治疗脱发、白发的天然中草药提取组合物及应用<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds<br />
|align = "justify"|Enhances the hair growth and healthier hairs<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02111941.4&leixin=fmzl&title=一种含中西药复方的育发剂&ipc=A61K7/06 CN1463693]<br>朱静建 2002<br />
|Hair growing preparation containing compound of Chinese medicine and Western medicine<br>一种含中西药复方的育发剂<br />
|align = "justify"|Hair matrix activator<br />
|Mixture of Herbal extracts and western medicine<br />
|align = "justify"|Persimmon leaf, oriental arbor-vitae leaf, ginseng leaf, yellow qi, fruit of the glossy privet, polygonum multiflorum, Kudzu root, dry ginger; Plus:Minoxidil, Vitamins and derivative, cystine, serine, leucine.<br />
|align = "justify"|Better and faster hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN02155404.8&leixin=fmzl&title=毛囊激活液&ipc=A61K35/78 CN1506103]<br>赵章光2002<br />
|align = "justify"|Hair follice activating liquid<br>毛囊激活液<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers<br />
|align = "justify"|Activates the hair-follicle and enhances the hair growth.<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN01127395.X&leixin=fmzl&title=一种止脱生发药物及其制备方法&ipc=A61K35/78 CN1403100]<br>范希田 2001<br />
|align = "justify"|Trichogen and its prepn<br>一种止脱生发药物及其制备方法<br />
|align = "justify"|Vasodilators<br />
|align = "justify"|Herbal extract<br />
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed<br />
|align = "justify"|Promote blood circulation and enhance hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96116925.7&leixin=fmzl&title=免洗养发生发香波&ipc=C11D3/48 CN1165181]<br>殷国健 1996<br />
|Washing free shampoo for nourishing and growing hair<br>免洗养发生发香波<br />
|align = "justify"|Vasodilator<br />
|Vitamin composition<br />
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum<br />
|align = "justify"|Stimulate hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN96109964.X&leixin=fmzl&title=一种治疗脂溢性脱发的高效低副作用外用药物&ipc=A61K35/78 CN1150043]<br>梅晓春 1996<br />
|Efficient low-side effect external use medicine for curing seborrheic baldness<br>一种治疗脂溢性脱发的高效低副作用外用药物<br />
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator<br />
|Mixture of Herbal extracts and organic compounds<br />
|align = "justify"|Polygonum multiflorum, Ligustrum lucidum, Morus alba, Rehmannia glutinosa, Eclipta prostrata, Saliva miltiorrhiza, Carthamus tinctorius, Cnidium monnieri, Sophora flavescens, Dictamnus dasycarpus, Kochia scoparia, and antioxidants<br />
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth<br />
|-<br />
|align = "justify"|[http://search.sipo.gov.cn/sipo/zljs/hyjs-yx-new.jsp?recid=CN88103853.9&leixin=fmzl&title=一种通络生发香波&ipc=A61K7/06 CN1031022]<br>天津市轻工业化学研究所 1988<br />
|Channel-stimulating and hair-growing hair shampoo<br>一种通络生发香波<br />
|align = "justify"|Vasodilators<br />
|Herbal extract <nowiki>+</nowiki> detergent<br />
|align = "justify"|<font color="#454545">Herbal extracts, Penetration media, Detergents.</font><br />
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los<br />
|-<br />
|}<br clear="all"><br />
<br />
<br />
==<span style="color:#C41E3A">Like this report?</span>==<br />
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'''Dolcera can provide a comprehensive report customized to your needs'''</p><br />
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|-<br />
|}<br />
<br><br />
<br />
== Conclusions ==<br />
* Hair loss medication is a very active area of research and intellectual property development.<br />
* One of the most promising areas of development is the area of Anti-androgens.<br />
* The top companies are Merck, L’Oreal and Smithkline.<br />
<br />
==Contact Dolcera==<br />
<br />
{| style="border:1px solid #AAA; background:#E9E9E9" align="center"<br />
|-<br />
! style="background:lightgrey" | Contact Dolcera<br />
|-<br />
| '''Email''': [mailto:info@dolcera.com info@dolcera.com]<br />
|-<br />
| '''Phone''': +1-650-269-7952<br />
|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:4887766.zip&diff=11042File:4887766.zip2014-02-11T03:30:05Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=More_on_market_overview...&diff=11041More on market overview...2014-02-11T03:25:52Z<p>Vishal.jaiswal: /* Market Analysis */</p>
<hr />
<div><font color="#212121">Urinary incontinence (any involuntary leakage of urine) is a significant health problem in the United States and worldwide. It has a considerable social and economic impact on individuals and society. When discussing the epidemiology and impact of incontinence, it is important to distinguish it between prevalence and incidence.<br />
<br />
'''Prevalence''' is the probability of having a disease or condition, in this case incontinence, within a defined population at a defined point in time. For example, prevalence would be the number of 60-year-old women in the United States in the year 2001 experiencing the symptom of incontinence.<br />
<br />
'''Incidence''', on the other hand, is the probability of developing a disease or condition during a defined period of time. Thus, the percentage of continent women in 2001 that will develop incontinence over the next year would define the incidence of incontinence over a 1-year period.<br />
<br />
</font><br />
<br />
*Incontinence in Women<br />
<br />
<font color="#212121">A 1995 review on the prevalence of incontinence in the general population summarized 11 studies conducted with a mixed population of females of various ages and a variety of causes of incontinence. Figure 1 shows that the prevalence is relatively low early in life, has a peak around the time of menopause, and then rises steadily between the ages of 60 and 80 years. The prevalence of 10% in 15–19-year-olds and 18% in 20–24-year-olds seems a bit high when one considers the number of young women who actually seek treatment for incontinence. This may be a result of including a large number of young women with "insignificant" or non-bothersome incontinence in the survey. ([http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1476070/ National Institutes of Health ])<br />
<br />
</font>'''[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1476070/figure/F1/ Figure 1]'''<br />
[[Image:P&I.jpg]]<br />
<br />
<br />
<font color="#212121">Prevalence of incontinence in general population of females reported in 13 different studies. Young adult, 20% to 30%; Middle age, 30% to 40%; Elderly, 30% to 50%. Reprinted from Sandvik, with permission.</font><br />
<br />
<font color="#212121">Many studies have looked at the relative prevalence of stress, urge, and mixed incontinence in specific populations. The overall prevalence of stress incontinence and mixed incontinence (stress and urge incontinence) is quite high, whereas the overall percentage of urge incontinence is lower. When looking at such data, it is important to consider that although a majority of patients have the symptom of stress incontinence, urge incontinence (including lesser degrees of urge incontinence), tends to be considerably more bothersome than similar degrees of stress incontinence.</font><br />
<br />
*Incontinence in Men<br />
<font color="#212121">The prevalence of incontinence in men of all ages is certainly lower than that for women. Large studies have indicated that there is a 3% to 11% overall prevalence rate of incontinence in the male population with urge incontinence being the prominent symptom reported in 40% to 80% of patients. Next, mixed incontinence is the most prevalent at 10% to 30%, whereas isolated stress incontinence accounts for less than 10% of incontinence in male patients. Stress incontinence in men is rare unless the patient has undergone some type of prostate surgery or has suffered neurological injury or trauma. Incontinence in men increases with age and appears to rise more steadily than it does in women. That is, there are no spikes in prevalence similar to those that occur for women around menopause. However, the estimates for severe incontinence in men in their 70<nowiki>’</nowiki>s and 80<nowiki>’</nowiki>s is still only about half of that in women. A major consideration in the incontinent male patient, especially with urge incontinence, is the potential contribution of bladder outlet obstruction to bladder over activity. Many men suffering from bladder over activity will also have bladder outlet obstruction. Such a situation can affect therapeutic options for patients.</font><br />
<br />
==Habitual Patterns==<br />
<br />
Before analyzing the habitual and behavioral patterns that lead to implantation of a ureteral stent we must understand what all medical conditions require a stent. <br />
There are a variety of reasons why a stent has been placed. <br />
* For patients with stone surgery, the stent allows passage of residual fragments without blocking the ureter. <br />
* Patients who have had ureteroscopy (a look up the ureter) have a stent placed to allow the ureter to remain open while the normal postoperative swelling of the ureter resolves.<br />
* Patients who have had any form of surgery on the ureter have a stent placed to allow healing of the ureter in the proper open fashion.<br />
<br />
<br />
'''Prominent medical problems which may necessitate ureteral stent ''' <br />
<br />
*Kidney stone - [[Inhibitors of stone formation]], [[Calcium]] ,[[Role of dietary animal protein]] and [[Other factors]](Alcohol, vitamin supplements, temperature, space travel etc)<br />
Source [http://en.wikipedia.org/wiki/Kidney_stone Source]<br />
<br />
*Urinary Tract Infection (UTI) and Diabetes<br />
<br />
Urinary Tract Infection, (UTI) is a common ailment and can affect people of all ages, sex, and from all cultures. However, there are certain groups of people that are more prone to UTI than others. Women, for example, for reasons yet to be firmly established, carry a greater risk of UTI. Diabetic patients too fall under this category. Going further, pregnant women with diabetes are probably amongst the most vulnerable to UTI. [[UTI and diabetes complete article]]<br />
<br />
*Diabetes include- [[Alcohol Consumption]] and [[Smoking]]<br />
<br />
*Other prominent reasons like prostrate cancers and tumours, narrowing of the ureter, scarring of the ureter wall etc do not directly relate to any behavioral or habitual patterns. Though genes and hereditary increase the probability of these.<br />
<br />
<br />
Uretral stents are used to ensure the patency of a [http://en.wikipedia.org/wiki/Ureter ureter], which may be compromised, for example, by a [http://en.wikipedia.org/wiki/Kidney_stone kidney stone]. This method is sometimes used as a temporary measure, to prevent damage to a blocked kidney, until a procedure to remove the stone can be performed. Following are the statistics from the national institute of diabetes and digestive and kidney diseases showing the prevalence and incidence rate of urinary incontinence which might result from any of these primary diseases: ([http://www.usrds.org/qtr/default.html Source])<br />
<br />
• Diabetes<br />
<br />
• Hypertension<br />
<br />
• Glomerulonephritis<br />
<br />
• Cystic kidney<br />
<br />
• Urologic disease<br />
<br />
• All other<br />
<br />
==Market Analysis==<br />
Market for ureteral stent can be analyzed by estimating market for each of Ureteral Stent’s fundamental use. Other uses of Ureteral Stent include Post-surgical swelling/infection of uterus, Active kidney infection etc.<br />
<br />
'''Methodology'''<br />
''' <br />
[[Image:Method1.JPG|700px]]<br />
'''<br />
<br />
'''Kidney Stones Market'''<br />
There are four main types of treatments available for curing kidney stones based on type of Kidney Stone, listed as follows<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Sr. No.'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Treatment'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Indications'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Requirement of Ureteral Stent'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''% of cases in general'''</font><br />
|-<br />
|align = "right" bgcolor = "#DBE5F1"|1<br />
|bgcolor = "#DBE5F1"|Lithotripsy<br />
|bgcolor = "#DBE5F1"|Radiolucent calculi, Renal stones <nowiki><</nowiki>2 cm, Ureteral stones <nowiki><</nowiki>1 cm<br />
|bgcolor = "#DBE5F1"|No<br />
|align = "right" bgcolor = "#DBE5F1"|49.07%<nowiki>*</nowiki><br />
|-<br />
|align = "right"|2<br />
|Ureteroscopy<br />
|Ureteral stones<br />
|Yes<br />
|align = "right"|15.48%<nowiki>*</nowiki><br />
|-<br />
|align = "right" bgcolor = "#DBE5F1"|3<br />
|bgcolor = "#DBE5F1"|Ureterorenoscopy<br />
|bgcolor = "#DBE5F1"|Renal stones <nowiki><</nowiki>2 cm<br />
|bgcolor = "#DBE5F1"|Yes<br />
|align = "right" bgcolor = "#DBE5F1"|0.47%<nowiki>*</nowiki><br />
|-<br />
|align = "right"|4<br />
|Percutaneous nephrolithotomy<br />
|Renal stones <nowiki>></nowiki>2 cm, Proximal ureteral stones <nowiki>></nowiki>1 cm<br />
|No<br />
|align = "right"|34.98%<nowiki>*</nowiki><br />
|-<br />
|}<br />
<br />
<nowiki>*</nowiki>Dolcera Estimate 2011<br />
<br />
As seen in table ureteral stent is required for Ureteroscopy and Ureterorenoscopy which together constitute for around 16% of Kidney stone cases.<br />
<br />
Total Number of Kidney Stone Cases in US in 2006: 166,000<br />
<br />
Approximate Stents required in 2006 = 166,000<nowiki>*</nowiki>0.16=26560<br />
<br />
'''Kidney Transplant Market''' <br />
Every kidney transplant operation required ureteral stent to be placed in Patient<nowiki>’</nowiki>s body for few days till newly placed kidney adapts to Patients<nowiki>’</nowiki> body<br />
<br />
Total No. of Kidney Transplants done in United States in 2007 are approx. 17,513<br />
<br />
Total Market for Ureteral Stents in 2007 is 17,513<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="54%"<br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Year'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''No. of Kidney Transplants'''</font><br />
|-<br />
|align = "right"|'''2007'''<br />
| 17,513<br />
|-<br />
|align = "right"|'''2006'''<br />
| 18,056<br />
|-<br />
|align = "right"|'''2005'''<br />
| 17,443<br />
|-<br />
|align = "right"|'''2000'''<br />
| 14,611<br />
|-<br />
|align = "right"|'''1995'''<br />
| 12,160<br />
|-<br />
|align = "right"|'''1990'''<br />
| 10,029<br />
|-<br />
|align = "right"|'''1985'''<br />
| 7,504<br />
|-<br />
|align = "right"|'''1980'''<br />
| 3,785<br />
|-<br />
|}<br />
<br />
'''Urinary Incontinence Market'''<br />
'''Inpatient hospital stays:'''The estimated number of hospital admissions among adults ages 18 or older with urinary incontinence listed as a diagnosis:<br>'''(2000):''' 47,802 hospital stays (1,332 men; 46,470 women)<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="40%" <br />
|align = "center" bgcolor = "#5CB3FF" colspan = "2"|'''Prevalence of Urinary Incontinece in US (Women)'''<br />
|-<br />
|bgcolor = "#5CB3FF"|'''Age (in years)'''<br />
|'''Population with Urinary Incontinence (in %)'''<br />
|-<br />
|bgcolor = "#5CB3FF"|30-39<br />
|align = "center"|28<br />
|-<br />
|bgcolor = "#5CB3FF"|40-49<br />
|align = "center"|41<br />
|-<br />
|bgcolor = "#5CB3FF"|50-59<br />
|align = "center"|48<br />
|-<br />
|bgcolor = "#5CB3FF"|60-69<br />
|align = "center"|51<br />
|-<br />
|bgcolor = "#5CB3FF"|70-79<br />
|align = "center"|55<br />
|-<br />
|bgcolor = "#5CB3FF"|≥ 80<br />
|align = "center"|54<br />
|-<br />
|}<br />
<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="102%"<br />
|align = "center" colspan = "6"|'''Estimated cases for ureteral stents in US, 2010'''<br />
|-<br />
|bgcolor = "#5CB3FF"|Age groups<br />
|bgcolor = "#5CB3FF"|A) Female population (Million)<br />
|bgcolor = "#5CB3FF"|B) Prevalence rate in female (%)<br />
|bgcolor = "#5CB3FF"|C=A<nowiki>*</nowiki>B Affected population<br>(Million)<br />
|bgcolor = "#5CB3FF"|D) Catherization rate (%)<br />
|bgcolor = "#5CB3FF"|E=C<nowiki>*</nowiki>D<br>Stent market based on catherization<br />
|-<br />
|bgcolor = "#5CB3FF"|30-39<br />
|align = "right"|20.10<br />
|align = "right"|28<br />
|align = "right"|5.62<br />
|align = "right"|0.043<br />
|2420.42<br />
|-<br />
|bgcolor = "#5CB3FF"|40-49<br />
|align = "right"|21.99<br />
|align = "right"|41<br />
|align = "right"|9.01<br />
|align = "right"|0.123<br />
|11092.83<br />
|-<br />
|bgcolor = "#5CB3FF"|50-59<br />
|align = "right"|21.50<br />
|align = "right"|48<br />
|align = "right"|10.32<br />
|align = "right"|0.124<br />
|12800.37<br />
|-<br />
|bgcolor = "#5CB3FF"|60-69<br />
|align = "right"|15.32<br />
|align = "right"|51<br />
|align = "right"|7.81<br />
|align = "right"|0.160<br />
|12503.68<br />
|-<br />
|bgcolor = "#5CB3FF"|70-79<br />
|align = "right"|9.16<br />
|align = "right"|55<br />
|align = "right"|5.04<br />
|align = "right"|0.172<br />
|8674.44<br />
|-<br />
|bgcolor = "#5CB3FF"|≥ 80<br />
|align = "right"|7.15<br />
|align = "right"|54<br />
|align = "right"|3.86<br />
|align = "right"|0.044<br />
|1699.48<br />
|-<br />
|bgcolor = "#5CB3FF"|Total<br />
|align = "right"|95.25<br />
|&nbsp;<br />
|align = "right"|41.69<br />
| <br />
| <br />
|-<br />
|}<br />
<br />
<br />
* '''Catherization rate''' depicts the actual number of people going in for ureteral stents.<br />
* Prevalence rate in US women is growing at a CAGR of 1.26%<br />
<br />
Assuming that each admission in hospital required one ureteral stent, market from Urinary Incontinence is around 47,802 stents per year<br />
<br />
'''Total Market for Ureteral Stent'''<br />
Following table displays approximate stent market per year<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="64%"<br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''Category'''</font><br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">'''No. of Stents Required'''</font><br />
|-<br />
|bgcolor = "#DBE5F1"|Stent Market for Kidney Stones<br />
|align = "center" bgcolor = "#DBE5F1"|26560<br />
|-<br />
|Stent Market for Kidney Transplant<br />
|align = "center"|17513<br />
|-<br />
|bgcolor = "#DBE5F1"|Stent Market for Urinary Incontinence<br />
|align = "center" bgcolor = "#DBE5F1"|47802<br />
|-<br />
|bgcolor = "#4F81BD"|<font color="#FFFFFF">Total</font><br />
|align = "center" bgcolor = "#4F81BD"|<font color="#FFFFFF">91875</font><br />
|-<br />
|}<br />
<br />
<br />
<br />
* Ureteral stent market is growing at a CAGR of 1.58%<br />
<br />
<br />
<br />
'''Ureteral stent market forecast in US (women)'''<br />
''' <br />
[[Image:stent_forcast.jpeg]]<br />
'''<br />
<br/><br />
<br/><br />
[[media:4887766.zip |Detailed_calculation_workbook]]<br />
<br />
== Government Policy==<br />
<br />
Medicare carriers may issue local coverage decisions (LCDs) listing criteria that must be met prior to coverage.<br />
<br />
Physicians are urged to review these policies [http://www.cms.hhs.gov/mcd/search.asp], and are encouraged to contact their local carrier medical director or commercial insurers to determine if a procedure is covered.<br />
<br />
The coding covers the following -<br />
<br />
* Placement<br />
<br />
* Removal<br />
<br />
* Imaging<br />
<br />
* Outpatient hospital<br />
<br />
* Inpatient hospital<br />
<br />
[[media:cook.pdf|Click here]] for coding details and payment.<br />
<br />
==Ureteral Stent Pricing==<br />
<br />
<u>'''Boston Scientific and Cook INC'''</u><br />
<br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center" bgcolor = "#5CB3FF"|'''Manufacturer'''<br />
|align = "center" bgcolor = "#5CB3FF"|'''Stent'''<br />
|align = "center" bgcolor = "#5CB3FF"|'''Price (in USD)'''<br />
|-<br />
|bgcolor = "#5CB3FF"|Boston Scientific<br />
|Percuflex Plus Ureteral Stent<br />
|16.99-24.99<br />
|-<br />
|bgcolor = "#5CB3FF"|Boston Scientific<br />
|Polaris Ureteral Stent<br />
|24.99<br />
|-<br />
|bgcolor = "#5CB3FF"|Boston Scientific<br />
|Polaris Ultra Ureteral Stent<br />
|16.99-24.99<br />
|-<br />
|bgcolor = "#5CB3FF"|Cook INC<br />
|Ureteral Stent Set<br />
|19.99<br />
|-<br />
|bgcolor = "#5CB3FF"|Cook INC<br />
|Resonance Metallic Ureteral Stent and Introducer<br />
|179.99-224.99<br />
|-<br />
|}<br />
'''Source: '''[http://www.medsurplusonline.com/ medsurplusonline]<br />
<br />
'''<nowiki>*</nowiki>''' Most of the products apart from speciality products of both the companies have the same name and price.<br />
<br />
Their is just a slight modification in the stent which can be found out on the website given above according to the item number.<br />
<br />
Paid report ([http://www.medtechinsight.com/ReportA251.html medtechinsight] and [http://www.lifescienceintelligence.com/market-reports-page.php?id=A255 lifescienceintelligence]) on pricing and ordering information.<br />
<br />
'''Ureteral Stent Substitutes'''<br />
<br />
Ureteral Stents are not very expensive so the primary reason to seek alternatives arise out of the disadvantages of using a ureteral stent.<br />
<br />
About 50% of patients will have some type of side-effect associated with their stent. It is not possible to predict who will have stent-associated difficulties or when the stent symptoms will resolve. Some patients have stent symptoms for just a few days, while others find their symptoms persist throughout their entire stent duration. <br />
<br />
[[Main article- Ureteral stent difficulties]]<br />
<br />
It may be reasonable not to leave a ureteral stent if obstruction is likely to be transient. Your surgeon decides at the time of the procedure whether or not your circumstance warrants “stent free.” Occasionally, it may be possible to place a tube externally that drains the kidney. This tube is placed directly through the skin, through the kidney, and into the urinary space, called a [http://en.wikipedia.org/wiki/Nephrostomy nephrostomy] tube. This is placed under ultrasound or fluoroscopic Xray guidance. As the tube remains outside the body, it is slightly more inconvenient, has higher infection rates, and can sometimes get pulled out by accident. The advantage of a nephrostomy tube is better drainage, ability to place contrast into the kidney to evaluate for obstruction or leakage, and removal that does not require a [http://en.wikipedia.org/wiki/Cystoscopy cystoscopic] procedure.<br />
<br />
<font size = "2">'''Cost analysis of different treatments'''</font><br />
<br />
<br><br />
{|border="2" cellspacing="0" cellpadding="4" width="100%"<br />
|align = "center" bgcolor = "#5CB3FF"|'''Treatment/Procedure'''<br />
|align = "center" bgcolor = "#5CB3FF"|'''Cost (In USD)'''<br />
|-<br />
|bgcolor = "#5CB3FF"|Ureteral Stent implant<br />
|1500-2500<br />
|-<br />
|bgcolor = "#5CB3FF"|[http://en.wikipedia.org/wiki/Laser_lithotripsy Laser lithotripsy]<br />
|5000-7000<br />
|-<br />
|bgcolor = "#5CB3FF"|[[Urine alkalinization]]<br />
|<font color="#0000FF"><u>[http://www.everydayhealth.com/drugs/c/urinary-alkalinization Cost comparison (Drug based)]</u></font><br />
|-<br />
|bgcolor = "#5CB3FF"|[[Allopurinol]]<br />
|<font color="#0000FF"><u>[http://pharmacychecker.com/Pricing.asp?DrugName=Allopurinol&DrugId=18415&DrugStrengthId=30083 Drug wise prices]</u></font><br />
|-<br />
|bgcolor = "#5CB3FF"|[http://en.wikipedia.org/wiki/Extracorporeal_shock_wave_lithotripsy Extracorporeal shock wave lithotripsy]<br />
|Not available<br />
|-<br />
|bgcolor = "#5CB3FF"|[[Alpha Blockers]]<br />
|Not available<br />
|-<br />
|}<br />
<br />
<br />
Source - [http://www.medsolution.com/surgery_urogen-lithotripsy.asp medsolution]</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Sample_Analysis_with_Problem_Solution_Approach&diff=11040Sample Analysis with Problem Solution Approach2014-02-06T07:41:00Z<p>Vishal.jaiswal: </p>
<hr />
<div>{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''S.No. '''<br />
|align = "center" bgcolor = "#FAC090"|'''Patent/Publication No.'''<br />
|align = "center" bgcolor = "#FAC090"|'''Publication Year'''<br />
|align = "center" bgcolor = "#FAC090"|'''Assignee / Applicant'''<br />
|align = "center" bgcolor = "#FAC090"|'''Title'''<br />
|align = "center" bgcolor = "#FAC090"|'''Problem '''<br />
|align = "center" bgcolor = "#FAC090"|'''Solution '''<br />
|align = "center" bgcolor = "#FAC090"|'''Image'''<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''1'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8459537.PN.&OS=PN/8459537&RS=PN/8459537 US8459537B2]</u></font><br />
|align = "center"|2013<br />
|align = "center" |Barilla G. e R. Fratelli S.p.A. <nowiki>|</nowiki> Moglia, Roberto <nowiki>|</nowiki> Amigoni, Michele <nowiki>|</nowiki> Innocente, Mario<br />
|align = "center"|Easy reclosing system for a container for dry foodstuffs and related container<br />
|align = "center"|To develop a new and easy reclosing system for a container of dry foodstuffs which is economical, simplified in operation of opening and closing, guaranteeing adequate seal in the closure position, without jeopardising the pouring capacity<br />
|align = "center"|An easy reclosing system for dry foods formed by a first flap and a second flap which overlap to form the closure. The first flap is inserted between the two notches placed laterally to the tongue which is semi-circular<br />
|align = "center"|[[Image:US8459537B2.jpg|thumb|center|150px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''2'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8240505.PN.&OS=PN/8240505&RS=PN/8240505 US8240505B1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|None<br />
|align = "center"|Easy-open sealing type food container<br />
|align = "center"|To provide a food container, which achieves excellent sealing effects and facilitates opening<br />
|align = "center"|A peripheral wall of the container body has one recessed wall portion disposed in one corner and forms a retracted external space area and concave camber between the recessed wall portion and a hem. A pull tab extends from an outer side of a cover sealing rib and is inserted into above said concave camber<br />
|align = "center"|[[Image:US8240505B1.jpg|thumb|center|150px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''3'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2208685 EP2208685B1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Shikoku Kakoh Co., Ltd.<br />
|align = "center"|Film for food packaging<br />
|align = "center"|To provide a food packaging film which is excellent in workability, processability, productivity, gas barrier properties, low-temperature heat sealing properties, safety and mechanical strengths and can be used as an alternative film for cellophane/wax films<br />
|align = "center"|A packaging film for melting cheese comprises at least five layers of a heat seal layer/an adhesive layer/a gas barrier layer/an adhesive layer/a heat seal layer. The heat seal layer comprises an olefin-based resin and melts between 60°C and 90°C.<br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''4'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2081990 EP2081990B1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Nova Chemicals (International) S.A.<br />
|align = "center"|Barrier film for food packaging<br />
|align = "center"|To prepare a HDPE film with barrier properties <br />
|align = "center"|Barrier films are prepared from a blend of two high density polyethylene components with substantially different melt indices using a high performance organic nucleating agent.<br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''5'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2128036 EP2128036B1]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Girnet internacional, s.l.<br />
|align = "center"|Bag for packaging food products<br />
|align = "center"|To provide a bag for packaging food products such as fruit and vegetable products<br />
|align = "center"|The bag contains a flexible tubular body of a woven or extruded tubular mesh, a central portion which is designed to house the products contained in the bag and the longitudinal ends which are closed. A flexible oblong element such as a strip is joined to both closed ends which acts as a handle. <br />
|align = "center"|[[Image:EP2128036B1.jpg|thumb|center|150px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''6'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2025620 EP2025620A4]</u></font><br />
|align = "center"|2010<br />
|align = "center"|None<br />
|align = "center"|Active packaging that inhibits food pathogens<br />
|align = "center"|To provide a pathogen inhibiting food packaging<br />
|align = "center"|The pathogen inhibiting actives in the packaging include paraffin and natrual extracts such as cinnamon, thyme, clove, oregano or any combination.<br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''7'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2079315 EP2079315A2]</u></font><br />
|align = "center"|2009<br />
|align = "center"|Kuhne anlagenbau gmbh<br />
|align = "center"|Antimicrobial food packaging<br />
|align = "center"|To provide a multi-layer food packaging that is resistant to pathogenic microbes <br />
|align = "center"|A 3-or 5-or 7 layer food packaging where the antimicrobial properties are obtained from a finely divided metal and its salt<br />
|align = "center"|N/A<br />
<br />
|}<br />
<br />
:* Click here to view list of [[Media:Patent Analysis Sheet-Colgate proposal.xls|Old Analysis sheet]]</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Antimicrobial_films-Colgate.mm&diff=11039File:Antimicrobial films-Colgate.mm2014-02-06T07:39:54Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Taxonomy_of_Antimicrobial_films&diff=11038Taxonomy of Antimicrobial films2014-02-06T07:37:43Z<p>Vishal.jaiswal: </p>
<hr />
<div>==[[Taxonomy of Antimicrobial films]]==</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Food_Packaging_and_Salmonella_Prevention_through_Packaging&diff=11037Food Packaging and Salmonella Prevention through Packaging2014-02-06T07:31:28Z<p>Vishal.jaiswal: /* Sample Analysis Sheet */</p>
<hr />
<div>==Objective==<br />
<br />
The objective is to provide a landscape of the latest Food Packaging technologies that provide added consumer benefits. We will explore patent data bases to extract these technologies and highlight any claims mentioned that discuss new and beneficial consumer benefits. In addition, this final report will show where this technology is being developed, who is developing technologies in food packaging and white space potential.<br />
<br />
==Background==<br />
<br />
The major role of packaging is to protect the food product it contains against water, water vapor, air, oxygen, microorganisms, insects, other intruders, dirt, pilferage, etc. Besides protection, containment, communication, unitization, sanitation, dispensing, convenience, are some of the other package functions. One major benefit to the consumer from packaging is the safety of the product that it holds. [http://www.enq.ufsc.br/disci/eqa5216/material_didatico/DEVELOPINGNEWFOOD/TX67784_08.pdf Book on Development of Packaging for Food Products]. Active packaging interacts with a product by releasing or absorbing substances to/from the packed food product and thereby extending shelf-life and improving food safety and quality. Some of the active packaging concepts include anti-microbial films, anti-oxidant films, and scavenging concepts such as oxygen scavenging, ethylene scavenging, moisture regulation etc. to preserve the freshness of the food product. [http://www.paperimpact.org/what-is-active-packaging-289.html Paperimpact]. Researchers have also shown the migration of the antimicrobial compound such as ethyl lauryl arginate (LAE) to chicken breast to be within the regulated limits when using an active packaging. LAE has been shown to be effective against Listeria. [http://www.foodproductiondaily.com/Quality-Safety/Migration-levels-of-antimicrobial-packaging-material-found-to-be-safe FoodProduction Daily]. Release of salicylic acid from polymer films can<br />
prevent the formation of Salmonella typhimurium biofilms. [http://foodsci.rutgers.edu/chikindas/MChikindas%20Manuscripts/JAPR-2009-3-193.pdf Review article of Rutgers University].<br />
<br />
[[Image:Antimicrobial_packaging.jpg|thumb|center|1000px|]]<br />
<br />
=Food Packaging=<br />
<br />
==[[Old Sample patents]]==<br />
<br />
==[[Revised Sample patents]]==<br />
<br />
==Revised Sample patents-Consumer Perspective ==<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FCD5B4"|'''S. No.'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Patent/Publication No.'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Publication Year'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Assignee / Applicant'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Title'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Dolcera summary '''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Image'''<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''1'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8481134.PN.&OS=PN/8481134&RS=PN/8481134 US8481134B2]</u></font><br />
|align = "center"|2013<br />
|align = "center"|L<nowiki>’</nowiki>oreal. <nowiki>|</nowiki> atis, balanda <nowiki>|</nowiki> pradier, françois <nowiki>|</nowiki> kanji, mohamed <nowiki>|</nowiki> brereton, evelyn <nowiki>|</nowiki> gavin, linda<br />
|align = "center"|Biodegradable moisture-impermeable packages for consumer goods<br />
|align = "center"|<font color="#FF0000">Biodegradable and moisture impermeable</font><br />
|[[Image:US8481134B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''2'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8485378.PN.&OS=PN/8485378&RS=PN/8485378 US8485378B2]</u></font><br />
|align = "center"|2013<br />
|align = "center" |General mills, inc. <nowiki>|</nowiki> zoss, robert a. <nowiki>|</nowiki> scholtes, bryan <nowiki>|</nowiki> genord, dan<br />
|align = "center"|Multi-container packages for dispensing liquid and dry food<br />
|align = "center"|Package for <font color="#FF0000">multi-component such as cereal and milk</font><br />
|[[Image:US8485378B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''3'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8475856.PN.&OS=PN/8475856&RS=PN/8475856 US8475856B2]</u></font><br />
|align = "center"|2013<br />
|align = "center" |Sheehan, andrew <nowiki>|</nowiki> sheehan, andrew<br />
|align = "center"|OTG (on the go) specialty multi-beverage container systems<br />
|align = "center"|<font color="#FF0000">On the go specialty multicontainer </font>for mixing and transporting a variety of powder-based beverages<br />
|[[Image:US8475856B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''4'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8403164.PN.&OS=PN/8403164&RS=PN/8403164 US8403164B2]</u></font><br />
|align = "center"|2013<br />
|align = "center"|Samson, ilan<br />
|align = "center"|Cap for a spill-proof beverage container<br />
|align = "center"|<font color="#FF0000">Cap for a spill-proof cup </font>with a reliable seal between the rigid and flexible members of the demand valve.<br />
|[[Image:US8403164B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''5'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8377529.PN.&OS=PN/8377529&RS=PN/8377529 US8377529B2]</u></font><br />
|align = "center"|2013<br />
|align = "center" |Cryovac, inc. <nowiki>|</nowiki> bekele, solomon<br />
|align = "center"|Ultra high barrier aseptic film and package<br />
|align = "center"|A coextruded film with <font color="#FF0000">good oxygen barrier properties </font>for pouches made in a <font color="#FF0000">VFFS aseptic system</font>, that exhibits extended shelf life for the contained product by providing<br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''6'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2013085911 WO2013085911A2]</u></font><br />
|align = "center"|2013<br />
|align = "center"|Sepehr, cyrus, a.<br />
|align = "center"|Consumer oriented system for delivery of product including single serving package for preservative-free fruit pieces<br />
|align = "center"|<font color="#FF0000">Single serve packaging </font>for preservative free fruit pieces<br />
|[[Image:WO2013085911A2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''7'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8231272.PN.&OS=PN/8231272&RS=PN/8231272 US8231272B2]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Goglio s.p.a.<br />
|align = "center"|Stand-up, easy-open and easy-close package of flexible material, particularly for liquid, viscous, pasty, granular or powdered products<br />
|align = "center"|Flexible package for viscous, granular or powdered substances with peelable closure for <font color="#FF0000">easy open and close</font><br />
|[[Image:US8231272B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''8'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8198571.PN.&OS=PN/8198571&RS=PN/8198571 US8198571B2]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Graphic packaging international, inc.<br />
|align = "center"|Multi-compartment microwave heating package<br />
|align = "center"|A <font color="#FF0000">microwave package </font>for heating, browning, and/or crisping a food<br />
|[[Image:US8198571B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''9'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8167487.PN.&OS=PN/8167487&RS=PN/8167487 US8167487B2]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Milprint, inc.<br />
|align = "center"|Secure access easy opening tamper evident feature for sealable bags<br />
|align = "center"|<font color="#FF0000">Bags with a tamper evident feature </font>having an easy rupturable opening <br />
|[[Image:US8167487B2.jpg|thumb|center|300px|]]<br />
<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''10'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8151985.PN.&OS=PN/8151985&RS=PN/8151985 US8151985B2]</u></font><br />
|align = "center"|2012<br />
|align = "center"|None<br />
|align = "center"|Containers for storing at least two substances for subsequent mixing<br />
|align = "center"|<font color="#FF0000">Disposable recyclable container </font>for keeping two substances separate until mixed. The container can be enclosed in a tamper-evident film that includes a perforated pull strip<br />
|[[Image:UUS8151985B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''11'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2284099 EP2284099B1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Graphic packaging international, inc.<br />
|align = "center"|Microwave packaging for multi-component meals<br />
|align = "center"|<font color="#FF0000">Packaging constructs </font>in the form of trays, and other package forms for <font color="#FF0000">heating, browning, and/or crisping at least one food item in a microwave oven</font><br />
|[[Image:EP2284099B1.jpg|thumb|center|300px|]]<br />
<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''12'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2208604 EP2208604B1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Amcor flexibles kreuzlingen ltd.<br />
|align = "center"|Packaging pouch with food flow properties<br />
|align = "center"|<font color="#FF0000">Packaging pouch </font>made of a flexible mono or multilayer film for packaging viscous jelly and/or gravy matrix food in <font color="#FF0000">a thermo cycle such as retort, pasteurisation, hot filling or aseptic conditions</font><br />
|[[Image:EP2208604B1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''13'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220120168025%22.PGNR.&OS=DN/20120168025&RS=DN/20120168025 US20120168025A1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Nestec s.a.<br />
|align = "center"|Disposable very lightweight package<br />
|align = "center"|A <font color="#FF0000">biodegradable flexible pouch-like disposable package </font>with a hermetic seal<br />
|[[Image:US20120168025A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''14'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2459463 EP2459463A1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Nestec s.a.<br />
|align = "center"|Easy opening packaging for liquid or gel products<br />
|align = "center"|A flexible package for a food product such as gel having <font color="#FF0000">a closure which is suitable for one hand operation</font><br />
|[[Image:EP2459463A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''15'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8080770.PN.&OS=PN/8080770&RS=PN/8080770 US8080770B2]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Ball corporation<br />
|align = "center"|Microwavable metallic container<br />
|align = "center"|<font color="#FF0000">A metallic microwavable container </font>which is hermetically sealed and capable of storing foodstuffs for long periods of time<br />
|[[Image:US8080770B2.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''16'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7981408.PN.&OS=PN/7981408&RS=PN/7981408 US7981408B2]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Boston brands, inc.<br />
|align = "center"|Method of preserving food using antimicrobial packaging<br />
|align = "center"|<font color="#FF0000">Antimicrobial film </font>for food packaging<br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''17'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=1888430 EP1888430B1]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Graphic packaging international, inc.<br />
|align = "center"|Microwavable food package having an easy-open feature<br />
|align = "center"|Package construct for <font color="#FF0000">cooking or heating a food item in a microwave oven</font>. <br />
|align = "center"|N/A<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''18'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=GB&NR=2476365 GB2476365A]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Avondale foods, limited<br />
|align = "center"|Food packaging for two different food products to be stored separately<br />
|align = "center"|<font color="#FF0000">A Microwaveable food packaging </font>containing a first outer bowl for a first food and a separable insert tray for a second food where the insert tray fits within the first bowl.<br />
|[[Image:GB2476365A.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''19'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220100108680%22.PGNR.&OS=DN/20100108680&RS=DN/20100108680 US20100108680A1]</u></font><br />
|align = "center"|2010<br />
|align = "center"|None<br />
|align = "center"|Enhanced tamper evident container with tear-apart parts<br />
|align = "center"|<font color="#FF0000">Easily openable tamper evident container </font>where a large sustained pull force has to be applied to separate a lid from a peripheral cover portion that is fixed to a peripheral base portion of the base<br />
|[[Image:US20100108680A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''20'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=1777173 EP1777173B1]</u></font><br />
|align = "center"|2010<br />
|align = "center"|Mora negrin, pedro ramon<br />
|align = "center"|Easily opened flexible vacuum packaging for single portions of pasty fluids<br />
|align = "center"|<font color="#FF0000">Easy-open flexible vacuum container for single dose</font>s of viscous fluids<br />
|[[Image:EP1777173B1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''21'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=2141085 EP2141085A1]</u></font><br />
|align = "center"|2010<br />
|align = "center"|Nestec s.a.<br />
|align = "center"|Easy opening packaging for food products<br />
|align = "center"|<font color="#FF0000">Easy open flexible packaging </font>for energy bars <font color="#FF0000">providing a bigger surface for consumer information</font><br />
|[[Image:EP2141085A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''22'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220090285941%22.PGNR.&OS=DN/20090285941&RS=DN/20090285941 US20090285941A1]</u></font><br />
|align = "center"|2009<br />
|align = "center"|None<br />
|align = "center"|Combination package of liquid and solid foodstuff<br />
|align = "center"|<font color="#FF0000">A multi-compartment package for convenience and portability </font>to a favorite snack such as cookies and milk<br />
|[[Image:US20090285941A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''23'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220090214723%22.PGNR.&OS=DN/20090214723&RS=DN/20090214723 US20090214723A1]</u></font><br />
|align = "center"|2009<br />
|align = "center"|None<br />
|align = "center"|Two component package for simultaneous heating<br />
|align = "center"|A package for simultaneous heating of <font color="#FF0000">a crispy food product and a non-crispy food product in microwave.</font><br />
|[[Image:US20090214723A1.jpg|thumb|center|300px|]]<br />
<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''24'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220090032487%22.PGNR.&OS=DN/20090032487&RS=DN/20090032487 US20090032487A1]</u></font><br />
|align = "center"|2009<br />
|align = "center"|Stephen s. Rekstad<br />
|align = "center"|Spill resistant caps and container systems<br />
|align = "center"|<font color="#FF0000">A spill resistant cap </font>for a standard commercially available beverage bottle containing water, milk, juice, soda or other beverage.<br />
|[[Image:US20090032487A1.jpg|thumb|center|300px|]]<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''25'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7494279.PN.&OS=PN/7494279&RS=PN/7494279 US7494279B2]</u></font><br />
|align = "center"|2009<br />
|align = "center"|Mars incorporated<br />
|align = "center"|Ergonomic bag assembly for foods<br />
|align = "center"|<font color="#FF0000">An ergonomic bag assembly </font>for granular foods contains two bags mutually joined by a gripping element comprising a handle<br />
|[[Image:US7494279B2.jpg|thumb|center|300px|]]<br />
<br />
|}<br />
<br />
<br />
<br />
==Search Methodology==<br />
<br />
===Relevant Class Codes and Definitions ===<br />
=====IPC/ECLA=====<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''Class'''<br />
|align = "center" bgcolor = "#FAC090"|'''Definition'''<br />
<br />
|-<br />
|align = "center"|A23L<br />
|Foods, foodstuffs, or non-alcoholic beverages<br />
<br />
|-<br />
|align = "center"|A23L0001*<br />
|Foods or foodstuffs; their preparation or treatment<br />
<br />
|-<br />
|align = "center"|B32B*<br />
|Layered products, i.e. Products built-up of strata of flat or non-flat, e.g. Cellular or honeycomb, form<br />
<br />
|-<br />
|align = "center"|B65B* <br />
|Machines, apparatus or devices for, or methods of, packaging articles or materials; unpacking<br />
<br />
|-<br />
|align = "center"|B65D*<br />
|Containers for storage or transport of articles or materials, e.g. Bags, barrels, bottles, boxes, cans, cartons, crates, drums, jars, tanks, hoppers, forwarding containers; accessories, closures, or fittings therefor; packaging elements; packages <br />
<br />
|-<br />
|align = "center"|C09J*<br />
|Adhesives; non-mechanical aspects of adhesive processes in general; adhesive processes not provided for elsewhere; use of materials as adhesives<br />
<br />
|-<br />
|align = "center"| D21H*<br />
|Pulp compositions; preparation<br />
<br />
|-<br />
|align = "center"|G01N*<br />
|Investigating or analysing materials by determining their chemical or physical properties<br />
<br />
|}<br />
<br />
=====US Class=====<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''Class'''<br />
|align = "center" bgcolor = "#FAC090"|'''Definition'''<br />
<br />
|-<br />
|align = "center"|428*<br />
|Stock material or miscellaneous articles<br />
<br />
|}<br />
<br />
===[[Patent search]]===<br />
<br />
===Revised Patent Search===<br />
<br />
*Search Engine:Thomson Innovation<br />
* Time line: 1836-01-01 to 2013-07-22<br />
* Databases: US Grant, WO App, FR App, US App, GB App, DE Util, EP Grant, DE Grant, EP App, DE App, JP Util, CN Util, JP Grant, CN App, JP App, Other<br />
<br />
<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FCD5B4"|'''S. No.'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Scope'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Concept'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''Query'''<br />
|align = "center" bgcolor = "#FCD5B4"|'''No. of hits'''<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4" rowspan = "2"|'''1'''<br />
|align = "center"|Any IPC or CPC or US class<br />
|align = "center"|Food class<br />
|align = "center"|AIC=(A23L0001*) OR UC=(426*) AND<br />
|align = "center" rowspan = "2"|550686<br />
<br />
|-<br />
|align = "center"|Title<br />
|align = "center"|Packaging KW<br />
|align = "center"| (TI=((*Packag* or *container* or *receptacl* or bag* or sack* or pouch*2 or sachet* or *carton* or barrel* or bottle* or closure* or cap or caps or lid* or *seal or reseal* or *clos* or reclos* or zipper* or slide* or dispens*))) AND (DP<nowiki>></nowiki>=(18360101) AND DP<nowiki><</nowiki>=(20130722));<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4" rowspan = "2"|'''2'''<br />
|align = "center"|Any IPC or CPC or US class<br />
|align = "center"|Packaging class<br />
|align = "center"|(AIC=(B65D* or B65B* or B32B* or D21H* or G01N* or C09J*) OR UCC=(428*)) <br />
|align = "center" rowspan = "2"|866669<br />
<br />
|-<br />
|align = "center"|Title<br />
|align = "center"|Packaging KW<br />
|align = "center"| (TI=((*Pack* or *container* or *receptacl* or bag* or sack* or pouch*2 or sachet* or *carton* or tray* or tub* or barrel* or bottle* or closure* or cap or caps or lid* or *seal or reseal* or *clos* or reclos* or tamper or zipper* or slide* or dispens*))) AND (DP<nowiki>></nowiki>=(18360101) AND DP<nowiki><</nowiki>=(20130722)); <br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''3'''<br />
|align = "center"|CTAB<br />
|align = "center"|Food KW<br />
|align = "center"|CTB=(*food* or *beverage* or snack* or past* or meal*1 or entree*1 or *soup*) AND DP<nowiki>></nowiki>=(18360101) AND DP<nowiki><</nowiki>=(20130722); <br />
|align = "center"|1970718<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''4'''<br />
|align = "center" colspan = "2"|Combined query <br />
|align = "center"|2 and 3<br />
|align = "center"|95607<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''5'''<br />
|align = "center" colspan = "2"|Combined query <br />
|align = "center"|1 or 4<br />
|align = "center"|640980(14971)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''6'''<br />
|align = "center"|CTAB<br />
|align = "center"|KW of customer interest<br />
|align = "center"|CTB=((barrier near2 propert*3) or (shelf adj2 life) or (Unique near2 (shape*1 or design*1)) or aseptic*4 or retort*4 or microwave*4 or light-weight*3 or (environmentally adj2 friendly) or biodegrad*4 or recycl*4 or ((dual or duplex) adj2 (dispens* or chamber* or discharg*4)) or (single adj2 serve) or ((individual or single) adj2 (serving or portion*1)) or unitized or (eas*3 near3 (carry*4 or tear*4 or peel*4 or grip*4 or tilt*4 or open*3 or handl*3 or pour* or dispens* or transport*4)) or convenien*4 or (consumer near3 (appeal*3 or acceptance or safety or orient*2 or favour*4)) or (one adj2 hand adj2 (open*3 or operat*4)) or "OTG" or "on the go" or ergonomic or (tamper adj2 (proof or resist*4 or prevent*4)) or (child adj2 proof) or (single adj1 handed) or dripless or ((leak*3 or spill*3 or mess or drip*3 or splash*4) adj2 (prevent*3 or resistan*2 or proof)) or nonspill*3 or (non adj2 spill*3) or ((enhanc*3 or colorful or colourful) near2 graphics)) AND DP<nowiki>></nowiki>=(18360101) AND DP<nowiki><</nowiki>=(20130722); <br />
|align = "center"|1277116<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''7'''<br />
|align = "center" colspan = "2"|Combined query <br />
|align = "center"|5 and 6<br />
|align = "center"|34465(17463)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''8'''<br />
|align = "center" bgcolor = "#FCD5B4" colspan = "2"|Time restriction for 5 years <br />
|align = "center" bgcolor = "#FCD5B4"|DP<nowiki>></nowiki>=(20080722) AND DP<nowiki><</nowiki>=(20130722);<br />
|align = "center" bgcolor = "#FCD5B4"|9329(6056)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''9'''<br />
|align = "center" bgcolor = "#FCD5B4" colspan = "2"|Time restriction for 4 years <br />
|align = "center" bgcolor = "#FCD5B4"|DP<nowiki>></nowiki>=(20090722) AND DP<nowiki><</nowiki>=(20130722)<br />
|align = "center" bgcolor = "#FCD5B4"|7774(5298)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''10'''<br />
|align = "center" bgcolor = "#FCD5B4" colspan = "2"|Time restriction for 3 years <br />
|align = "center" bgcolor = "#FCD5B4"|DP<nowiki>></nowiki>=(20100722) AND DP<nowiki><</nowiki>=(20130722)<br />
|align = "center" bgcolor = "#FCD5B4"|5625(3872)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''11'''<br />
|align = "center" bgcolor = "#FCD5B4" colspan = "2"|Time restriction for 2 years <br />
|align = "center" bgcolor = "#FCD5B4"|DP<nowiki>></nowiki>=(20110722) AND DP<nowiki><</nowiki>=(20130722)<br />
|align = "center" bgcolor = "#FCD5B4"|3047(2088)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FCD5B4"|'''12'''<br />
|align = "center" bgcolor = "#FCD5B4" colspan = "2"|Time restriction for 1 year <br />
|align = "center" bgcolor = "#FCD5B4"|DP<nowiki>></nowiki>=(20120722) AND DP<nowiki><</nowiki>=(20130722)<br />
|align = "center" bgcolor = "#FCD5B4"|1336(1081)<br />
<br />
|}<br />
<br />
==[[Taxonomy of Food Packaging]]==<br />
<br />
==[[Interactive Taxonomy]]==<br />
<br />
== Revised Interactive Taxonomy==<br />
<br />
<mm>[[Revised_Food_Packaging_Colgate.mm|750px]]</mm><br />
<br />
== Sample Analysis Sheet==<br />
:* Click here to download [[Media: Sample_analysis_for_Food_packaging.xls|'''Sample patent analysis sheet''']]<br />
<br />
<br />
:* Click here to download [[Media: Revised_Sample_analysis_for_Food_packaging_colgate.xls|'''Revised Sample patent analysis sheet''']]<br />
<br />
==Dashboard link==<br />
[https://www.dolcera.com/auth/dashboard/dashboard.php?workfile_id=1683 '''Please click for the dashboard link''']<br />
<br />
NOTE: You need to install Internet Explorer 8.0 and Adobe Flash Player to view the Dashboard.<br />
<br />
Please download [http://www.microsoft.com/windows/internet-explorer/default.aspx '''Internet Explorer 8.0'''] and [http://get.adobe.com/flashplayer/?promoid=DRHWS '''Adobe Flash player''']<br />
<br />
'''Note:''' <br />
<br />
*''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy''<br />
*''Click on the red arrow adjacent to the node name to view the content for that particular node in the dashboard''<br />
<br />
=Antimicrobial films=<br />
<br />
==Sample Patents==<br />
<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
| bgcolor = "#FAC090"|'''S. No.'''<br />
|align = "center" bgcolor = "#FAC090"|'''Patent/Publication No.'''<br />
|align = "center" bgcolor = "#FAC090"|'''Publication Year'''<br />
|align = "center" bgcolor = "#FAC090"|'''Assignee / Applicant'''<br />
|align = "center" bgcolor = "#FAC090"|'''Title'''<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''1'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8318282.PN.&OS=PN/8318282&RS=PN/8318282 US8318282B2]</u></font><br />
|align = "center"|2012<br />
|align = "center"|3m innovative properties company<br />
|align = "center"|Microstructured antimicrobial film<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''2'''<br />
|align = "center"|<font color="#0000FF"><u>[http://appft1.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220120087968%22.PGNR.&OS=DN/20120087968&RS=DN/20120087968 US20120087968A1]</u></font><br />
|align = "center"|2012<br />
|align = "center"|Cryovac inc.<br />
|align = "center"|Antimicrobial Packaging Material and Methods of Making and Using the Same<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''3'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8017667.PN.&OS=PN/8017667&RS=PN/8017667 US8017667B2]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Victoria university <nowiki>|</nowiki> technion research and development foundation ltd.<br />
|align = "center"|Antimicrobial packaging material<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''4'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7915325.PN.&OS=PN/7915325&RS=PN/7915325 US7915325B2]</u></font><br />
|align = "center"|2011<br />
|align = "center"|Kuhne anlagenbau gmbh<br />
|align = "center"|Antimicrobial food packaging<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''5'''<br />
|align = "center"|<font color="#0000FF"><u>[http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=7705078.PN.&OS=PN/7705078&RS=PN/7705078 US7705078B2]</u></font><br />
|align = "center"|2010<br />
|align = "center"|Dupont teijin films u.s. Limited partnership<br />
|align = "center"|Antimicrobial polymeric film<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''6'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=GB&NR=2450475 GB2450475A]</u></font><br />
|align = "center"|2008<br />
|align = "center"|Nottingham trent university<br />
|align = "center"|Antimicrobial polymer nanocomposite<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|'''7'''<br />
|align = "center"|<font color="#0000FF"><u>[http://worldwide.espacenet.com/publicationDetails/biblio?CC=GB&NR=2449876 GB2449876A]</u></font><br />
|align = "center"|2008<br />
|align = "center"|Post harvest solutions, limited<br />
|align = "center"|Active packaging materials incorporating micro-porous solids and essential oils<br />
<br />
|}<br />
<br />
==Search Methodology==<br />
<br />
===Relevant Class Codes and Definitions ===<br />
=====IPC/ECLA=====<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''Class'''<br />
|align = "center" bgcolor = "#FAC090"|'''Definition'''<br />
<br />
|-<br />
|align = "center"|A23L<br />
|Foods, foodstuffs, or non-alcoholic beverages<br />
<br />
|-<br />
|align = "center"|A23L0001*<br />
|Foods or foodstuffs; their preparation or treatment<br />
<br />
|-<br />
|align = "center"|A01N*<br />
|Preservation of bodies of humans or animals or plants or parts thereof; biocides, e.g. As disinfectants, as pesticides, as herbicides<br />
<br />
|-<br />
|align = "center"|B32B*<br />
|Layered products, i.e. Products built-up of strata of flat or non-flat, e.g. Cellular or honeycomb, form<br />
<br />
|}<br />
<br />
===Patent search===<br />
<br />
*Search Engine:Thomson Innovation<br />
* Time line: 18.June.2008 to 18.June.2013<br />
* Databases: US Grant, WO App, FR App, US App, GB App, DE Util, EP Grant, DE Grant, EP App, DE App, JP Util, CN Util, JP Grant, CN App, JP App, Other<br />
<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''S.no. '''<br />
|align = "center" bgcolor = "#FAC090"|'''Concept '''<br />
|align = "center" bgcolor = "#FAC090"|'''Scope'''<br />
|align = "center" bgcolor = "#FAC090"|'''Search query'''<br />
|align = "center" bgcolor = "#FAC090"|'''No. of hits'''<br />
<br />
|-<br />
|align = "center" rowspan = "2"|1<br />
|align = "center"|Preservation or layered products class<br />
|align = "center"|Any IPC or CPC<br />
|align = "center"|A01N* or B32B*<br />
|align = "center" rowspan = "2"|615(358)<br />
<br />
|-<br />
|align = "center"|Antimicrobial film kw <br />
|align = "center"|Title<br />
|align = "center"|(antimicrobial or antibacterial or (anti adj2 (bacterial or microbial)) or smart) AND (packag* or film* or sheet* or laminat* or polymer* or *composite*)<br />
<br />
|-<br />
|align = "center"|2<br />
|align = "center"|Food Kw<br />
|align = "center"|Full text<br />
|align = "center"|Food*<br />
|align = "center"|707301<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|3<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Combined query<br />
|align = "center" bgcolor = "#FAC090"|1 and 2<br />
|align = "center" bgcolor = "#FAC090"|269(148)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090" rowspan = "2"|4<br />
|align = "center" bgcolor = "#FAC090"|Food Class<br />
|align = "center" bgcolor = "#FAC090"|Any IPC or CPC<br />
|align = "center" bgcolor = "#FAC090"|A23L0001*<br />
|align = "center" bgcolor = "#FAC090" rowspan = "2"|8(7)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|Antimicrobial film kw <br />
|align = "center" bgcolor = "#FAC090"|Title<br />
|align = "center" bgcolor = "#FAC090"|(antimicrobial or antibacterial or (anti adj2 (bacterial or microbial)) or smart) AND (packag* or film* or sheet* or laminat* or polymer* or *composite*)<br />
<br />
|-<br />
|align = "center"|5<br />
|align = "center" colspan = "2"|Combined query<br />
|align = "center"|3 or 4<br />
|align = "center"|273(152)<br />
<br />
|-<br />
|align = "center"|6<br />
|align = "center" colspan = "2"|Control patents<br />
|align = "center"|US8318282B2 US8017667B2 US7705078B2 US7915325B2 US20120087968A1 GB2450475A GB2449876A<br />
|align = "center"|7<br />
<br />
|-<br />
|align = "center"|7<br />
|align = "center" colspan = "2"|Combined query<br />
|align = "center"|5 and 6<br />
|align = "center"|7<br />
<br />
|}<br />
<br />
<br />
<br />
==[[Taxonomy of Antimicrobial films]]==<br />
<br />
==Interactive Taxonomy==<br />
<br />
<mm>[[Antimicrobial_films-Colgate.mm|750px]]</mm><br />
<br />
==[[Sample Analysis with Problem Solution Approach]]==<br />
<br />
== Revised Sample Analysis Sheet==<br />
:* Click here to download [[Media: Sample_analysis_for_Antimicrobial films.xlsx|'''Revised Sample patent analysis sheet''']]<br />
<br />
==Dashboard link==<br />
[https://www.dolcera.com/auth/dashboard/dashboard.php?workfile_id=1684 '''Please click for the dashboard link''']<br />
<br />
NOTE: You need to install Internet Explorer 8.0 and Adobe Flash Player to view the Dashboard.<br />
<br />
Please download [http://www.microsoft.com/windows/internet-explorer/default.aspx '''Internet Explorer 8.0'''] and [http://get.adobe.com/flashplayer/?promoid=DRHWS '''Adobe Flash player''']<br />
<br />
'''Note:''' <br />
<br />
*''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy''<br />
*''Click on the red arrow adjacent to the node name to view the content for that particular node in the dashboard''</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Sample_analysis_for_Food_packaging.xls&diff=11036File:Sample analysis for Food packaging.xls2014-02-06T07:30:33Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Revised_Food_Packaging_Colgate.mm&diff=11035File:Revised Food Packaging Colgate.mm2014-02-06T07:25:37Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Interactive_Taxonomy&diff=11034Interactive Taxonomy2014-02-06T07:24:24Z<p>Vishal.jaiswal: </p>
<hr />
<div><mm>[[Food_Packaging-Colgate.mm|750px]]</mm></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Interactive_Taxonomy&diff=11033Interactive Taxonomy2014-02-06T07:23:11Z<p>Vishal.jaiswal: </p>
<hr />
<div>== Revised Interactive Taxonomy==<br />
<br />
<mm>[[Revised_Food_Packaging_Colgate.mm|750px]]</mm></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Food_Packaging-Colgate.mm&diff=11032File:Food Packaging-Colgate.mm2014-02-06T07:21:52Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Interactive_Taxonomy&diff=11031Interactive Taxonomy2014-02-06T07:21:14Z<p>Vishal.jaiswal: </p>
<hr />
<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Interactive_Taxonomy&diff=11030Interactive Taxonomy2014-02-06T07:20:56Z<p>Vishal.jaiswal: </p>
<hr />
<div>==[[Interactive Taxonomy]]==</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:Food_packaging.mm&diff=11029File:Food packaging.mm2014-02-06T07:17:59Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Taxonomy_of_Food_Packaging&diff=11028Taxonomy of Food Packaging2014-02-06T07:17:28Z<p>Vishal.jaiswal: </p>
<hr />
<div><mm>[[Food_packaging.mm|750px]]</mm></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=Patent_search&diff=11027Patent search2014-02-06T07:13:57Z<p>Vishal.jaiswal: </p>
<hr />
<div>*Search Engine:Thomson Innovation<br />
* Time line: 18.June, 2008 to 18.June.2013<br />
* Databases: US Grant, WO App, FR App, US App, GB App, DE Util, EP Grant, DE Grant, EP App, DE App, JP Util, CN Util, JP Grant, CN App, JP App, Other<br />
<br />
<br />
<br />
{|border="2" cellspacing="0" cellpadding="4" align = "center" width="80%"<br />
|align = "center" bgcolor = "#FAC090"|'''S.no. '''<br />
|align = "center" bgcolor = "#FAC090"|'''Concept '''<br />
|align = "center" bgcolor = "#FAC090"|'''Scope'''<br />
|align = "center" bgcolor = "#FAC090"|'''Search query'''<br />
|align = "center" bgcolor = "#FAC090"|'''No. of hits'''<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090" rowspan = "2"|1<br />
|align = "center" bgcolor = "#FAC090"|Food class<br />
|align = "center" bgcolor = "#FAC090"|Any IPC or CPC<br />
|align = "center" bgcolor = "#FAC090"|A23L0001*<br />
|align = "center" bgcolor = "#FAC090" rowspan = "2"|3259(2310)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|Packaging KW<br />
|align = "center" bgcolor = "#FAC090"|Title<br />
|align = "center" bgcolor = "#FAC090"|(*Packag* or *container* or *receptacl* or film* or laminat* or bag* or sack* or pouch*2 or sachet* or *carton* or can or cans or barrel* or bottle* or closure* or cap or caps or lid* or *seal or reseal* or *clos* or reclos* or tamper or zipper* or slide* or label* or decorat* or dispens*)<br />
<br />
|-<br />
|align = "center" rowspan = "2"|2<br />
|align = "center"|Packaging related classes<br />
|align = "center"|Any IPC or CPC or US<br />
|align = "center"|B65D* or B65B* or B32B* or D21H* or G01N* or C09J* or 428*<br />
|align = "center" rowspan = "2"|246058(24271)<br />
<br />
|-<br />
|align = "center"|Packaging KW<br />
|align = "center"|Title<br />
|align = "center"|(*Pack* or *container* or *receptacl* or film* or laminat* or bag* or sack* or pouch*2 or sachet* or *carton* or tray* or tub* or can or cans or barrel* or bottle* or closure* or cap or caps or lid* or *seal or reseal* or *clos* or reclos* or tamper or zipper* or slide* or label* or decorat* or dispens*)<br />
<br />
|-<br />
|align = "center"|3<br />
|align = "center"|Food kw<br />
|align = "center"|CTAB<br />
|align = "center"|food*<br />
|align = "center"|203153(27170)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|4<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Combined query <br />
|align = "center" bgcolor = "#FAC090"|2 AND 3<br />
|align = "center" bgcolor = "#FAC090"|14672(9348)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|5<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Final query <br />
|align = "center" bgcolor = "#FAC090"|1 or 4 (5 years)<br />
|align = "center" bgcolor = "#FAC090"|17356(11250)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|6<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Final query <br />
|align = "center" bgcolor = "#FAC090"|4 year restriction <br />
|align = "center" bgcolor = "#FAC090"|14066(9457)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|7<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Final query <br />
|align = "center" bgcolor = "#FAC090"|3 year restriction <br />
|align = "center" bgcolor = "#FAC090"|10706(7580)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|8<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Final query <br />
|align = "center" bgcolor = "#FAC090"|2 year restriction<br />
|align = "center" bgcolor = "#FAC090"|7278 (5517)<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|9<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Final query <br />
|align = "center" bgcolor = "#FAC090"|1 year restriction <br />
|align = "center" bgcolor = "#FAC090"|3591(3017)<br />
<br />
|-<br />
|align = "center"|10<br />
|align = "center" colspan = "2"|Control patents <br />
|align = "center"|WO12047947A3 US8459537B2 US8240505B1 US7791003B2 US7793391B2 EP2451644 WO12156082 WO12154909A3 WO11139268 GB2491557 GB2454748 GB2465121 GB2476365 WO13002639 WO13008938 WO12038615 EP2128036B1 EP2081990B1 EP2113466 EP1905696B1 EP1840036B1 EP2208685B1 EP2143658B1 EP1377448 EP2141085B1EP2307285 EP2025620A4 EP2323917 EP2079315 WO09141213 WO10040965 WO09131232<br />
|align = "center"|31<br />
<br />
|-<br />
|align = "center" bgcolor = "#FAC090"|11<br />
|align = "center" bgcolor = "#FAC090" colspan = "2"|Combined query <br />
|align = "center" bgcolor = "#FAC090"|5 and 10 <br />
|align = "center" bgcolor = "#FAC090"|31<br />
<br />
|}</div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US7494279B2.jpg&diff=11026File:US7494279B2.jpg2014-02-06T07:13:17Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US20090032487A1.jpg&diff=11025File:US20090032487A1.jpg2014-02-06T07:11:59Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US20090214723A1.jpg&diff=11024File:US20090214723A1.jpg2014-02-06T07:10:48Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US20090285941A1.jpg&diff=11023File:US20090285941A1.jpg2014-02-06T07:09:51Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:EP2141085A1.jpg&diff=11022File:EP2141085A1.jpg2014-02-06T07:08:52Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:EP1777173B1.jpg&diff=11021File:EP1777173B1.jpg2014-02-06T07:07:19Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US20100108680A1.jpg&diff=11020File:US20100108680A1.jpg2014-02-06T07:03:00Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:GB2476365A.jpg&diff=11019File:GB2476365A.jpg2014-02-06T07:01:50Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US8080770B2.jpg&diff=11018File:US8080770B2.jpg2014-02-06T07:01:12Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:EP2459463A1.jpg&diff=11017File:EP2459463A1.jpg2014-02-06T07:00:32Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US20120168025A1.jpg&diff=11016File:US20120168025A1.jpg2014-02-06T06:58:06Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:EP2208604B1.jpg&diff=11015File:EP2208604B1.jpg2014-02-06T06:57:32Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:EP2284099B1.jpg&diff=11014File:EP2284099B1.jpg2014-02-06T06:56:40Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:UUS8151985B2.jpg&diff=11013File:UUS8151985B2.jpg2014-02-06T06:08:50Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US8167487B2.jpg&diff=11012File:US8167487B2.jpg2014-02-06T06:05:50Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswalhttps://www.dolcera.com/wiki/index.php?title=File:US8198571B2.jpg&diff=11011File:US8198571B2.jpg2014-02-06T06:04:29Z<p>Vishal.jaiswal: </p>
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<div></div>Vishal.jaiswal