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Inflammation and cardiovascular drugs

2012-04-20T15:29:55Z

Abhay.goel.1: /* Cardiovascular diseases */

==Targeting inflammation – Pharmaceutical focus==

The pharmaceutical industry is one of the most profitable sectors of the Fortune 500 with profits of approximately 18% of revenue compared to a median of 5% for other industry segments. However, this market is facing increasing competitive pressure due to escalating R&D costs, shortened patent life due to the long product approval process, increased sales and marketing costs, pricing pressures, and entrance of more competitors into the industry. It is estimated that large pharmaceutical companies (or Pharma as they are generally referred to in the industry) require 3-5 new lead drug candidates (defined as New Chemical Entities or NCEs) each year to sustain doubledigit growth rates. Despite the fact that R&D costs have been increasing (typically $300-500 million per NCE), the average number of NCEs have been dropping over the last decade to under one per year across the industry. Thus, there is increasing pressure on Pharma to find newer discovery and development paradigms.

Inflammation is one of the key processes linked to various diseases and disorders. There are many opportunities for designing and developing specific new drugs for inflammatory responses.

[[image:market.png|center|1200 px|thumb|[http://www.chromos.com/documents/roadshowsept14_003.pdf Source]]]
----

==Overview of inflammation==
Inflammation is a process by which the body<nowiki>’</nowiki>s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses. [[Image:Targeting_inflammation_04.jpg|300 px|right|thumb]]

In some diseases, however, the body’s defense system (immune system) inappropriately triggers an inflammatory response when there are no foreign substances to fight off, these are called autoimmune diseases, where the body’s normally protective immune system causes damage to its own tissues. When inflammation occurs normally, chemicals from the body’s white blood cells are released to protect us from foreign substances.

Inflammation is characterized by:

* increased blood flow to the tissue
* increased temperature,
* redness,
* swelling, and
* pain.
 
 
 

[[image:inflammation overview.png|thumb|center|600 px]]

Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. Thease includes rheumatoid arthritis, osteoarthritis and inflammatory lung disease, including inflammatory bowel disease, atherosclerosis and psoriasis.

Chronic inflammatory disorders are a substantial burden in social and economic terms for the Australian community. Arthritis alone afflicts 3.4 million Australians and the financial costs were in excess of $19.25 billion in 2004 (Access Economics 2005).

Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their cause, treatment or cure, despite intensive global research.
----

===Various inflammatory diseases===
* '''Rheumatoid arthritis (RA)''' is a disease that most commonly affects the joints, but can sometimes also cause damage to other organs. RA is an auto-immune disease, that is, a disease where a person’s immune system attacks his or her own body tissues. This auto-immune reaction causes inflammation of the joints, particularly of the synovial membrane which lines them. There is an over-production of synovial (joint) fluid and this, combined with the inflammation, causes joints to become swollen and painful.

* '''Chronic Obstructive Pulmonary Disease, or COPD''', is a group of progressive lung diseases characterized by airflow obstruction or limitation that is not fully reversible. The restricted airflow is generally progressive and associated with abnormal inflammatory response of the lungs to irritants." They are most commonly caused by tobacco smoking. The family of diseases includes chronic bronchitis, emphysema and bronchiectasis. COPD develops slowly and it may be many years before symptoms such as breathing difficulties are noticed. Thus COPD is usually diagnosed in middle-aged or older people. COPD is also characterized by exacerbations which are often associated with a rapid progression of symptoms such as shortness of breath, wheezing, and sputum production, sometimes leading to respiratory failure. Exacerbations are most commonly brought on by infectious agents. Bronchodilators, antibiotics, and oral or intravenous steroids are used to treat these episodes.

* '''Osteoarthritis (OA)''' is the most common form of arthritis and is characterised by mild to debilitating pain, which can involve almost any joint but, in particular, weight bearing joints such as the hip, knee, spine and feet. OA refers to a degeneration of the articular cartilage that makes up the joint surface. This breakdown removes the soft buffer between the bones and can, when severe, result in bone against bone friction, which can cause severe pain and loss of movement.

* '''Inflammatory Bowel Disease (IBD)''' is the name of a group of disorders that cause the intestines to become inflamed (red and swollen). IBD can be painful and debilitating and causes chronic inflammation of the digestive tract. The two most common forms of IBD are ulcerative colitis and Crohn<nowiki>’</nowiki>s Disease. Both conditions inflame the lining of your digestive tract and both can cause severe bouts of watery diarrhoea and abdominal pain.
* '''Psoriasis''' is a common immune-mediated chronic skin disease that comes in different forms and differing levels of severity. It is a condition that is generally found on the knees, elbows, scalp, hands, feet or lower back, and generally appears as patches of raised red skin covered by a flaky white build up. It can cause intense itching and burning.
* '''Artherosclerosis''' is the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of an artery. It is a slow and progressive disease that may start in childhood. If left untreated, artherosclerosis can lead to heart attack or stroke. The first symptom of a narrowing artery may be pain or cramps at times when the blood flow can<nowiki>’</nowiki>t keep up with the body<nowiki>’</nowiki>s demand for oxygen. For example, during exercise a person may feel chest pain because of a lack of oxygen to the heart or while walking, a person may feel leg cramps because of a lack of oxygen to the legs.
* '''Pelvic inflammatory disease (PID)''' is a general term that refers to infection and inflammation of the upper genital tract in women. It can affect the uterus (womb), fallopian tubes (tubes that carry eggs from the ovaries to the uterus), ovaries, and other organs related to reproduction. The scarring that results on these organs can lead to infertility, tubal (ectopic) pregnancy, chronic pelvic pain, abscesses (sores containing pus), and other serious problems.
* '''Cardiovascular diseases''': C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Recent studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it’s been opened by balloon angioplasty. Most studies show that the higher the hs-CRP levels, the higher the risk of developing heart attack. [http://www.americanheart.org/presenter.jhtml?identifier=4648 Source]
* '''Metabolic disease''': Scientists at Galileo Pharmaceuticals, Inc. have demonstrated a direct relationship between inflammation and glucose levels. Inhibiting lipoxygenases, known mediators of inflammatory response, significantly lowers blood glucose levels in animal models of diabetes. Lipoxygenases are enzymes which play a key role in the synthesis of inflammatory mediators called leukotrienes, and trigger the progression of several diseases mediated by inflammation. Two key members of the lipoxygenase pathway, 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) have been indicated in a number of diseases states including asthma, arthritis, atherosclerosis, diabetes, osteoporosis, and cancer. [http://www.medicalnewstoday.com/medicalnews.php?newsid=27884 Source]
* '''Neurodegenerative disorder''': Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aß derived from misprocessing of amyloid precursor protein (APP). Aß deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. [http://stke.sciencemag.org/cgi/content/abstract/2002/162/tw461 Source]

----

===Factors associated with inflammations===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Players of inflammation'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Mast Cells'''
|Mast cells appear to be key players in the initiation of inflammation. Mast cells are found in the tissues. Their cytoplasm is loaded with granules containing mediators of inflammation. Their surface is coated with a variety of receptors which, when engaged by the appropriate ligand, trigger exocytosis of the granules. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Tumor Necrosis Factor-alpha (TNF-α)'''
|Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Chemokines'''
|These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Reactive Oxygen Species (ROS)'''
|These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Histamine'''
|The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Interleukin-1 (IL-1)'''
|Macrophages and monocytes are the main source of this cytokine. IL-1 has both • paracrine effects on cells in the vicinity, e.g., • causing them to produce tissue factor and thus triggering the blood clotting cascade. • stimulating the synthesis and secretion of a variety of other interleukins • helping to activate T cells and thus initiate an adaptive immune response • endocrine (hormonal) effects as it is carried in the blood throughout the body. • decreasing blood pressure • inducing fever. IL-1 causes fever by stimulating the release of prostaglandins, which act on the temperature control center of the hypothalamus. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Inflammasomes'''
|IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Leukotrienes and Prostaglandins'''
|These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and • the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways: one leading to the production of several • prostaglandins (PG); the other leading to the production of • thromboxanes (Tx). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----
===Current treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Treatment approach'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Steroids'''
|Like the glucocorticoid cortisol. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Nonsteroidal anti-inflammatory drugs (NSAIDs)'''
|The NSAIDs achieve their effects by blocking the activity of cyclooxygenase. NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''COX-1 and COX-2'''
|The body produces several different forms of cyclooxygenase (COX), including • COX-1, which is involved in pain, clotting, and protecting the stomach; • COX-2, which is involved in the pain produced by inflammation. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Therapeutic Proteins'''
|Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation. • an IL-1 antagonist that binds and inactivates the IL-1 receptor. • etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. • recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation. • infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows promise against some inflammatory diseases such as rheumatoid arthritis. (Side-effect: can convert a latent case of tuberculosis into active disease.) [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----

===Key signaling pathways===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Pathways'''
|align = "center" bgcolor = "#CCFFFF"|'''Activation'''
|align = "center" bgcolor = "#CCFFFF"|'''Key molecules'''
|align = "center" bgcolor = "#CCFFFF"|'''Target disease'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|MAPK Pathways
|Stress and Inflammation
| 
|Chronic inflammation, heart disease, stroke, diabetes mellitus
|[http://physrev.physiology.org/cgi/content/abstract/81/2/807 Source]
|-
|JNK Pathways
|Cytokines or environmental stress
| 
|Cellular proliferation, apoptosis, and tissue morphogenesis
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9561845&dopt=Citation Source]
|-
|Cytokine Pathways
| 
|TNF-alpha, IL-1, IL-6, IL-10, IL-4
|Joint Inflammation in Rheumatoid Arthritis
|[http://content.nejm.org/cgi/content/extract/344/12/907?ck=nck Source]
|-
|NF-κB pathway
|Diverse signal transduction cascades
|IκB kinases, IKKα and IKKβ
|Inflammation and cancer
|[http://www.jci.org/cgi/reprint/107/2/135.pdf Source]
|-
|Protein Kinase Cascades
|Mitogens but by cellular stresses and inflammatory cytokines
|ERKs, MEKs, SAPKs, Ras/MAPK, p38
|Stress and Inflammation
|[http://www.jbc.org/cgi/reprint/271/40/24313 Source]
|-
|TNF Pathways
| 
|TNF-R1
|Sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases
|[http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107 Source]
|-
|p38 Pathway (MAPK pathway)
|Bacterial pathogens and cytokines
|(ERKs, JNK/SAPK, ERK5/big MAP kinase 1 (BMK1), p38 group of protein kinases
|Inflammation, cell growth, cell differentiation, the cell cycle, and cell death
|[http://www.sci.sdsu.edu/classes/bio630/pdf/Ono2000.pdf Source]
|-
|TRAF6-NFκB
| 
|TLR/IL-1R, CD40, transcription factors NFκB and AP1
|Autoimmune disease
|align = "justify"|[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175050 Source]
|-
|STAT4 Pathways
| 
|Chemokines
|Allergic Airway Inflammation
|[http://www.jimmunol.org/cgi/content/full/170/7/3859 Source]
|-
|Toll-like receptors (TLRs) Pathways
|Cytokine-driven inflammation and tissue destruction
|Toll-like receptors (TLRs)
|Rheumatoid arthritis, Crohn<nowiki>’</nowiki>s disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis
|[http://cat.inist.fr/?aModele=afficheN&cpsidt=16287680 Source]
|-
|Multiple signaling pathways
| 
|C-reactive protein, ICAM-1, VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate, Clotting or coagulation factors, Fibrinolysis factors, angiotensin II, Prostaglandins, TGF-<nowiki>[</nowiki>beta<nowiki>]</nowiki>, (PDGF, NO and endothelin-1
|Atherosclerosis and cardiovascular disease
|[http://www.findarticles.com/p/articles/mi_m0FDN/is_1_9/ai_n5990649/pg_2 Source]
|-
|G protein-coupled receptors (GPCRs) Pathways
| 
|RGS proteins, PI3K
|Cardiovascular diseases
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15746448 Source]
|-
|}

----

==Cardiovascular diseases==
* It has become clear that CVD is an '''inflammatory disease''', although what triggers the inflammation is still unknown.
* Diagnosis of CVD through inflammatory markers is an active area of research. Although several classes of anti-hypertensive drugs exist, there are still several treatment goals that remain to be achieved, such as better blood pressure control, greater protection against organ damage, and better tolerability.
* Several angiogenic and myogenic stem cell therapies are under investigation and promise in the long run to advance cardiac rehabilitation and even prevent heart failure. Despite the development of improved therapies, millions of Americans continue to live with life-threatening cardiovascular diseases.

[[image:cardiovascilar diseases.png|center|thumb|2000px| [http://www-ermm.cbcu.cam.ac.uk/0500918Xh.htm Source]]]

----
===Market analysis===
* The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003.
* CVD is the leading cause of death in most regions throughout the world. Cardiovascular drugs constitute the world's largest pharmaceutical sector, with annual global sales over $70 billion.
* Risk factor management for CVD is an emerging market. Developing more effective ways of delivering pharmacological, nutritional, and preventative therapies are recognized as important targets that are under continual development. Aging populations and dietary and lifestyle induced disease processes ensure a growing need for cardiovascular devices.
* Reducing the costs for such devices by appropriately treating cardiovascular risk factors has become a major focus of the pharmaceutical and healthcare industries. Here are just some of the considerable market opportunities within the CVD Market:
** Increased use of cholesterol-controlling statins will cause prices to fall and generic brands to appear as knowledge of their benefits spread among general practitioners.
** Develop anti-glycosylation therapies to prevent the cross-linking that weakens aging heart muscle, and to reduce the diabetic risk factor.
** Create new vaccines to raise high density lipoprotein (HDL) levels, which help stave off heart disease.
** Develop new angiotensin receptor blockers to offer greater competition against ACE inhibitors
** Develop angiogenesis drugs such as VEGF (vascular endothelial growth factor) that will obviate the need for much bypass surgery by growing new arteries on damaged hearts.

----
===Common cardiac drugs===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" colspan = "4" bgcolor = "#CCFFFF"|'''[http://www.bmb.leeds.ac.uk/illingworth/cardio/index.htm Common cardiac drugs]'''
|-
|align = "center" bgcolor = "#CCFFFF" | '''Drugs'''
|align = "center" bgcolor = "#CCFFFF" | '''Main effects'''
|align = "center" bgcolor = "#CCFFFF" | '''Mechanism'''
|align = "center" bgcolor = "#CCFFFF" | '''Sites of action'''
|-
|Abciximab
|Anticoagulant stops platelet activation
|Monoclonal antibody to fibrinogen receptors
|Platelets
|-
|Amiloride (combination with frusemide is ''frumil'')
|Potassium sparing diuretic
|Plasmalemma sodium & chloride channels
|Kidney (distal tubules)
|-
|Amiodarone
|Class III anti-arrhythmic
|Prolongs action potential duration
|Myocardium
|-
|Aspirin
|Anticoagulant stops platelet activation
|COX inhibitor, blocks TXA2 synthesis
|Platelets
|-
|Atropine (sometimes used to stop vagus bradycardia)
|Parasympatholytic, increases heart rate
|Blocks muscarinic acch receptors
|Pacemaker cells (sino-atrial node)
|-
|Captopril
|Reduces arterial blood pressure
|ACE inhibitor
|Relaxes vascular smooth muscle
|-
|Clopidogrel
|Anticoagulant stops platelet activation
|Blocks ADP receptor
|Platelets
|-
|Digitalis and ouabain
|Increase cardiac contractility, delay AV node triggering
|Block Na / K atpase raising intracellular sodium, then calcium
|All tissues, but the Na/Ca exchanger is mainly in heart
|-
|Dipyridamole (often used for X-ray imaging)
|Coronary vasodilation
|Inhibition of adenosine uptake
|Coronary vasculature
|-
|Furosemide (= frusemide)
|Diuretic
|Plasmalemma sodium & chloride channels
|Kidney (loop of Henle)
|-
|Isoprenaline (and other adrenaline analogues)
|Increase cardiac contractility
|Beta agonist raises cyclic AMP
|Many tissues
|-
|Losartan
|Reduces arterial blood pressure
|Angiotensin AT1 receptor blockade
|Relaxes vascular smooth muscle
|-
|Lovastatin
|Reduces blood cholesterol levels
|HMG-coa reductase inhibitor
|Liver
|-
|Morphine
|Pain relief (mainly)
|Opiate receptors
|Brain
|-
|Nitroglycerine (and many other organic nitrates)
|Reduce cardiac work load
|Metabolised to NO
|Relaxes vascular smooth muscle
|-
|Propranolol
|Reduces cardiac contractility, class II anti-arrhythmic
|Beta blocker lowers cyclic AMP
|Many tissues
|-
|Quinidine, novocaine and other local anaesthetics
|Class I anti-arrhythmics
|Delay recovery of sarcolemma sodium channels after AP
|Myocardium
|-
|Spironolactone (usually added to other diuretics)
|Reduces diuretic potassium losses
|Aldosterone antagonist
|Kidney (distal tubules)
|-
|Urokinase (streptokinase is cheaper but antigenic)
|Dissolves blood clots (fibrinolytic)
|Activates plasminogen to plasmin (protease)
|Blood clots
|-
|Verapamil, nifedipine and other dihydropyridines
|Reduce cardiac work load, class IV anti-arrhythmic
|Block sarcolemma calcium channels
|Myocardium; relax vascular smooth muscle
|-
|Warfarin
|Anticoagulant Vit. K antagonist
|Blocks -carboxy glutamate synthesis
|Liver
|-
|} 

----

==Drug targets==

Target molecule (or target protein) are the molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule— a drug— to bind to the target molecule and block its action.

[[image:drug targets.gif|center|thumb|500 px| [http://www.locomogene.com/english/strategy/concept.html Source]]]

----
===Emerging drug targets===
Drug targets are generally proteins. Nucleic acids are possible drug targets, and approaches such as RNA interference (RNAi) may indeed have advantages over proteins, but they have not so far been developed extensively. Protein targets consist mainly of enzymes, regulatory molecules such as cytokines, receptors for hormones or other regulatory molecules, transporters, and ion channels. Proteins that interact with small molecules are considered the most promising targets, because it is often possible to design or discover small molecule activators or inhibitors based on the natural ligands. Such substances are relatively straightforward to develop as drugs. Overall, enzyme targets account for over 50% of marketed drugs, and GPCR targets represent more than 20%, including 23 of the 100 best-selling drugs in the US. Hence the other target classes between them make up the remaining 25-30% of marketed drugs. Aberrant signal transduction plays a key part in the pathology of many serious diseases including cancer, inflammatory, cardiovascular, metabolic, and neuropsychiatric diseases. Proteins involved in signal transduction pathways therefore represent important drug targets. Three prominent superfamilies of proteins involved in signal transduction are: GPCRs, protein kinases, and nuclear receptors. [http://www.marketresearch.com/product/display.asp?productid=1204095&g=1 Source]

----
===Classification of drug targets===
[[image:drug class distribution.jpeg|right|450 px|thumb|Biochemical classes of drug targets. [http://www.bioinformation.net/1/76-1-2006.htm Source]]]
The introduction of genomics, proteomics and metabolomics has paved the way for biology-driven process, leading to plethora of drug targets. The list of potential drug targets encoded in a genome includes most natural choice of virulent genes and species-specific genes. Other options include targeting RNA, enzymes of the intermediary metabolism, systems for DNA replication, translation apparatus or repair and membrane proteins.

* Species-specific genes as drug targets
* RNA as drug target
* Nucleic acid as drug targets
* Proteins as drug targets
* Membranes as drug targets

The comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. [http://www.scripps.edu/newsandviews/e_20020422/print-drug.html Source]

{|border="2" cellspacing="0" cellpadding="4" width="60%" align = "center"
|align = "center" bgcolor = "#CCFFFF"|'''Drug targets'''
|align = "center" bgcolor = "#CCFFFF"|'''2001'''
|align = "center" bgcolor = "#CCFFFF"|'''2005'''
|-
|GPCRs
|align = "center"|30%
|align = "center"|20%
|-
|Ion Channel
|align = "center"|20%
|align = "center"|30%
|-
|Enzymes
|align = "center"|30%
|align = "center"|20%
|-
|Hormones/Vitamins
|align = "center"|12%
|align = "center"|4%
|-
|RNA-Proteins/DNA-Proteins
|align = "center"|<nowiki>-</nowiki>
|align = "center"|10%
|-
|Protein-Protein
|align = "center"|<nowiki>-</nowiki>
|align = "center"|20%
|-
|Unknown Mechanism
|align = "center"|8%
|align = "center"|<nowiki>-</nowiki>
|-
|}
----

==Drug targets for cardiovascular diseases==
===G- protein-coupled receptors (GPCRs)===
GPCRs are the largest and most important class of receptors in humans because they are the targets of more than half of all drugs used clinically, especially for treating diseases of the cardiovascular and nervous systems. GPCRs are also the targets of many drugs of abuse.

G Protein-Coupled Receptors (GPCRs) account for 50% of the current drug targets, and remain about one-third of the drug discovery effort in the drug discovery-development community. As a result of the sequencing of the human genome, more than 150 orphan and non-chemosensory GPCRs have been identified for which their cognate ligands or biological functions are unknown. De-orphanization of those receptors could bring novel therapeutic targets to the industry against which novel therapeutics could be designed. In addition, current GPCR-based drugs only target ~30% of the approximately 200 known GPCRs in the genome. This is a rich target class that is highly-druggable. [http://www.marketresearch.com/product/display.asp?productid=1092267&SID=66002803-375208398-363996861&kw=G%2DProtein%09Coupled%09Receptors%09GPCRs Source]

Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as:
* Cardiovascular,
* Metabolic,
* Neurodegenerative,
* Psychiatric,
* Cancer and
* Infectious diseases.

The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are a promising future approach for tailor-made drug development. [http://www.citeulike.org/user/xdeupi/article/928331 Source]

[[image:G-protein pathway.jpeg|700 px|center|thumb| [http://genome.ib.sci.yamaguchi-u.ac.jp/~pnp/frame_petri_net_pathway_gprotein.html Source]]]

[http://www.maxanim.com/biochemistry/Membrane-Bound%20Receptors/Membrane-Bound%20Receptors.htm Animation]

----

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===C-reactive protein (CRP)===
[[image:c-protein 1.gif|right|thumb|400px|[http://images.google.com/images?q=tbn:A7NTUBLxNDV1JM:http://www-ermm.cbcu.cam.ac.uk/fig002gkd.gif Source]]]
C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. It is a member of the pentraxin family of proteins. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes[4], hypertension and cardiovascular disease. [http://en.wikipedia.org/wiki/C-reactive_protein]

CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated). [http://www.haps.nsw.gov.au/edrsrch/edinfo/crp.html Source]

'''The role of C-reactive protein in atherogenesis'''

(A) Endothelial dysfunction

(B) Endothelial cell activation

(C) Plaque formation

(D) Plaque rupture

(E) Inhibition of EPC survival and function
[[image:c-protein.jpeg|center|thumb|400 px|[http://www.nature.com/ncpcardio/journal/v2/n1/fig_tab/ncpcardio0074_F2.html Source]]]

'''Treatment approaches''' - '''Lowering level of CRP'''
* Vitamin E
* Vitamin B6
* Aspirin
* Gugulipid
* Proteolytic Enzymes (VRP’s UniZyme formula)
* Other anti-inflammatory compunds (Herbs, Turmeric and Boswellia, and fish oil) [http://www.vrp.com/art/1130.asp?c=1155552556156&k=/det/1121.asp&m=/&p=no&s=0 Source]

----

===Renin-angiotensin system===

Vascular inflammation is now recognized to be an independent risk factor for the development of atherosclerosis. Chronic elevations of circulating IL-6 or its biomarkers are predictors for increased risk for the development or progression of ischemic heart disease. Our laboratory has been investigating the role of the renin-angiotensin system in accelerating vascular inflammation. The potent vasopressor peptide, angiotensin II, induces the expression of cardioactive cytokines, such as IL-6, in vascular smooth muscle cells. We are particularly interested in the role of the NF-kB transcription factor in signaling the inflammatory response in the vessel wall. In this project, we are pursuing the hypothesis that NF-kB is a central mediator of inflammation and atherosclerosis in the large vessels. [http://bioinfo.utmb.edu/Brasier_Lab/projects/index.html Source]

[[image:vascular inflammation.gif|center|600 px|thumb]]

----
===LXR signaling pathways===
[[Image: LXR signaling pathway.gif|right|350 px|thumb]]
The liver X receptors {alpha} and {beta} (LXR{alpha} and LXR{beta}) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease. [http://mend.endojournals.org/cgi/content/abstract/me.2003-0061v1 Source]

Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. [http://www.biocarta.com/pathfiles/h_fxrPathway.asp Source]

----

===Cardiac Adrenergic Signaling===
[[image:cardiac signaling.gif|right|250 px|thumb]]
The adrenergic receptors are G-protein–coupled transmembrane receptors. On binding to ligands, the G proteins dissociate from the intracellular domain of the receptor to propagate signals by modulating the activity of downstream effector molecules such as adenylate cyclase, phospholipases, and ion channels. The {beta}1-Adrenergic receptor and {beta}2-adrenergic receptor are both normally coupled to the stimulatory G protein (Gs), and through this protein, they activate adenylate cyclase, augmenting myocyte contractility and inducing myocyte hypertrophy or heart failure. This regulation of cell growth involves multiple downstream molecules including mitogen-activated protein kinases in a complex regulatory network. {beta}2-Adrenergic receptors may also couple to the inhibitory G protein (Gi) and reduce adenylate cyclase activity while activating the mitogen-activated protein kinase pathway. The role of the {beta}3-adrenergic receptors is less clear, but they seem to activate nitric oxide synthase through Gi. {alpha}-Adrenergic signaling also has an important role in cardiac physiology. When stimulated, {alpha}1-adrenergic receptors (not shown) are potent mediators of cardiomyocyte hypertrophy, acting through another subtype of G protein (Gq), which stimulates mitogen-activated protein kinase pathways. The two subtypes of {alpha}2-adrenergic receptors ({alpha}2A and {alpha}2C) depicted here operate as presynaptic inhibitors of norepinephrine release, but are also known to have postsynaptic functions. The {alpha}2A-adrenergic receptor is important for central and peripheral nervous system inhibition of norepinephrine release at high action-potential frequencies, whereas the {alpha}2C-adrenergic receptor is more important for regulating lower-frequency stimulation. These {alpha}2-adrenergic receptors inhibit the release not only of norepinephrine but also of other neurotransmitters that are not ligands for the adrenergic receptors. [http://content.nejm.org/cgi/figsearch?andorexacttitleabs=and&tmonth=Feb&searchtitle=Figures&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&search_tab=figures&searchterm=cardiac+signaling&sendit=GO Source]

----

===Nitroso–Redox Balance ===
The interaction between nitric oxide (NO) and superoxide (O2–) production — the nitroso–redox balance — plays fundamental roles in cell and organ failure at key sites throughout the cardiovascular system. Physiologically, the level and location of nitric oxide and superoxide production are balanced within the cell, facilitating appropriate post-translational modification of effector proteins. In patients with heart failure, the production of superoxide is increased and the level or location of nitric oxide synthesis is disrupted, interrupting effector signaling and thus causing cellular dysfunction as a result of vasoconstriction of small and large blood vessels and cardiac contractility or, if prolonged, cell death or damage. Isosorbide dinitrate, a drug that stimulates the nitric oxide pathway, and hydralazine, an antioxidant that inhibits superoxide synthesis, may therefore restore the balance of nitric oxide and superoxide production, converting the pathologic pathways to physiologic pathways in both the heart and the blood vessels. [http://content.nejm.org/cgi/content/full/351/20/2112?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiac+signaling&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]

[[image:Nitroso–Redox Balance.gif|center|600 px|thumb]]

----
=== HDL Cholesterol Levels===

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre-{beta}-HDL (green arrow). Pre-{beta}-HDL is converted into mature {alpha}-HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase. [http://content.nejm.org/cgi/content/full/350/15/1491?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiovascular+pathway&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]
[[image:Increasing HDL Cholesterol Levels.jpeg|center|400 px|thumb]]

----

==Intellectual property - G-proteins and cardiovascular diseases==
=== IP activity===
IP activity (based on priority year) in the G- protein-coupled receptors (GPCRs) space initiated during the year 1996, and is continuously increasing, with highest activity during the year 2000.

[[image:Publication-priority year.jpeg|center|thumb|800 px]]

''NOTE'': Decline in activity in the graph is due to the 18 months period for the patent publication.

----

===Competitor's activity===
Bayer Aktiengesellschaft, Pfizer, Millennium Pharmaceutical are the top players.

[[image:competitors- year.jpeg|center|thumb|500 px]]

----
===Technology classification based on IPC class===
Most of the patenting activity is edivent in IPC class "C07K", pertains to peptides.
[[image:IPC-patent.jpeg|center|thumb|500 px]]

{|border="2" cellspacing="0" align = "center" cellpadding="4" width="60%"
|align = "center"|'''Top IPC class'''
|align = "center"|'''Definition'''
|-
|C07K
|Peptides
|-
|A61K
|Preparation for medical purposes
|-
|G01N
|Investigating or analyzing materials by determining their chemical or physical properties
|-
|}

----

===Interactive signaling pathways and patents===

Interactive signaling pathway of G- protein represented below with information on few patents targeting different sites. Click on the Hypertext molecules in the main pathway, to visualize the patent details.
<center><gflash>800 800 http://www.dolcera.com/website/assets/G-protein.swf</gflash></center>

==Research activities==

Recent research progress (year 2007) in the area of G-proteins is illustrated below, with interactive gene linking.
<center><gflash>800 800 http://www.dolcera.com/website/assets/Gene-Interaction.swf</gflash></center>
===Future potential areas===

# In vivo activation of '''G{alpha}q/PKC pathways'' could upregulate GRK2 expression in cardiovascular cells, thus contributing to the increased desensitization of ß-adrenergic and other GPCR systems, is of potential physiological relevance. Detailed mechanisms of regulation of GRK2 expression in different types of cells of the cardiovascular system, particularly in cardiac cell lines, and the determination of possible changes in GRK2 levels in VSMCs of patients with cardiovascular diseases are interesting fields for future research and may help to develop new therapeutic strategies based on the modulation of GRK2 expression. [http://circ.ahajournals.org/cgi/content/full/circulationaha;101/17/2083]]

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Inflammation and cardiovascular drugs

2012-04-20T15:17:44Z

Abhay.goel.1: /* Overview of inflammation */

==Targeting inflammation – Pharmaceutical focus==

The pharmaceutical industry is one of the most profitable sectors of the Fortune 500 with profits of approximately 18% of revenue compared to a median of 5% for other industry segments. However, this market is facing increasing competitive pressure due to escalating R&D costs, shortened patent life due to the long product approval process, increased sales and marketing costs, pricing pressures, and entrance of more competitors into the industry. It is estimated that large pharmaceutical companies (or Pharma as they are generally referred to in the industry) require 3-5 new lead drug candidates (defined as New Chemical Entities or NCEs) each year to sustain doubledigit growth rates. Despite the fact that R&D costs have been increasing (typically $300-500 million per NCE), the average number of NCEs have been dropping over the last decade to under one per year across the industry. Thus, there is increasing pressure on Pharma to find newer discovery and development paradigms.

Inflammation is one of the key processes linked to various diseases and disorders. There are many opportunities for designing and developing specific new drugs for inflammatory responses.

[[image:market.png|center|1200 px|thumb|[http://www.chromos.com/documents/roadshowsept14_003.pdf Source]]]
----

==Overview of inflammation==
Inflammation is a process by which the body<nowiki>’</nowiki>s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses. [[Image:Targeting_inflammation_04.jpg|300 px|right|thumb]]

In some diseases, however, the body’s defense system (immune system) inappropriately triggers an inflammatory response when there are no foreign substances to fight off, these are called autoimmune diseases, where the body’s normally protective immune system causes damage to its own tissues. When inflammation occurs normally, chemicals from the body’s white blood cells are released to protect us from foreign substances.

Inflammation is characterized by:

* increased blood flow to the tissue
* increased temperature,
* redness,
* swelling, and
* pain.
 
 
 

[[image:inflammation overview.png|thumb|center|600 px]]

Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. Thease includes rheumatoid arthritis, osteoarthritis and inflammatory lung disease, including inflammatory bowel disease, atherosclerosis and psoriasis.

Chronic inflammatory disorders are a substantial burden in social and economic terms for the Australian community. Arthritis alone afflicts 3.4 million Australians and the financial costs were in excess of $19.25 billion in 2004 (Access Economics 2005).

Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their cause, treatment or cure, despite intensive global research.
----

===Various inflammatory diseases===
* '''Rheumatoid arthritis (RA)''' is a disease that most commonly affects the joints, but can sometimes also cause damage to other organs. RA is an auto-immune disease, that is, a disease where a person’s immune system attacks his or her own body tissues. This auto-immune reaction causes inflammation of the joints, particularly of the synovial membrane which lines them. There is an over-production of synovial (joint) fluid and this, combined with the inflammation, causes joints to become swollen and painful.

* '''Chronic Obstructive Pulmonary Disease, or COPD''', is a group of progressive lung diseases characterized by airflow obstruction or limitation that is not fully reversible. The restricted airflow is generally progressive and associated with abnormal inflammatory response of the lungs to irritants." They are most commonly caused by tobacco smoking. The family of diseases includes chronic bronchitis, emphysema and bronchiectasis. COPD develops slowly and it may be many years before symptoms such as breathing difficulties are noticed. Thus COPD is usually diagnosed in middle-aged or older people. COPD is also characterized by exacerbations which are often associated with a rapid progression of symptoms such as shortness of breath, wheezing, and sputum production, sometimes leading to respiratory failure. Exacerbations are most commonly brought on by infectious agents. Bronchodilators, antibiotics, and oral or intravenous steroids are used to treat these episodes.

* '''Osteoarthritis (OA)''' is the most common form of arthritis and is characterised by mild to debilitating pain, which can involve almost any joint but, in particular, weight bearing joints such as the hip, knee, spine and feet. OA refers to a degeneration of the articular cartilage that makes up the joint surface. This breakdown removes the soft buffer between the bones and can, when severe, result in bone against bone friction, which can cause severe pain and loss of movement.

* '''Inflammatory Bowel Disease (IBD)''' is the name of a group of disorders that cause the intestines to become inflamed (red and swollen). IBD can be painful and debilitating and causes chronic inflammation of the digestive tract. The two most common forms of IBD are ulcerative colitis and Crohn<nowiki>’</nowiki>s Disease. Both conditions inflame the lining of your digestive tract and both can cause severe bouts of watery diarrhoea and abdominal pain.
* '''Psoriasis''' is a common immune-mediated chronic skin disease that comes in different forms and differing levels of severity. It is a condition that is generally found on the knees, elbows, scalp, hands, feet or lower back, and generally appears as patches of raised red skin covered by a flaky white build up. It can cause intense itching and burning.
* '''Artherosclerosis''' is the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of an artery. It is a slow and progressive disease that may start in childhood. If left untreated, artherosclerosis can lead to heart attack or stroke. The first symptom of a narrowing artery may be pain or cramps at times when the blood flow can<nowiki>’</nowiki>t keep up with the body<nowiki>’</nowiki>s demand for oxygen. For example, during exercise a person may feel chest pain because of a lack of oxygen to the heart or while walking, a person may feel leg cramps because of a lack of oxygen to the legs.
* '''Pelvic inflammatory disease (PID)''' is a general term that refers to infection and inflammation of the upper genital tract in women. It can affect the uterus (womb), fallopian tubes (tubes that carry eggs from the ovaries to the uterus), ovaries, and other organs related to reproduction. The scarring that results on these organs can lead to infertility, tubal (ectopic) pregnancy, chronic pelvic pain, abscesses (sores containing pus), and other serious problems.
* '''Cardiovascular diseases''': C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Recent studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it’s been opened by balloon angioplasty. Most studies show that the higher the hs-CRP levels, the higher the risk of developing heart attack. [http://www.americanheart.org/presenter.jhtml?identifier=4648 Source]
* '''Metabolic disease''': Scientists at Galileo Pharmaceuticals, Inc. have demonstrated a direct relationship between inflammation and glucose levels. Inhibiting lipoxygenases, known mediators of inflammatory response, significantly lowers blood glucose levels in animal models of diabetes. Lipoxygenases are enzymes which play a key role in the synthesis of inflammatory mediators called leukotrienes, and trigger the progression of several diseases mediated by inflammation. Two key members of the lipoxygenase pathway, 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) have been indicated in a number of diseases states including asthma, arthritis, atherosclerosis, diabetes, osteoporosis, and cancer. [http://www.medicalnewstoday.com/medicalnews.php?newsid=27884 Source]
* '''Neurodegenerative disorder''': Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aß derived from misprocessing of amyloid precursor protein (APP). Aß deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. [http://stke.sciencemag.org/cgi/content/abstract/2002/162/tw461 Source]

----

===Factors associated with inflammations===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Players of inflammation'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Mast Cells'''
|Mast cells appear to be key players in the initiation of inflammation. Mast cells are found in the tissues. Their cytoplasm is loaded with granules containing mediators of inflammation. Their surface is coated with a variety of receptors which, when engaged by the appropriate ligand, trigger exocytosis of the granules. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Tumor Necrosis Factor-alpha (TNF-α)'''
|Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Chemokines'''
|These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Reactive Oxygen Species (ROS)'''
|These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Histamine'''
|The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Interleukin-1 (IL-1)'''
|Macrophages and monocytes are the main source of this cytokine. IL-1 has both • paracrine effects on cells in the vicinity, e.g., • causing them to produce tissue factor and thus triggering the blood clotting cascade. • stimulating the synthesis and secretion of a variety of other interleukins • helping to activate T cells and thus initiate an adaptive immune response • endocrine (hormonal) effects as it is carried in the blood throughout the body. • decreasing blood pressure • inducing fever. IL-1 causes fever by stimulating the release of prostaglandins, which act on the temperature control center of the hypothalamus. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Inflammasomes'''
|IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Leukotrienes and Prostaglandins'''
|These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and • the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways: one leading to the production of several • prostaglandins (PG); the other leading to the production of • thromboxanes (Tx). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----
===Current treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Treatment approach'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Steroids'''
|Like the glucocorticoid cortisol. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Nonsteroidal anti-inflammatory drugs (NSAIDs)'''
|The NSAIDs achieve their effects by blocking the activity of cyclooxygenase. NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''COX-1 and COX-2'''
|The body produces several different forms of cyclooxygenase (COX), including • COX-1, which is involved in pain, clotting, and protecting the stomach; • COX-2, which is involved in the pain produced by inflammation. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Therapeutic Proteins'''
|Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation. • an IL-1 antagonist that binds and inactivates the IL-1 receptor. • etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. • recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation. • infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows promise against some inflammatory diseases such as rheumatoid arthritis. (Side-effect: can convert a latent case of tuberculosis into active disease.) [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----

===Key signaling pathways===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Pathways'''
|align = "center" bgcolor = "#CCFFFF"|'''Activation'''
|align = "center" bgcolor = "#CCFFFF"|'''Key molecules'''
|align = "center" bgcolor = "#CCFFFF"|'''Target disease'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|MAPK Pathways
|Stress and Inflammation
| 
|Chronic inflammation, heart disease, stroke, diabetes mellitus
|[http://physrev.physiology.org/cgi/content/abstract/81/2/807 Source]
|-
|JNK Pathways
|Cytokines or environmental stress
| 
|Cellular proliferation, apoptosis, and tissue morphogenesis
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9561845&dopt=Citation Source]
|-
|Cytokine Pathways
| 
|TNF-alpha, IL-1, IL-6, IL-10, IL-4
|Joint Inflammation in Rheumatoid Arthritis
|[http://content.nejm.org/cgi/content/extract/344/12/907?ck=nck Source]
|-
|NF-κB pathway
|Diverse signal transduction cascades
|IκB kinases, IKKα and IKKβ
|Inflammation and cancer
|[http://www.jci.org/cgi/reprint/107/2/135.pdf Source]
|-
|Protein Kinase Cascades
|Mitogens but by cellular stresses and inflammatory cytokines
|ERKs, MEKs, SAPKs, Ras/MAPK, p38
|Stress and Inflammation
|[http://www.jbc.org/cgi/reprint/271/40/24313 Source]
|-
|TNF Pathways
| 
|TNF-R1
|Sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases
|[http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107 Source]
|-
|p38 Pathway (MAPK pathway)
|Bacterial pathogens and cytokines
|(ERKs, JNK/SAPK, ERK5/big MAP kinase 1 (BMK1), p38 group of protein kinases
|Inflammation, cell growth, cell differentiation, the cell cycle, and cell death
|[http://www.sci.sdsu.edu/classes/bio630/pdf/Ono2000.pdf Source]
|-
|TRAF6-NFκB
| 
|TLR/IL-1R, CD40, transcription factors NFκB and AP1
|Autoimmune disease
|align = "justify"|[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175050 Source]
|-
|STAT4 Pathways
| 
|Chemokines
|Allergic Airway Inflammation
|[http://www.jimmunol.org/cgi/content/full/170/7/3859 Source]
|-
|Toll-like receptors (TLRs) Pathways
|Cytokine-driven inflammation and tissue destruction
|Toll-like receptors (TLRs)
|Rheumatoid arthritis, Crohn<nowiki>’</nowiki>s disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis
|[http://cat.inist.fr/?aModele=afficheN&cpsidt=16287680 Source]
|-
|Multiple signaling pathways
| 
|C-reactive protein, ICAM-1, VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate, Clotting or coagulation factors, Fibrinolysis factors, angiotensin II, Prostaglandins, TGF-<nowiki>[</nowiki>beta<nowiki>]</nowiki>, (PDGF, NO and endothelin-1
|Atherosclerosis and cardiovascular disease
|[http://www.findarticles.com/p/articles/mi_m0FDN/is_1_9/ai_n5990649/pg_2 Source]
|-
|G protein-coupled receptors (GPCRs) Pathways
| 
|RGS proteins, PI3K
|Cardiovascular diseases
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15746448 Source]
|-
|}

----

==Cardiovascular diseases==
* It has become clear that CVD is an '''inflammatory disease''', although what triggers the inflammation is still unknown.
* Diagnosis of CVD through inflammatory markers is an active area of research. Although several classes of anti-hypertensive drugs exist, there are still several treatment goals that remain to be achieved, such as better blood pressure control, greater protection against organ damage, and better tolerability.
* Several angiogenic and myogenic stem cell therapies are under investigation and promise in the long run to advance cardiac rehabilitation and even prevent heart failure. Despite the development of improved therapies, millions of Americans continue to live with life-threatening cardiovascular diseases.

[[image:cardiovascilar diseases.png|center|thumb|800 px| [http://www-ermm.cbcu.cam.ac.uk/0500918Xh.htm Source]]]

----
===Market analysis===
* The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003.
* CVD is the leading cause of death in most regions throughout the world. Cardiovascular drugs constitute the world's largest pharmaceutical sector, with annual global sales over $70 billion.
* Risk factor management for CVD is an emerging market. Developing more effective ways of delivering pharmacological, nutritional, and preventative therapies are recognized as important targets that are under continual development. Aging populations and dietary and lifestyle induced disease processes ensure a growing need for cardiovascular devices.
* Reducing the costs for such devices by appropriately treating cardiovascular risk factors has become a major focus of the pharmaceutical and healthcare industries. Here are just some of the considerable market opportunities within the CVD Market:
** Increased use of cholesterol-controlling statins will cause prices to fall and generic brands to appear as knowledge of their benefits spread among general practitioners.
** Develop anti-glycosylation therapies to prevent the cross-linking that weakens aging heart muscle, and to reduce the diabetic risk factor.
** Create new vaccines to raise high density lipoprotein (HDL) levels, which help stave off heart disease.
** Develop new angiotensin receptor blockers to offer greater competition against ACE inhibitors
** Develop angiogenesis drugs such as VEGF (vascular endothelial growth factor) that will obviate the need for much bypass surgery by growing new arteries on damaged hearts.

----
===Common cardiac drugs===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" colspan = "4" bgcolor = "#CCFFFF"|'''[http://www.bmb.leeds.ac.uk/illingworth/cardio/index.htm Common cardiac drugs]'''
|-
|align = "center" bgcolor = "#CCFFFF" | '''Drugs'''
|align = "center" bgcolor = "#CCFFFF" | '''Main effects'''
|align = "center" bgcolor = "#CCFFFF" | '''Mechanism'''
|align = "center" bgcolor = "#CCFFFF" | '''Sites of action'''
|-
|Abciximab
|Anticoagulant stops platelet activation
|Monoclonal antibody to fibrinogen receptors
|Platelets
|-
|Amiloride (combination with frusemide is ''frumil'')
|Potassium sparing diuretic
|Plasmalemma sodium & chloride channels
|Kidney (distal tubules)
|-
|Amiodarone
|Class III anti-arrhythmic
|Prolongs action potential duration
|Myocardium
|-
|Aspirin
|Anticoagulant stops platelet activation
|COX inhibitor, blocks TXA2 synthesis
|Platelets
|-
|Atropine (sometimes used to stop vagus bradycardia)
|Parasympatholytic, increases heart rate
|Blocks muscarinic acch receptors
|Pacemaker cells (sino-atrial node)
|-
|Captopril
|Reduces arterial blood pressure
|ACE inhibitor
|Relaxes vascular smooth muscle
|-
|Clopidogrel
|Anticoagulant stops platelet activation
|Blocks ADP receptor
|Platelets
|-
|Digitalis and ouabain
|Increase cardiac contractility, delay AV node triggering
|Block Na / K atpase raising intracellular sodium, then calcium
|All tissues, but the Na/Ca exchanger is mainly in heart
|-
|Dipyridamole (often used for X-ray imaging)
|Coronary vasodilation
|Inhibition of adenosine uptake
|Coronary vasculature
|-
|Furosemide (= frusemide)
|Diuretic
|Plasmalemma sodium & chloride channels
|Kidney (loop of Henle)
|-
|Isoprenaline (and other adrenaline analogues)
|Increase cardiac contractility
|Beta agonist raises cyclic AMP
|Many tissues
|-
|Losartan
|Reduces arterial blood pressure
|Angiotensin AT1 receptor blockade
|Relaxes vascular smooth muscle
|-
|Lovastatin
|Reduces blood cholesterol levels
|HMG-coa reductase inhibitor
|Liver
|-
|Morphine
|Pain relief (mainly)
|Opiate receptors
|Brain
|-
|Nitroglycerine (and many other organic nitrates)
|Reduce cardiac work load
|Metabolised to NO
|Relaxes vascular smooth muscle
|-
|Propranolol
|Reduces cardiac contractility, class II anti-arrhythmic
|Beta blocker lowers cyclic AMP
|Many tissues
|-
|Quinidine, novocaine and other local anaesthetics
|Class I anti-arrhythmics
|Delay recovery of sarcolemma sodium channels after AP
|Myocardium
|-
|Spironolactone (usually added to other diuretics)
|Reduces diuretic potassium losses
|Aldosterone antagonist
|Kidney (distal tubules)
|-
|Urokinase (streptokinase is cheaper but antigenic)
|Dissolves blood clots (fibrinolytic)
|Activates plasminogen to plasmin (protease)
|Blood clots
|-
|Verapamil, nifedipine and other dihydropyridines
|Reduce cardiac work load, class IV anti-arrhythmic
|Block sarcolemma calcium channels
|Myocardium; relax vascular smooth muscle
|-
|Warfarin
|Anticoagulant Vit. K antagonist
|Blocks -carboxy glutamate synthesis
|Liver
|-
|} 

----
==Drug targets==

Target molecule (or target protein) are the molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule— a drug— to bind to the target molecule and block its action.

[[image:drug targets.gif|center|thumb|500 px| [http://www.locomogene.com/english/strategy/concept.html Source]]]

----
===Emerging drug targets===
Drug targets are generally proteins. Nucleic acids are possible drug targets, and approaches such as RNA interference (RNAi) may indeed have advantages over proteins, but they have not so far been developed extensively. Protein targets consist mainly of enzymes, regulatory molecules such as cytokines, receptors for hormones or other regulatory molecules, transporters, and ion channels. Proteins that interact with small molecules are considered the most promising targets, because it is often possible to design or discover small molecule activators or inhibitors based on the natural ligands. Such substances are relatively straightforward to develop as drugs. Overall, enzyme targets account for over 50% of marketed drugs, and GPCR targets represent more than 20%, including 23 of the 100 best-selling drugs in the US. Hence the other target classes between them make up the remaining 25-30% of marketed drugs. Aberrant signal transduction plays a key part in the pathology of many serious diseases including cancer, inflammatory, cardiovascular, metabolic, and neuropsychiatric diseases. Proteins involved in signal transduction pathways therefore represent important drug targets. Three prominent superfamilies of proteins involved in signal transduction are: GPCRs, protein kinases, and nuclear receptors. [http://www.marketresearch.com/product/display.asp?productid=1204095&g=1 Source]

----
===Classification of drug targets===
[[image:drug class distribution.jpeg|right|450 px|thumb|Biochemical classes of drug targets. [http://www.bioinformation.net/1/76-1-2006.htm Source]]]
The introduction of genomics, proteomics and metabolomics has paved the way for biology-driven process, leading to plethora of drug targets. The list of potential drug targets encoded in a genome includes most natural choice of virulent genes and species-specific genes. Other options include targeting RNA, enzymes of the intermediary metabolism, systems for DNA replication, translation apparatus or repair and membrane proteins.

* Species-specific genes as drug targets
* RNA as drug target
* Nucleic acid as drug targets
* Proteins as drug targets
* Membranes as drug targets

The comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. [http://www.scripps.edu/newsandviews/e_20020422/print-drug.html Source]

{|border="2" cellspacing="0" cellpadding="4" width="60%" align = "center"
|align = "center" bgcolor = "#CCFFFF"|'''Drug targets'''
|align = "center" bgcolor = "#CCFFFF"|'''2001'''
|align = "center" bgcolor = "#CCFFFF"|'''2005'''
|-
|GPCRs
|align = "center"|30%
|align = "center"|20%
|-
|Ion Channel
|align = "center"|20%
|align = "center"|30%
|-
|Enzymes
|align = "center"|30%
|align = "center"|20%
|-
|Hormones/Vitamins
|align = "center"|12%
|align = "center"|4%
|-
|RNA-Proteins/DNA-Proteins
|align = "center"|<nowiki>-</nowiki>
|align = "center"|10%
|-
|Protein-Protein
|align = "center"|<nowiki>-</nowiki>
|align = "center"|20%
|-
|Unknown Mechanism
|align = "center"|8%
|align = "center"|<nowiki>-</nowiki>
|-
|}
----

==Drug targets for cardiovascular diseases==
===G- protein-coupled receptors (GPCRs)===
GPCRs are the largest and most important class of receptors in humans because they are the targets of more than half of all drugs used clinically, especially for treating diseases of the cardiovascular and nervous systems. GPCRs are also the targets of many drugs of abuse.

G Protein-Coupled Receptors (GPCRs) account for 50% of the current drug targets, and remain about one-third of the drug discovery effort in the drug discovery-development community. As a result of the sequencing of the human genome, more than 150 orphan and non-chemosensory GPCRs have been identified for which their cognate ligands or biological functions are unknown. De-orphanization of those receptors could bring novel therapeutic targets to the industry against which novel therapeutics could be designed. In addition, current GPCR-based drugs only target ~30% of the approximately 200 known GPCRs in the genome. This is a rich target class that is highly-druggable. [http://www.marketresearch.com/product/display.asp?productid=1092267&SID=66002803-375208398-363996861&kw=G%2DProtein%09Coupled%09Receptors%09GPCRs Source]

Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as:
* Cardiovascular,
* Metabolic,
* Neurodegenerative,
* Psychiatric,
* Cancer and
* Infectious diseases.

The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are a promising future approach for tailor-made drug development. [http://www.citeulike.org/user/xdeupi/article/928331 Source]

[[image:G-protein pathway.jpeg|700 px|center|thumb| [http://genome.ib.sci.yamaguchi-u.ac.jp/~pnp/frame_petri_net_pathway_gprotein.html Source]]]

[http://www.maxanim.com/biochemistry/Membrane-Bound%20Receptors/Membrane-Bound%20Receptors.htm Animation]

----

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===C-reactive protein (CRP)===
[[image:c-protein 1.gif|right|thumb|400px|[http://images.google.com/images?q=tbn:A7NTUBLxNDV1JM:http://www-ermm.cbcu.cam.ac.uk/fig002gkd.gif Source]]]
C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. It is a member of the pentraxin family of proteins. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes[4], hypertension and cardiovascular disease. [http://en.wikipedia.org/wiki/C-reactive_protein]

CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated). [http://www.haps.nsw.gov.au/edrsrch/edinfo/crp.html Source]

'''The role of C-reactive protein in atherogenesis'''

(A) Endothelial dysfunction

(B) Endothelial cell activation

(C) Plaque formation

(D) Plaque rupture

(E) Inhibition of EPC survival and function
[[image:c-protein.jpeg|center|thumb|400 px|[http://www.nature.com/ncpcardio/journal/v2/n1/fig_tab/ncpcardio0074_F2.html Source]]]

'''Treatment approaches''' - '''Lowering level of CRP'''
* Vitamin E
* Vitamin B6
* Aspirin
* Gugulipid
* Proteolytic Enzymes (VRP’s UniZyme formula)
* Other anti-inflammatory compunds (Herbs, Turmeric and Boswellia, and fish oil) [http://www.vrp.com/art/1130.asp?c=1155552556156&k=/det/1121.asp&m=/&p=no&s=0 Source]

----

===Renin-angiotensin system===

Vascular inflammation is now recognized to be an independent risk factor for the development of atherosclerosis. Chronic elevations of circulating IL-6 or its biomarkers are predictors for increased risk for the development or progression of ischemic heart disease. Our laboratory has been investigating the role of the renin-angiotensin system in accelerating vascular inflammation. The potent vasopressor peptide, angiotensin II, induces the expression of cardioactive cytokines, such as IL-6, in vascular smooth muscle cells. We are particularly interested in the role of the NF-kB transcription factor in signaling the inflammatory response in the vessel wall. In this project, we are pursuing the hypothesis that NF-kB is a central mediator of inflammation and atherosclerosis in the large vessels. [http://bioinfo.utmb.edu/Brasier_Lab/projects/index.html Source]

[[image:vascular inflammation.gif|center|600 px|thumb]]

----
===LXR signaling pathways===
[[Image: LXR signaling pathway.gif|right|350 px|thumb]]
The liver X receptors {alpha} and {beta} (LXR{alpha} and LXR{beta}) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease. [http://mend.endojournals.org/cgi/content/abstract/me.2003-0061v1 Source]

Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. [http://www.biocarta.com/pathfiles/h_fxrPathway.asp Source]

----

===Cardiac Adrenergic Signaling===
[[image:cardiac signaling.gif|right|250 px|thumb]]
The adrenergic receptors are G-protein–coupled transmembrane receptors. On binding to ligands, the G proteins dissociate from the intracellular domain of the receptor to propagate signals by modulating the activity of downstream effector molecules such as adenylate cyclase, phospholipases, and ion channels. The {beta}1-Adrenergic receptor and {beta}2-adrenergic receptor are both normally coupled to the stimulatory G protein (Gs), and through this protein, they activate adenylate cyclase, augmenting myocyte contractility and inducing myocyte hypertrophy or heart failure. This regulation of cell growth involves multiple downstream molecules including mitogen-activated protein kinases in a complex regulatory network. {beta}2-Adrenergic receptors may also couple to the inhibitory G protein (Gi) and reduce adenylate cyclase activity while activating the mitogen-activated protein kinase pathway. The role of the {beta}3-adrenergic receptors is less clear, but they seem to activate nitric oxide synthase through Gi. {alpha}-Adrenergic signaling also has an important role in cardiac physiology. When stimulated, {alpha}1-adrenergic receptors (not shown) are potent mediators of cardiomyocyte hypertrophy, acting through another subtype of G protein (Gq), which stimulates mitogen-activated protein kinase pathways. The two subtypes of {alpha}2-adrenergic receptors ({alpha}2A and {alpha}2C) depicted here operate as presynaptic inhibitors of norepinephrine release, but are also known to have postsynaptic functions. The {alpha}2A-adrenergic receptor is important for central and peripheral nervous system inhibition of norepinephrine release at high action-potential frequencies, whereas the {alpha}2C-adrenergic receptor is more important for regulating lower-frequency stimulation. These {alpha}2-adrenergic receptors inhibit the release not only of norepinephrine but also of other neurotransmitters that are not ligands for the adrenergic receptors. [http://content.nejm.org/cgi/figsearch?andorexacttitleabs=and&tmonth=Feb&searchtitle=Figures&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&search_tab=figures&searchterm=cardiac+signaling&sendit=GO Source]

----

===Nitroso–Redox Balance ===
The interaction between nitric oxide (NO) and superoxide (O2–) production — the nitroso–redox balance — plays fundamental roles in cell and organ failure at key sites throughout the cardiovascular system. Physiologically, the level and location of nitric oxide and superoxide production are balanced within the cell, facilitating appropriate post-translational modification of effector proteins. In patients with heart failure, the production of superoxide is increased and the level or location of nitric oxide synthesis is disrupted, interrupting effector signaling and thus causing cellular dysfunction as a result of vasoconstriction of small and large blood vessels and cardiac contractility or, if prolonged, cell death or damage. Isosorbide dinitrate, a drug that stimulates the nitric oxide pathway, and hydralazine, an antioxidant that inhibits superoxide synthesis, may therefore restore the balance of nitric oxide and superoxide production, converting the pathologic pathways to physiologic pathways in both the heart and the blood vessels. [http://content.nejm.org/cgi/content/full/351/20/2112?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiac+signaling&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]

[[image:Nitroso–Redox Balance.gif|center|600 px|thumb]]

----
=== HDL Cholesterol Levels===

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre-{beta}-HDL (green arrow). Pre-{beta}-HDL is converted into mature {alpha}-HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase. [http://content.nejm.org/cgi/content/full/350/15/1491?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiovascular+pathway&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]
[[image:Increasing HDL Cholesterol Levels.jpeg|center|400 px|thumb]]

----

==Intellectual property - G-proteins and cardiovascular diseases==
=== IP activity===
IP activity (based on priority year) in the G- protein-coupled receptors (GPCRs) space initiated during the year 1996, and is continuously increasing, with highest activity during the year 2000.

[[image:Publication-priority year.jpeg|center|thumb|800 px]]

''NOTE'': Decline in activity in the graph is due to the 18 months period for the patent publication.

----

===Competitor's activity===
Bayer Aktiengesellschaft, Pfizer, Millennium Pharmaceutical are the top players.

[[image:competitors- year.jpeg|center|thumb|500 px]]

----
===Technology classification based on IPC class===
Most of the patenting activity is edivent in IPC class "C07K", pertains to peptides.
[[image:IPC-patent.jpeg|center|thumb|500 px]]

{|border="2" cellspacing="0" align = "center" cellpadding="4" width="60%"
|align = "center"|'''Top IPC class'''
|align = "center"|'''Definition'''
|-
|C07K
|Peptides
|-
|A61K
|Preparation for medical purposes
|-
|G01N
|Investigating or analyzing materials by determining their chemical or physical properties
|-
|}

----

===Interactive signaling pathways and patents===

Interactive signaling pathway of G- protein represented below with information on few patents targeting different sites. Click on the Hypertext molecules in the main pathway, to visualize the patent details.
<center><gflash>800 800 http://www.dolcera.com/website/assets/G-protein.swf</gflash></center>

==Research activities==

Recent research progress (year 2007) in the area of G-proteins is illustrated below, with interactive gene linking.
<center><gflash>800 800 http://www.dolcera.com/website/assets/Gene-Interaction.swf</gflash></center>
===Future potential areas===

# In vivo activation of '''G{alpha}q/PKC pathways'' could upregulate GRK2 expression in cardiovascular cells, thus contributing to the increased desensitization of ß-adrenergic and other GPCR systems, is of potential physiological relevance. Detailed mechanisms of regulation of GRK2 expression in different types of cells of the cardiovascular system, particularly in cardiac cell lines, and the determination of possible changes in GRK2 levels in VSMCs of patients with cardiovascular diseases are interesting fields for future research and may help to develop new therapeutic strategies based on the modulation of GRK2 expression. [http://circ.ahajournals.org/cgi/content/full/circulationaha;101/17/2083]]

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Inflammation and cardiovascular drugs

2012-04-20T15:16:09Z

Abhay.goel.1: /* Targeting inflammation – Pharmaceutical focus */

==Targeting inflammation – Pharmaceutical focus==

The pharmaceutical industry is one of the most profitable sectors of the Fortune 500 with profits of approximately 18% of revenue compared to a median of 5% for other industry segments. However, this market is facing increasing competitive pressure due to escalating R&D costs, shortened patent life due to the long product approval process, increased sales and marketing costs, pricing pressures, and entrance of more competitors into the industry. It is estimated that large pharmaceutical companies (or Pharma as they are generally referred to in the industry) require 3-5 new lead drug candidates (defined as New Chemical Entities or NCEs) each year to sustain doubledigit growth rates. Despite the fact that R&D costs have been increasing (typically $300-500 million per NCE), the average number of NCEs have been dropping over the last decade to under one per year across the industry. Thus, there is increasing pressure on Pharma to find newer discovery and development paradigms.

Inflammation is one of the key processes linked to various diseases and disorders. There are many opportunities for designing and developing specific new drugs for inflammatory responses.

[[image:market.png|center|1200 px|thumb|[http://www.chromos.com/documents/roadshowsept14_003.pdf Source]]]
----

==Overview of inflammation==
Inflammation is a process by which the body<nowiki>’</nowiki>s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses. [[Image:Targeting_inflammation_04.jpg|300 px|right|thumb]]

In some diseases, however, the body’s defense system (immune system) inappropriately triggers an inflammatory response when there are no foreign substances to fight off, these are called autoimmune diseases, where the body’s normally protective immune system causes damage to its own tissues. When inflammation occurs normally, chemicals from the body’s white blood cells are released to protect us from foreign substances.

Inflammation is characterized by:

* increased blood flow to the tissue causing
* increased temperature,
* redness,
* swelling, and
* pain.
 
 
 

[[image:inflammation overview.png|thumb|center|600 px]]

Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. Thease includes rheumatoid arthritis, osteoarthritis and inflammatory lung disease, including inflammatory bowel disease, atherosclerosis and psoriasis.

Chronic inflammatory disorders are a substantial burden in social and economic terms for the Australian community. Arthritis alone afflicts 3.4 million Australians and the financial costs were in excess of $19.25 billion in 2004 (Access Economics 2005).

Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their cause, treatment or cure, despite intensive global research.
----

===Various inflammatory diseases===
* '''Rheumatoid arthritis (RA)''' is a disease that most commonly affects the joints, but can sometimes also cause damage to other organs. RA is an auto-immune disease, that is, a disease where a person’s immune system attacks his or her own body tissues. This auto-immune reaction causes inflammation of the joints, particularly of the synovial membrane which lines them. There is an over-production of synovial (joint) fluid and this, combined with the inflammation, causes joints to become swollen and painful.

* '''Chronic Obstructive Pulmonary Disease, or COPD''', is a group of progressive lung diseases characterized by airflow obstruction or limitation that is not fully reversible. The restricted airflow is generally progressive and associated with abnormal inflammatory response of the lungs to irritants." They are most commonly caused by tobacco smoking. The family of diseases includes chronic bronchitis, emphysema and bronchiectasis. COPD develops slowly and it may be many years before symptoms such as breathing difficulties are noticed. Thus COPD is usually diagnosed in middle-aged or older people. COPD is also characterized by exacerbations which are often associated with a rapid progression of symptoms such as shortness of breath, wheezing, and sputum production, sometimes leading to respiratory failure. Exacerbations are most commonly brought on by infectious agents. Bronchodilators, antibiotics, and oral or intravenous steroids are used to treat these episodes.

* '''Osteoarthritis (OA)''' is the most common form of arthritis and is characterised by mild to debilitating pain, which can involve almost any joint but, in particular, weight bearing joints such as the hip, knee, spine and feet. OA refers to a degeneration of the articular cartilage that makes up the joint surface. This breakdown removes the soft buffer between the bones and can, when severe, result in bone against bone friction, which can cause severe pain and loss of movement.

* '''Inflammatory Bowel Disease (IBD)''' is the name of a group of disorders that cause the intestines to become inflamed (red and swollen). IBD can be painful and debilitating and causes chronic inflammation of the digestive tract. The two most common forms of IBD are ulcerative colitis and Crohn<nowiki>’</nowiki>s Disease. Both conditions inflame the lining of your digestive tract and both can cause severe bouts of watery diarrhoea and abdominal pain.
* '''Psoriasis''' is a common immune-mediated chronic skin disease that comes in different forms and differing levels of severity. It is a condition that is generally found on the knees, elbows, scalp, hands, feet or lower back, and generally appears as patches of raised red skin covered by a flaky white build up. It can cause intense itching and burning.
* '''Artherosclerosis''' is the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of an artery. It is a slow and progressive disease that may start in childhood. If left untreated, artherosclerosis can lead to heart attack or stroke. The first symptom of a narrowing artery may be pain or cramps at times when the blood flow can<nowiki>’</nowiki>t keep up with the body<nowiki>’</nowiki>s demand for oxygen. For example, during exercise a person may feel chest pain because of a lack of oxygen to the heart or while walking, a person may feel leg cramps because of a lack of oxygen to the legs.
* '''Pelvic inflammatory disease (PID)''' is a general term that refers to infection and inflammation of the upper genital tract in women. It can affect the uterus (womb), fallopian tubes (tubes that carry eggs from the ovaries to the uterus), ovaries, and other organs related to reproduction. The scarring that results on these organs can lead to infertility, tubal (ectopic) pregnancy, chronic pelvic pain, abscesses (sores containing pus), and other serious problems.
* '''Cardiovascular diseases''': C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Recent studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it’s been opened by balloon angioplasty. Most studies show that the higher the hs-CRP levels, the higher the risk of developing heart attack. [http://www.americanheart.org/presenter.jhtml?identifier=4648 Source]
* '''Metabolic disease''': Scientists at Galileo Pharmaceuticals, Inc. have demonstrated a direct relationship between inflammation and glucose levels. Inhibiting lipoxygenases, known mediators of inflammatory response, significantly lowers blood glucose levels in animal models of diabetes. Lipoxygenases are enzymes which play a key role in the synthesis of inflammatory mediators called leukotrienes, and trigger the progression of several diseases mediated by inflammation. Two key members of the lipoxygenase pathway, 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) have been indicated in a number of diseases states including asthma, arthritis, atherosclerosis, diabetes, osteoporosis, and cancer. [http://www.medicalnewstoday.com/medicalnews.php?newsid=27884 Source]
* '''Neurodegenerative disorder''': Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aß derived from misprocessing of amyloid precursor protein (APP). Aß deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. [http://stke.sciencemag.org/cgi/content/abstract/2002/162/tw461 Source]

----

===Factors associated with inflammations===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Players of inflammation'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Mast Cells'''
|Mast cells appear to be key players in the initiation of inflammation. Mast cells are found in the tissues. Their cytoplasm is loaded with granules containing mediators of inflammation. Their surface is coated with a variety of receptors which, when engaged by the appropriate ligand, trigger exocytosis of the granules. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Tumor Necrosis Factor-alpha (TNF-α)'''
|Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Chemokines'''
|These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Reactive Oxygen Species (ROS)'''
|These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Histamine'''
|The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Interleukin-1 (IL-1)'''
|Macrophages and monocytes are the main source of this cytokine. IL-1 has both • paracrine effects on cells in the vicinity, e.g., • causing them to produce tissue factor and thus triggering the blood clotting cascade. • stimulating the synthesis and secretion of a variety of other interleukins • helping to activate T cells and thus initiate an adaptive immune response • endocrine (hormonal) effects as it is carried in the blood throughout the body. • decreasing blood pressure • inducing fever. IL-1 causes fever by stimulating the release of prostaglandins, which act on the temperature control center of the hypothalamus. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Inflammasomes'''
|IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Leukotrienes and Prostaglandins'''
|These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and • the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways: one leading to the production of several • prostaglandins (PG); the other leading to the production of • thromboxanes (Tx). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----
===Current treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Treatment approach'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Steroids'''
|Like the glucocorticoid cortisol. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Nonsteroidal anti-inflammatory drugs (NSAIDs)'''
|The NSAIDs achieve their effects by blocking the activity of cyclooxygenase. NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''COX-1 and COX-2'''
|The body produces several different forms of cyclooxygenase (COX), including • COX-1, which is involved in pain, clotting, and protecting the stomach; • COX-2, which is involved in the pain produced by inflammation. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Therapeutic Proteins'''
|Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation. • an IL-1 antagonist that binds and inactivates the IL-1 receptor. • etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. • recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation. • infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows promise against some inflammatory diseases such as rheumatoid arthritis. (Side-effect: can convert a latent case of tuberculosis into active disease.) [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----

===Key signaling pathways===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Pathways'''
|align = "center" bgcolor = "#CCFFFF"|'''Activation'''
|align = "center" bgcolor = "#CCFFFF"|'''Key molecules'''
|align = "center" bgcolor = "#CCFFFF"|'''Target disease'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|MAPK Pathways
|Stress and Inflammation
| 
|Chronic inflammation, heart disease, stroke, diabetes mellitus
|[http://physrev.physiology.org/cgi/content/abstract/81/2/807 Source]
|-
|JNK Pathways
|Cytokines or environmental stress
| 
|Cellular proliferation, apoptosis, and tissue morphogenesis
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9561845&dopt=Citation Source]
|-
|Cytokine Pathways
| 
|TNF-alpha, IL-1, IL-6, IL-10, IL-4
|Joint Inflammation in Rheumatoid Arthritis
|[http://content.nejm.org/cgi/content/extract/344/12/907?ck=nck Source]
|-
|NF-κB pathway
|Diverse signal transduction cascades
|IκB kinases, IKKα and IKKβ
|Inflammation and cancer
|[http://www.jci.org/cgi/reprint/107/2/135.pdf Source]
|-
|Protein Kinase Cascades
|Mitogens but by cellular stresses and inflammatory cytokines
|ERKs, MEKs, SAPKs, Ras/MAPK, p38
|Stress and Inflammation
|[http://www.jbc.org/cgi/reprint/271/40/24313 Source]
|-
|TNF Pathways
| 
|TNF-R1
|Sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases
|[http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107 Source]
|-
|p38 Pathway (MAPK pathway)
|Bacterial pathogens and cytokines
|(ERKs, JNK/SAPK, ERK5/big MAP kinase 1 (BMK1), p38 group of protein kinases
|Inflammation, cell growth, cell differentiation, the cell cycle, and cell death
|[http://www.sci.sdsu.edu/classes/bio630/pdf/Ono2000.pdf Source]
|-
|TRAF6-NFκB
| 
|TLR/IL-1R, CD40, transcription factors NFκB and AP1
|Autoimmune disease
|align = "justify"|[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175050 Source]
|-
|STAT4 Pathways
| 
|Chemokines
|Allergic Airway Inflammation
|[http://www.jimmunol.org/cgi/content/full/170/7/3859 Source]
|-
|Toll-like receptors (TLRs) Pathways
|Cytokine-driven inflammation and tissue destruction
|Toll-like receptors (TLRs)
|Rheumatoid arthritis, Crohn<nowiki>’</nowiki>s disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis
|[http://cat.inist.fr/?aModele=afficheN&cpsidt=16287680 Source]
|-
|Multiple signaling pathways
| 
|C-reactive protein, ICAM-1, VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate, Clotting or coagulation factors, Fibrinolysis factors, angiotensin II, Prostaglandins, TGF-<nowiki>[</nowiki>beta<nowiki>]</nowiki>, (PDGF, NO and endothelin-1
|Atherosclerosis and cardiovascular disease
|[http://www.findarticles.com/p/articles/mi_m0FDN/is_1_9/ai_n5990649/pg_2 Source]
|-
|G protein-coupled receptors (GPCRs) Pathways
| 
|RGS proteins, PI3K
|Cardiovascular diseases
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15746448 Source]
|-
|}

----

==Cardiovascular diseases==
* It has become clear that CVD is an '''inflammatory disease''', although what triggers the inflammation is still unknown.
* Diagnosis of CVD through inflammatory markers is an active area of research. Although several classes of anti-hypertensive drugs exist, there are still several treatment goals that remain to be achieved, such as better blood pressure control, greater protection against organ damage, and better tolerability.
* Several angiogenic and myogenic stem cell therapies are under investigation and promise in the long run to advance cardiac rehabilitation and even prevent heart failure. Despite the development of improved therapies, millions of Americans continue to live with life-threatening cardiovascular diseases.

[[image:cardiovascilar diseases.png|center|thumb|800 px| [http://www-ermm.cbcu.cam.ac.uk/0500918Xh.htm Source]]]

----
===Market analysis===
* The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003.
* CVD is the leading cause of death in most regions throughout the world. Cardiovascular drugs constitute the world's largest pharmaceutical sector, with annual global sales over $70 billion.
* Risk factor management for CVD is an emerging market. Developing more effective ways of delivering pharmacological, nutritional, and preventative therapies are recognized as important targets that are under continual development. Aging populations and dietary and lifestyle induced disease processes ensure a growing need for cardiovascular devices.
* Reducing the costs for such devices by appropriately treating cardiovascular risk factors has become a major focus of the pharmaceutical and healthcare industries. Here are just some of the considerable market opportunities within the CVD Market:
** Increased use of cholesterol-controlling statins will cause prices to fall and generic brands to appear as knowledge of their benefits spread among general practitioners.
** Develop anti-glycosylation therapies to prevent the cross-linking that weakens aging heart muscle, and to reduce the diabetic risk factor.
** Create new vaccines to raise high density lipoprotein (HDL) levels, which help stave off heart disease.
** Develop new angiotensin receptor blockers to offer greater competition against ACE inhibitors
** Develop angiogenesis drugs such as VEGF (vascular endothelial growth factor) that will obviate the need for much bypass surgery by growing new arteries on damaged hearts.

----
===Common cardiac drugs===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" colspan = "4" bgcolor = "#CCFFFF"|'''[http://www.bmb.leeds.ac.uk/illingworth/cardio/index.htm Common cardiac drugs]'''
|-
|align = "center" bgcolor = "#CCFFFF" | '''Drugs'''
|align = "center" bgcolor = "#CCFFFF" | '''Main effects'''
|align = "center" bgcolor = "#CCFFFF" | '''Mechanism'''
|align = "center" bgcolor = "#CCFFFF" | '''Sites of action'''
|-
|Abciximab
|Anticoagulant stops platelet activation
|Monoclonal antibody to fibrinogen receptors
|Platelets
|-
|Amiloride (combination with frusemide is ''frumil'')
|Potassium sparing diuretic
|Plasmalemma sodium & chloride channels
|Kidney (distal tubules)
|-
|Amiodarone
|Class III anti-arrhythmic
|Prolongs action potential duration
|Myocardium
|-
|Aspirin
|Anticoagulant stops platelet activation
|COX inhibitor, blocks TXA2 synthesis
|Platelets
|-
|Atropine (sometimes used to stop vagus bradycardia)
|Parasympatholytic, increases heart rate
|Blocks muscarinic acch receptors
|Pacemaker cells (sino-atrial node)
|-
|Captopril
|Reduces arterial blood pressure
|ACE inhibitor
|Relaxes vascular smooth muscle
|-
|Clopidogrel
|Anticoagulant stops platelet activation
|Blocks ADP receptor
|Platelets
|-
|Digitalis and ouabain
|Increase cardiac contractility, delay AV node triggering
|Block Na / K atpase raising intracellular sodium, then calcium
|All tissues, but the Na/Ca exchanger is mainly in heart
|-
|Dipyridamole (often used for X-ray imaging)
|Coronary vasodilation
|Inhibition of adenosine uptake
|Coronary vasculature
|-
|Furosemide (= frusemide)
|Diuretic
|Plasmalemma sodium & chloride channels
|Kidney (loop of Henle)
|-
|Isoprenaline (and other adrenaline analogues)
|Increase cardiac contractility
|Beta agonist raises cyclic AMP
|Many tissues
|-
|Losartan
|Reduces arterial blood pressure
|Angiotensin AT1 receptor blockade
|Relaxes vascular smooth muscle
|-
|Lovastatin
|Reduces blood cholesterol levels
|HMG-coa reductase inhibitor
|Liver
|-
|Morphine
|Pain relief (mainly)
|Opiate receptors
|Brain
|-
|Nitroglycerine (and many other organic nitrates)
|Reduce cardiac work load
|Metabolised to NO
|Relaxes vascular smooth muscle
|-
|Propranolol
|Reduces cardiac contractility, class II anti-arrhythmic
|Beta blocker lowers cyclic AMP
|Many tissues
|-
|Quinidine, novocaine and other local anaesthetics
|Class I anti-arrhythmics
|Delay recovery of sarcolemma sodium channels after AP
|Myocardium
|-
|Spironolactone (usually added to other diuretics)
|Reduces diuretic potassium losses
|Aldosterone antagonist
|Kidney (distal tubules)
|-
|Urokinase (streptokinase is cheaper but antigenic)
|Dissolves blood clots (fibrinolytic)
|Activates plasminogen to plasmin (protease)
|Blood clots
|-
|Verapamil, nifedipine and other dihydropyridines
|Reduce cardiac work load, class IV anti-arrhythmic
|Block sarcolemma calcium channels
|Myocardium; relax vascular smooth muscle
|-
|Warfarin
|Anticoagulant Vit. K antagonist
|Blocks -carboxy glutamate synthesis
|Liver
|-
|} 

----
==Drug targets==

Target molecule (or target protein) are the molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule— a drug— to bind to the target molecule and block its action.

[[image:drug targets.gif|center|thumb|500 px| [http://www.locomogene.com/english/strategy/concept.html Source]]]

----
===Emerging drug targets===
Drug targets are generally proteins. Nucleic acids are possible drug targets, and approaches such as RNA interference (RNAi) may indeed have advantages over proteins, but they have not so far been developed extensively. Protein targets consist mainly of enzymes, regulatory molecules such as cytokines, receptors for hormones or other regulatory molecules, transporters, and ion channels. Proteins that interact with small molecules are considered the most promising targets, because it is often possible to design or discover small molecule activators or inhibitors based on the natural ligands. Such substances are relatively straightforward to develop as drugs. Overall, enzyme targets account for over 50% of marketed drugs, and GPCR targets represent more than 20%, including 23 of the 100 best-selling drugs in the US. Hence the other target classes between them make up the remaining 25-30% of marketed drugs. Aberrant signal transduction plays a key part in the pathology of many serious diseases including cancer, inflammatory, cardiovascular, metabolic, and neuropsychiatric diseases. Proteins involved in signal transduction pathways therefore represent important drug targets. Three prominent superfamilies of proteins involved in signal transduction are: GPCRs, protein kinases, and nuclear receptors. [http://www.marketresearch.com/product/display.asp?productid=1204095&g=1 Source]

----
===Classification of drug targets===
[[image:drug class distribution.jpeg|right|450 px|thumb|Biochemical classes of drug targets. [http://www.bioinformation.net/1/76-1-2006.htm Source]]]
The introduction of genomics, proteomics and metabolomics has paved the way for biology-driven process, leading to plethora of drug targets. The list of potential drug targets encoded in a genome includes most natural choice of virulent genes and species-specific genes. Other options include targeting RNA, enzymes of the intermediary metabolism, systems for DNA replication, translation apparatus or repair and membrane proteins.

* Species-specific genes as drug targets
* RNA as drug target
* Nucleic acid as drug targets
* Proteins as drug targets
* Membranes as drug targets

The comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. [http://www.scripps.edu/newsandviews/e_20020422/print-drug.html Source]

{|border="2" cellspacing="0" cellpadding="4" width="60%" align = "center"
|align = "center" bgcolor = "#CCFFFF"|'''Drug targets'''
|align = "center" bgcolor = "#CCFFFF"|'''2001'''
|align = "center" bgcolor = "#CCFFFF"|'''2005'''
|-
|GPCRs
|align = "center"|30%
|align = "center"|20%
|-
|Ion Channel
|align = "center"|20%
|align = "center"|30%
|-
|Enzymes
|align = "center"|30%
|align = "center"|20%
|-
|Hormones/Vitamins
|align = "center"|12%
|align = "center"|4%
|-
|RNA-Proteins/DNA-Proteins
|align = "center"|<nowiki>-</nowiki>
|align = "center"|10%
|-
|Protein-Protein
|align = "center"|<nowiki>-</nowiki>
|align = "center"|20%
|-
|Unknown Mechanism
|align = "center"|8%
|align = "center"|<nowiki>-</nowiki>
|-
|}
----

==Drug targets for cardiovascular diseases==
===G- protein-coupled receptors (GPCRs)===
GPCRs are the largest and most important class of receptors in humans because they are the targets of more than half of all drugs used clinically, especially for treating diseases of the cardiovascular and nervous systems. GPCRs are also the targets of many drugs of abuse.

G Protein-Coupled Receptors (GPCRs) account for 50% of the current drug targets, and remain about one-third of the drug discovery effort in the drug discovery-development community. As a result of the sequencing of the human genome, more than 150 orphan and non-chemosensory GPCRs have been identified for which their cognate ligands or biological functions are unknown. De-orphanization of those receptors could bring novel therapeutic targets to the industry against which novel therapeutics could be designed. In addition, current GPCR-based drugs only target ~30% of the approximately 200 known GPCRs in the genome. This is a rich target class that is highly-druggable. [http://www.marketresearch.com/product/display.asp?productid=1092267&SID=66002803-375208398-363996861&kw=G%2DProtein%09Coupled%09Receptors%09GPCRs Source]

Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as:
* Cardiovascular,
* Metabolic,
* Neurodegenerative,
* Psychiatric,
* Cancer and
* Infectious diseases.

The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are a promising future approach for tailor-made drug development. [http://www.citeulike.org/user/xdeupi/article/928331 Source]

[[image:G-protein pathway.jpeg|700 px|center|thumb| [http://genome.ib.sci.yamaguchi-u.ac.jp/~pnp/frame_petri_net_pathway_gprotein.html Source]]]

[http://www.maxanim.com/biochemistry/Membrane-Bound%20Receptors/Membrane-Bound%20Receptors.htm Animation]

----

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===C-reactive protein (CRP)===
[[image:c-protein 1.gif|right|thumb|400px|[http://images.google.com/images?q=tbn:A7NTUBLxNDV1JM:http://www-ermm.cbcu.cam.ac.uk/fig002gkd.gif Source]]]
C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. It is a member of the pentraxin family of proteins. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes[4], hypertension and cardiovascular disease. [http://en.wikipedia.org/wiki/C-reactive_protein]

CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated). [http://www.haps.nsw.gov.au/edrsrch/edinfo/crp.html Source]

'''The role of C-reactive protein in atherogenesis'''

(A) Endothelial dysfunction

(B) Endothelial cell activation

(C) Plaque formation

(D) Plaque rupture

(E) Inhibition of EPC survival and function
[[image:c-protein.jpeg|center|thumb|400 px|[http://www.nature.com/ncpcardio/journal/v2/n1/fig_tab/ncpcardio0074_F2.html Source]]]

'''Treatment approaches''' - '''Lowering level of CRP'''
* Vitamin E
* Vitamin B6
* Aspirin
* Gugulipid
* Proteolytic Enzymes (VRP’s UniZyme formula)
* Other anti-inflammatory compunds (Herbs, Turmeric and Boswellia, and fish oil) [http://www.vrp.com/art/1130.asp?c=1155552556156&k=/det/1121.asp&m=/&p=no&s=0 Source]

----

===Renin-angiotensin system===

Vascular inflammation is now recognized to be an independent risk factor for the development of atherosclerosis. Chronic elevations of circulating IL-6 or its biomarkers are predictors for increased risk for the development or progression of ischemic heart disease. Our laboratory has been investigating the role of the renin-angiotensin system in accelerating vascular inflammation. The potent vasopressor peptide, angiotensin II, induces the expression of cardioactive cytokines, such as IL-6, in vascular smooth muscle cells. We are particularly interested in the role of the NF-kB transcription factor in signaling the inflammatory response in the vessel wall. In this project, we are pursuing the hypothesis that NF-kB is a central mediator of inflammation and atherosclerosis in the large vessels. [http://bioinfo.utmb.edu/Brasier_Lab/projects/index.html Source]

[[image:vascular inflammation.gif|center|600 px|thumb]]

----
===LXR signaling pathways===
[[Image: LXR signaling pathway.gif|right|350 px|thumb]]
The liver X receptors {alpha} and {beta} (LXR{alpha} and LXR{beta}) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease. [http://mend.endojournals.org/cgi/content/abstract/me.2003-0061v1 Source]

Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. [http://www.biocarta.com/pathfiles/h_fxrPathway.asp Source]

----

===Cardiac Adrenergic Signaling===
[[image:cardiac signaling.gif|right|250 px|thumb]]
The adrenergic receptors are G-protein–coupled transmembrane receptors. On binding to ligands, the G proteins dissociate from the intracellular domain of the receptor to propagate signals by modulating the activity of downstream effector molecules such as adenylate cyclase, phospholipases, and ion channels. The {beta}1-Adrenergic receptor and {beta}2-adrenergic receptor are both normally coupled to the stimulatory G protein (Gs), and through this protein, they activate adenylate cyclase, augmenting myocyte contractility and inducing myocyte hypertrophy or heart failure. This regulation of cell growth involves multiple downstream molecules including mitogen-activated protein kinases in a complex regulatory network. {beta}2-Adrenergic receptors may also couple to the inhibitory G protein (Gi) and reduce adenylate cyclase activity while activating the mitogen-activated protein kinase pathway. The role of the {beta}3-adrenergic receptors is less clear, but they seem to activate nitric oxide synthase through Gi. {alpha}-Adrenergic signaling also has an important role in cardiac physiology. When stimulated, {alpha}1-adrenergic receptors (not shown) are potent mediators of cardiomyocyte hypertrophy, acting through another subtype of G protein (Gq), which stimulates mitogen-activated protein kinase pathways. The two subtypes of {alpha}2-adrenergic receptors ({alpha}2A and {alpha}2C) depicted here operate as presynaptic inhibitors of norepinephrine release, but are also known to have postsynaptic functions. The {alpha}2A-adrenergic receptor is important for central and peripheral nervous system inhibition of norepinephrine release at high action-potential frequencies, whereas the {alpha}2C-adrenergic receptor is more important for regulating lower-frequency stimulation. These {alpha}2-adrenergic receptors inhibit the release not only of norepinephrine but also of other neurotransmitters that are not ligands for the adrenergic receptors. [http://content.nejm.org/cgi/figsearch?andorexacttitleabs=and&tmonth=Feb&searchtitle=Figures&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&search_tab=figures&searchterm=cardiac+signaling&sendit=GO Source]

----

===Nitroso–Redox Balance ===
The interaction between nitric oxide (NO) and superoxide (O2–) production — the nitroso–redox balance — plays fundamental roles in cell and organ failure at key sites throughout the cardiovascular system. Physiologically, the level and location of nitric oxide and superoxide production are balanced within the cell, facilitating appropriate post-translational modification of effector proteins. In patients with heart failure, the production of superoxide is increased and the level or location of nitric oxide synthesis is disrupted, interrupting effector signaling and thus causing cellular dysfunction as a result of vasoconstriction of small and large blood vessels and cardiac contractility or, if prolonged, cell death or damage. Isosorbide dinitrate, a drug that stimulates the nitric oxide pathway, and hydralazine, an antioxidant that inhibits superoxide synthesis, may therefore restore the balance of nitric oxide and superoxide production, converting the pathologic pathways to physiologic pathways in both the heart and the blood vessels. [http://content.nejm.org/cgi/content/full/351/20/2112?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiac+signaling&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]

[[image:Nitroso–Redox Balance.gif|center|600 px|thumb]]

----
=== HDL Cholesterol Levels===

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre-{beta}-HDL (green arrow). Pre-{beta}-HDL is converted into mature {alpha}-HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase. [http://content.nejm.org/cgi/content/full/350/15/1491?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiovascular+pathway&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]
[[image:Increasing HDL Cholesterol Levels.jpeg|center|400 px|thumb]]

----

==Intellectual property - G-proteins and cardiovascular diseases==
=== IP activity===
IP activity (based on priority year) in the G- protein-coupled receptors (GPCRs) space initiated during the year 1996, and is continuously increasing, with highest activity during the year 2000.

[[image:Publication-priority year.jpeg|center|thumb|800 px]]

''NOTE'': Decline in activity in the graph is due to the 18 months period for the patent publication.

----

===Competitor's activity===
Bayer Aktiengesellschaft, Pfizer, Millennium Pharmaceutical are the top players.

[[image:competitors- year.jpeg|center|thumb|500 px]]

----
===Technology classification based on IPC class===
Most of the patenting activity is edivent in IPC class "C07K", pertains to peptides.
[[image:IPC-patent.jpeg|center|thumb|500 px]]

{|border="2" cellspacing="0" align = "center" cellpadding="4" width="60%"
|align = "center"|'''Top IPC class'''
|align = "center"|'''Definition'''
|-
|C07K
|Peptides
|-
|A61K
|Preparation for medical purposes
|-
|G01N
|Investigating or analyzing materials by determining their chemical or physical properties
|-
|}

----

===Interactive signaling pathways and patents===

Interactive signaling pathway of G- protein represented below with information on few patents targeting different sites. Click on the Hypertext molecules in the main pathway, to visualize the patent details.
<center><gflash>800 800 http://www.dolcera.com/website/assets/G-protein.swf</gflash></center>

==Research activities==

Recent research progress (year 2007) in the area of G-proteins is illustrated below, with interactive gene linking.
<center><gflash>800 800 http://www.dolcera.com/website/assets/Gene-Interaction.swf</gflash></center>
===Future potential areas===

# In vivo activation of '''G{alpha}q/PKC pathways'' could upregulate GRK2 expression in cardiovascular cells, thus contributing to the increased desensitization of ß-adrenergic and other GPCR systems, is of potential physiological relevance. Detailed mechanisms of regulation of GRK2 expression in different types of cells of the cardiovascular system, particularly in cardiac cell lines, and the determination of possible changes in GRK2 levels in VSMCs of patients with cardiovascular diseases are interesting fields for future research and may help to develop new therapeutic strategies based on the modulation of GRK2 expression. [http://circ.ahajournals.org/cgi/content/full/circulationaha;101/17/2083]]

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Inflammation and cardiovascular drugs

2012-04-20T15:15:03Z

Abhay.goel.1: /* Targeting inflammation – Pharmaceutical focus */

==Targeting inflammation – Pharmaceutical focus==

The pharmaceutical industry is one of the most profitable sectors of the Fortune 500 with profits of approximately 18% of revenue compared to a median of 5% for other industry segments. However, this market is facing increasing competitive pressure due to escalating R&D costs, shortened patent life due to the long product approval process, increased sales and marketing costs, pricing pressures, and entrance of more competitors into the industry. It is estimated that large pharmaceutical companies (or Pharma as they are generally referred to in the industry) require 3-5 new lead drug candidates (defined as New Chemical Entities or NCEs) each year to sustain doubledigit growth rates. Despite the fact that R&D costs have been increasing (typically $300-500 million per NCE), the average number of NCEs have been dropping over the last decade to under one per year across the industry. Thus, there is increasing pressure on Pharma to find newer discovery and development paradigms.

Inflammation is one of the key processes linked to various diseases and disorders. There are many opportunities for designing and developing specific new drugs for inflammatory responses.

[[image:market.png|center|800 px|thumb|[http://www.chromos.com/documents/roadshowsept14_003.pdf Source]]]
----

==Overview of inflammation==
Inflammation is a process by which the body<nowiki>’</nowiki>s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses. [[Image:Targeting_inflammation_04.jpg|300 px|right|thumb]]

In some diseases, however, the body’s defense system (immune system) inappropriately triggers an inflammatory response when there are no foreign substances to fight off, these are called autoimmune diseases, where the body’s normally protective immune system causes damage to its own tissues. When inflammation occurs normally, chemicals from the body’s white blood cells are released to protect us from foreign substances.

Inflammation is characterized by:

* increased blood flow to the tissue causing
* increased temperature,
* redness,
* swelling, and
* pain.
 
 
 

[[image:inflammation overview.png|thumb|center|600 px]]

Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. Thease includes rheumatoid arthritis, osteoarthritis and inflammatory lung disease, including inflammatory bowel disease, atherosclerosis and psoriasis.

Chronic inflammatory disorders are a substantial burden in social and economic terms for the Australian community. Arthritis alone afflicts 3.4 million Australians and the financial costs were in excess of $19.25 billion in 2004 (Access Economics 2005).

Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their cause, treatment or cure, despite intensive global research.
----

===Various inflammatory diseases===
* '''Rheumatoid arthritis (RA)''' is a disease that most commonly affects the joints, but can sometimes also cause damage to other organs. RA is an auto-immune disease, that is, a disease where a person’s immune system attacks his or her own body tissues. This auto-immune reaction causes inflammation of the joints, particularly of the synovial membrane which lines them. There is an over-production of synovial (joint) fluid and this, combined with the inflammation, causes joints to become swollen and painful.

* '''Chronic Obstructive Pulmonary Disease, or COPD''', is a group of progressive lung diseases characterized by airflow obstruction or limitation that is not fully reversible. The restricted airflow is generally progressive and associated with abnormal inflammatory response of the lungs to irritants." They are most commonly caused by tobacco smoking. The family of diseases includes chronic bronchitis, emphysema and bronchiectasis. COPD develops slowly and it may be many years before symptoms such as breathing difficulties are noticed. Thus COPD is usually diagnosed in middle-aged or older people. COPD is also characterized by exacerbations which are often associated with a rapid progression of symptoms such as shortness of breath, wheezing, and sputum production, sometimes leading to respiratory failure. Exacerbations are most commonly brought on by infectious agents. Bronchodilators, antibiotics, and oral or intravenous steroids are used to treat these episodes.

* '''Osteoarthritis (OA)''' is the most common form of arthritis and is characterised by mild to debilitating pain, which can involve almost any joint but, in particular, weight bearing joints such as the hip, knee, spine and feet. OA refers to a degeneration of the articular cartilage that makes up the joint surface. This breakdown removes the soft buffer between the bones and can, when severe, result in bone against bone friction, which can cause severe pain and loss of movement.

* '''Inflammatory Bowel Disease (IBD)''' is the name of a group of disorders that cause the intestines to become inflamed (red and swollen). IBD can be painful and debilitating and causes chronic inflammation of the digestive tract. The two most common forms of IBD are ulcerative colitis and Crohn<nowiki>’</nowiki>s Disease. Both conditions inflame the lining of your digestive tract and both can cause severe bouts of watery diarrhoea and abdominal pain.
* '''Psoriasis''' is a common immune-mediated chronic skin disease that comes in different forms and differing levels of severity. It is a condition that is generally found on the knees, elbows, scalp, hands, feet or lower back, and generally appears as patches of raised red skin covered by a flaky white build up. It can cause intense itching and burning.
* '''Artherosclerosis''' is the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of an artery. It is a slow and progressive disease that may start in childhood. If left untreated, artherosclerosis can lead to heart attack or stroke. The first symptom of a narrowing artery may be pain or cramps at times when the blood flow can<nowiki>’</nowiki>t keep up with the body<nowiki>’</nowiki>s demand for oxygen. For example, during exercise a person may feel chest pain because of a lack of oxygen to the heart or while walking, a person may feel leg cramps because of a lack of oxygen to the legs.
* '''Pelvic inflammatory disease (PID)''' is a general term that refers to infection and inflammation of the upper genital tract in women. It can affect the uterus (womb), fallopian tubes (tubes that carry eggs from the ovaries to the uterus), ovaries, and other organs related to reproduction. The scarring that results on these organs can lead to infertility, tubal (ectopic) pregnancy, chronic pelvic pain, abscesses (sores containing pus), and other serious problems.
* '''Cardiovascular diseases''': C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Recent studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it’s been opened by balloon angioplasty. Most studies show that the higher the hs-CRP levels, the higher the risk of developing heart attack. [http://www.americanheart.org/presenter.jhtml?identifier=4648 Source]
* '''Metabolic disease''': Scientists at Galileo Pharmaceuticals, Inc. have demonstrated a direct relationship between inflammation and glucose levels. Inhibiting lipoxygenases, known mediators of inflammatory response, significantly lowers blood glucose levels in animal models of diabetes. Lipoxygenases are enzymes which play a key role in the synthesis of inflammatory mediators called leukotrienes, and trigger the progression of several diseases mediated by inflammation. Two key members of the lipoxygenase pathway, 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) have been indicated in a number of diseases states including asthma, arthritis, atherosclerosis, diabetes, osteoporosis, and cancer. [http://www.medicalnewstoday.com/medicalnews.php?newsid=27884 Source]
* '''Neurodegenerative disorder''': Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aß derived from misprocessing of amyloid precursor protein (APP). Aß deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. [http://stke.sciencemag.org/cgi/content/abstract/2002/162/tw461 Source]

----

===Factors associated with inflammations===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Players of inflammation'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Mast Cells'''
|Mast cells appear to be key players in the initiation of inflammation. Mast cells are found in the tissues. Their cytoplasm is loaded with granules containing mediators of inflammation. Their surface is coated with a variety of receptors which, when engaged by the appropriate ligand, trigger exocytosis of the granules. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Tumor Necrosis Factor-alpha (TNF-α)'''
|Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Chemokines'''
|These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Reactive Oxygen Species (ROS)'''
|These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Histamine'''
|The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Interleukin-1 (IL-1)'''
|Macrophages and monocytes are the main source of this cytokine. IL-1 has both • paracrine effects on cells in the vicinity, e.g., • causing them to produce tissue factor and thus triggering the blood clotting cascade. • stimulating the synthesis and secretion of a variety of other interleukins • helping to activate T cells and thus initiate an adaptive immune response • endocrine (hormonal) effects as it is carried in the blood throughout the body. • decreasing blood pressure • inducing fever. IL-1 causes fever by stimulating the release of prostaglandins, which act on the temperature control center of the hypothalamus. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Inflammasomes'''
|IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Leukotrienes and Prostaglandins'''
|These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and • the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways: one leading to the production of several • prostaglandins (PG); the other leading to the production of • thromboxanes (Tx). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----
===Current treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Treatment approach'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Steroids'''
|Like the glucocorticoid cortisol. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Nonsteroidal anti-inflammatory drugs (NSAIDs)'''
|The NSAIDs achieve their effects by blocking the activity of cyclooxygenase. NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''COX-1 and COX-2'''
|The body produces several different forms of cyclooxygenase (COX), including • COX-1, which is involved in pain, clotting, and protecting the stomach; • COX-2, which is involved in the pain produced by inflammation. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Therapeutic Proteins'''
|Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation. • an IL-1 antagonist that binds and inactivates the IL-1 receptor. • etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. • recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation. • infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows promise against some inflammatory diseases such as rheumatoid arthritis. (Side-effect: can convert a latent case of tuberculosis into active disease.) [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----

===Key signaling pathways===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Pathways'''
|align = "center" bgcolor = "#CCFFFF"|'''Activation'''
|align = "center" bgcolor = "#CCFFFF"|'''Key molecules'''
|align = "center" bgcolor = "#CCFFFF"|'''Target disease'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|MAPK Pathways
|Stress and Inflammation
| 
|Chronic inflammation, heart disease, stroke, diabetes mellitus
|[http://physrev.physiology.org/cgi/content/abstract/81/2/807 Source]
|-
|JNK Pathways
|Cytokines or environmental stress
| 
|Cellular proliferation, apoptosis, and tissue morphogenesis
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9561845&dopt=Citation Source]
|-
|Cytokine Pathways
| 
|TNF-alpha, IL-1, IL-6, IL-10, IL-4
|Joint Inflammation in Rheumatoid Arthritis
|[http://content.nejm.org/cgi/content/extract/344/12/907?ck=nck Source]
|-
|NF-κB pathway
|Diverse signal transduction cascades
|IκB kinases, IKKα and IKKβ
|Inflammation and cancer
|[http://www.jci.org/cgi/reprint/107/2/135.pdf Source]
|-
|Protein Kinase Cascades
|Mitogens but by cellular stresses and inflammatory cytokines
|ERKs, MEKs, SAPKs, Ras/MAPK, p38
|Stress and Inflammation
|[http://www.jbc.org/cgi/reprint/271/40/24313 Source]
|-
|TNF Pathways
| 
|TNF-R1
|Sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases
|[http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107 Source]
|-
|p38 Pathway (MAPK pathway)
|Bacterial pathogens and cytokines
|(ERKs, JNK/SAPK, ERK5/big MAP kinase 1 (BMK1), p38 group of protein kinases
|Inflammation, cell growth, cell differentiation, the cell cycle, and cell death
|[http://www.sci.sdsu.edu/classes/bio630/pdf/Ono2000.pdf Source]
|-
|TRAF6-NFκB
| 
|TLR/IL-1R, CD40, transcription factors NFκB and AP1
|Autoimmune disease
|align = "justify"|[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175050 Source]
|-
|STAT4 Pathways
| 
|Chemokines
|Allergic Airway Inflammation
|[http://www.jimmunol.org/cgi/content/full/170/7/3859 Source]
|-
|Toll-like receptors (TLRs) Pathways
|Cytokine-driven inflammation and tissue destruction
|Toll-like receptors (TLRs)
|Rheumatoid arthritis, Crohn<nowiki>’</nowiki>s disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis
|[http://cat.inist.fr/?aModele=afficheN&cpsidt=16287680 Source]
|-
|Multiple signaling pathways
| 
|C-reactive protein, ICAM-1, VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate, Clotting or coagulation factors, Fibrinolysis factors, angiotensin II, Prostaglandins, TGF-<nowiki>[</nowiki>beta<nowiki>]</nowiki>, (PDGF, NO and endothelin-1
|Atherosclerosis and cardiovascular disease
|[http://www.findarticles.com/p/articles/mi_m0FDN/is_1_9/ai_n5990649/pg_2 Source]
|-
|G protein-coupled receptors (GPCRs) Pathways
| 
|RGS proteins, PI3K
|Cardiovascular diseases
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15746448 Source]
|-
|}

----

==Cardiovascular diseases==
* It has become clear that CVD is an '''inflammatory disease''', although what triggers the inflammation is still unknown.
* Diagnosis of CVD through inflammatory markers is an active area of research. Although several classes of anti-hypertensive drugs exist, there are still several treatment goals that remain to be achieved, such as better blood pressure control, greater protection against organ damage, and better tolerability.
* Several angiogenic and myogenic stem cell therapies are under investigation and promise in the long run to advance cardiac rehabilitation and even prevent heart failure. Despite the development of improved therapies, millions of Americans continue to live with life-threatening cardiovascular diseases.

[[image:cardiovascilar diseases.png|center|thumb|800 px| [http://www-ermm.cbcu.cam.ac.uk/0500918Xh.htm Source]]]

----
===Market analysis===
* The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003.
* CVD is the leading cause of death in most regions throughout the world. Cardiovascular drugs constitute the world's largest pharmaceutical sector, with annual global sales over $70 billion.
* Risk factor management for CVD is an emerging market. Developing more effective ways of delivering pharmacological, nutritional, and preventative therapies are recognized as important targets that are under continual development. Aging populations and dietary and lifestyle induced disease processes ensure a growing need for cardiovascular devices.
* Reducing the costs for such devices by appropriately treating cardiovascular risk factors has become a major focus of the pharmaceutical and healthcare industries. Here are just some of the considerable market opportunities within the CVD Market:
** Increased use of cholesterol-controlling statins will cause prices to fall and generic brands to appear as knowledge of their benefits spread among general practitioners.
** Develop anti-glycosylation therapies to prevent the cross-linking that weakens aging heart muscle, and to reduce the diabetic risk factor.
** Create new vaccines to raise high density lipoprotein (HDL) levels, which help stave off heart disease.
** Develop new angiotensin receptor blockers to offer greater competition against ACE inhibitors
** Develop angiogenesis drugs such as VEGF (vascular endothelial growth factor) that will obviate the need for much bypass surgery by growing new arteries on damaged hearts.

----
===Common cardiac drugs===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" colspan = "4" bgcolor = "#CCFFFF"|'''[http://www.bmb.leeds.ac.uk/illingworth/cardio/index.htm Common cardiac drugs]'''
|-
|align = "center" bgcolor = "#CCFFFF" | '''Drugs'''
|align = "center" bgcolor = "#CCFFFF" | '''Main effects'''
|align = "center" bgcolor = "#CCFFFF" | '''Mechanism'''
|align = "center" bgcolor = "#CCFFFF" | '''Sites of action'''
|-
|Abciximab
|Anticoagulant stops platelet activation
|Monoclonal antibody to fibrinogen receptors
|Platelets
|-
|Amiloride (combination with frusemide is ''frumil'')
|Potassium sparing diuretic
|Plasmalemma sodium & chloride channels
|Kidney (distal tubules)
|-
|Amiodarone
|Class III anti-arrhythmic
|Prolongs action potential duration
|Myocardium
|-
|Aspirin
|Anticoagulant stops platelet activation
|COX inhibitor, blocks TXA2 synthesis
|Platelets
|-
|Atropine (sometimes used to stop vagus bradycardia)
|Parasympatholytic, increases heart rate
|Blocks muscarinic acch receptors
|Pacemaker cells (sino-atrial node)
|-
|Captopril
|Reduces arterial blood pressure
|ACE inhibitor
|Relaxes vascular smooth muscle
|-
|Clopidogrel
|Anticoagulant stops platelet activation
|Blocks ADP receptor
|Platelets
|-
|Digitalis and ouabain
|Increase cardiac contractility, delay AV node triggering
|Block Na / K atpase raising intracellular sodium, then calcium
|All tissues, but the Na/Ca exchanger is mainly in heart
|-
|Dipyridamole (often used for X-ray imaging)
|Coronary vasodilation
|Inhibition of adenosine uptake
|Coronary vasculature
|-
|Furosemide (= frusemide)
|Diuretic
|Plasmalemma sodium & chloride channels
|Kidney (loop of Henle)
|-
|Isoprenaline (and other adrenaline analogues)
|Increase cardiac contractility
|Beta agonist raises cyclic AMP
|Many tissues
|-
|Losartan
|Reduces arterial blood pressure
|Angiotensin AT1 receptor blockade
|Relaxes vascular smooth muscle
|-
|Lovastatin
|Reduces blood cholesterol levels
|HMG-coa reductase inhibitor
|Liver
|-
|Morphine
|Pain relief (mainly)
|Opiate receptors
|Brain
|-
|Nitroglycerine (and many other organic nitrates)
|Reduce cardiac work load
|Metabolised to NO
|Relaxes vascular smooth muscle
|-
|Propranolol
|Reduces cardiac contractility, class II anti-arrhythmic
|Beta blocker lowers cyclic AMP
|Many tissues
|-
|Quinidine, novocaine and other local anaesthetics
|Class I anti-arrhythmics
|Delay recovery of sarcolemma sodium channels after AP
|Myocardium
|-
|Spironolactone (usually added to other diuretics)
|Reduces diuretic potassium losses
|Aldosterone antagonist
|Kidney (distal tubules)
|-
|Urokinase (streptokinase is cheaper but antigenic)
|Dissolves blood clots (fibrinolytic)
|Activates plasminogen to plasmin (protease)
|Blood clots
|-
|Verapamil, nifedipine and other dihydropyridines
|Reduce cardiac work load, class IV anti-arrhythmic
|Block sarcolemma calcium channels
|Myocardium; relax vascular smooth muscle
|-
|Warfarin
|Anticoagulant Vit. K antagonist
|Blocks -carboxy glutamate synthesis
|Liver
|-
|} 

----
==Drug targets==

Target molecule (or target protein) are the molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule— a drug— to bind to the target molecule and block its action.

[[image:drug targets.gif|center|thumb|500 px| [http://www.locomogene.com/english/strategy/concept.html Source]]]

----
===Emerging drug targets===
Drug targets are generally proteins. Nucleic acids are possible drug targets, and approaches such as RNA interference (RNAi) may indeed have advantages over proteins, but they have not so far been developed extensively. Protein targets consist mainly of enzymes, regulatory molecules such as cytokines, receptors for hormones or other regulatory molecules, transporters, and ion channels. Proteins that interact with small molecules are considered the most promising targets, because it is often possible to design or discover small molecule activators or inhibitors based on the natural ligands. Such substances are relatively straightforward to develop as drugs. Overall, enzyme targets account for over 50% of marketed drugs, and GPCR targets represent more than 20%, including 23 of the 100 best-selling drugs in the US. Hence the other target classes between them make up the remaining 25-30% of marketed drugs. Aberrant signal transduction plays a key part in the pathology of many serious diseases including cancer, inflammatory, cardiovascular, metabolic, and neuropsychiatric diseases. Proteins involved in signal transduction pathways therefore represent important drug targets. Three prominent superfamilies of proteins involved in signal transduction are: GPCRs, protein kinases, and nuclear receptors. [http://www.marketresearch.com/product/display.asp?productid=1204095&g=1 Source]

----
===Classification of drug targets===
[[image:drug class distribution.jpeg|right|450 px|thumb|Biochemical classes of drug targets. [http://www.bioinformation.net/1/76-1-2006.htm Source]]]
The introduction of genomics, proteomics and metabolomics has paved the way for biology-driven process, leading to plethora of drug targets. The list of potential drug targets encoded in a genome includes most natural choice of virulent genes and species-specific genes. Other options include targeting RNA, enzymes of the intermediary metabolism, systems for DNA replication, translation apparatus or repair and membrane proteins.

* Species-specific genes as drug targets
* RNA as drug target
* Nucleic acid as drug targets
* Proteins as drug targets
* Membranes as drug targets

The comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. [http://www.scripps.edu/newsandviews/e_20020422/print-drug.html Source]

{|border="2" cellspacing="0" cellpadding="4" width="60%" align = "center"
|align = "center" bgcolor = "#CCFFFF"|'''Drug targets'''
|align = "center" bgcolor = "#CCFFFF"|'''2001'''
|align = "center" bgcolor = "#CCFFFF"|'''2005'''
|-
|GPCRs
|align = "center"|30%
|align = "center"|20%
|-
|Ion Channel
|align = "center"|20%
|align = "center"|30%
|-
|Enzymes
|align = "center"|30%
|align = "center"|20%
|-
|Hormones/Vitamins
|align = "center"|12%
|align = "center"|4%
|-
|RNA-Proteins/DNA-Proteins
|align = "center"|<nowiki>-</nowiki>
|align = "center"|10%
|-
|Protein-Protein
|align = "center"|<nowiki>-</nowiki>
|align = "center"|20%
|-
|Unknown Mechanism
|align = "center"|8%
|align = "center"|<nowiki>-</nowiki>
|-
|}
----

==Drug targets for cardiovascular diseases==
===G- protein-coupled receptors (GPCRs)===
GPCRs are the largest and most important class of receptors in humans because they are the targets of more than half of all drugs used clinically, especially for treating diseases of the cardiovascular and nervous systems. GPCRs are also the targets of many drugs of abuse.

G Protein-Coupled Receptors (GPCRs) account for 50% of the current drug targets, and remain about one-third of the drug discovery effort in the drug discovery-development community. As a result of the sequencing of the human genome, more than 150 orphan and non-chemosensory GPCRs have been identified for which their cognate ligands or biological functions are unknown. De-orphanization of those receptors could bring novel therapeutic targets to the industry against which novel therapeutics could be designed. In addition, current GPCR-based drugs only target ~30% of the approximately 200 known GPCRs in the genome. This is a rich target class that is highly-druggable. [http://www.marketresearch.com/product/display.asp?productid=1092267&SID=66002803-375208398-363996861&kw=G%2DProtein%09Coupled%09Receptors%09GPCRs Source]

Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as:
* Cardiovascular,
* Metabolic,
* Neurodegenerative,
* Psychiatric,
* Cancer and
* Infectious diseases.

The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are a promising future approach for tailor-made drug development. [http://www.citeulike.org/user/xdeupi/article/928331 Source]

[[image:G-protein pathway.jpeg|700 px|center|thumb| [http://genome.ib.sci.yamaguchi-u.ac.jp/~pnp/frame_petri_net_pathway_gprotein.html Source]]]

[http://www.maxanim.com/biochemistry/Membrane-Bound%20Receptors/Membrane-Bound%20Receptors.htm Animation]

----

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===C-reactive protein (CRP)===
[[image:c-protein 1.gif|right|thumb|400px|[http://images.google.com/images?q=tbn:A7NTUBLxNDV1JM:http://www-ermm.cbcu.cam.ac.uk/fig002gkd.gif Source]]]
C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. It is a member of the pentraxin family of proteins. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes[4], hypertension and cardiovascular disease. [http://en.wikipedia.org/wiki/C-reactive_protein]

CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated). [http://www.haps.nsw.gov.au/edrsrch/edinfo/crp.html Source]

'''The role of C-reactive protein in atherogenesis'''

(A) Endothelial dysfunction

(B) Endothelial cell activation

(C) Plaque formation

(D) Plaque rupture

(E) Inhibition of EPC survival and function
[[image:c-protein.jpeg|center|thumb|400 px|[http://www.nature.com/ncpcardio/journal/v2/n1/fig_tab/ncpcardio0074_F2.html Source]]]

'''Treatment approaches''' - '''Lowering level of CRP'''
* Vitamin E
* Vitamin B6
* Aspirin
* Gugulipid
* Proteolytic Enzymes (VRP’s UniZyme formula)
* Other anti-inflammatory compunds (Herbs, Turmeric and Boswellia, and fish oil) [http://www.vrp.com/art/1130.asp?c=1155552556156&k=/det/1121.asp&m=/&p=no&s=0 Source]

----

===Renin-angiotensin system===

Vascular inflammation is now recognized to be an independent risk factor for the development of atherosclerosis. Chronic elevations of circulating IL-6 or its biomarkers are predictors for increased risk for the development or progression of ischemic heart disease. Our laboratory has been investigating the role of the renin-angiotensin system in accelerating vascular inflammation. The potent vasopressor peptide, angiotensin II, induces the expression of cardioactive cytokines, such as IL-6, in vascular smooth muscle cells. We are particularly interested in the role of the NF-kB transcription factor in signaling the inflammatory response in the vessel wall. In this project, we are pursuing the hypothesis that NF-kB is a central mediator of inflammation and atherosclerosis in the large vessels. [http://bioinfo.utmb.edu/Brasier_Lab/projects/index.html Source]

[[image:vascular inflammation.gif|center|600 px|thumb]]

----
===LXR signaling pathways===
[[Image: LXR signaling pathway.gif|right|350 px|thumb]]
The liver X receptors {alpha} and {beta} (LXR{alpha} and LXR{beta}) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease. [http://mend.endojournals.org/cgi/content/abstract/me.2003-0061v1 Source]

Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. [http://www.biocarta.com/pathfiles/h_fxrPathway.asp Source]

----

===Cardiac Adrenergic Signaling===
[[image:cardiac signaling.gif|right|250 px|thumb]]
The adrenergic receptors are G-protein–coupled transmembrane receptors. On binding to ligands, the G proteins dissociate from the intracellular domain of the receptor to propagate signals by modulating the activity of downstream effector molecules such as adenylate cyclase, phospholipases, and ion channels. The {beta}1-Adrenergic receptor and {beta}2-adrenergic receptor are both normally coupled to the stimulatory G protein (Gs), and through this protein, they activate adenylate cyclase, augmenting myocyte contractility and inducing myocyte hypertrophy or heart failure. This regulation of cell growth involves multiple downstream molecules including mitogen-activated protein kinases in a complex regulatory network. {beta}2-Adrenergic receptors may also couple to the inhibitory G protein (Gi) and reduce adenylate cyclase activity while activating the mitogen-activated protein kinase pathway. The role of the {beta}3-adrenergic receptors is less clear, but they seem to activate nitric oxide synthase through Gi. {alpha}-Adrenergic signaling also has an important role in cardiac physiology. When stimulated, {alpha}1-adrenergic receptors (not shown) are potent mediators of cardiomyocyte hypertrophy, acting through another subtype of G protein (Gq), which stimulates mitogen-activated protein kinase pathways. The two subtypes of {alpha}2-adrenergic receptors ({alpha}2A and {alpha}2C) depicted here operate as presynaptic inhibitors of norepinephrine release, but are also known to have postsynaptic functions. The {alpha}2A-adrenergic receptor is important for central and peripheral nervous system inhibition of norepinephrine release at high action-potential frequencies, whereas the {alpha}2C-adrenergic receptor is more important for regulating lower-frequency stimulation. These {alpha}2-adrenergic receptors inhibit the release not only of norepinephrine but also of other neurotransmitters that are not ligands for the adrenergic receptors. [http://content.nejm.org/cgi/figsearch?andorexacttitleabs=and&tmonth=Feb&searchtitle=Figures&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&search_tab=figures&searchterm=cardiac+signaling&sendit=GO Source]

----

===Nitroso–Redox Balance ===
The interaction between nitric oxide (NO) and superoxide (O2–) production — the nitroso–redox balance — plays fundamental roles in cell and organ failure at key sites throughout the cardiovascular system. Physiologically, the level and location of nitric oxide and superoxide production are balanced within the cell, facilitating appropriate post-translational modification of effector proteins. In patients with heart failure, the production of superoxide is increased and the level or location of nitric oxide synthesis is disrupted, interrupting effector signaling and thus causing cellular dysfunction as a result of vasoconstriction of small and large blood vessels and cardiac contractility or, if prolonged, cell death or damage. Isosorbide dinitrate, a drug that stimulates the nitric oxide pathway, and hydralazine, an antioxidant that inhibits superoxide synthesis, may therefore restore the balance of nitric oxide and superoxide production, converting the pathologic pathways to physiologic pathways in both the heart and the blood vessels. [http://content.nejm.org/cgi/content/full/351/20/2112?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiac+signaling&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]

[[image:Nitroso–Redox Balance.gif|center|600 px|thumb]]

----
=== HDL Cholesterol Levels===

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre-{beta}-HDL (green arrow). Pre-{beta}-HDL is converted into mature {alpha}-HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase. [http://content.nejm.org/cgi/content/full/350/15/1491?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiovascular+pathway&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]
[[image:Increasing HDL Cholesterol Levels.jpeg|center|400 px|thumb]]

----

==Intellectual property - G-proteins and cardiovascular diseases==
=== IP activity===
IP activity (based on priority year) in the G- protein-coupled receptors (GPCRs) space initiated during the year 1996, and is continuously increasing, with highest activity during the year 2000.

[[image:Publication-priority year.jpeg|center|thumb|800 px]]

''NOTE'': Decline in activity in the graph is due to the 18 months period for the patent publication.

----

===Competitor's activity===
Bayer Aktiengesellschaft, Pfizer, Millennium Pharmaceutical are the top players.

[[image:competitors- year.jpeg|center|thumb|500 px]]

----
===Technology classification based on IPC class===
Most of the patenting activity is edivent in IPC class "C07K", pertains to peptides.
[[image:IPC-patent.jpeg|center|thumb|500 px]]

{|border="2" cellspacing="0" align = "center" cellpadding="4" width="60%"
|align = "center"|'''Top IPC class'''
|align = "center"|'''Definition'''
|-
|C07K
|Peptides
|-
|A61K
|Preparation for medical purposes
|-
|G01N
|Investigating or analyzing materials by determining their chemical or physical properties
|-
|}

----

===Interactive signaling pathways and patents===

Interactive signaling pathway of G- protein represented below with information on few patents targeting different sites. Click on the Hypertext molecules in the main pathway, to visualize the patent details.
<center><gflash>800 800 http://www.dolcera.com/website/assets/G-protein.swf</gflash></center>

==Research activities==

Recent research progress (year 2007) in the area of G-proteins is illustrated below, with interactive gene linking.
<center><gflash>800 800 http://www.dolcera.com/website/assets/Gene-Interaction.swf</gflash></center>
===Future potential areas===

# In vivo activation of '''G{alpha}q/PKC pathways'' could upregulate GRK2 expression in cardiovascular cells, thus contributing to the increased desensitization of ß-adrenergic and other GPCR systems, is of potential physiological relevance. Detailed mechanisms of regulation of GRK2 expression in different types of cells of the cardiovascular system, particularly in cardiac cell lines, and the determination of possible changes in GRK2 levels in VSMCs of patients with cardiovascular diseases are interesting fields for future research and may help to develop new therapeutic strategies based on the modulation of GRK2 expression. [http://circ.ahajournals.org/cgi/content/full/circulationaha;101/17/2083]]

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Inflammation and cardiovascular drugs

2012-04-20T15:14:49Z

Abhay.goel.1: /* Targeting inflammation – Pharmaceutical focus */

==Targeting inflammation – Pharmaceutical focus==

The pharmaceutical industry is one of the most profitable sectors of the Fortune 500 with profits of approximately 18% of revenue compared to a median of 5% for other industry segments. However, this market is facing increasing competitive pressure due to escalating R&D costs, shortened patent life due to the long product approval process, increased sales and marketing costs, pricing pressures, and entrance of more competitors into the industry. It is estimated that large pharmaceutical companies (or Pharma as they are generally referred to in the industry) require 3-5 new lead drug candidates (defined as New Chemical Entities or NCEs) each year to sustain doubledigit growth rates. Despite the fact that R&D costs have been increasing (typically $300-500 million per NCE), the average number of NCEs have been dropping over the last decade to under one per year across the industry. Thus, there is increasing pressure on Pharma to find newer discovery and development paradigms.

Inflammation is one of the key processes linked to various diseases and disorders. There are many opportunities for designing and developing specific new drugs for inflammatory responses.

[[image:market.png|center|500 px|thumb|[http://www.chromos.com/documents/roadshowsept14_003.pdf Source]]]
----

==Overview of inflammation==
Inflammation is a process by which the body<nowiki>’</nowiki>s white blood cells and chemicals protect us from infection and foreign substances such as bacteria and viruses. [[Image:Targeting_inflammation_04.jpg|300 px|right|thumb]]

In some diseases, however, the body’s defense system (immune system) inappropriately triggers an inflammatory response when there are no foreign substances to fight off, these are called autoimmune diseases, where the body’s normally protective immune system causes damage to its own tissues. When inflammation occurs normally, chemicals from the body’s white blood cells are released to protect us from foreign substances.

Inflammation is characterized by:

* increased blood flow to the tissue causing
* increased temperature,
* redness,
* swelling, and
* pain.
 
 
 

[[image:inflammation overview.png|thumb|center|600 px]]

Chronic inflammatory diseases afflict millions of people across the world leading to untold suffering, economic loss and premature death. Thease includes rheumatoid arthritis, osteoarthritis and inflammatory lung disease, including inflammatory bowel disease, atherosclerosis and psoriasis.

Chronic inflammatory disorders are a substantial burden in social and economic terms for the Australian community. Arthritis alone afflicts 3.4 million Australians and the financial costs were in excess of $19.25 billion in 2004 (Access Economics 2005).

Despite the importance of these diseases, there have been relatively few innovative breakthroughs into their cause, treatment or cure, despite intensive global research.
----

===Various inflammatory diseases===
* '''Rheumatoid arthritis (RA)''' is a disease that most commonly affects the joints, but can sometimes also cause damage to other organs. RA is an auto-immune disease, that is, a disease where a person’s immune system attacks his or her own body tissues. This auto-immune reaction causes inflammation of the joints, particularly of the synovial membrane which lines them. There is an over-production of synovial (joint) fluid and this, combined with the inflammation, causes joints to become swollen and painful.

* '''Chronic Obstructive Pulmonary Disease, or COPD''', is a group of progressive lung diseases characterized by airflow obstruction or limitation that is not fully reversible. The restricted airflow is generally progressive and associated with abnormal inflammatory response of the lungs to irritants." They are most commonly caused by tobacco smoking. The family of diseases includes chronic bronchitis, emphysema and bronchiectasis. COPD develops slowly and it may be many years before symptoms such as breathing difficulties are noticed. Thus COPD is usually diagnosed in middle-aged or older people. COPD is also characterized by exacerbations which are often associated with a rapid progression of symptoms such as shortness of breath, wheezing, and sputum production, sometimes leading to respiratory failure. Exacerbations are most commonly brought on by infectious agents. Bronchodilators, antibiotics, and oral or intravenous steroids are used to treat these episodes.

* '''Osteoarthritis (OA)''' is the most common form of arthritis and is characterised by mild to debilitating pain, which can involve almost any joint but, in particular, weight bearing joints such as the hip, knee, spine and feet. OA refers to a degeneration of the articular cartilage that makes up the joint surface. This breakdown removes the soft buffer between the bones and can, when severe, result in bone against bone friction, which can cause severe pain and loss of movement.

* '''Inflammatory Bowel Disease (IBD)''' is the name of a group of disorders that cause the intestines to become inflamed (red and swollen). IBD can be painful and debilitating and causes chronic inflammation of the digestive tract. The two most common forms of IBD are ulcerative colitis and Crohn<nowiki>’</nowiki>s Disease. Both conditions inflame the lining of your digestive tract and both can cause severe bouts of watery diarrhoea and abdominal pain.
* '''Psoriasis''' is a common immune-mediated chronic skin disease that comes in different forms and differing levels of severity. It is a condition that is generally found on the knees, elbows, scalp, hands, feet or lower back, and generally appears as patches of raised red skin covered by a flaky white build up. It can cause intense itching and burning.
* '''Artherosclerosis''' is the term for the process of fatty substances, cholesterol, cellular waste products, calcium and fibrin building up in the inner lining of an artery. It is a slow and progressive disease that may start in childhood. If left untreated, artherosclerosis can lead to heart attack or stroke. The first symptom of a narrowing artery may be pain or cramps at times when the blood flow can<nowiki>’</nowiki>t keep up with the body<nowiki>’</nowiki>s demand for oxygen. For example, during exercise a person may feel chest pain because of a lack of oxygen to the heart or while walking, a person may feel leg cramps because of a lack of oxygen to the legs.
* '''Pelvic inflammatory disease (PID)''' is a general term that refers to infection and inflammation of the upper genital tract in women. It can affect the uterus (womb), fallopian tubes (tubes that carry eggs from the ovaries to the uterus), ovaries, and other organs related to reproduction. The scarring that results on these organs can lead to infertility, tubal (ectopic) pregnancy, chronic pelvic pain, abscesses (sores containing pus), and other serious problems.
* '''Cardiovascular diseases''': C-reactive protein (CRP) is one of the acute phase proteins that increase during systemic inflammation. Recent studies also suggest that higher levels of hs-CRP may increase the risk that an artery will reclose after it’s been opened by balloon angioplasty. Most studies show that the higher the hs-CRP levels, the higher the risk of developing heart attack. [http://www.americanheart.org/presenter.jhtml?identifier=4648 Source]
* '''Metabolic disease''': Scientists at Galileo Pharmaceuticals, Inc. have demonstrated a direct relationship between inflammation and glucose levels. Inhibiting lipoxygenases, known mediators of inflammatory response, significantly lowers blood glucose levels in animal models of diabetes. Lipoxygenases are enzymes which play a key role in the synthesis of inflammatory mediators called leukotrienes, and trigger the progression of several diseases mediated by inflammation. Two key members of the lipoxygenase pathway, 5-lipoxygenase (5-LO) and 15-lipoxygenase (15-LO) have been indicated in a number of diseases states including asthma, arthritis, atherosclerosis, diabetes, osteoporosis, and cancer. [http://www.medicalnewstoday.com/medicalnews.php?newsid=27884 Source]
* '''Neurodegenerative disorder''': Alzheimer's disease, the most common neurodegenerative disorder, is characterized by aggregates of fibrillar Aß derived from misprocessing of amyloid precursor protein (APP). Aß deposits are surrounded by activated microglia and astrocytes, which have been postulated to contribute to Alzheimer's pathophysiology by establishing a chronic inflammatory state. [http://stke.sciencemag.org/cgi/content/abstract/2002/162/tw461 Source]

----

===Factors associated with inflammations===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Players of inflammation'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Mast Cells'''
|Mast cells appear to be key players in the initiation of inflammation. Mast cells are found in the tissues. Their cytoplasm is loaded with granules containing mediators of inflammation. Their surface is coated with a variety of receptors which, when engaged by the appropriate ligand, trigger exocytosis of the granules. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Tumor Necrosis Factor-alpha (TNF-α)'''
|Large amounts of TNF-α are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-α, and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Chemokines'''
|These are chemotactic cytokines; that is, secreted proteins that attract other leukocytes into the area. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Reactive Oxygen Species (ROS)'''
|These are produced by activated phagocytes: macrophages and neutrophils. They are toxic for microorganisms but can also lead to tissue injury. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Histamine'''
|The granules of mast cells are loaded with histamine and their exocytosis releases this potent mediator. Histamine increases the blood flow to the area and the leakage of fluid and proteins from the blood into the tissue space. Thus the quick release of histamine is largely responsible for the redness and swelling associated with inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Interleukin-1 (IL-1)'''
|Macrophages and monocytes are the main source of this cytokine. IL-1 has both • paracrine effects on cells in the vicinity, e.g., • causing them to produce tissue factor and thus triggering the blood clotting cascade. • stimulating the synthesis and secretion of a variety of other interleukins • helping to activate T cells and thus initiate an adaptive immune response • endocrine (hormonal) effects as it is carried in the blood throughout the body. • decreasing blood pressure • inducing fever. IL-1 causes fever by stimulating the release of prostaglandins, which act on the temperature control center of the hypothalamus. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Inflammasomes'''
|IL-1 is synthesized from a larger precursor that is cleaved by a caspase (caspase-1). Caspase-1 is part of two (or more) multi-protein complexes in the cytosol of macrophages and neutrophils that are called inflammasomes. Inflammasomes are activated by several different products produced by invading bacteria. Some of these are first "seen" by toll-like receptors (TLRs) thus providing a link between the innate immune system and inflammation. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Leukotrienes and Prostaglandins'''
|These potent mediators of inflammation are derivatives of arachidonic acid (AA) a 20-carbon unsaturated fatty acid produced from membrane phospholipids. The principal pathways of arachidonic acid metabolism are • the 5-lipoxygenase pathway, which produces a collection of leukotrienes (LT) and • the cyclooxygenase (COX) pathway, which produces prostaglandin H2 (PGH2). PGH2 serves as the substrate for two enzymatic pathways: one leading to the production of several • prostaglandins (PG); the other leading to the production of • thromboxanes (Tx). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----
===Current treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Treatment approach'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|'''Steroids'''
|Like the glucocorticoid cortisol. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Nonsteroidal anti-inflammatory drugs (NSAIDs)'''
|The NSAIDs achieve their effects by blocking the activity of cyclooxygenase. NSAIDs also inhibit clotting. They do this by interfering with the synthesis of thromboxane A2 in platelets. [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''COX-1 and COX-2'''
|The body produces several different forms of cyclooxygenase (COX), including • COX-1, which is involved in pain, clotting, and protecting the stomach; • COX-2, which is involved in the pain produced by inflammation. COX-2 inhibitors are effective against inflammation and seem to avoid damage to the GI tract. But, unfortunately, they increase the risk of blood clots — which can cause heart attacks and strokes — because they do not block the synthesis of thromboxane A2 by platelets (which contain only COX-1). [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|'''Therapeutic Proteins'''
|Recombinant DNA and monoclonal antibody technology have produced some new therapies that are being enlisted in the battle against damaging inflammation. • an IL-1 antagonist that binds and inactivates the IL-1 receptor. • etanercept (Embrel®). A soluble version of the TNF-α receptor. It binds TNF-α preventing it from carrying out its many inflammatory actions. Potent but carries a severe risk of allowing infections to develop. • recombinant protein C. To help the body dissolve the tiny clots that are triggered during inflammation. • infliximab (Remicade®). A monoclonal antibody that binds to TNF-α. Shows promise against some inflammatory diseases such as rheumatoid arthritis. (Side-effect: can convert a latent case of tuberculosis into active disease.) [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html Source]
|-
|}
----

===Key signaling pathways===

{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center" bgcolor = "#CCFFFF"|'''Pathways'''
|align = "center" bgcolor = "#CCFFFF"|'''Activation'''
|align = "center" bgcolor = "#CCFFFF"|'''Key molecules'''
|align = "center" bgcolor = "#CCFFFF"|'''Target disease'''
|align = "center" bgcolor = "#CCFFFF"|'''Description'''
|-
|MAPK Pathways
|Stress and Inflammation
| 
|Chronic inflammation, heart disease, stroke, diabetes mellitus
|[http://physrev.physiology.org/cgi/content/abstract/81/2/807 Source]
|-
|JNK Pathways
|Cytokines or environmental stress
| 
|Cellular proliferation, apoptosis, and tissue morphogenesis
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9561845&dopt=Citation Source]
|-
|Cytokine Pathways
| 
|TNF-alpha, IL-1, IL-6, IL-10, IL-4
|Joint Inflammation in Rheumatoid Arthritis
|[http://content.nejm.org/cgi/content/extract/344/12/907?ck=nck Source]
|-
|NF-κB pathway
|Diverse signal transduction cascades
|IκB kinases, IKKα and IKKβ
|Inflammation and cancer
|[http://www.jci.org/cgi/reprint/107/2/135.pdf Source]
|-
|Protein Kinase Cascades
|Mitogens but by cellular stresses and inflammatory cytokines
|ERKs, MEKs, SAPKs, Ras/MAPK, p38
|Stress and Inflammation
|[http://www.jbc.org/cgi/reprint/271/40/24313 Source]
|-
|TNF Pathways
| 
|TNF-R1
|Sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases
|[http://stke.sciencemag.org/cgi/cm/stkecm;CMP_7107 Source]
|-
|p38 Pathway (MAPK pathway)
|Bacterial pathogens and cytokines
|(ERKs, JNK/SAPK, ERK5/big MAP kinase 1 (BMK1), p38 group of protein kinases
|Inflammation, cell growth, cell differentiation, the cell cycle, and cell death
|[http://www.sci.sdsu.edu/classes/bio630/pdf/Ono2000.pdf Source]
|-
|TRAF6-NFκB
| 
|TLR/IL-1R, CD40, transcription factors NFκB and AP1
|Autoimmune disease
|align = "justify"|[http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1175050 Source]
|-
|STAT4 Pathways
| 
|Chemokines
|Allergic Airway Inflammation
|[http://www.jimmunol.org/cgi/content/full/170/7/3859 Source]
|-
|Toll-like receptors (TLRs) Pathways
|Cytokine-driven inflammation and tissue destruction
|Toll-like receptors (TLRs)
|Rheumatoid arthritis, Crohn<nowiki>’</nowiki>s disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis
|[http://cat.inist.fr/?aModele=afficheN&cpsidt=16287680 Source]
|-
|Multiple signaling pathways
| 
|C-reactive protein, ICAM-1, VCAM-1), fibronectin, selectins, interleukin-1, heparin sulfate, Clotting or coagulation factors, Fibrinolysis factors, angiotensin II, Prostaglandins, TGF-<nowiki>[</nowiki>beta<nowiki>]</nowiki>, (PDGF, NO and endothelin-1
|Atherosclerosis and cardiovascular disease
|[http://www.findarticles.com/p/articles/mi_m0FDN/is_1_9/ai_n5990649/pg_2 Source]
|-
|G protein-coupled receptors (GPCRs) Pathways
| 
|RGS proteins, PI3K
|Cardiovascular diseases
|[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=15746448 Source]
|-
|}

----

==Cardiovascular diseases==
* It has become clear that CVD is an '''inflammatory disease''', although what triggers the inflammation is still unknown.
* Diagnosis of CVD through inflammatory markers is an active area of research. Although several classes of anti-hypertensive drugs exist, there are still several treatment goals that remain to be achieved, such as better blood pressure control, greater protection against organ damage, and better tolerability.
* Several angiogenic and myogenic stem cell therapies are under investigation and promise in the long run to advance cardiac rehabilitation and even prevent heart failure. Despite the development of improved therapies, millions of Americans continue to live with life-threatening cardiovascular diseases.

[[image:cardiovascilar diseases.png|center|thumb|800 px| [http://www-ermm.cbcu.cam.ac.uk/0500918Xh.htm Source]]]

----
===Market analysis===
* The total worldwide cardiovascular market is expected to show revenues of $91.2 billion in 2008, an increase of 6.9% compared with 2003.
* CVD is the leading cause of death in most regions throughout the world. Cardiovascular drugs constitute the world's largest pharmaceutical sector, with annual global sales over $70 billion.
* Risk factor management for CVD is an emerging market. Developing more effective ways of delivering pharmacological, nutritional, and preventative therapies are recognized as important targets that are under continual development. Aging populations and dietary and lifestyle induced disease processes ensure a growing need for cardiovascular devices.
* Reducing the costs for such devices by appropriately treating cardiovascular risk factors has become a major focus of the pharmaceutical and healthcare industries. Here are just some of the considerable market opportunities within the CVD Market:
** Increased use of cholesterol-controlling statins will cause prices to fall and generic brands to appear as knowledge of their benefits spread among general practitioners.
** Develop anti-glycosylation therapies to prevent the cross-linking that weakens aging heart muscle, and to reduce the diabetic risk factor.
** Create new vaccines to raise high density lipoprotein (HDL) levels, which help stave off heart disease.
** Develop new angiotensin receptor blockers to offer greater competition against ACE inhibitors
** Develop angiogenesis drugs such as VEGF (vascular endothelial growth factor) that will obviate the need for much bypass surgery by growing new arteries on damaged hearts.

----
===Common cardiac drugs===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" colspan = "4" bgcolor = "#CCFFFF"|'''[http://www.bmb.leeds.ac.uk/illingworth/cardio/index.htm Common cardiac drugs]'''
|-
|align = "center" bgcolor = "#CCFFFF" | '''Drugs'''
|align = "center" bgcolor = "#CCFFFF" | '''Main effects'''
|align = "center" bgcolor = "#CCFFFF" | '''Mechanism'''
|align = "center" bgcolor = "#CCFFFF" | '''Sites of action'''
|-
|Abciximab
|Anticoagulant stops platelet activation
|Monoclonal antibody to fibrinogen receptors
|Platelets
|-
|Amiloride (combination with frusemide is ''frumil'')
|Potassium sparing diuretic
|Plasmalemma sodium & chloride channels
|Kidney (distal tubules)
|-
|Amiodarone
|Class III anti-arrhythmic
|Prolongs action potential duration
|Myocardium
|-
|Aspirin
|Anticoagulant stops platelet activation
|COX inhibitor, blocks TXA2 synthesis
|Platelets
|-
|Atropine (sometimes used to stop vagus bradycardia)
|Parasympatholytic, increases heart rate
|Blocks muscarinic acch receptors
|Pacemaker cells (sino-atrial node)
|-
|Captopril
|Reduces arterial blood pressure
|ACE inhibitor
|Relaxes vascular smooth muscle
|-
|Clopidogrel
|Anticoagulant stops platelet activation
|Blocks ADP receptor
|Platelets
|-
|Digitalis and ouabain
|Increase cardiac contractility, delay AV node triggering
|Block Na / K atpase raising intracellular sodium, then calcium
|All tissues, but the Na/Ca exchanger is mainly in heart
|-
|Dipyridamole (often used for X-ray imaging)
|Coronary vasodilation
|Inhibition of adenosine uptake
|Coronary vasculature
|-
|Furosemide (= frusemide)
|Diuretic
|Plasmalemma sodium & chloride channels
|Kidney (loop of Henle)
|-
|Isoprenaline (and other adrenaline analogues)
|Increase cardiac contractility
|Beta agonist raises cyclic AMP
|Many tissues
|-
|Losartan
|Reduces arterial blood pressure
|Angiotensin AT1 receptor blockade
|Relaxes vascular smooth muscle
|-
|Lovastatin
|Reduces blood cholesterol levels
|HMG-coa reductase inhibitor
|Liver
|-
|Morphine
|Pain relief (mainly)
|Opiate receptors
|Brain
|-
|Nitroglycerine (and many other organic nitrates)
|Reduce cardiac work load
|Metabolised to NO
|Relaxes vascular smooth muscle
|-
|Propranolol
|Reduces cardiac contractility, class II anti-arrhythmic
|Beta blocker lowers cyclic AMP
|Many tissues
|-
|Quinidine, novocaine and other local anaesthetics
|Class I anti-arrhythmics
|Delay recovery of sarcolemma sodium channels after AP
|Myocardium
|-
|Spironolactone (usually added to other diuretics)
|Reduces diuretic potassium losses
|Aldosterone antagonist
|Kidney (distal tubules)
|-
|Urokinase (streptokinase is cheaper but antigenic)
|Dissolves blood clots (fibrinolytic)
|Activates plasminogen to plasmin (protease)
|Blood clots
|-
|Verapamil, nifedipine and other dihydropyridines
|Reduce cardiac work load, class IV anti-arrhythmic
|Block sarcolemma calcium channels
|Myocardium; relax vascular smooth muscle
|-
|Warfarin
|Anticoagulant Vit. K antagonist
|Blocks -carboxy glutamate synthesis
|Liver
|-
|} 

----
==Drug targets==

Target molecule (or target protein) are the molecule on which pharmaceutical researchers focus when designing a drug. Often, the target molecule is from a virus or bacterium, or is an abnormal human protein. In these cases, the researchers usually seek to design a small molecule— a drug— to bind to the target molecule and block its action.

[[image:drug targets.gif|center|thumb|500 px| [http://www.locomogene.com/english/strategy/concept.html Source]]]

----
===Emerging drug targets===
Drug targets are generally proteins. Nucleic acids are possible drug targets, and approaches such as RNA interference (RNAi) may indeed have advantages over proteins, but they have not so far been developed extensively. Protein targets consist mainly of enzymes, regulatory molecules such as cytokines, receptors for hormones or other regulatory molecules, transporters, and ion channels. Proteins that interact with small molecules are considered the most promising targets, because it is often possible to design or discover small molecule activators or inhibitors based on the natural ligands. Such substances are relatively straightforward to develop as drugs. Overall, enzyme targets account for over 50% of marketed drugs, and GPCR targets represent more than 20%, including 23 of the 100 best-selling drugs in the US. Hence the other target classes between them make up the remaining 25-30% of marketed drugs. Aberrant signal transduction plays a key part in the pathology of many serious diseases including cancer, inflammatory, cardiovascular, metabolic, and neuropsychiatric diseases. Proteins involved in signal transduction pathways therefore represent important drug targets. Three prominent superfamilies of proteins involved in signal transduction are: GPCRs, protein kinases, and nuclear receptors. [http://www.marketresearch.com/product/display.asp?productid=1204095&g=1 Source]

----
===Classification of drug targets===
[[image:drug class distribution.jpeg|right|450 px|thumb|Biochemical classes of drug targets. [http://www.bioinformation.net/1/76-1-2006.htm Source]]]
The introduction of genomics, proteomics and metabolomics has paved the way for biology-driven process, leading to plethora of drug targets. The list of potential drug targets encoded in a genome includes most natural choice of virulent genes and species-specific genes. Other options include targeting RNA, enzymes of the intermediary metabolism, systems for DNA replication, translation apparatus or repair and membrane proteins.

* Species-specific genes as drug targets
* RNA as drug target
* Nucleic acid as drug targets
* Proteins as drug targets
* Membranes as drug targets

The comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. [http://www.scripps.edu/newsandviews/e_20020422/print-drug.html Source]

{|border="2" cellspacing="0" cellpadding="4" width="60%" align = "center"
|align = "center" bgcolor = "#CCFFFF"|'''Drug targets'''
|align = "center" bgcolor = "#CCFFFF"|'''2001'''
|align = "center" bgcolor = "#CCFFFF"|'''2005'''
|-
|GPCRs
|align = "center"|30%
|align = "center"|20%
|-
|Ion Channel
|align = "center"|20%
|align = "center"|30%
|-
|Enzymes
|align = "center"|30%
|align = "center"|20%
|-
|Hormones/Vitamins
|align = "center"|12%
|align = "center"|4%
|-
|RNA-Proteins/DNA-Proteins
|align = "center"|<nowiki>-</nowiki>
|align = "center"|10%
|-
|Protein-Protein
|align = "center"|<nowiki>-</nowiki>
|align = "center"|20%
|-
|Unknown Mechanism
|align = "center"|8%
|align = "center"|<nowiki>-</nowiki>
|-
|}
----

==Drug targets for cardiovascular diseases==
===G- protein-coupled receptors (GPCRs)===
GPCRs are the largest and most important class of receptors in humans because they are the targets of more than half of all drugs used clinically, especially for treating diseases of the cardiovascular and nervous systems. GPCRs are also the targets of many drugs of abuse.

G Protein-Coupled Receptors (GPCRs) account for 50% of the current drug targets, and remain about one-third of the drug discovery effort in the drug discovery-development community. As a result of the sequencing of the human genome, more than 150 orphan and non-chemosensory GPCRs have been identified for which their cognate ligands or biological functions are unknown. De-orphanization of those receptors could bring novel therapeutic targets to the industry against which novel therapeutics could be designed. In addition, current GPCR-based drugs only target ~30% of the approximately 200 known GPCRs in the genome. This is a rich target class that is highly-druggable. [http://www.marketresearch.com/product/display.asp?productid=1092267&SID=66002803-375208398-363996861&kw=G%2DProtein%09Coupled%09Receptors%09GPCRs Source]

Today, more than 50% of drug targets are based on GPCRs and the annual worldwide sales exceeds 50 billion dollars. GPCRs are involved in all major disease areas such as:
* Cardiovascular,
* Metabolic,
* Neurodegenerative,
* Psychiatric,
* Cancer and
* Infectious diseases.

The major efforts established through large networks of structural genomics on GPCRs, where recombinantly expressed GPCRs are subjected to purification and crystallization attempts with the intention of obtaining high-resolution structures, are a promising future approach for tailor-made drug development. [http://www.citeulike.org/user/xdeupi/article/928331 Source]

[[image:G-protein pathway.jpeg|700 px|center|thumb| [http://genome.ib.sci.yamaguchi-u.ac.jp/~pnp/frame_petri_net_pathway_gprotein.html Source]]]

[http://www.maxanim.com/biochemistry/Membrane-Bound%20Receptors/Membrane-Bound%20Receptors.htm Animation]

----

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===C-reactive protein (CRP)===
[[image:c-protein 1.gif|right|thumb|400px|[http://images.google.com/images?q=tbn:A7NTUBLxNDV1JM:http://www-ermm.cbcu.cam.ac.uk/fig002gkd.gif Source]]]
C-reactive protein (CRP) is a plasma protein, an acute phase protein produced by the liver. It is a member of the pentraxin family of proteins. Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for diabetes[4], hypertension and cardiovascular disease. [http://en.wikipedia.org/wiki/C-reactive_protein]

CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated). [http://www.haps.nsw.gov.au/edrsrch/edinfo/crp.html Source]

'''The role of C-reactive protein in atherogenesis'''

(A) Endothelial dysfunction

(B) Endothelial cell activation

(C) Plaque formation

(D) Plaque rupture

(E) Inhibition of EPC survival and function
[[image:c-protein.jpeg|center|thumb|400 px|[http://www.nature.com/ncpcardio/journal/v2/n1/fig_tab/ncpcardio0074_F2.html Source]]]

'''Treatment approaches''' - '''Lowering level of CRP'''
* Vitamin E
* Vitamin B6
* Aspirin
* Gugulipid
* Proteolytic Enzymes (VRP’s UniZyme formula)
* Other anti-inflammatory compunds (Herbs, Turmeric and Boswellia, and fish oil) [http://www.vrp.com/art/1130.asp?c=1155552556156&k=/det/1121.asp&m=/&p=no&s=0 Source]

----

===Renin-angiotensin system===

Vascular inflammation is now recognized to be an independent risk factor for the development of atherosclerosis. Chronic elevations of circulating IL-6 or its biomarkers are predictors for increased risk for the development or progression of ischemic heart disease. Our laboratory has been investigating the role of the renin-angiotensin system in accelerating vascular inflammation. The potent vasopressor peptide, angiotensin II, induces the expression of cardioactive cytokines, such as IL-6, in vascular smooth muscle cells. We are particularly interested in the role of the NF-kB transcription factor in signaling the inflammatory response in the vessel wall. In this project, we are pursuing the hypothesis that NF-kB is a central mediator of inflammation and atherosclerosis in the large vessels. [http://bioinfo.utmb.edu/Brasier_Lab/projects/index.html Source]

[[image:vascular inflammation.gif|center|600 px|thumb]]

----
===LXR signaling pathways===
[[Image: LXR signaling pathway.gif|right|350 px|thumb]]
The liver X receptors {alpha} and {beta} (LXR{alpha} and LXR{beta}) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease. [http://mend.endojournals.org/cgi/content/abstract/me.2003-0061v1 Source]

Cholesterol is essential for life and a key in the development of heart disease. Cholesterol homeostasis is achieved through regulation of cholesterol uptake, cholesterol biosynthesis, cholesterol conversion to bile acids and excretion of bile acids. Inhibition of cholesterol biosynthesis upregulates LDLR expression and is the mechanism of action of many drugs used to lower plasma LDL to reduce coronary heart disease. Many aspects of cholesterol homeostasis are regulated by the nuclear receptors FXR and LXR, both nuclear receptor transcription factors that form heterodimers with the retinoic acid RXR receptors and that are activated by cholesterol metabolites. One of the primary tissues in cholesterol metabolism is the liver, a key site of cholesterol biosynthesis and where cholesterol low-density lipoprotein (LDL) is taken up from the plasma by the LDL-receptor. When cholesterol accumulates in liver cells, some of the cholesterol is oxidized to create oxysterols. Oxysterols activate LXR through LXR/RXR heterodimers to activate genes such as the CYP7A1 enzyme that catalyzes the rate-limiting step in bile acid biosynthesis and a major route for the elimination of cholesterol. Animals lacking the CYP7A1 enzyme accumulate cholesterol in the liver. In the intestine LXR activates the ABC-1 gene, a transporter that actively transports cholesterol out of cells to clear it from the body. Activation of ABC-1 expression by LXR in macrophages in atherosclerotic plaques appears to be another mechanism by which LXR plays a role in heart disease. The FXR receptor is activated by bile acids. In the liver, activation of FXR-RXR heterodimers by bile acids results in the feedback inhibition of CYP7A expression and reduced biosynthesis of bile acids. In the intestine, FXR activates expression of I-BABP, a protein that increases the transport of bile acids back to the liver from the intestine, reducing their excretion. Drugs targeting the FXR and LXR receptors could play an important role in modulating cholesterol homeostasis and heart disease in the future. [http://www.biocarta.com/pathfiles/h_fxrPathway.asp Source]

----

===Cardiac Adrenergic Signaling===
[[image:cardiac signaling.gif|right|250 px|thumb]]
The adrenergic receptors are G-protein–coupled transmembrane receptors. On binding to ligands, the G proteins dissociate from the intracellular domain of the receptor to propagate signals by modulating the activity of downstream effector molecules such as adenylate cyclase, phospholipases, and ion channels. The {beta}1-Adrenergic receptor and {beta}2-adrenergic receptor are both normally coupled to the stimulatory G protein (Gs), and through this protein, they activate adenylate cyclase, augmenting myocyte contractility and inducing myocyte hypertrophy or heart failure. This regulation of cell growth involves multiple downstream molecules including mitogen-activated protein kinases in a complex regulatory network. {beta}2-Adrenergic receptors may also couple to the inhibitory G protein (Gi) and reduce adenylate cyclase activity while activating the mitogen-activated protein kinase pathway. The role of the {beta}3-adrenergic receptors is less clear, but they seem to activate nitric oxide synthase through Gi. {alpha}-Adrenergic signaling also has an important role in cardiac physiology. When stimulated, {alpha}1-adrenergic receptors (not shown) are potent mediators of cardiomyocyte hypertrophy, acting through another subtype of G protein (Gq), which stimulates mitogen-activated protein kinase pathways. The two subtypes of {alpha}2-adrenergic receptors ({alpha}2A and {alpha}2C) depicted here operate as presynaptic inhibitors of norepinephrine release, but are also known to have postsynaptic functions. The {alpha}2A-adrenergic receptor is important for central and peripheral nervous system inhibition of norepinephrine release at high action-potential frequencies, whereas the {alpha}2C-adrenergic receptor is more important for regulating lower-frequency stimulation. These {alpha}2-adrenergic receptors inhibit the release not only of norepinephrine but also of other neurotransmitters that are not ligands for the adrenergic receptors. [http://content.nejm.org/cgi/figsearch?andorexacttitleabs=and&tmonth=Feb&searchtitle=Figures&sortspec=Score+desc+PUBDATE_SORTDATE+desc&excludeflag=TWEEK_element&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&search_tab=figures&searchterm=cardiac+signaling&sendit=GO Source]

----

===Nitroso–Redox Balance ===
The interaction between nitric oxide (NO) and superoxide (O2–) production — the nitroso–redox balance — plays fundamental roles in cell and organ failure at key sites throughout the cardiovascular system. Physiologically, the level and location of nitric oxide and superoxide production are balanced within the cell, facilitating appropriate post-translational modification of effector proteins. In patients with heart failure, the production of superoxide is increased and the level or location of nitric oxide synthesis is disrupted, interrupting effector signaling and thus causing cellular dysfunction as a result of vasoconstriction of small and large blood vessels and cardiac contractility or, if prolonged, cell death or damage. Isosorbide dinitrate, a drug that stimulates the nitric oxide pathway, and hydralazine, an antioxidant that inhibits superoxide synthesis, may therefore restore the balance of nitric oxide and superoxide production, converting the pathologic pathways to physiologic pathways in both the heart and the blood vessels. [http://content.nejm.org/cgi/content/full/351/20/2112?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiac+signaling&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]

[[image:Nitroso–Redox Balance.gif|center|600 px|thumb]]

----
=== HDL Cholesterol Levels===

Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre-{beta}-HDL (green arrow). Pre-{beta}-HDL is converted into mature {alpha}-HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase. [http://content.nejm.org/cgi/content/full/350/15/1491?andorexacttitleabs=and&search_tab=figures&tmonth=Feb&searchtitle=Figures&excludeflag=TWEEK_element&sortspec=Score+desc+PUBDATE_SORTDATE+desc&hits=20&where=fulltext&tyear=2007&andorexactfulltext=and&resourcetype=3&fyear=1997&fmonth=Feb&sendit=GO&searchterm=cardiovascular+pathway&searchid=1&FIRSTINDEX=0&resourcetype=HWFIG Source]
[[image:Increasing HDL Cholesterol Levels.jpeg|center|400 px|thumb]]

----

==Intellectual property - G-proteins and cardiovascular diseases==
=== IP activity===
IP activity (based on priority year) in the G- protein-coupled receptors (GPCRs) space initiated during the year 1996, and is continuously increasing, with highest activity during the year 2000.

[[image:Publication-priority year.jpeg|center|thumb|800 px]]

''NOTE'': Decline in activity in the graph is due to the 18 months period for the patent publication.

----

===Competitor's activity===
Bayer Aktiengesellschaft, Pfizer, Millennium Pharmaceutical are the top players.

[[image:competitors- year.jpeg|center|thumb|500 px]]

----
===Technology classification based on IPC class===
Most of the patenting activity is edivent in IPC class "C07K", pertains to peptides.
[[image:IPC-patent.jpeg|center|thumb|500 px]]

{|border="2" cellspacing="0" align = "center" cellpadding="4" width="60%"
|align = "center"|'''Top IPC class'''
|align = "center"|'''Definition'''
|-
|C07K
|Peptides
|-
|A61K
|Preparation for medical purposes
|-
|G01N
|Investigating or analyzing materials by determining their chemical or physical properties
|-
|}

----

===Interactive signaling pathways and patents===

Interactive signaling pathway of G- protein represented below with information on few patents targeting different sites. Click on the Hypertext molecules in the main pathway, to visualize the patent details.
<center><gflash>800 800 http://www.dolcera.com/website/assets/G-protein.swf</gflash></center>

==Research activities==

Recent research progress (year 2007) in the area of G-proteins is illustrated below, with interactive gene linking.
<center><gflash>800 800 http://www.dolcera.com/website/assets/Gene-Interaction.swf</gflash></center>
===Future potential areas===

# In vivo activation of '''G{alpha}q/PKC pathways'' could upregulate GRK2 expression in cardiovascular cells, thus contributing to the increased desensitization of ß-adrenergic and other GPCR systems, is of potential physiological relevance. Detailed mechanisms of regulation of GRK2 expression in different types of cells of the cardiovascular system, particularly in cardiac cell lines, and the determination of possible changes in GRK2 levels in VSMCs of patients with cardiovascular diseases are interesting fields for future research and may help to develop new therapeutic strategies based on the modulation of GRK2 expression. [http://circ.ahajournals.org/cgi/content/full/circulationaha;101/17/2083]]

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Alopecia - Hair Loss

2012-04-20T14:22:41Z

Abhay.goel.1: /* Major players */

{{TOCrightEx}}
== Rationale ==
* "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]
* "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]
* "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] 
 

== Introduction ==

=== Hair basics ===
* Hair is a complex and delicate part of the body.
* Keeping it healthy and beautiful is a challenge.
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.
* Hair is basically a form of skin.
* Hair is made up of a protein called keratin.
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin.
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]

[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]

=== What causes hair loss? ===
* Decrease in growth of hair
* Increase in shedding of hair
* Breakage of hair
* Conversion of thick terminal hairs to thin vellus hairs
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]
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".

=== Types of alopecia===

* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.
* Alopecia Totalis (AT): Total loss of the hair on the scalp.
* Alopecia Universalis (AU): Total loss of all hair on the body.
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.
* 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.
* 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.
* 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.
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.
* 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])

=== Androgenetic alopecia ===
* Gradual onset
* 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
* Characterized by a receding hairline and/or hair loss on the top of the head

'''Main causes'''
* Genetic predisposition
* Hormonal effect of androgen
* Reduction of blood circulation around hair follicle
* Deactivation of hair matrix cells

'''Some facts from Japan'''

* Market size: ¥ 30 Billion
* Number of products: more than 100

(JICST-EPlus - Japanese Science & Technology)

== IP activity over the years ==
The graph indicates:
* Number of patents filed every 5 years (except for first 7 years).
* First solution proposed in 1973
* Filing trend indicates steep rise in activity recently.
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]

== Major players ==
[[Image:players.jpg|thumb|left|500px|Assignees with more than 20 patents ]]
[[Image:players1.jpg|thumb|center|500px|Assignees with fewer than 20 patents ]] 

* '''Active assignees'''
Assignees currently active with more than 5 patents to their credit during 2000-2005.
* Warner with 9 patents,
* Bristol with 6 and
* Abbott with 5.

[[Image:Active.jpg|thumb|center|500px|Active Assignees]]

== Taxonomy ==

[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]

== Interactive Taxonomy ==
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' 
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard''

<mm>[[Map12.mm]]</mm>

== Treatment Approaches==
Composition of treatment for causes are identified and categorized as follows:

* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]
* Double action (Anti-androgen + Vasodilator)
* Hair matrix cells activator

{|border="1" cellpadding="2", style="#008080" align="center"
|- style="font-weight:bold" valign="top"
! Cause !! Treatment approach !! Pathways affected

|- valign="top"
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway

|- valign="top"
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway

|- valign="top"
| Deactivation of hair matrix cells || Hair matrix cells activator
|
* Wnt pathway
* STAT pathway
* TGF beta/BMP Pathway
* FGF Pathway
* MAPK Pathway
* NOTCH Pathway
* Hedgehog Pathway
|}

=== Anti-androgens ===
* Anti-androgens are used in hormone therapy.
* 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.

'''What causes hair loss?'''
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.
* DHT attaches to androgen receptor sites at the hair follicle.
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.

'''How do anti-androgens treat hair loss?'''
* Anti-androgens compete with DHT to bind to the androgen receptor.
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.

==== Functions of Anti-androgen ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen]

[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]

==== IP Map for anti-androgen ====

{| border="1" cellpadding="0", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="450" bgcolor=DodgerBlue|'''Composition'''
!width="400" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:20px"
|bgcolor=LightCyan|[[US20060009430]]
BLOTECH (2004)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone
Sterols - Mechanism of action unknown.

Quercetin results in cell growth cycle.

Beta-sitosterol reduce inflammation on scalp
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
APHIOS Corp (2003)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
Fundacion Pablo Cassara (2003)
|bgcolor=LightCyan|Nucleotide
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
PFIZER INC (2001)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A (1995)
|bgcolor=LightCyan|Peptides/nucleic acid
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor
|- style="height:20px"
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
KAO Corp (1987)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent
|bgcolor=LightCyan|Blocks formation of DHT
|}

=== Minoxidil (Vasodilators) ===
* Minoxidil is a "potassium channel opener" that leads to vasodilation.
* 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.

'''What causes hair loss?'''
* 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.
* 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.

'''How does Minoxidil treat hair loss?'''
* 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.
* 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])
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.

==== Functions of Vasodilators ====

[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]

==== IP Map for Vasodilators ====

{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="600" bgcolor=DodgerBlue|'''Composition'''
!width="300" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2002)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Benzopyran compounds
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
LG HOUSEHOLD & HEALTH CARE(2001)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels
|}

=== Double action (Anti-androgen + Vasodilator) ===
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.

'''What is the problem with using only Anti-androgen therapy?'''
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.
* 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.

'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''
* 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.
* 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.

'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.
* Combination therapy therefore proves to be much more effective than individual therapy.

==== Functions of (Anti-androgen + Vasodilators) ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]

==== IP Map for (Anti-androgen + Vasodilators) ====
{| border="1" cellpadding="3"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="500" bgcolor=DodgerBlue|'''Composition'''
!width="500" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A(2000)
|bgcolor=LightCyan|Peptides
|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
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(2000)
|bgcolor=LightCyan|Peptides
|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
|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
|- style="height:100px"
|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]
COLOMER GROUP(1999)
|bgcolor=LightCyan|Natural extract
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)
|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
|}

=== Hair matrix cell activator ===
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.

'''What causes hair loss?'''
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.
* 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.
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.

'''How does hair cell matrix activator treat hair loss?'''
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.

==== Functions of Hair matrix cell activator ====
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]

==== IP Map for Hair matrix cell activator ====
{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="200" bgcolor=DodgerBlue|'''Composition'''
!width="600" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
SHISEIDO(1999)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(1998)
|bgcolor=LightCyan|Peptides
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions
|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)
|}

== Technology mapping based on patents analyzed ==

=== IPMap: Composition nature matrix ===

{| border="1" cellpadding="11", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Year'''
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''
!width="200" bgcolor=DodgerBlue|'''Natural extracts'''
!width="200" bgcolor=DodgerBlue|'''Peptides'''
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''
|- style="height:10px"
|bgcolor=LightCyan|2005
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|UNILEVER (1)
|-
|bgcolor=LightCyan|2004
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|BLOTECH (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|-
|bgcolor=LightCyan|2003
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|APHIOS (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|FUNDACION (1)
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2002
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2001
|bgcolor=LightCyan |PFIZER (1)
|bgcolor=LightCyan|LG HEALTH-CARE (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2000
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1999
|bgcolor=LightCyan|SHISEDIO (1)
|bgcolor=LightCyan|COLOMER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1998
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1995
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1987
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1982
|bgcolor=LightCyan|UNILEVER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|}
=== Focus of patents ===

{| border="1" cellpadding="17", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|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
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Method of decreasing sebum production and pore size
|bgcolor=LightCyan|[http://appft1.uspto.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 ]
|bgcolor=LightCyan|16
|-
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin
|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]
|bgcolor=LightCyan|17
|}

=== Technology focus===
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]
=== Distribution of patents ===

==== By patent types ====
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]

==== By key ingredients ====
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]

==== By target disease ====
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]

==== Key ingredients vs. Target disease ====
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]

==== Target species ====
[[Image:Species.jpg|thumb|center|700px|Target species]]

==== Mode of administration ====
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]

==== Product type vs. Product form ====
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]

==== Patents by target diseases ====
{| border="1" cellpadding="16", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|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
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Male pattern alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Alopecia, androgenic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|bgcolor=LightCyan|Male pattern alopecia
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Curing other scalp related problems
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|16
|}

==== [[List of patents]] ====
== Pathways and linkages ==

=== Pathways associated with hair matrix cell activation===

'''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.

* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.
* '''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.
* '''STAT pathway'''
* '''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
* '''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.
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.
* '''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.

=== Pathways associated with Anti Androgen===
[[Image:Slide1.GIF|thumb|center|700 px|Alopecia pathways]]
==== Players of WNT inhibition Pathway ====
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]
{| border="1" cellpadding="15", style="#008080"
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="200" bgcolor=DodgerBlue|'''Key compound'''
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''
|- style="height:10px"
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|CDK,GSK3
|-
|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]
|bgcolor=LightCyan|Pyrimidine derivative
|bgcolor=LightCyan|GSK3
|-
|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]
|bgcolor=LightCyan|Heterocyclic compounds
|bgcolor=LightCyan|AKT3, GSK-3, ERK2
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Aza-oxindole derivatives
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]
|bgcolor=LightCyan|Pyrazolon derivatives
|bgcolor=LightCyan|GSK3, ß-catenin
|-
|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]
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|a-catenin, ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|}

==== Role of Pyrazole compounds in Wnt Pathway====
'''Pyrazole'''
* '''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.
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.
* Structurally related compounds are pyrazoline and pyrazolidine.
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]

==== GSK3 inhibition by pyrazole compounds ====
[[Image:bold3.jpg]]
{| border="1" cellpadding="2", style="#008080"
!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]
[[Image:US6989385.jpg]]
!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]
[[Image:US6664247.jpg]]
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
[[Image:WO2005012256.jpg]]
|-
|bgcolor=lightcyan|R1=T-Ring D, wherein
T is a valence bond and
Ring D = 5-6 membered aryl or heteroaryl ring;

R2 = hydrogen or C1-4 aliphatic and
R2'= hydrogen;

R3 = -R, -OR, or -N(R4)2, wherein
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and
L is -O-, -S-, or -NH-; and
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

|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;

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;

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

R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;
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).
|}

==== Inhibition by amine derivatives ====

'''Patent Number''': US6989385
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol1.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]

'''Patent Number''': US7008948
'''Applicant''': Vertex Pharmaceuticals Incorporated
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure'''

[[Image:pyrazol2.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]

'''Patent Number''': US6977262
'''Assignee''': Mitsubishi Pharma Corporation
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof

'''Basic Structure''':

[[Image:pyrazol3.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]

----
'''Patent Number''': US6664247
'''Assignee''': Vertex Pharmaceuticals Incorporated
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''

'''Basic Structure''':

[[Image:pyrazol4.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]

----
'''Patent Number''': US2004224944
'''Assignee''': VERTEX PHARMACEUTICALS INC
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol5.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]

[[Other derivates for alopecia]]

==== GSK-3 Inhibition Mechanism - Phosphorylation====
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]
* 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.

* 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.

* 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.

* 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.

'''[[More details on GSK-3]]'''

'''Key points'''

* 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]
* 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]
* 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]
* 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]

'''GK3 Inhibition:'''

* GSK3 is regulated by phosphorylation.
* 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]
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]
* 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]
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP.

[[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]]]

* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation.
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation.
* 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.

'''Serine - pyrazole reaction'''

[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]

* 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.

* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.

* 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.

* 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.

* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.

* 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.

'''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]

# inactivation of GSK-3 through serine phosphorylation
# activation of GSK-3 through tyrosine phosphorylation
# inactivation of GSK-3 through tyrosine dephosphorylation
# Covalant modifications of substrates through priming phosphorylation
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins
# targeting of GSK-3 to different subcellular localizations
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity
# integration of parellel signals conveyed by a signal stimulus.

'''Key Finding'''
* '''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]

=== Pathway associated with anti-androgen ===

* Dihydrotestosterone
** Formed by peripheral conversion of testosterone by 5-alpha reductase
** Binds to androgen receptor on susceptible hair follicles
* 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

[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]

==== Structure-Activity Relationships(SARs) ====
[[Image:SAR_map.gif|center|600px]]

=== Pathway associated with Minoxidil (vasodilators) ===
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.
[[image:vasodiator-rev.jpg|800 px|center]]

== Alopecia IPMap ==
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]

== Patent activity in China ==
===Treatment approaches===
{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center"|'''Treatment approach'''
|align = "center"|'''Patent number'''
|align = "center"|'''Priority year'''
|align = "center"|'''Assignee/Inventor'''
|-
|rowspan = "7"|Vasodilators
|[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]
|2005
|叶明伟
|-
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]
|2005
|王亚杰
|-
|[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]
|2003
|谈汝标
|-
|[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]
|2002
|赵章光
|-
|[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]
|2001
|范希田
|-
|[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]
|1996
|殷国健
|-
|[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]
|1988
|天津市轻工业化学研究所
|-
|Hair matrix activator
|[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]
|2002
|朱静建
|-
|Anti-androgen <nowiki>+</nowiki> Vasodilator
|[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]
|1996
|梅晓春
|-
|}

=== Details of treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"
|align = "center"|'''Patent number'''
|align = "center"|'''Patent title'''
|align = "center"|'''Treatment approach'''
|align = "center"|'''Composition nature'''
|align = "center"|'''Composition'''
|align = "center"|'''Composition action'''
|-
|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] YE MINGWEI (CN) 叶明伟 (2005)
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn 治疗瘀血阻滞型脱发的中草药汤剂及制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower
|align = "justify"|Promote blood circulation
|-
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139 ]WANG YAJIE (CN) 王亚杰 2005
|align = "justify"|Alopecia areata treating medicine 一种治疗斑秃的药物
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc
|align = "justify"|Promote blood circulation
|-
|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] TAN RUBIAO (CN) 谈汝标 2003
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application 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
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds
|align = "justify"|Enhances the hair growth and healthier hairs
|-
|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] 朱静建 2002
|Hair growing preparation containing compound of Chinese medicine and Western medicine 一种含中西药复方的育发剂
|align = "justify"|Hair matrix activator
|Mixture of Herbal extracts and western medicine
|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.
|align = "justify"|Better and faster hair growth
|-
|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] 赵章光2002
|align = "justify"|Hair follice activating liquid 毛囊激活液
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers
|align = "justify"|Activates the hair-follicle and enhances the hair growth.
|-
|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] 范希田 2001
|align = "justify"|Trichogen and its prepn 一种止脱生发药物及其制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed
|align = "justify"|Promote blood circulation and enhance hair growth
|-
|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] 殷国健 1996
|Washing free shampoo for nourishing and growing hair 免洗养发生发香波
|align = "justify"|Vasodilator
|Vitamin composition
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum
|align = "justify"|Stimulate hair growth
|-
|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] 梅晓春 1996
|Efficient low-side effect external use medicine for curing seborrheic baldness 一种治疗脂溢性脱发的高效低副作用外用药物
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator
|Mixture of Herbal extracts and organic compounds
|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
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth
|-
|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] 天津市轻工业化学研究所 1988
|Channel-stimulating and hair-growing hair shampoo 一种通络生发香波
|align = "justify"|Vasodilators
|Herbal extract <nowiki>+</nowiki> detergent
|align = "justify"|Herbal extracts, Penetration media, Detergents.
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los
|-
|} 

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== Conclusions ==
* Hair loss medication is a very active area of research and intellectual property development.
* One of the most promising areas of development is the area of Anti-androgens.
* The top companies are Merck, L’Oreal and Smithkline.

==Contact Dolcera==

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Alopecia - Hair Loss

2012-04-19T15:18:05Z

Abhay.goel.1: /* Rationale */

{{TOCrightEx}}
== Rationale ==
* "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]
* "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]
* "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] 
 

== Introduction ==

=== Hair basics ===
* Hair is a complex and delicate part of the body.
* Keeping it healthy and beautiful is a challenge.
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.
* Hair is basically a form of skin.
* Hair is made up of a protein called keratin.
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin.
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]

[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]

=== What causes hair loss? ===
* Decrease in growth of hair
* Increase in shedding of hair
* Breakage of hair
* Conversion of thick terminal hairs to thin vellus hairs
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]
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".

=== Types of alopecia===

* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.
* Alopecia Totalis (AT): Total loss of the hair on the scalp.
* Alopecia Universalis (AU): Total loss of all hair on the body.
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.
* 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.
* 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.
* 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.
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.
* 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])

=== Androgenetic alopecia ===
* Gradual onset
* 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
* Characterized by a receding hairline and/or hair loss on the top of the head

'''Main causes'''
* Genetic predisposition
* Hormonal effect of androgen
* Reduction of blood circulation around hair follicle
* Deactivation of hair matrix cells

'''Some facts from Japan'''

* Market size: ¥ 30 Billion
* Number of products: more than 100

(JICST-EPlus - Japanese Science & Technology)

== IP activity over the years ==
The graph indicates:
* Number of patents filed every 5 years (except for first 7 years).
* First solution proposed in 1973
* Filing trend indicates steep rise in activity recently.
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]

== Major players ==
[[Image:players.jpg|thumb|left|300px|Assignees with more than 20 patents ]]
[[Image:players1.jpg|thumb|center|300px|Assignees with fewer than 20 patents ]] 

* '''Active assignees'''
Assignees currently active with more than 5 patents to their credit during 2000-2005.
* Warner with 9 patents,
* Bristol with 6 and
* Abbott with 5.

[[Image:Active.jpg|thumb|center|500px|Active Assignees]]

== Taxonomy ==

[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]

== Interactive Taxonomy ==
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' 
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard''

<mm>[[Map12.mm]]</mm>

== Treatment Approaches==
Composition of treatment for causes are identified and categorized as follows:

* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]
* Double action (Anti-androgen + Vasodilator)
* Hair matrix cells activator

{|border="1" cellpadding="2", style="#008080" align="center"
|- style="font-weight:bold" valign="top"
! Cause !! Treatment approach !! Pathways affected

|- valign="top"
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway

|- valign="top"
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway

|- valign="top"
| Deactivation of hair matrix cells || Hair matrix cells activator
|
* Wnt pathway
* STAT pathway
* TGF beta/BMP Pathway
* FGF Pathway
* MAPK Pathway
* NOTCH Pathway
* Hedgehog Pathway
|}

=== Anti-androgens ===
* Anti-androgens are used in hormone therapy.
* 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.

'''What causes hair loss?'''
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.
* DHT attaches to androgen receptor sites at the hair follicle.
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.

'''How do anti-androgens treat hair loss?'''
* Anti-androgens compete with DHT to bind to the androgen receptor.
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.

==== Functions of Anti-androgen ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen]

[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]

==== IP Map for anti-androgen ====

{| border="1" cellpadding="0", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="450" bgcolor=DodgerBlue|'''Composition'''
!width="400" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:20px"
|bgcolor=LightCyan|[[US20060009430]]
BLOTECH (2004)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone
Sterols - Mechanism of action unknown.

Quercetin results in cell growth cycle.

Beta-sitosterol reduce inflammation on scalp
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
APHIOS Corp (2003)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
Fundacion Pablo Cassara (2003)
|bgcolor=LightCyan|Nucleotide
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
PFIZER INC (2001)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A (1995)
|bgcolor=LightCyan|Peptides/nucleic acid
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor
|- style="height:20px"
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
KAO Corp (1987)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent
|bgcolor=LightCyan|Blocks formation of DHT
|}

=== Minoxidil (Vasodilators) ===
* Minoxidil is a "potassium channel opener" that leads to vasodilation.
* 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.

'''What causes hair loss?'''
* 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.
* 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.

'''How does Minoxidil treat hair loss?'''
* 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.
* 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])
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.

==== Functions of Vasodilators ====

[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]

==== IP Map for Vasodilators ====

{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="600" bgcolor=DodgerBlue|'''Composition'''
!width="300" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2002)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Benzopyran compounds
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
LG HOUSEHOLD & HEALTH CARE(2001)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels
|}

=== Double action (Anti-androgen + Vasodilator) ===
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.

'''What is the problem with using only Anti-androgen therapy?'''
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.
* 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.

'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''
* 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.
* 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.

'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.
* Combination therapy therefore proves to be much more effective than individual therapy.

==== Functions of (Anti-androgen + Vasodilators) ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]

==== IP Map for (Anti-androgen + Vasodilators) ====
{| border="1" cellpadding="3"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="500" bgcolor=DodgerBlue|'''Composition'''
!width="500" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A(2000)
|bgcolor=LightCyan|Peptides
|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
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(2000)
|bgcolor=LightCyan|Peptides
|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
|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
|- style="height:100px"
|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]
COLOMER GROUP(1999)
|bgcolor=LightCyan|Natural extract
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)
|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
|}

=== Hair matrix cell activator ===
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.

'''What causes hair loss?'''
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.
* 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.
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.

'''How does hair cell matrix activator treat hair loss?'''
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.

==== Functions of Hair matrix cell activator ====
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]

==== IP Map for Hair matrix cell activator ====
{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="200" bgcolor=DodgerBlue|'''Composition'''
!width="600" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
SHISEIDO(1999)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(1998)
|bgcolor=LightCyan|Peptides
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions
|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)
|}

== Technology mapping based on patents analyzed ==

=== IPMap: Composition nature matrix ===

{| border="1" cellpadding="11", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Year'''
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''
!width="200" bgcolor=DodgerBlue|'''Natural extracts'''
!width="200" bgcolor=DodgerBlue|'''Peptides'''
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''
|- style="height:10px"
|bgcolor=LightCyan|2005
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|UNILEVER (1)
|-
|bgcolor=LightCyan|2004
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|BLOTECH (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|-
|bgcolor=LightCyan|2003
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|APHIOS (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|FUNDACION (1)
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2002
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2001
|bgcolor=LightCyan |PFIZER (1)
|bgcolor=LightCyan|LG HEALTH-CARE (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2000
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1999
|bgcolor=LightCyan|SHISEDIO (1)
|bgcolor=LightCyan|COLOMER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1998
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1995
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1987
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1982
|bgcolor=LightCyan|UNILEVER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|}
=== Focus of patents ===

{| border="1" cellpadding="17", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|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
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Method of decreasing sebum production and pore size
|bgcolor=LightCyan|[http://appft1.uspto.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 ]
|bgcolor=LightCyan|16
|-
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin
|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]
|bgcolor=LightCyan|17
|}

=== Technology focus===
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]
=== Distribution of patents ===

==== By patent types ====
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]

==== By key ingredients ====
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]

==== By target disease ====
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]

==== Key ingredients vs. Target disease ====
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]

==== Target species ====
[[Image:Species.jpg|thumb|center|700px|Target species]]

==== Mode of administration ====
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]

==== Product type vs. Product form ====
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]

==== Patents by target diseases ====
{| border="1" cellpadding="16", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|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
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Male pattern alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Alopecia, androgenic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|bgcolor=LightCyan|Male pattern alopecia
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Curing other scalp related problems
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|16
|}

==== [[List of patents]] ====
== Pathways and linkages ==

=== Pathways associated with hair matrix cell activation===

'''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.

* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.
* '''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.
* '''STAT pathway'''
* '''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
* '''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.
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.
* '''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.

=== Pathways associated with Anti Androgen===
[[Image:Slide1.GIF|thumb|center|700 px|Alopecia pathways]]
==== Players of WNT inhibition Pathway ====
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]
{| border="1" cellpadding="15", style="#008080"
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="200" bgcolor=DodgerBlue|'''Key compound'''
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''
|- style="height:10px"
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|CDK,GSK3
|-
|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]
|bgcolor=LightCyan|Pyrimidine derivative
|bgcolor=LightCyan|GSK3
|-
|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]
|bgcolor=LightCyan|Heterocyclic compounds
|bgcolor=LightCyan|AKT3, GSK-3, ERK2
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Aza-oxindole derivatives
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]
|bgcolor=LightCyan|Pyrazolon derivatives
|bgcolor=LightCyan|GSK3, ß-catenin
|-
|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]
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|a-catenin, ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|}

==== Role of Pyrazole compounds in Wnt Pathway====
'''Pyrazole'''
* '''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.
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.
* Structurally related compounds are pyrazoline and pyrazolidine.
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]

==== GSK3 inhibition by pyrazole compounds ====
[[Image:bold3.jpg]]
{| border="1" cellpadding="2", style="#008080"
!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]
[[Image:US6989385.jpg]]
!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]
[[Image:US6664247.jpg]]
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
[[Image:WO2005012256.jpg]]
|-
|bgcolor=lightcyan|R1=T-Ring D, wherein
T is a valence bond and
Ring D = 5-6 membered aryl or heteroaryl ring;

R2 = hydrogen or C1-4 aliphatic and
R2'= hydrogen;

R3 = -R, -OR, or -N(R4)2, wherein
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and
L is -O-, -S-, or -NH-; and
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

|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;

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;

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

R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;
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).
|}

==== Inhibition by amine derivatives ====

'''Patent Number''': US6989385
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol1.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]

'''Patent Number''': US7008948
'''Applicant''': Vertex Pharmaceuticals Incorporated
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure'''

[[Image:pyrazol2.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]

'''Patent Number''': US6977262
'''Assignee''': Mitsubishi Pharma Corporation
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof

'''Basic Structure''':

[[Image:pyrazol3.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]

----
'''Patent Number''': US6664247
'''Assignee''': Vertex Pharmaceuticals Incorporated
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''

'''Basic Structure''':

[[Image:pyrazol4.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]

----
'''Patent Number''': US2004224944
'''Assignee''': VERTEX PHARMACEUTICALS INC
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol5.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]

[[Other derivates for alopecia]]

==== GSK-3 Inhibition Mechanism - Phosphorylation====
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]
* 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.

* 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.

* 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.

* 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.

'''[[More details on GSK-3]]'''

'''Key points'''

* 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]
* 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]
* 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]
* 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]

'''GK3 Inhibition:'''

* GSK3 is regulated by phosphorylation.
* 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]
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]
* 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]
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP.

[[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]]]

* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation.
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation.
* 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.

'''Serine - pyrazole reaction'''

[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]

* 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.

* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.

* 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.

* 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.

* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.

* 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.

'''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]

# inactivation of GSK-3 through serine phosphorylation
# activation of GSK-3 through tyrosine phosphorylation
# inactivation of GSK-3 through tyrosine dephosphorylation
# Covalant modifications of substrates through priming phosphorylation
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins
# targeting of GSK-3 to different subcellular localizations
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity
# integration of parellel signals conveyed by a signal stimulus.

'''Key Finding'''
* '''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]

=== Pathway associated with anti-androgen ===

* Dihydrotestosterone
** Formed by peripheral conversion of testosterone by 5-alpha reductase
** Binds to androgen receptor on susceptible hair follicles
* 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

[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]

==== Structure-Activity Relationships(SARs) ====
[[Image:SAR_map.gif|center|600px]]

=== Pathway associated with Minoxidil (vasodilators) ===
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.
[[image:vasodiator-rev.jpg|800 px|center]]

== Alopecia IPMap ==
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]

== Patent activity in China ==
===Treatment approaches===
{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center"|'''Treatment approach'''
|align = "center"|'''Patent number'''
|align = "center"|'''Priority year'''
|align = "center"|'''Assignee/Inventor'''
|-
|rowspan = "7"|Vasodilators
|[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]
|2005
|叶明伟
|-
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]
|2005
|王亚杰
|-
|[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]
|2003
|谈汝标
|-
|[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]
|2002
|赵章光
|-
|[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]
|2001
|范希田
|-
|[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]
|1996
|殷国健
|-
|[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]
|1988
|天津市轻工业化学研究所
|-
|Hair matrix activator
|[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]
|2002
|朱静建
|-
|Anti-androgen <nowiki>+</nowiki> Vasodilator
|[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]
|1996
|梅晓春
|-
|}

=== Details of treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"
|align = "center"|'''Patent number'''
|align = "center"|'''Patent title'''
|align = "center"|'''Treatment approach'''
|align = "center"|'''Composition nature'''
|align = "center"|'''Composition'''
|align = "center"|'''Composition action'''
|-
|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] YE MINGWEI (CN) 叶明伟 (2005)
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn 治疗瘀血阻滞型脱发的中草药汤剂及制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower
|align = "justify"|Promote blood circulation
|-
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139 ]WANG YAJIE (CN) 王亚杰 2005
|align = "justify"|Alopecia areata treating medicine 一种治疗斑秃的药物
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc
|align = "justify"|Promote blood circulation
|-
|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] TAN RUBIAO (CN) 谈汝标 2003
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application 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
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds
|align = "justify"|Enhances the hair growth and healthier hairs
|-
|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] 朱静建 2002
|Hair growing preparation containing compound of Chinese medicine and Western medicine 一种含中西药复方的育发剂
|align = "justify"|Hair matrix activator
|Mixture of Herbal extracts and western medicine
|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.
|align = "justify"|Better and faster hair growth
|-
|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] 赵章光2002
|align = "justify"|Hair follice activating liquid 毛囊激活液
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers
|align = "justify"|Activates the hair-follicle and enhances the hair growth.
|-
|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] 范希田 2001
|align = "justify"|Trichogen and its prepn 一种止脱生发药物及其制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed
|align = "justify"|Promote blood circulation and enhance hair growth
|-
|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] 殷国健 1996
|Washing free shampoo for nourishing and growing hair 免洗养发生发香波
|align = "justify"|Vasodilator
|Vitamin composition
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum
|align = "justify"|Stimulate hair growth
|-
|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] 梅晓春 1996
|Efficient low-side effect external use medicine for curing seborrheic baldness 一种治疗脂溢性脱发的高效低副作用外用药物
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator
|Mixture of Herbal extracts and organic compounds
|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
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth
|-
|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] 天津市轻工业化学研究所 1988
|Channel-stimulating and hair-growing hair shampoo 一种通络生发香波
|align = "justify"|Vasodilators
|Herbal extract <nowiki>+</nowiki> detergent
|align = "justify"|Herbal extracts, Penetration media, Detergents.
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los
|-
|} 

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== Conclusions ==
* Hair loss medication is a very active area of research and intellectual property development.
* One of the most promising areas of development is the area of Anti-androgens.
* The top companies are Merck, L’Oreal and Smithkline.

==Contact Dolcera==

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Alopecia - Hair Loss

2012-04-19T15:17:43Z

Abhay.goel.1:

{{TOCrightEx}}
== Rationale ==
* "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]
* "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]
* "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] 

 
== Introduction ==

=== Hair basics ===
* Hair is a complex and delicate part of the body.
* Keeping it healthy and beautiful is a challenge.
* Hair grows everywhere on the body with the exception of lips, eyelids, palms of the hands and soles of the feet.
* Hair is basically a form of skin.
* Hair is made up of a protein called keratin.
* Each shaft of hair is made of two or three inter-twined layers of keratin which grow from a follicle beneath the skin.
* Hair Structure - [http://www.pg.com/science/haircare/hair_twh_12.htm Source]
* Hair Cycle - [http://www.follicle.com/hair-structure-life-cycle.html Source]

[[Image:Hairbasics.jpg|center|400px|Structure of Hair root and Hair bulb]]

=== What causes hair loss? ===
* Decrease in growth of hair
* Increase in shedding of hair
* Breakage of hair
* Conversion of thick terminal hairs to thin vellus hairs
[[Image:Facts.jpg|thumb|right|250px|Survey results from Japan]]
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".

=== Types of alopecia===

* Alopecia Areata (AA): Hair loss occurring in patches anywhere on the body.
* Alopecia Totalis (AT): Total loss of the hair on the scalp.
* Alopecia Universalis (AU): Total loss of all hair on the body.
* Alopecia Barbae: Loss of facial hair (for a man) especially in the beard area.
* Alopecia Mucinosa: A type of alopecia which results in scaley patches.
* 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.
* 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.
* 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.
* Scarring Alopecia: A form of alopecia which leaves scarring on the area of hair loss.
* 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])

=== Androgenetic alopecia ===
* Gradual onset
* 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
* Characterized by a receding hairline and/or hair loss on the top of the head

'''Main causes'''
* Genetic predisposition
* Hormonal effect of androgen
* Reduction of blood circulation around hair follicle
* Deactivation of hair matrix cells

'''Some facts from Japan'''

* Market size: ¥ 30 Billion
* Number of products: more than 100

(JICST-EPlus - Japanese Science & Technology)

== IP activity over the years ==
The graph indicates:
* Number of patents filed every 5 years (except for first 7 years).
* First solution proposed in 1973
* Filing trend indicates steep rise in activity recently.
[[Image:Year1.jpg|thumb|center|400px|IP Activity over years]]

== Major players ==
[[Image:players.jpg|thumb|left|300px|Assignees with more than 20 patents ]]
[[Image:players1.jpg|thumb|center|300px|Assignees with fewer than 20 patents ]] 

* '''Active assignees'''
Assignees currently active with more than 5 patents to their credit during 2000-2005.
* Warner with 9 patents,
* Bristol with 6 and
* Abbott with 5.

[[Image:Active.jpg|thumb|center|500px|Active Assignees]]

== Taxonomy ==

[[Image:Alopecia toxonomy.jpg|thumb|center|800px]]

== Interactive Taxonomy ==
''Use the mouse(click and drag/scroll up or down/click on nodes) to explore nodes in the detailed taxonomy'' 
''Click on the red arrow on the side of a node name to view the content for that particular node in the dashboard''

<mm>[[Map12.mm]]</mm>

== Treatment Approaches==
Composition of treatment for causes are identified and categorized as follows:

* Anti-androgens (Finasteride) [http://www.emedicine.com/DERM/topic21.htm source]
* Vasodilators (Minoxidil) [http://www.emedicine.com/DERM/topic21.htm source]
* Double action (Anti-androgen + Vasodilator)
* Hair matrix cells activator

{|border="1" cellpadding="2", style="#008080" align="center"
|- style="font-weight:bold" valign="top"
! Cause !! Treatment approach !! Pathways affected

|- valign="top"
| Hormonal effect of androgen || Anti-androgens || Testosterone pathway

|- valign="top"
| Reduction of blood circulation around hair follicle || Vasodilators (eg. Minoxidil) || NO/cGMP Pathway

|- valign="top"
| Deactivation of hair matrix cells || Hair matrix cells activator
|
* Wnt pathway
* STAT pathway
* TGF beta/BMP Pathway
* FGF Pathway
* MAPK Pathway
* NOTCH Pathway
* Hedgehog Pathway
|}

=== Anti-androgens ===
* Anti-androgens are used in hormone therapy.
* 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.

'''What causes hair loss?'''
* Testosterone is reduced to its active metabolite, Dihydrotestosterone (DHT) by the enzyme 5 alpha reductase.
* DHT attaches to androgen receptor sites at the hair follicle.
* DHT causes gradual miniaturization of the follicle, which eventually results in hair loss.

'''How do anti-androgens treat hair loss?'''
* Anti-androgens compete with DHT to bind to the androgen receptor.
* Upon binding of anti-androgen in place of DHT, follicle miniaturization is lowered and hair loss prevented.

==== Functions of Anti-androgen ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen]

[[Image:Andogen1.jpg|thumb|center|500px|Functions of Anti-androgen]]

==== IP Map for anti-androgen ====

{| border="1" cellpadding="0", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="450" bgcolor=DodgerBlue|'''Composition'''
!width="400" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:20px"
|bgcolor=LightCyan|[[US20060009430]]
BLOTECH (2004)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Fatty acids – Inhibit testosterone
Sterols - Mechanism of action unknown.

Quercetin results in cell growth cycle.

Beta-sitosterol reduce inflammation on scalp
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 4-cycloalkoxy benzonitrile derivatives and salts
|bgcolor=LightCyan|Acts as androgen receptor modulator and blocks formation of DHT.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2004)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|New class of 6-sulfonamido-quinolin-2-one and 6-sulfonamido-2-oxo-chromene derivatives.
|bgcolor=LightCyan|The compounds inhibit, or decrease, activation of androgen receptor by androgens.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
APHIOS Corp (2003)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto and Sperol (Serenoa repens berry) and their analogs or derivatives.
|bgcolor=LightCyan|Modulates androgenic activity by inhibiting 5.alpha.-reductase activity.
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
Fundacion Pablo Cassara (2003)
|bgcolor=LightCyan|Nucleotide
|bgcolor=LightCyan|Pharmacologically active oligonucleotides (encompass both DNA and S-DNA bond)
|bgcolor=LightCyan|Oligonucleotides inhibit androgen receptor (AR) expression at very low concentrations in skin and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
PFIZER INC (2001)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Thyromimetic compounds (structurally similar to thyronine) with finasteride, or cyproterone acetate
|bgcolor=LightCyan|Activates thyroid hormone receptors in hair follicle which in turn promote elasticisation of follicle walls and hair follicle
|- style="height:20px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A (1995)
|bgcolor=LightCyan|Peptides/nucleic acid
|bgcolor=LightCyan|Bradykinin antagonist (peptide of plasma origin from kininogen precursor-kallikrein)
|bgcolor=LightCyan|Inhibits synthesis of bradykinin receptors or compounds by binding to B2 receptor
|- style="height:20px"
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
KAO Corp (1987)
|bgcolor=LightCyan|Natural extracts
|bgcolor=LightCyan|Walnut extract (leaves/pericarps) with an organic solvent
|bgcolor=LightCyan|Blocks formation of DHT
|}

=== Minoxidil (Vasodilators) ===
* Minoxidil is a "potassium channel opener" that leads to vasodilation.
* 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.

'''What causes hair loss?'''
* 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.
* 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.

'''How does Minoxidil treat hair loss?'''
* 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.
* 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])
* Minoxidil sulfate (MS) appears to be the active metabolite responsible for hair growth stimulation.

==== Functions of Vasodilators ====

[[Image:minoxidil1.jpg|thumb|center|500px|Functions of Monoxidil [http://www.nurseminerva.co.uk/diagrams.htm#Diagram%201 source]]]

==== IP Map for Vasodilators ====

{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="600" bgcolor=DodgerBlue|'''Composition'''
!width="300" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
WARNER LAMBERT(2002)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|Benzopyran compounds
|bgcolor=LightCyan|Rapidly metabolizes, and causes reduced cardiovascular effects as compared to other known potassium channel openers
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
LG HOUSEHOLD & HEALTH CARE(2001)
|bgcolor=LightCyan|Natural extracts
|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)
|bgcolor=LightCyan|Promotes function of cell activity and dilates blood vessels
|}

=== Double action (Anti-androgen + Vasodilator) ===
* Combination of Vasodilator + Anti-androgen (double action) composition for effective treatment of Male-Pattern Baldness.

'''What is the problem with using only Anti-androgen therapy?'''
* Anti-androgen is not effective in addressing the issue of vasocontriction around hair follicles due to sebum oil build up.
* 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.

'''What is the problem with using only Vasodilator (or Minoxidil only) therapy?'''
* 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.
* 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.

'''How is the combination of Anti-androgens and Vasodilator (or Minoxidil) effective?'''
* Anti-androgens target the problem of DHT binding to androgen receptors and prevents follicle miniaturization.
* Vasodilators like Minoxidil cause vasodilation and therefore improve supply of oxygen and nutrients to the hair follicle and roots.
* Combination therapy therefore proves to be much more effective than individual therapy.

==== Functions of (Anti-androgen + Vasodilators) ====
[http://www.revivogen.com/revivogen/work.html Anti-androgen ]and [http://www.xandrox.net/articles/article01.htm Minoxidil]
[[Image:Doubleaction1.jpg|thumb|center|500px|Functions of (Anti-androgen + Vasodilators)]]

==== IP Map for (Anti-androgen + Vasodilators) ====
{| border="1" cellpadding="3"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="75" bgcolor=DodgerBlue|'''Nature'''
!width="500" bgcolor=DodgerBlue|'''Composition'''
!width="500" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
N/A(2000)
|bgcolor=LightCyan|Peptides
|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
|bgcolor=LightCyan|Inhibits 5.alpha.-reductase activity (block DHT) and increase blood flow on the scalp
|- style="height:100px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(2000)
|bgcolor=LightCyan|Peptides
|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
|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
|- style="height:100px"
|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]
COLOMER GROUP(1999)
|bgcolor=LightCyan|Natural extract
|bgcolor=LightCyan|Hop extract (oil contains terpenes and humulene), Rosemary extract (hydroalcohol), Swertia extract (glycol with a swertiamarin), Silanodiol salicylate (biologically active silicon compound)
|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
|}

=== Hair matrix cell activator ===
Hair matrix cell activator is a substance that acts at the matrix cells in the hair follicle preventing their degradation.

'''What causes hair loss?'''
* Stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge.
* 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.
* Perifollicular matrix cells undergo slow degradation which prevents follicle stimulation.
* Hair follicle activation is required for hair growth and thus inhibition of follicle activation eventually leads to hair loss.

'''How does hair cell matrix activator treat hair loss?'''
* Hair cell matrix activator slows down and inhibits degradation of the perifollicular matrix.
* This leads to an increase in hair follicle matrix cells that differentiate from progenitor stem cells.
* Matrix activator allows activation of hair matrix cells and therefore follicle stimulation leading to hair growth.

==== Functions of Hair matrix cell activator ====
[http://www.ijdb.ehu.es/fullaccess/fulltext.04023/ft163.pdf Hair matrix cell activator]
[[Image:Hair matrix.jpg|thumb|center|500px|Functions of Hair matrix cell activator ]]

==== IP Map for Hair matrix cell activator ====
{| border="1" cellpadding="2"
!width="120" bgcolor=DodgerBlue|'''Pat/Pub#'''
!width="100" bgcolor=DodgerBlue|'''Nature'''
!width="200" bgcolor=DodgerBlue|'''Composition'''
!width="600" bgcolor=DodgerBlue|'''Composition action'''
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
SHISEIDO(1999)
|bgcolor=LightCyan|Organic compound
|bgcolor=LightCyan|(2-substituted oxyphenyl) alkanamide derivative and its salt
|bgcolor=LightCyan|Mechanism of action has not been made clear, having excellent hair follicle activating action and regrowth promoting effect
|- style="height:50px"
|bgcolor=LightCyan|[http://appft1.uspto.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]
L'OREAL(1998)
|bgcolor=LightCyan|Peptides
|bgcolor=LightCyan|Metalloprotease (MMP-9) inhibitor (thiol or a hydroxamate) other than chelating calcium ions
|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)
|}

== Technology mapping based on patents analyzed ==

=== IPMap: Composition nature matrix ===

{| border="1" cellpadding="11", style="#008080"
!width="120" bgcolor=DodgerBlue|'''Year'''
!width="200" bgcolor=DodgerBlue|'''Organic Compound'''
!width="200" bgcolor=DodgerBlue|'''Natural extracts'''
!width="200" bgcolor=DodgerBlue|'''Peptides'''
!width="200" bgcolor=DodgerBlue|'''Nucleotides'''
!width="200" bgcolor=DodgerBlue|'''Natural extract + Organic comp'''
|- style="height:10px"
|bgcolor=LightCyan|2005
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|UNILEVER (1)
|-
|bgcolor=LightCyan|2004
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|BLOTECH (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|-
|bgcolor=LightCyan|2003
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|APHIOS (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|FUNDACION (1)
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2002
|bgcolor=LightCyan|WARNER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2001
|bgcolor=LightCyan |PFIZER (1)
|bgcolor=LightCyan|LG HEALTH-CARE (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|2000
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1) / N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1999
|bgcolor=LightCyan|SHISEDIO (1)
|bgcolor=LightCyan|COLOMER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1998
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|L’OREAL (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1995
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|N/A (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1987
|bgcolor=LightCyan|....
|bgcolor=LightCyan|KAO (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|-
|bgcolor=LightCyan|1982
|bgcolor=LightCyan|UNILEVER (1)
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|bgcolor=LightCyan|....
|}
=== Focus of patents ===

{| border="1" cellpadding="17", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Focus of patents'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="100" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|2-substituted oxyphenyl alkanamide derivative having excellent hair growth effect.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Thyromimetic compounds, and its role in treating hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Saw Palmetto berry extract, pumpkin seed extract, sitosterol and quercetin for the treatment and prevention of the biologically detrimental effects of DHT
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|4-cycloalkoxy benzonitriles and its use as androgen receptor modulators
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Supercritical fluid isolate of Saw Palmetto, Sperol for inhibition of 5-.alpha.-reductase activity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|New class of quinolin-2-ones and chromen-2-ones andtheir use as androgen receptor antagonists
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Antiandrogen oligonucleotides usable for the treatment of dermatological androgen-related disorders
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Extract from walnut leaves and/or pericarps as 5 alpha -reductase inhibitor
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|bgcolor=LightCyan|Stimulating hair growth using benzopyrans
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Sophora flavescens extract, Coicis semen extract, clove extract, etc for promoting hair growth, function of cell activity and dilating peripheral blood vessels.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Compositions to prevent or reduce hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Prostaglandin EP-3 receptor antagonists for reducing hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|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
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Metalloprotease inhibitors to induce and/or stimulate the growth
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Method of decreasing sebum production and pore size
|bgcolor=LightCyan|[http://appft1.uspto.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 ]
|bgcolor=LightCyan|16
|-
|bgcolor=LightCyan|Method for reducing sebum on the hair and skin
|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]
|bgcolor=LightCyan|17
|}

=== Technology focus===
[[Image:Technologyfocus2.jpg|thumb|center|700px|Technology focus]]
=== Distribution of patents ===

==== By patent types ====
[[Image:Didtribution.jpg|thumb|center|700px|Distribution based on patent types ]]

==== By key ingredients ====
[[Image:key1.jpg|thumb|center|700px|Distribution of key ingredients]]

==== By target disease ====
[[Image:target.jpg|thumb|center|700px|Distribution based on target diseases]]

==== Key ingredients vs. Target disease ====
[[Image:key&target1.jpg|thumb|center|1000px|Key ingredients vs. Target disease]]

==== Target species ====
[[Image:Species.jpg|thumb|center|700px|Target species]]

==== Mode of administration ====
[[Image:Mode.jpg|thumb|center|700px|Mode of administration]]

==== Product type vs. Product form ====
[[Image:prod.jpg|thumb|center|700px|Product type vs. Product form]]

==== Patents by target diseases ====
{| border="1" cellpadding="16", style="#008080"
!width="800" bgcolor=DodgerBlue|'''Target disease/ disorder'''
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="150" bgcolor=DodgerBlue|'''Rec. no.'''
|-
|bgcolor=LightCyan|Alopecia areata, alopecia pityrodes or alopecia seborrheica, or androgenic alopecia (i.e. male pattern baldness)
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|1
|-
|bgcolor=LightCyan|Alopecia areata, male pattern baldness and female pattern baldness
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|2
|-
|bgcolor=LightCyan|Androgenic alopecia (i.e. male pattern baldness), prostatic hyperplasia or both.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|3
|-
|bgcolor=LightCyan|Inappropriate activation of the androgen receptor, acne, oily skin, alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|4
|-
|bgcolor=LightCyan|Prostatic hyperplasia, prostatic cancer, hirsutism, acne, male pattern baldness, seborrhea, and other diseases related to androgen hyperactivity
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|5
|-
|bgcolor=LightCyan|Alopecia, acne, oily skin, prostrate cancer, hirsutism, and benign prostate hyperplasia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|6
|-
|bgcolor=LightCyan|Androgen-associated hair loss and androgen-skin related disorders.
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|7
|-
|bgcolor=LightCyan|Androgenetic or androgenic alopecia or androgeno-genetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|8
|-
|bgcolor=LightCyan|Diseases caused by testosterone (male-pattern alopecia)
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP0279010&F=0 EP0279010]
|bgcolor=LightCyan|9
|-
|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
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|10
|-
|bgcolor=LightCyan|Male pattern alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|11
|-
|bgcolor=LightCyan|Alopecia, androgenic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|12
|-
|bgcolor=LightCyan|Hair loss
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|13
|-
|bgcolor=LightCyan|Male pattern alopecia
|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]
|bgcolor=LightCyan|14
|-
|bgcolor=LightCyan|Androgenetic, androgenic or androgenogenetic alopecia
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|15
|-
|bgcolor=LightCyan|Curing other scalp related problems
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|16
|}

==== [[List of patents]] ====
== Pathways and linkages ==

=== Pathways associated with hair matrix cell activation===

'''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.

* '''Wnt pathway:''' Maintains hair-inducing activity of the dermal papilla.
* '''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.
* '''STAT pathway'''
* '''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
* '''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.
* '''MAPK Pathway:''' Mitogen-activated protein kinase (MAPK) activation, increases keratinocyte turnover.
* '''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.

=== Pathways associated with Anti Androgen===
[[Image:Slide1.GIF|thumb|center|700 px|Alopecia pathways]]
==== Players of WNT inhibition Pathway ====
[[Image:wnt.jpg|thumb|right|200 px|Wnt inhibition]]
{| border="1" cellpadding="15", style="#008080"
!width="150" bgcolor=DodgerBlue|'''Patent no.'''
!width="200" bgcolor=DodgerBlue|'''Key compound'''
!width="200" bgcolor=DodgerBlue|'''Players of inhibition'''
|- style="height:10px"
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|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]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|GSK3
|-
|bgcolor=lightyellow|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
|bgcolor=lightyellow|Pyrazole compounds
|bgcolor=lightyellow|CDK,GSK3
|-
|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]
|bgcolor=LightCyan|Pyrimidine derivative
|bgcolor=LightCyan|GSK3
|-
|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]
|bgcolor=LightCyan|Heterocyclic compounds
|bgcolor=LightCyan|AKT3, GSK-3, ERK2
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Pyrrolo[3,2-d]pyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://appft1.uspto.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]
|bgcolor=LightCyan|Aza-oxindole derivatives
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=EP1477489&F=0 EP1477489]
|bgcolor=LightCyan|Pyrrolopyrimidine derivatives
|bgcolor=LightCyan|GSK3
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO0056710&F=0 WO0056710]
|bgcolor=LightCyan|3-(Anilinomethylene) oxindoles
|bgcolor=LightCyan|GSK3, AKT, PKC
|-
|bgcolor=LightCyan|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO03011287&F=0 WO2003011287]
|bgcolor=LightCyan|Pyrazolon derivatives
|bgcolor=LightCyan|GSK3, ß-catenin
|-
|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]
|bgcolor=LightCyan|Lithium chloride, Wnt3/4/ 7
|bgcolor=LightCyan|ß-catenin, GSK3, Wnt
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence
|bgcolor=LightCyan|a-catenin, ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|-
|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]
|bgcolor=LightCyan|Peptide sequence LXXLL
|bgcolor=LightCyan|ß-catenin
|}

==== Role of Pyrazole compounds in Wnt Pathway====
'''Pyrazole'''
* '''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.
* Pyrazoles are produced synthetically through the reaction of a,ß-unsaturated aldehydes with hydrazine and subsequent dehydrogenation
[[Image:pyrazole1.jpg|thumb|center|500px|Pyrazole (C3H4N2)]]
* Pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities.
* Structurally related compounds are pyrazoline and pyrazolidine.
[[Image:pyrazole2.jpg|thumb|center|500px|Structurally related compounds]]

==== GSK3 inhibition by pyrazole compounds ====
[[Image:bold3.jpg]]
{| border="1" cellpadding="2", style="#008080"
!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]
[[Image:US6989385.jpg]]
!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]
[[Image:US6664247.jpg]]
!width="350"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=WO2005012256&F=0 WO2005012256]
[[Image:WO2005012256.jpg]]
|-
|bgcolor=lightcyan|R1=T-Ring D, wherein
T is a valence bond and
Ring D = 5-6 membered aryl or heteroaryl ring;

R2 = hydrogen or C1-4 aliphatic and
R2'= hydrogen;

R3 = -R, -OR, or -N(R4)2, wherein
R = hydrogen, C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and
L is -O-, -S-, or -NH-; and
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

|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;

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;

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

R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

|bgcolor=lightcyan|X is a groupR1-A-NR4-or a 5-or 6-membered carbocyclic or heterocyclic ring;
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).
|}

==== Inhibition by amine derivatives ====

'''Patent Number''': US6989385
'''Applicant''': ''Vertex Pharmaceuticals Incorporated''
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol1.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6989385 patent]]

'''Patent Number''': US7008948
'''Applicant''': Vertex Pharmaceuticals Incorporated
'''Title''': Fused pyrimidyl pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure'''

[[Image:pyrazol2.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US7008948 patent]]

'''Patent Number''': US6977262
'''Assignee''': Mitsubishi Pharma Corporation
'''Title''': Dihydropyrazolopyridine compounds and pharmaceutical use thereof

'''Basic Structure''':

[[Image:pyrazol3.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6977262 patent]]

----
'''Patent Number''': US6664247
'''Assignee''': Vertex Pharmaceuticals Incorporated
'''Title''': Pyrazole compounds useful as protein kinase inhibitors'''

'''Basic Structure''':

[[Image:pyrazol4.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US6664247 patent]]

----
'''Patent Number''': US2004224944
'''Assignee''': VERTEX PHARMACEUTICALS INC
'''Title''': Pyrazole compounds useful as protein kinase inhibitors

'''Basic Structure''':

[[Image:pyrazol5.jpeg]]

[[Derivatives of pyrimidine-pyrazole amine disclosed in US2004224944 patent]]

[[Other derivates for alopecia]]

==== GSK-3 Inhibition Mechanism - Phosphorylation====
* ''GSK-3 inhibition targets treatment of chemotherapy-induced alopecia'' [http://www.biomedcentral.com/1471-2199/5/15 source]
* 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.

* 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.

* 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.

* 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.

'''[[More details on GSK-3]]'''

'''Key points'''

* 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]
* 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]
* 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]
* 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]

'''GK3 Inhibition:'''

* GSK3 is regulated by phosphorylation.
* 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]
* GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. [http://lib.bioinfo.pl/auth:Friedman,AB source]
* 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]
* A phosphorylation cascade starts from GSK3 itself and initiates it in beta-catenin. [http://www.genesdev.org/cgi/content/full/16/16/2073 source]
* Thus our goal is to stop the phosphorylation of the serine and threonine residue of GSK3.
* The figure below illustrates the phosphorylation mechanism of serine and threonine by ATP.

[[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]]]

* We can't stop conversion of ADP to ATP that relaseas Phosphorous group causing Phosphorylation.
* We can only block the oxygen atom on serine and threonine as a result which will in turn stop Phosphorylation.
* 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.

'''Serine - pyrazole reaction'''

[[image:serine-pyrazol.jpg|600 px|center|thumb|Serine and Pyrazole reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03134 source]]]

* 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.

* Thus, T-loop tyrosine might facilitate substrate phosphorylation but is not strictly required for kinase activity.

* 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.

* 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.

* A consequence of this is that primed substrates, in high enough concentrations, out-compete the pesudosubstrate and thus become phosphorylated.

* 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.

'''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]

# inactivation of GSK-3 through serine phosphorylation
# activation of GSK-3 through tyrosine phosphorylation
# inactivation of GSK-3 through tyrosine dephosphorylation
# Covalant modifications of substrates through priming phosphorylation
# inhibition or facilation of GSK-3 mediated substrate phosphorylation thriugh interation of GSK-3 with binding or scaffolding proteins
# targeting of GSK-3 to different subcellular localizations
# differential usage of isoforms or splice variants to alter subcellular localization or substrate specificity
# integration of parellel signals conveyed by a signal stimulus.

'''Key Finding'''
* '''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]

=== Pathway associated with anti-androgen ===

* Dihydrotestosterone
** Formed by peripheral conversion of testosterone by 5-alpha reductase
** Binds to androgen receptor on susceptible hair follicles
* 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

[[Image:5-alpha-reductase inhibition.jpeg|center|500 px]]

==== Structure-Activity Relationships(SARs) ====
[[Image:SAR_map.gif|center|600px]]

=== Pathway associated with Minoxidil (vasodilators) ===
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.
[[image:vasodiator-rev.jpg|800 px|center]]

== Alopecia IPMap ==
[http://www.dolcera.com/client/d8r3/hairloss_map.htm Dolcera IPMap for Alopecia]

== Patent activity in China ==
===Treatment approaches===
{|border="2" cellspacing="0" cellpadding="4" width="100%"
|align = "center"|'''Treatment approach'''
|align = "center"|'''Patent number'''
|align = "center"|'''Priority year'''
|align = "center"|'''Assignee/Inventor'''
|-
|rowspan = "7"|Vasodilators
|[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]
|2005
|叶明伟
|-
|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139]
|2005
|王亚杰
|-
|[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]
|2003
|谈汝标
|-
|[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]
|2002
|赵章光
|-
|[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]
|2001
|范希田
|-
|[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]
|1996
|殷国健
|-
|[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]
|1988
|天津市轻工业化学研究所
|-
|Hair matrix activator
|[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]
|2002
|朱静建
|-
|Anti-androgen <nowiki>+</nowiki> Vasodilator
|[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]
|1996
|梅晓春
|-
|}

=== Details of treatment approaches===

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="left"
|align = "center"|'''Patent number'''
|align = "center"|'''Patent title'''
|align = "center"|'''Treatment approach'''
|align = "center"|'''Composition nature'''
|align = "center"|'''Composition'''
|align = "center"|'''Composition action'''
|-
|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] YE MINGWEI (CN) 叶明伟 (2005)
|align = "justify"|Chinese herbal medicine decoction for treating blood stasis obstruction type alopecia and its prepn 治疗瘀血阻滞型脱发的中草药汤剂及制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Astragalus root, prepared rhizome of rehmannia, white peony root, angelica, peach kernel and sufflower
|align = "justify"|Promote blood circulation
|-
|align = "justify"|[http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=CN1772139&F=0 CN1772139 ]WANG YAJIE (CN) 王亚杰 2005
|align = "justify"|Alopecia areata treating medicine 一种治疗斑秃的药物
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Pinellia tuber, fleeceflower root, arborvitae seed, chickení s gizzard membrane, prepared rhizome of rehmannia, Poris cocos, Codonopsis pilosula, etc
|align = "justify"|Promote blood circulation
|-
|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] TAN RUBIAO (CN) 谈汝标 2003
|align = "justify"|Natural Chinese herb composition for treating alopecia and leucotrichia and its application 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
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginger, Cinnamomum cassia, myrrh, clove, mace nutmeg, Loranthus mulberry mistletoe, rhizoma dioscoreae, ligustrum japonicum, drynaria, fleece-flower root, and black sesame seeds
|align = "justify"|Enhances the hair growth and healthier hairs
|-
|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] 朱静建 2002
|Hair growing preparation containing compound of Chinese medicine and Western medicine 一种含中西药复方的育发剂
|align = "justify"|Hair matrix activator
|Mixture of Herbal extracts and western medicine
|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.
|align = "justify"|Better and faster hair growth
|-
|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] 赵章光2002
|align = "justify"|Hair follice activating liquid 毛囊激活液
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, twists the stock blue, the licorice, the Sophora flavescens and hot peppers
|align = "justify"|Activates the hair-follicle and enhances the hair growth.
|-
|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] 范希田 2001
|align = "justify"|Trichogen and its prepn 一种止脱生发药物及其制备方法
|align = "justify"|Vasodilators
|align = "justify"|Herbal extract
|align = "justify"|Ginseng, ganoderma lucidum, Chinese rhubarb, polygonum multiflorum, Chinese prickly ash, ginger, grass seed
|align = "justify"|Promote blood circulation and enhance hair growth
|-
|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] 殷国健 1996
|Washing free shampoo for nourishing and growing hair 免洗养发生发香波
|align = "justify"|Vasodilator
|Vitamin composition
|align = "justify"|Vitamin P (Bioflavonoids), Vitamin B15, Vitamin B2, nicotinic acid, bromo—geramineum
|align = "justify"|Stimulate hair growth
|-
|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] 梅晓春 1996
|Efficient low-side effect external use medicine for curing seborrheic baldness 一种治疗脂溢性脱发的高效低副作用外用药物
|align = "justify"|Anti-androgen <nowiki>+</nowiki> Vasodilator
|Mixture of Herbal extracts and organic compounds
|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
|align = "justify"|Inhibit the excess secretion of the sebaceous glands, increase the blood circulation on scalp and enhance the hair growth
|-
|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] 天津市轻工业化学研究所 1988
|Channel-stimulating and hair-growing hair shampoo 一种通络生发香波
|align = "justify"|Vasodilators
|Herbal extract <nowiki>+</nowiki> detergent
|align = "justify"|Herbal extracts, Penetration media, Detergents.
|align = "justify"|Increases the blood circulation under the scalp, reduces the hair los
|-
|} 

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== Conclusions ==
* Hair loss medication is a very active area of research and intellectual property development.
* One of the most promising areas of development is the area of Anti-androgens.
* The top companies are Merck, L’Oreal and Smithkline.

==Contact Dolcera==

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File:Comparison of methods.png

2012-01-06T19:54:35Z

Abhay.goel.1:

Transplant Diagnostics (HLA) Market Landscape

2012-01-06T19:49:49Z

Abhay.goel.1:

=Introduction=
Human leukocyte antigens (HLA) are molecules found on cell surfaces that regulate how the body recognizes and thus possibly rejects foreign tissue transplants. Molecular profiling of HLA sequences, or tissue typing is performed prior to organ or bone marrow transplantations. HLA testing is a key component in determining the compatibility between potential donors and recipients prior to transplantation to maximize the chances of graft survival and minimize serious immunologic transplant complications. The better the match of HLA types, the higher the likelihood of a successful transplant.
[[Image:HLA image.png|thumb|center|580px|Gene map of the human leukocyte antigen (HLA) region Source: Cambridge University Press]]
*The HLA molecules control the immune response through recognition of 'self' and 'non-self' and the main function of the HLA molecules is presenting the antigen to the T Lymphocytes and initiating the specific immune response
*HLA system constitutes an immunological barrier which must be avoided or otherwise overcome in clinical transplantation
*For Haemopoietic Stem Cell (HSC) transplants, the degree of HLA matching is critical in determining the probability of Graft-versus-Host disease (GvHD)
*In an attempt to minimise these alloresponses, the HLA class I and class II types of the donor and recipient are matched as closely as possible
 
The HLA is located on chromosome 6p21.31 and covers a region of about 3.6 Mbp depending on the haplotype. The classical HLA antigens encoded in each region are HLAA, -B, and -Cw in the class I region, and HLA-DR, -DQ and -DP in the class II region. All class I genes are between 3 and 6 kb, whereas class II genes are 4-11 kb long.

One of the main characteristics of the HLA is its extreme polymorphism. Among the expressed loci, the HLA has the greatest degree of polymorphism in the human genome.
[[Image:HLA alignment.png|thumb|center|611px|Source:European Bioinformatics Institute IMGT/HLA Database [http://hla.alleles.org/alleles/index.html hla.alleles.org]]]

=HLA Typing Methods=
Histocompatibility Testing can be performed using various assays.
*HLA typing by serology is the most common method in routine clinical setting
*Due to rapid advances in technology, molecular assays are now regarded as the 'Method of Choice'
[[Image:HLA Typing Methods1.png|center|732px]]

=Comparison of HLA Typing Techniques=
[[Image:Comparison of methods.png|center|806px]]

=Market Size=
*The market for HLA Testing Services was estimated to be $ 260 million in 2008
*The indicative annual market growth rate is 10% for this space.
[[Image:HLA market.png|thumb|center|800px|Source: NorDiag & Gen-Probe Investor Presentations]]

=Major Players=
[[Image:Major players1.png|center|623px]]

=One Lambda Profile=
==Company Overview==
One Lambda, Inc. is a medical diagnostic company based in Canoga Park, California. It was founded by Paul Terasaki and George Ayoub in April, 1984.

One Lambda develops and distributes histocompatibility reagents and semi-automated laboratory equipment for hospitals, research centers, and institutions involved in human organ transplantation and paternity testing. The reagents produced are primarily used to determine genetic compatibility between an organ donor and a recipient. Using the Terasaki tray design, Human Leukocyte Antigen (HLA) typing tests or histocompatibility tests are produced with these reagents.

The company markets several lines of HLA typing tests utilizing both serological and molecular technologies. One Lambda also manufactures a comprehensive line of laboratory instrumentation and computer software products that are used to simplify and automate testing procedures and final test evaluation.

One Lambda presently services more than 1,400 laboratories worldwide.
==Key Facts==
{|border="2" cellspacing="0" cellpadding="4" width="51%" align="center"
|align = "center" bgcolor = "#8DB4E3"|'''Website'''
|align = "center"|[http://www.onelambda.com www.onelambda.com]
|-
|align = "center" bgcolor = "#8DB4E3"|'''Administrative Department'''
|align = "center"|21200 Oxnard Street Woodland Hills, CA 91367, USA
|-
|align = "center" bgcolor = "#8DB4E3"|'''R&D and Manufacturing'''
|align = "center"|21001 Kittridge Street Canoga Park, CA 91303, USA Tel: <nowiki>+</nowiki>1 818 702 0042 Fax: <nowiki>+</nowiki>1 818 702 6904
|-
|align = "center" bgcolor = "#8DB4E3"|'''Regional Office'''
|align = "center"|Synergie - Le Millenaire 770, Rue Alfred Nobel 34000 Montpellier, France Tel: <nowiki>+</nowiki>33 4 99 13 60 20 Fax: <nowiki>+</nowiki>33 4 67 64 60 40
|-
|align = "center" bgcolor = "#8DB4E3"|'''Ownership'''
|align = "center"|Private
|-
|align = "center" bgcolor = "#8DB4E3"|'''Fiscal Year Ending'''
|align = "center"|31, December
|-
|align = "center" bgcolor = "#8DB4E3"|'''Employees (2011)'''
|align = "center"|340
|-
|align = "center" bgcolor = "#8DB4E3"|'''Revenues (2010)'''
|align = "center"|$ 87 M
|-
|}

==Financials==
*One Lambda has recorded revenues of $ 87 Million in 2010 according to Privco, a private company information database. According to Experian credit report it was $ 87.5 Million in 2010.
*CAGR of revenues for the period 2004 - 2010 is 7.62%
[[Image:Revenues.png|thumb|center|800px|Source: Privco Report & Experian Credit Report]]

==Human Resource Metrics==
*Total number of employees in One Lambda at present (2011) are about 340
*CAGR of employees for the period 2003 - 2011 is 9.88%
*CAGR of employees for the period 2004 - 2010 is 8.89%
[[Image:Employees.png|center|thumb|800px|Source:Privco Report]]
===Function-wise Data===
[[Image:Employees Composition.png|center|thumb|600px|Source:Linkedin]]
{|border="2" cellspacing="0" cellpadding="4" width="50%" align="center"
|align = "center" bgcolor = "#8DB4E3"|'''Function'''
|align = "center" bgcolor = "#8DB4E3"|'''Growth Rate (Nov 2010 - Oct 2011)'''
|-
|align = "center"|R&D
|align = "center"|29%
|-
|align = "center"|General & Administrative
|align = "center"|0%
|-
|align = "center"|Sales & Marketing
|align = "center"|<nowiki>-</nowiki>17%
|-
|align = "center"|Executive Leadership
|align = "center"|0%
|-
|}

==Funding Details==
{|border="2" cellspacing="0" cellpadding="4" width="60%" align="center"
|align="center" bgcolor = "#8DB4E3"|'''Date'''
|align="center" bgcolor = "#8DB4E3"|'''Investor'''
|align="center" bgcolor = "#8DB4E3"|'''Value ($)'''
|align="center" bgcolor = "#8DB4E3"|'''Funding Type'''
|-
|align="center"|2005
|align="center"|National Institute of Health
|align="center"|885,379
|align="center"|Grant
|-
|align="center"|2006
|align="center"|National Institute of Health
|align="center"|836,774
|align="center"|Grant
|-
|align="center"|2007
|align="center"|National Institute of Health
|align="center"|779,516
|align="center"|Grant
|-
|}
Source: Privco Report, News Articles

==Recent News and Developments==

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|align = "center" bgcolor = "#8DB4E3"|'''S.No.'''
|align = "center" bgcolor = "#8DB4E3" width="10%"|'''Date'''
|align = "center" bgcolor = "#8DB4E3"|'''Details'''
|-
|align = "center"| 1
|align = "center"|October 2011
|One Lambda, Inc. won a $1.5 million federal contract from the U.S. Naval Medical Logistics Command, Fort Detrick, Md., to develop the next generation high resolution human leukocyte antigen (HLA) typing reagents for the NMRC HLA Typing Program and Bone Marrow Research Directorate
|-
|align = "center"| 2
|align = "center"|April 2011
|One Lambda, Inc. and the National Kidney Registry announced the introduction of The Toolbox, a new innovative Web module. The Toolbox is designed to help medical professionals make intelligent decisions on donor selection based on antibody profiles of patients
|-
|align = "center"| 3
|align = "center"|December 2010
|Luminex Corporation and One Lambda, Inc. have agreed to a long-term renewal of their 10-year strategic partnership aimed at developing platforms and technologies for human leukocyte antigen (HLA) typing and antibody screening for the organ transplantation market
|-
|}
Source: News Articles

=Flash Representation=
{|align="center"
|<gflash>900 700 http://dolcera.com/upload/files/Transplant_Diagnostics_HLA_Market_Landscape.swf</gflash>
|-
|}

File:HLA market.png

2012-01-06T19:45:38Z

Abhay.goel.1:

File:Revenues.png

2012-01-06T19:44:16Z

Abhay.goel.1:

File:Major players1.png

2012-01-06T19:43:40Z

Abhay.goel.1:

File:HLA Typing Methods1.png

2012-01-06T19:40:22Z

Abhay.goel.1:

File:HLA image.png

2012-01-06T19:39:19Z

Abhay.goel.1:

File:HLA alignment.png

2012-01-06T19:38:37Z

Abhay.goel.1:

File:Employees Composition.png

2012-01-06T19:37:51Z

Abhay.goel.1:

File:Employees.png

2012-01-06T19:37:12Z

Abhay.goel.1:

File:798px-Comparison of methods.png

2012-01-06T19:36:15Z

Abhay.goel.1:

Transplant Diagnostics (HLA) Market Landscape

2012-01-06T19:30:16Z

Abhay.goel.1:

Main Page

2012-01-06T19:29:24Z

Abhay.goel.1: /* Business & Information Research Services */

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File:Knee2.pdf

2012-01-04T14:50:50Z

Abhay.goel.1:

File:Knee1.pdf

2012-01-04T14:34:13Z

Abhay.goel.1:

File:Steps Choice based conjoint.jpeg

2012-01-04T14:31:13Z

Abhay.goel.1:

File:Knee Replacement pie chart.jpeg

2012-01-04T14:30:27Z

Abhay.goel.1:

File:Causes for TKR2.png

2012-01-04T14:29:50Z

Abhay.goel.1:

File:Causes for TKR1.png

2012-01-04T14:29:12Z

Abhay.goel.1:

Application of Conjoint Analysis for Total Knee Replacement Surgery Alternatives

2012-01-04T14:26:14Z

Abhay.goel.1:

The objective of this report is to calculate the market share of the surgery options available for Total Knee Replacement. It uses choice based conjoint analysis to arrive at the market share of the surgeries. The scope of the report is that the primary research was conducted in US only. Hence the results of the report reflect the Total Knee Replacement Surgery market in US only. The attributes used for Conjoint Analysis were arrived at, using Secondary research, by reading literature on knee surgery. After finalizing the attributes for study, Orthopaedic Surgeons were given choices of various surgeries for Total Knee Replacement. Market share of these surgeries was then calculated using the responses of these surgeons.

 
==Introduction==
Total Knee Replacement surgery is done when the patient<nowiki>’</nowiki>s knee is severely damaged by arthritis or injury. It is considered as an option by surgeons when non-surgical treatments like medication, usage of supports to walk are no longer useful to the patient. It is a safe procedure to relieve pain, correct leg deformity, and help the patient resume normal activities.

===Causes of Knee Pain===
The most common cause of chronic knee pain and disability is arthritis. Although there are many types of arthritis, most knee pain is caused by just three types: osteoarthritis, rheumatoid arthritis, and post-traumatic arthritis.

* '''Osteoarthritis '''- This is an age-related "wear and tear" type of arthritis. It usually occurs in people 50 years of age and older, but may occur in younger people, too. The cartilage that cushions the bones of the knee softens and wears away. The bones then rub against one another, causing knee pain and stiffness.
* '''Rheumatoid arthritis''' - This is a disease in which the synovial membrane that surrounds the joint becomes inflamed and thickened. This chronic inflammation can damage the cartilage and eventually cause cartilage loss, pain, and stiffness. Rheumatoid arthritis is the most common form of a group of disorders termed "inflammatory arthritis."
* '''Post-traumatic arthritis''' - This can follow a serious knee injury. Fractures of the bones surrounding the knee or tears of the knee ligaments may damage the articular cartilage over time, causing knee pain and limiting knee function.

{|align = "center" width="80%"
|[[Image:Causes for TKR1.png|left|thumb|400px|[http://orthoinfo.aaos.org/topic.cfm?topic=A00389 Source: American Society of Orthopaedic Surgeons]]][[Image:Causes for TKR2.png|right|thumb|400px|[http://orthoinfo.aaos.org/topic.cfm?topic=A00389 Source: American Society of Orthopaedic Surgeons]]]
|-
|}

===Reasons to go for Total Knee Replacement===
There are several reasons for a surgeon to recommend Total Knee Replacement Surgery. Patients who would benefit from Total Knee Replacement Surgery would often have the following problems:

* Severe knee pain or stiffness that limits everyday activities, including walking, climbing stairs, and getting in and out of chairs. The patient might find it hard to walk more than a few blocks without significant pain and he might need to use a cane or walker
* Moderate or severe knee pain while resting, either day or night
* Chronic knee inflammation and swelling that does not improve with rest or medications
* Knee deformity — a bowing in or out of your knee
* Failure to substantially improve with other treatments such as anti-inflammatory medications, cortisone injections, lubricating injections, physical therapy, or other surgeries

===Candidates for Surgery===
* There are no absolute age or weight restrictions for total knee replacement surgery
* Recommendations for surgery are based on a patient<nowiki>’</nowiki>s pain and disability, not age
* Most patients who undergo total knee replacement are age 50 to 80, but orthopedic surgeons evaluate patients individually

===Types of Total Knee Replacement Surgeries===
====Traditional Total Knee Replacement Surgery====
The accuracy of alignment in conventional TKAs depends on the skill of the surgeon and the anatomy of the femur and tibia. Correct location of crucial alignment landmarks (centers of the femoral head and ankle joint) for determination of the mechanical axis can be difficult to achieve.

====Computer Assisted Navigation Surgery====
Computer-assisted TKA has been developed to improve alignment and implant positioning, to increase accuracy and reproducibility of the operative technique, to enable real-time kinematic analysis and soft-tissue balancing, and to reduce the risk of fat embolism and blood loss by not entering the intramedullary space.11,12 It is especially advantageous in obese patients or those with severe preoperative mal-alignment, in whom identification of anatomic landmarks and soft-tissue balancing can be particularly difficult.

====Custom Knee Replacement Surgery====
Custom Fit Total Knee Replacement Surgery is the newest technology in total knee replacement. The process starts several weeks before the surgery with an MRI scan. The MRI makes precise measurements of the knee. Computer software transforms that MRI image into a 3-D model of the arthritic knee and then virtually corrects any deformity to return the knee to its pre-arthritic state. A computerized 3-D image of the implant to be used at the time of surgery is then matched to the anatomically correct knee model. This helps determine the correct implant size and placement based on that patient<nowiki>’</nowiki>s normal knee alignment. Using all this information, a set of custom cutting guides is then created for use during the individual surgery. Each knee is unique and each set of MRI computer matched custom surgical guides is one of a kind.

===Need gap===
* Lack of Total Knee Replacement market share information available in secondary databases
* Need for surgeon<nowiki>’</nowiki>s preferences given the options available for Total Knee Replacement surgery

 

==Model Explanation==
===Conjoint Analysis===
Conjoint analysis is the optimal market research approach for measuring the value that consumers place on features of a product or service. This commonly used approach combines real-life scenarios and statistical techniques with the modelling of actual market decisions.

====Choice-based Conjoint Analysis====
The Choice-based conjoint analysis (CBC) (also known as discrete-choice conjoint analysis) is the most common form of conjoint analysis. Choice-based conjoint requires the respondent to choose their most preferred full-profile concept. This choice is made repeatedly from sets of 3–5 full profile concepts. This choice activity is thought to simulate an actual buy¬ing situation, thereby mimicking actual shopping behavior.
The importance and preference for the factor features and levels can be mathematically deduced from the trade-offs made when selecting one (or none) of the available choices.
The output of a Choice-based conjoint analysis provides excellent estimates of the importance of the features, especially in regards to pricing. Results can estimate the value of each level and the combinations that make-up optimal products. Simulators report the preference and value of a selected package and the expected choice share (surrogate for market share).

===Methodology Used===
====Step 1 – Determine key factors====
The first phase involved the identification of the salient factors or that surgeons use to recommend the appropriate surgery method for a patient in need of a primary total knee replacement.

The factors identified during this study, takes into account all the major variables affecting the surgeons decision while recommending the appropriate surgery method for a patient in need of a primary total knee replacement. These factors have been considered after referring to academic and industrial research.

The factors identified affecting the surgeons decision for a total knee replacement surgery are:
* Time to recover
* Out of pocket expenses
* Knee Society Function Score
* Knee Society Knee Score

====Step 2 – Determine categories within the factors====
After the factors were identified, an in-depth analysis was done using secondary research by our in-house subject experts, to determine the category levels under each factor. The scale used for the categories was ordinal scale, and 3 categories were identified for each of the 4 factors.

====Step 3 – Create optimized profiles====
The maximum number of profiles possible in this case was 3^4=81, calculated using the already identified 4 factors and 3 categories for each of the factors. But, Latin Square Design method was used to optimize the number of profiles that have to be evaluated, while ensuring enough data is available for statistical analysis, resulting in a carefully controlled set of "profiles" for the respondents to consider, and a total of 12 profiles were finally arrived at.

====Step 4 – Create optimized comparison cards====
The following points were taken into consideration while preparing the set of comparison cards for the respondents (surgeons) to consider:
* All the 12 profiles were equally distributed across the set of comparison cards
* A set of 20 optimized comparison cards were build
* Each comparison card had 3 profiles and the surgeons chose one profile based on the factors included in the profiles
* The optimization of comparison cards ensured that each profiles is included 5 times
[[Image:Steps_Choice_based_conjoint.jpeg|centre|thumb|587*347px|Choice-based Conjoint Analysis - Steps]]

====Step 5 – Conduct primary research====
The data for the study was collected using a mail questionnaire that contained the set of 20 comparison cards developed as previously described. The questionnaire was mailed to 10 orthopedic surgeons specializing in knee replacement surgeries. A mail survey was required because of the need to present the rather complex choice options to the surgeons so that they could make meaningful selections.
The inclusion criteria for the respondents were:
* The surgeon specializes in orthopedics and has suitable knowledge in the field of total knee replacement surgery
* The patients in consideration experienced knee pain over the past month on most days and requires a primary total knee replacement
* The surgeon has all the possible treatment options (profiles) available to him and resource is not a problem

====Step 6 – Generate utilities====
The 10 individual responses for the 20 comparison cards were then used to generate utilities for each of the categories associated with all the factors. The importance level for each of the 4 factors was also derived at using the analysis.
Conjoint analysis allows us to evaluate the trade-offs that consumers make between product features. This is accomplished by evaluating and comparing sets of comparison cards and analyzing the choices made by the surgeons. Based on the choices made by respondent, it is possible to estimate the relative value or utility that the respondent must have associated with each level of each product factor to have made these choices.

====Step 7 – Conduct segmentation====
The available alternatives for total knee replacement surgery are:
* Traditional Total Knee Replacement Surgery
* Custom Knee Replacement Surgery
* Computer Assisted Navigation Surgery
The above 3 market profiles were then assigned the categories for the previously identified factors using secondary research by our in-house subject experts.

====Step 8 – Build model and calibrate to market====
The estimated utilities were then used to predict the percentages of consumers that would choose each profile from the comparison cards including any combination of all the unique profiles that can be constructed with the factors and factor levels employed for this study.
The stimulation model estimates market share for each product by estimating the value that each surgeon associates with each profile included in the particular simulation. This enables us to predict market shares of various alternative surgeries.

===Scope of the Study===
The scope of the study is defined as following:
* The study is limited to United States of America
* The non-surgical alternatives to total knee replacement have not been considered in our study

===Assumptions===
The following assumptions have been made while carrying the study:
* The patients in consideration experienced knee pain over the past month on most days and requires a primary total knee replacement
* The surgeon has all the possible treatment options (profiles) available to him and resource is not a problem
* All treatments have equal access to the market
* All patients have equal access to the surgeons

===Variables used in the Study===
'''i) Out of the Pocket Expense''': Out of pocket expense for the patient represents the share of the expenses that the insured party must pay directly to the health care provider, without a third-party (insurer, or state). In case of the 3 total knee replacement surgery alternatives considered in this study, only Traditional Total Knee Replacement Surgery is covered under all the major insurance in US. Out of the pocket expense was rated

'''ii) Knee Society Function Score''': Knee Society Function Score allocates points for walking distance and stair-climbing ability and makes deductions for the use of a walking aid; 100 represents unlimited walking distance and normal stair-climbing without the use of an aid.

'''iii) Knee Society Knee Score''': Knee Society Knee Score is given out of 100 points

Fifty of the 100 points in the knee score reflect pain assessment (a score of 50 points represents no pain). The Knee Society pain component requires the evaluator to rate the patient<nowiki>’</nowiki>s knee pain with one question that combines the frequency and severity of pain and has seven ordinal responses. The other 50 points reflect the clinical assessment of range of motion, stability, alignment, and muscle power; 50 points represents at least 0Â° to 125Â° of knee flexion with no active lag, no instability, and normal alignment.

'''iv) Time to recover''': Time to recover represents the total number days taken by the patient post total knee replacement surgery, for the knee to function normally.

'''Note:''' All the variables used in the model are measured on a relative scale. The absolute values of each of these variables have not been considered.

==Results Analysis==
===Utilities & Importance===
Based on the responses obtained from panel of surgeons, conjoint analysis was performed to find following attribute importance table.

{|border="2" cellspacing="0" cellpadding="4" width="51%" align="center"
|bgcolor = "#4F81BD"|'''Surgery Attributes'''
|bgcolor = "#4F81BD"|'''Relative Importance'''
|-
|bgcolor = "#DCE6F1"|Time to recover
|align = "right" bgcolor = "#DCE6F1"|27.362
|-
|Out of pocket expenses
|align = "right"|38.212
|-
|bgcolor = "#DCE6F1"|Knee Society Function Score
|align = "right" bgcolor = "#DCE6F1"|24.610
|-
|Knee Society Knee Score
|align = "right"|9.815
|-
|} 

As seen clearly from the table '''out of pocket expenses''' is the most important factor to make decision about surgery. Time to recover and Knee Society Function Score are the other important factors. Knee society Knee Score is seen as insignificant parameter.

===Individual utilities in attribute===
Following table lists average utilities observed for each of the attribute.

{|border="2" cellspacing="0" cellpadding="4" width="71%" align="center"
|align = "center" bgcolor = "#4F81BD"|'''Source'''
|align = "center" bgcolor = "#4F81BD"|'''Utilities'''
|align = "center" bgcolor = "#4F81BD"|'''Standard deviation'''
|-
|bgcolor = "#DCE6F1"|Time to recover-Fast
|align = "right" bgcolor = "#DCE6F1"|0.044
|align = "right" bgcolor = "#DCE6F1"|0.115
|-
|Time to recover-Moderate
|align = "right"|<nowiki>-</nowiki>0.008
|align = "right"|0.122
|-
|bgcolor = "#DCE6F1"|Time to recover-Slow
|align = "right" bgcolor = "#DCE6F1"|<nowiki>-</nowiki>0.036
|align = "right" bgcolor = "#DCE6F1"|0.137
|-
|Out of pocket expenses-High
|align = "right"|<nowiki>-</nowiki>0.160
|align = "right"|0.131
|-
|bgcolor = "#DCE6F1"|Out of pocket expenses-Very High
|align = "right" bgcolor = "#DCE6F1"|<nowiki>-</nowiki>0.770
|align = "right" bgcolor = "#DCE6F1"|0.122
|-
|Out of pocket expenses-Very Low
|align = "right"|0.930
|align = "right"|0.131
|-
|bgcolor = "#DCE6F1"|Knee Society Function Score-High
|align = "right" bgcolor = "#DCE6F1"|<nowiki>-</nowiki>0.016
|align = "right" bgcolor = "#DCE6F1"|0.122
|-
|Knee Society Function Score-Low
|align = "right"|<nowiki>-</nowiki>0.075
|align = "right"|0.112
|-
|bgcolor = "#DCE6F1"|Knee Society Function Score-Moderate
|align = "right" bgcolor = "#DCE6F1"|0.091
|align = "right" bgcolor = "#DCE6F1"|0.131
|-
|Knee Society Knee Score-High
|align = "right"|0.009
|align = "right"|0.126
|-
|bgcolor = "#DCE6F1"|Knee Society Knee Score-Low
|align = "right" bgcolor = "#DCE6F1"|<nowiki>-</nowiki>0.037
|align = "right" bgcolor = "#DCE6F1"|0.118
|-
|Knee Society Knee Score-Moderate
|align = "right"|0.029
|align = "right"|0.123
|-
|} 

Utility values for all levels of attribute add up to 0. Consequently utility values indicate relative utilities of individual options in an attribute

===Market Share Simulation===
Market share simulation is performed to see the relative performance of products given the choices made by survey participants. Following table lists the market share of each of the surgical method discussed in section

{|border="2" cellspacing="0" cellpadding="4" width="93%" align="center"
|bgcolor = "#4F81BD"|'''Product ID'''
|bgcolor = "#4F81BD"|'''Utilities'''
|bgcolor = "#4F81BD"|'''Market share (in %)'''
|-
|bgcolor = "#DCE6F1"|Computer Assisted Navigation Surgery
|align = "right" bgcolor = "#DCE6F1"|0.26
|align = "right" bgcolor = "#DCE6F1"|26.32
|-
|Custom Knee Replacement Surgery
|align = "right"|0.13
|align = "right"|13.27
|-
|bgcolor = "#DCE6F1"|Traditional Total Knee Replacement Surgery
|align = "right" bgcolor = "#DCE6F1"|0.60
|align = "right" bgcolor = "#DCE6F1"|60.41
|-
|} 

Traditional Total Knee Replacement Surgery account for 60% of the market share followed by Computer Assisted Navigation Surgery(26.32%) and Custom Knee Replacement Surgery(13.27%).

Most Important criteria is found to be out of the pocket expenses. Consequently Traditional Total Knee Replacement Surgery dominates the market with huge market share.

===Implications===
Out of pocket expense for patient is a dominating factor for surgeon<nowiki>’</nowiki>s choice of surgery. Even though other two methods namely Computer Assisted Navigation Surgery and Custom Knee Replacement Surgery are better than traditional methods in all factors except for cost, their market share is still very low compared to Traditional Total Knee Replacement Surgery.

In US, both these methods are generally not covered by insurance so Out of pocket expense is extremely high compared to traditional method. In order to promote use of better methods, these methods need to come under insurance cover. Probably even then out of pocket expense would be higher for these methods but still comparable to traditional method. Utility values will be higher for these advanced methods due to benefits in other areas apart from cost.

==Bibliography==
==Appendix==
===Factors Used===
Following factors were used to judge surgeon<nowiki>’</nowiki>s preferences.

{|border="2" cellspacing="0" cellpadding="4" width="44%" align="center"
|bgcolor = "#4F81BD"|'''Factors'''
|bgcolor = "#4F81BD"|'''Categories'''
|-
|bgcolor = "#DCE6F1"|Time to recover
|align = "right" bgcolor = "#DCE6F1"|3
|-
|Out of pocket expenses
|align = "right"|3
|-
|bgcolor = "#DCE6F1"|Knee Society Function Score
|align = "right" bgcolor = "#DCE6F1"|3
|-
|Knee Society Knee Score
|align = "right"|3
|-
|} 

Each factor is having following categories as shown in table.

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|bgcolor = "#4F81BD"|'''Categories'''
|bgcolor = "#4F81BD"|'''Time to recover'''
|bgcolor = "#4F81BD"|'''Out of pocket expenses'''
|bgcolor = "#4F81BD"|'''Knee Society Function Score'''
|bgcolor = "#4F81BD"|'''Knee Society Knee Score'''
|-
|bgcolor = "#DCE6F1"|'''Category 1'''
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|Moderate
|-
|'''Category 2'''
|Fast
|Very High
|High
|High
|-
|bgcolor = "#DCE6F1"|'''Category 3'''
|bgcolor = "#DCE6F1"|Slow
|bgcolor = "#DCE6F1"|Very Low
|bgcolor = "#DCE6F1"|Low
|bgcolor = "#DCE6F1"|Low
|-
|} 

===Profiles Optimization===
Following random profiles were made from factors. Profiles were made such that there will be some trade-off decision in every comparison.

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|bgcolor = "#4F81BD"|'''Observation'''
|bgcolor = "#4F81BD"|'''Time to recover'''
|bgcolor = "#4F81BD"|'''Out of pocket expenses'''
|bgcolor = "#4F81BD"|'''Knee Society Function Score'''
|bgcolor = "#4F81BD"|'''Knee Society Knee Score'''
|-
|bgcolor = "#DCE6F1"|Profile1
|bgcolor = "#DCE6F1"|Slow
|bgcolor = "#DCE6F1"|Very High
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|Low
|-
|Profile2
|Moderate
|Very High
|High
|Moderate
|-
|bgcolor = "#DCE6F1"|Profile3
|bgcolor = "#DCE6F1"|Fast
|bgcolor = "#DCE6F1"|Very High
|bgcolor = "#DCE6F1"|Low
|bgcolor = "#DCE6F1"|Moderate
|-
|Profile4
|Slow
|Very Low
|High
|High
|-
|bgcolor = "#DCE6F1"|Profile5
|bgcolor = "#DCE6F1"|Fast
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|Moderate
|-
|Profile6
|Fast
|High
|Moderate
|High
|-
|bgcolor = "#DCE6F1"|Profile7
|bgcolor = "#DCE6F1"|Slow
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|Low
|bgcolor = "#DCE6F1"|Moderate
|-
|Profile8
|Fast
|Very Low
|Low
|Low
|-
|bgcolor = "#DCE6F1"|Profile9
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|Very Low
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|Moderate
|-
|Profile10
|Moderate
|High
|Low
|Low
|-
|bgcolor = "#DCE6F1"|Profile11
|bgcolor = "#DCE6F1"|Fast
|bgcolor = "#DCE6F1"|Very High
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|Low
|-
|Profile12
|Moderate
|Very High
|Low
|High
|-
|} 

===Comparison Cards===
Every individual surgeon was asked to make 20 comparisons. In each comparison three profiles were compared to choose best combination. Following table lists the profile numbers used in every comparison.

{|border="2" cellspacing="0" cellpadding="4" width="78%" align="center"
|bgcolor = "#4F81BD"|'''Comparisons'''
|bgcolor = "#4F81BD"|'''Choice 1'''
|bgcolor = "#4F81BD"|'''Choice 2'''
|bgcolor = "#4F81BD"|'''Choice 3'''
|-
|bgcolor = "#DCE6F1"|Comparison 1
|align = "right" bgcolor = "#DCE6F1"|2
|align = "right" bgcolor = "#DCE6F1"|1
|align = "right" bgcolor = "#DCE6F1"|3
|-
|Comparison 2
|align = "right"|5
|align = "right"|4
|align = "right"|6
|-
|bgcolor = "#DCE6F1"|Comparison 3
|align = "right" bgcolor = "#DCE6F1"|8
|align = "right" bgcolor = "#DCE6F1"|7
|align = "right" bgcolor = "#DCE6F1"|9
|-
|Comparison 4
|align = "right"|11
|align = "right"|10
|align = "right"|12
|-
|bgcolor = "#DCE6F1"|Comparison 5
|align = "right" bgcolor = "#DCE6F1"|1
|align = "right" bgcolor = "#DCE6F1"|7
|align = "right" bgcolor = "#DCE6F1"|5
|-
|Comparison 6
|align = "right"|4
|align = "right"|8
|align = "right"|2
|-
|bgcolor = "#DCE6F1"|Comparison 7
|align = "right" bgcolor = "#DCE6F1"|3
|align = "right" bgcolor = "#DCE6F1"|6
|align = "right" bgcolor = "#DCE6F1"|10
|-
|Comparison 8
|align = "right"|11
|align = "right"|12
|align = "right"|9
|-
|bgcolor = "#DCE6F1"|Comparison 9
|align = "right" bgcolor = "#DCE6F1"|5
|align = "right" bgcolor = "#DCE6F1"|8
|align = "right" bgcolor = "#DCE6F1"|3
|-
|Comparison 10
|align = "right"|7
|align = "right"|4
|align = "right"|10
|-
|bgcolor = "#DCE6F1"|Comparison 11
|align = "right" bgcolor = "#DCE6F1"|6
|align = "right" bgcolor = "#DCE6F1"|9
|align = "right" bgcolor = "#DCE6F1"|1
|-
|Comparison 12
|align = "right"|12
|align = "right"|11
|align = "right"|2
|-
|bgcolor = "#DCE6F1"|Comparison 13
|align = "right" bgcolor = "#DCE6F1"|6
|align = "right" bgcolor = "#DCE6F1"|2
|align = "right" bgcolor = "#DCE6F1"|7
|-
|Comparison 14
|align = "right"|9
|align = "right"|3
|align = "right"|4
|-
|bgcolor = "#DCE6F1"|Comparison 15
|align = "right" bgcolor = "#DCE6F1"|8
|align = "right" bgcolor = "#DCE6F1"|12
|align = "right" bgcolor = "#DCE6F1"|1
|-
|Comparison 16
|align = "right"|10
|align = "right"|5
|align = "right"|11
|-
|bgcolor = "#DCE6F1"|Comparison 17
|align = "right" bgcolor = "#DCE6F1"|9
|align = "right" bgcolor = "#DCE6F1"|2
|align = "right" bgcolor = "#DCE6F1"|5
|-
|Comparison 18
|align = "right"|7
|align = "right"|3
|align = "right"|11
|-
|bgcolor = "#DCE6F1"|Comparison 19
|align = "right" bgcolor = "#DCE6F1"|10
|align = "right" bgcolor = "#DCE6F1"|6
|align = "right" bgcolor = "#DCE6F1"|8
|-
|Comparison 20
|align = "right"|4
|align = "right"|1
|align = "right"|12
|-
|} 

===Simulated Market===
Three alternatives were rated on all the factors. Following table displays our assessment of various surgery options over given factors.

{|border="2" cellspacing="0" cellpadding="4" width="100%" align="center"
|bgcolor = "#4F81BD"|'''Total Knee Replacement Surgery - Alternatives'''
|bgcolor = "#4F81BD"|'''Time to recover'''
|bgcolor = "#4F81BD"|'''Out of pocket expenses for the patient'''
|bgcolor = "#4F81BD"|'''Knee Society Function Score'''
|bgcolor = "#4F81BD"|'''Knee Society Knee Score'''
|-
|bgcolor = "#DCE6F1"|Computer Assisted Navigation Surgery
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|High
|bgcolor = "#DCE6F1"|Moderate
|bgcolor = "#DCE6F1"|Moderate
|-
|Custom Knee Replacement Surgery
|Fast
|Very High
|High
|High
|-
|bgcolor = "#DCE6F1"|Traditional Total Knee Replacement Surgery
|bgcolor = "#DCE6F1"|Slow
|bgcolor = "#DCE6F1"|Very Low
|bgcolor = "#DCE6F1"|Low
|bgcolor = "#DCE6F1"|Low
|-
|} 

===Market Share Analysis===
Following table lists the market share analysis obtained after running simulation

{|border="2" cellspacing="0" cellpadding="4" width="77%" align="center"
|bgcolor = "#4F81BD"|'''Product ID'''
|bgcolor = "#4F81BD"|'''Utilities'''
|bgcolor = "#4F81BD"|'''Market share (in %)'''
|-
|bgcolor = "#DCE6F1"|Computer Assisted Navigation Surgery
|align = "right" bgcolor = "#DCE6F1"|0.26
|align = "right" bgcolor = "#DCE6F1"|26.32
|-
|Custom Knee Replacement Surgery
|align = "right"|0.13
|align = "right"|13.27
|-
|bgcolor = "#DCE6F1"|Traditional Total Knee Replacement Surgery
|align = "right" bgcolor = "#DCE6F1"|0.60
|align = "right" bgcolor = "#DCE6F1"|60.41
|-
|} 
[[Image:Knee_Replacement_pie_chart.jpeg|centre|thumb|643px|Pie chart indicating predicted market share of individual methods]]

===Data used for the model===
Attributes for the analysis were decided by extensive secondary research on three surgery methods.

i) [[Media:knee1.pdf|Comparison of functional and radiological outcomes after computer-assisted versus conventional total knee arthroplasty: amatched-control retrospective study]]

ii) [[Media:knee2.pdf|Results with initial experience with custom fit positioning total knee anthroplasty in a series of 48 patients]]

Main Page

2012-01-04T14:25:24Z

Abhay.goel.1: /* Business & Information Research Services */

__NOTOC__

[[#Intellectual Property (IP) Services|Intellectual Property(IP) Services]] 
[[#Business & Information Research Services|Business and Information Research Services]] 
[[#Dolcera Technology Platforms|Dolcera Technology Platform]]

== Intellectual Property (IP) Services ==
{| style="border:1px solid #AAA; background:#E9E9E9;width:100%" align="center"
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! style="background:lightgrey;width:50%" valign = "top" align = "left"|
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|-
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STN Search Reports
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Dashboard
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*[[Holographic Image Display]]
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===Clinical Trial Database===
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== Business & Information Research Services ==
{| style="border:1px solid #AAA; background:#E9E9E9;width:100%" align="center"
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! style="background:lightgrey" | Samir Raiyani
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File:Asset Valuation.jpg

2011-11-29T22:21:35Z

Abhay.goel.1:

File:Dashboard Revenuewise.jpg

2011-11-29T22:20:58Z

Abhay.goel.1:

File:Dashboard - Overall.png

2011-11-29T22:16:35Z

Abhay.goel.1:

Asset Valuation Dashboard

2011-11-29T22:04:55Z

Abhay.goel.1:

== Sample Dashboard ==
* The sample dashboard contains various options to view the data - Overall data, By Revenue, By Cost, By Productivity Index and by Risk Distribution
* The sample dashboard contains Overall information which is a heat map. The Business Unit has to be selected in order to get the heat map for Development Phase vs Diseases (in that Business Unit)
* The Heat in the heat map represents the number of assets (drugs) in that Development stage for that disease
* When the user clicks on one of them, they get charts depicting the expected development cost and the productivity index for all the drugs in that development phase for that disease

[[Image:Dashboard - Overall.png|center|thumb|1177px]]
 

* The next dashboard depicts the heat map with the heat being Expected Revenue from that Development phase and Disease
* When the user clicks on any of them, they get the break up of expected revenue, drugwise and its geographical split
The following dashboard depicts the Revenue-wise heatmap
[[Image:Dashboard Revenuewise.jpg|center|thumb|1178px]]
 

* Heat maps can be made similarly for other labels as well

* The next dashboard depicts the valuation indicators for each asset
* To arrive at each asset, the user has to select the respective Business Unit, Development Phase and Disease
The following dashboard depicts the valuation for each asset

[[Image:Asset Valuation.jpg|center|thumb|1180px]]

Main Page

2011-11-29T22:04:22Z

Abhay.goel.1: /* Business & Information Research Services */

__NOTOC__

[[#Intellectual Property (IP) Services|Intellectual Property(IP) Services]] 
[[#Business & Information Research Services|Business and Information Research Services]] 
[[#Dolcera Technology Platforms|Dolcera Technology Platform]]

== Intellectual Property (IP) Services ==
{| style="border:1px solid #AAA; background:#E9E9E9;width:100%" align="center"
|-
! style="background:lightgrey;width:50%" valign = "top" align = "left"|
===Life Sciences and Chemistry===
! style="background:lightgrey; width:50%" valign = "top" align = "left"|

===Technology===
|-
| valign = "top" |
 Landscape reports 
* [[Alopecia - Hair Loss]] | ([http://www.youtube.com/watch?v=jAIoyKuKQ6o Video])
* [[Inflammation and cardiovascular drugs]] | ([http://www.youtube.com/watch?v=FVUFcz2dpIM Video])
* [[RNAi Database sample wiki]] | ([http://www.youtube.com/watch?v=nsZLUSPn3cg Video])
* [[Choline Bitartarate]]
* [[Non-wovens]]
* [[Pressure sensitive adhesives]] | ([http://www.youtube.com/watch?v=plP3TzjYsiQ Video])
* [[Ureteral Stent]]
* [[Smart Drug Delivery Systems]] | ([http://www.youtube.com/watch?v=vARe9eBFsq4 Video])
* [[Silicone Hydrogel contact lens]]
* [[SC Johnson]]
* [[Pinene: An off flavor in mango juice]] | ([http://www.youtube.com/watch?v=P4fI1rjPjSg Video])
* [[Bio-PET]]
* [[Interferon For Treatment of Melanoma]]
* [[Antibody against TNF]]
* [[Pressure sensitive adhesives in packaging]]
* [[Template - Production Of Therapeutic Glycoproteins]]
* [[Market Research Tools Landscape]]
| valign = "top" |

 Landscape reports 
* [[Hybrid Electric Vehicle Battery System]]
* [[Supply Chain RFID Applications]]
* [[Insurance sector]]
* [[CDMA Basics]]
* [[Quality of Service on CDMA platforms]]
* [[OLED - Organic Light Emitting Diode]]
* [[Carbon Nanotubes (CNT)]] | ([http://www.youtube.com/watch?v=HvZqBy8XvIE Video])
* [[Metallic and Ceramic construction materials]]
* [[Transactional memory]]
* [[Invalidation Search on a patent in the semiconductors space|Invalidation Search]]
* [[Golf Club Head Landscape]]
* [[Wind Energy]]
|-
| valign = "top" |

STN Search Reports
* [[Markush Search Report]]

Dashboard
* [http://client.dolcera.com/dashboard/dashboard.html?workfilegroup_id=10 Alopecia areata dashboard - live]
** ([[Alopecia Areata Dashboard Screenshots|Screenshots only]])
* [http://www.dolcera.com/ipmapdemo/stent_model.swf Stent dashboard]
* [http://www.dolcera.com/website/demos/dna/main.html Sequence dashboard]
* [[Legal Updates Demo|Legal updates dashboard]]
* [http://client.dolcera.com/dashboard/dashboard.html?workfile_id=587 RNAi Dashboard]
| valign = "top" |

Dashboard
* [http://client.dolcera.com/dashboard/dashboard.html?workfilegroup_id=27 Automotive dashboard - live]
** [[Automotive Dashboard Screenshots|Screenshots only]]
* [http://client.dolcera.com/dashboard/dashboard.html?workfile_id=54 WiMAX dashboard - live]
** [[WiMAX Dashboard Screenshots|Screenshots only]]
* [http://www.dolcera.com/ipmapdemo/rfid_model.swf RFID dashboard]

IP Valuation

*[[Holographic Image Display]]
|-
| valign = "top" |

Prior Art / Invalidation / FTO Search
* [http://dolcera.com/client/d8r3/hairloss_map.htm Alopecia/Hair loss IPMap]
* [[Markush Structure Search Sample]]
 Study: In re Bilski Impact
* [[In re Bilski Impact assessed from US PAIR Information]]
| valign = "top" |

Prior Art / Invalidation / FTO Search
* [[Prior Art Search Process]]
* [http://www.dolcera.com/ipmapdemo/satellite_antenna/ipmap.html Satellite Antenna IPMap]
* [http://www.dolcera.com/ipmapdemo/rfid/ipmap.html RFID IPMap]
* [http://www.dolcera.com/ipmapdemo/multimodal_apps/ipmap.html Multimodal Applications IPMap]
* [http://www.dolcera.com/ipmapdemo/Invalidation_US4825448.htm Invalidation Claim Chart Sample]
|-
|}

===Clinical Trial Database===
*[[Clinical Trial Database]]

== Business & Information Research Services ==
{| style="border:1px solid #AAA; background:#E9E9E9;width:100%" align="center"
|-
! style="background:lightgrey" valign=top width=50% align = "left"|
===Life Sciences and Chemistry===
! style="background:lightgrey" valign=top width=50% align = "left"|
===Technology===
|-
| valign=top |
* [[Cancer Vaccines - Clinical Trial Analysis]]
* [[Veterinary Vaccines Market Report]]
* [[Olympus Corporation- Company Profile]]
* [[Rx to OTC Switch-Market Analysis]]
* [[Ureteral Stent - Market Analysis]], Company Profile:[[Boston Scientific - Company Profile |Boston Scientific ]]
* [[Cardiac Pacemakers]]
* [[Botox - from Medical Procedure to Household Word]]
* [[Diabetes products and services]]
* [[Drug Metabolism]]
* [[Toxicology]]
* [[Osteoporosis]]
* [[Oral Diabetes Drugs]]
* [[Ureteral Stent]]
* [[Premium Coffee Consumers Market Segmentation|Premium Coffee - Market Positioning]]
* [[Dolcera's Poster on Industrial Biotechnology|Industrial biotechnology]]
* [[OTC products for acne treatment]]
* [[Digestive Remedies Market in India and China]]
* [[OTC vs. Prescription Drugs]]
* [[Vaccines Market in Western Countries]], Company Profile:[http://dolcera.com/wiki/index.php?title=GlaxoSmithKline_profile GlaxoSmithKline]
* [[Gastrointestinal Endoscopy -Landscape Report]]
* [[China ICU Ventilator Market]]
* [[Asset Valuation Dashboard]]

| valign=top |
* [[4G wireless technology developments]]
* [[LTE]]
* [[Femtocells]]
* [[HDTV in the US]]
* [http://www.dolcera.com/ipmapdemo/innovation_explorer/innovation_explorer.html Household robotics Innovation Explorer]
* [[Web video]]
* [[OLED Mobile Phones Market Research and Analysis Report]] | ([http://www.viddler.com/explore/dolcera/videos/6/ Video])
* [[Samsung Company Profile]]
* [[NFC Ecosystem]]
* [[Virtualization]]
* [[Cloud Computing]]
* [[Estimation of liquid carrying vehicles in USA]]
* [[A market study on Hybrid vehicles and the concept of V2G]]
* [[China ICU Ventilator Market]]
* [[Patent Valuation]]
* [[Automatic Faucets]]
|-
! style="background:lightgrey" valign=top width=50% align = "left"|

===Finance===
! style="background:lightgrey" valign=top width=50% align = "left"|
===Others and CPG===
|-
| valign=top |
* [[Innovative personal finance products]]
* [[Life Insurance Industry in US]]
| valign=top |
*[[Deodorants Market Analysis: Acquisition of Sanex by Colgate]]
*[[Partner in sales planning]]

|}

== Dolcera Technology Platforms ==
{| style="border:1px solid #AAA; background:#E9E9E9;width:100%" align="center"
|-
| align = "top" |

==== Dashboard 1.1 ====
* [http://www.dolcera.com/auth/dashboarddemo/dashboard.php?workfilegroup_id=154 Demo Dashboard (Alopecia)]
** [[Access details]]
* [[Sample list of patent numbers]]
* [http://www.dolcera.com/auth/index.php Dashboard login page]

==== [[Workflow for creating a Dashboard]] ====

==== IP and Products dashboard ====
* [http://client.dolcera.com/dashboard/dashboard.html?workfilegroup_id=10 Alopecia areata dashboard]
* [http://www.dolcera.com/ipmapdemo/stent_model.swf Stent dashboard]
* [[Legal Updates Demo|Legal updates dashboard]]
* [http://client.dolcera.com/dashboard/dashboard.html?workfile_id=54 4G wireless product and patent dashboard]

==== Patent-pathway mapping ====
* [[Inflammation and cardiovascular drugs#Interactive signaling pathways and patents|Patent-pathway mapping]]
==== Sequence dashboard ====
* [http://www.dolcera.com/website/demos/dna/main.html Sequence dashboard]

==== Design analysis ====
* [http://www.dolcera.com/website/demos/dental/main.html Dental Implant Design Analysis]

==== Innovation explorer ====
* [http://www.dolcera.com/ipmapdemo/innovation_explorer/innovation_explorer.html Household robotics innovation explorer]
==== KPort ====
* [http://dolcera.com/website/demos/kport/main.html Collaboration Portal]

|-
|}

== Buy Dolcera Reports ==
* [[Landscape report for HEMT]]
* [[Nanoemulsions in Foods]]
* [[Variable Valve Timing - Sample]]

Dolcera Offerings summary 
* [[Dolcera Offerings|Dolcera offerings summary]]

[[Technology Support]] 

Like any of these sample reports?
 '''These are sample reports with brief analysis''' 
'''Dolcera can provide a comprehensive report customized to your needs'''
{|border="2" cellspacing="0" cellpadding="4" align="center" "
|style="background:lightgrey" align = "center" colspan = "3"|'''[mailto:info@dolcera.com Buy the customized report from Dolcera]'''
|-
| align = "center"| [http://www.dolcera.com/website_prod/services/ip-patent-analytics-services Patent Analytics Services]
|align = "center"| [http://www.dolcera.com/website_prod/services/business-research-services Market Research Services]
|align = "center"| [http://www.dolcera.com/website_prod/tools/patent-dashboard Purchase Patent Dashboard]
|-
|align = "center"| [http://www.dolcera.com/website_prod/services/ip-patent-analytics-services/patent-search/patent-landscapes Patent Landscape Services]
|align = "center"| [http://www.dolcera.com/website_prod/research-processes Dolcera Processes]
|align = "center"| [http://www.dolcera.com/website_prod/industries Industry Focus]
|-
|align = "center"| [http://www.dolcera.com/website_prod/services/ip-patent-analytics-services/patent-search/patent-landscapes Patent Search Services]
|align = "center"| [http://www.dolcera.com/website_prod/services/ip-patent-analytics-services/alerts-and-updates Patent Alerting Services]
|align = "center"| [http://www.dolcera.com/website_prod/tools Dolcera Tools]
|-
|}
 

----
{| style="border:1px solid #AAA; background:#E9E9E9" align="center"
|-
! style="background:lightgrey" | Contact Dolcera
|-
! style="background:lightgrey" | Samir Raiyani
|-
| '''Email''': [mailto:info@dolcera.com info@dolcera.com]
|-
| '''Phone''': +1-650-269-7952, +91-40-2355-3493
|}