Gout drug success for Novartis

Canakinumab (trade name Ilaris, previously ACZ885) is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.

We know that, Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the US FDA on June 2009 and by the European Medicines Agency in October 2009. CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial has been discontinued. Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease.

Gout drug success for Novartis

Pfizer RA Drug Meets Study Goals

We knew that,  Tofacitinib (see structure, formerly tasocitinib is a drug being investigated by Pfizer for the treatment of rheumatoid arthritis (RA), psoriasis,inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. It is an inhibitor of the enzyme Janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway that transmits information outside the cell into the cell nucleus, influencing DNA transcription.

Now Pfizer now claims that the drug has   met its key goals of reducing signs and symptoms of the condition in separate studies on patients over a 12-month and six-month period. Rheumatoid arthritis is a chronic inflammatory disease typically affecting joints.

The company's Oral Standard study involved 717 patients over a 12-month period with moderate-to-severe rheumatoid arthritis who had an inadequate response to the drug methotrexate. Meanwhile, the Oral Step study involved 399 patients over a six-month period with moderate-to-severe rheumatoid arthritis who did not have an adequate response to TNF inhibitor drugs.  Pfizer said no new safety signals emerged in the Oral Standard and Oral Step studies. A more detailed analysis off the data will be submitted to a future scientific meeting. 

The most common side effects of treatment with tofacitinib have included bronchitis, headache, infections, and gastrointestinal symptoms like nausea, vomiting, and diarrhea. More serious side effects in a mid-stage trial included lower levels of a type of white blood cell called neutrophils, higher cholesterol levels and increased creatinine levels.

Tofacitinib is a key developing drug for Pfizer and is also being studied as a potential treatment for psoriasis, inflammatory bowel disease, and renal transplant. A topical version of the drug is being studied as a psoriasis treatment and a dry eye disease treatment....

Press Release...

Top-line results from Pfizer's tofacitinib Phase 3 studies in RA

In continuation of my update on drugs discovery on  rheumatoid arthritis, 

Top-line results from Pfizer's tofacitinib Phase 3 studies in RA..

FDA approves Chelsea Therapeutics' Phase II protocol for CH-4051 antifolate in rheumatoid arthritis

Chelsea Therapeutics International, Ltd. announced the  confirmation by the U.S. FDA,  that its proposed Phase II protocol for CH-4051  in rheumatoid arthritis has been approved by the agency. Chelsea plans to initiate patient screening next month and initiating treatment in October.

This multi-national, double-blind, randomized Phase II trial of CH-4051, an orally available metabolically stable antifolate, is intended to evaluate the safety and efficacy of CH-4051 in a 250-patient head-to-head study against methotrexate (MTX). Patients with rheumatoid arthritis who are experiencing an inadequate response to MTX treatment will be randomized to receive daily oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 3.0 mg plus folate of CH-4051 or 20 mg weekly dose of MTX plus folate supplement for 12 weeks following a two-week MTX-washout. The primary efficacy analysis will be conducted using the hybrid American College of Rheumatology, or ACR, score (hACR), which allows for a more comprehensive assessment of treatment benefit across all seven symptomatic and functional components of the standard ACR 20/50/70 evaluations historically used in RA trials.

"Although MTX is considered the standard of care in RA, both as a monotherapy and in combination with other RA treatments, the dosing and maximal therapeutic benefit of MTX is limited by well-documented tolerability issues, long-term safety concerns and variable bioavailability," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "Given that CH-4051 is metabolically stable and that all of our preclinical and clinical work suggests enhanced absorption, dramatically increased potency and improved tolerability over MTX, we believe CH-4051 will be safe and highly efficacious in a historically treatment-resistant patient population."

Chelsea intends to conduct an un-blinded interim efficacy analysis after approximately 50% of patients in the two lower CH-4051 dose groups complete treatment and expect to report results from this analysis in the third quarter of 2011. Full study results, inclusive of all dose groups, are expected in mid-2012.

As previously reported, results from Chelsea's Phase I single and multiple ascending dose studies demonstrated that CH-4051 was well tolerated at doses up to and including 7.5mg, a dose range likely to be effective for multiple autoimmune disorders. The 5mg dose was as well tolerated as placebo. No serious adverse events occurred during the study and pharmacokinetic data indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in the study were comparable to those seen in animal pharmacology studies in which CH-4051 demonstrated superior suppression of RA than both the maximally tolerated dose of methotrexate and equivalent doses of CH-1504 (see structure)....

Ref : http://www.irconnect.com/chtp/pages/news_releases.html?d=200159

Vinpocetine from the periwinkle plant, as a potent anti-inflammatory agent....

Vinpocetine (ethyl apovincaminate (see chemical structure,   is  a  semisynthetic   derivative   of  alkaloid   vincamine - an  extract  from the  periwinkle plant (see picture) Vinca minor) is a well-known natural product that was originally discovered nearly 30 years ago and is currently used as a dietary supplement for the prevention and treatment of cognitive disorders, such as stroke and memory loss, in Europe, Japan and China.

 

The therapy has no evidence of toxicity or noticeable side effects in human patients. Now scientists at the University of Rochester hope to reposition this compound as an anti-inflammatory agent for the treatment of COPD, and potentially other inflammatory conditions, such as asthma, otitis media, rheumatoid arthritis, atherosclerosis and psoriasis in the future.

As per the claim by the lead researcher Dr. Jian-Dong Li,  vinpocetine decreases inflammation by targeting the activity of a specific enzyme, known as IKK. IKK is responsible for regulating inflammation, and does so through the activation of a key protein, nuclear-factor kappaB (NF-κB). By directly inhibiting IKK, vinpocetine is able to switch off NF-κB, which normally produces pro-inflammatory molecules that cause inflammation. Halting the activity of NF-κB ultimately reduces inflammation. 

"Given vinpocetine's efficacy and solid safety profile, we believe there is great potential to bring this drug to market." claims co-author,  Dr. Bradford C. Berk...

Inflammatory diseases are a major cause of illness worldwide. For example, chronic obstructive pulmonary disease is the fourth leading cause of death in the United States. In people with COPD, airflow is blocked due to chronic bronchitis or emphysema, making it increasingly difficult to breathe. Most COPD is caused by long-term smoking, although genetics may play a role as well.....

Ref : http://www.urmc.rochester.edu/news/story/index.cfm?id=2836

MIF (Macrophage migration Inhibitory Factor) - a new molecular target for the treatment of depressant and anxiety...

Clinical depression affects 121 million people around the world,  according to the World Health Organization, but only 60% to 80% of cases are effectively treated with current medication and psychotherapy.  Now researchers from Ecole Polytechnique Fédérale de Lausann, (EPFL), have come up with an interesting target, i.e., macrophage migration inhibitory factor, MIF. 

MIF(see strucutre : wikipedia : a pro-inflammatory cytokine that is expressed in the CNS) is normally thought to play a role in tissue swelling (inflammatory mediator possibly associated with rheumatoid arthritis,  RA-severity) and even cancer development (metastatic potential in speculative models of cancer), but its precise location and function in the brain remained a mystery before Carmen Sandi's (lead researcher) study. 

 The research team, first detected a concentration of MIF protein in stem cells in the hippocampus, (a key area for memory formation and neuron generation during adulthood). New neurons are thought to be linked to the creation of new memories but they may also play an important role in curbing anxiety  (previous studies have shown that prolonged periods of stress reduce neurogenesis, and many anti-depressants actually boost the production of new neurons).

By genetically and pharmaceutically manipulating the level of MIF in the hippocampus of rats, the researchers discovered that the absence of MIF significantly reduced the production of neurons and increased anxiety They also found that the lack of MIF decreases the ability of anti-depressants to stimulate neurogenesis. 

Researchers, identified  MIF expression in neurogenic cells  (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1 - see (right side) chemical structure : (S,R)-3-(4-Hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid, methyl ester) approaches. 

As per the claim by the researchers,  genetic deletion of MIF resulted in increased anxiety and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Researchers conclude that,   MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition....

Ref : Carmen Sandi et. al., Molecular Psychiatry, 23 February 2010

 

Minocycline - Effective defense against HIV ?

We know that Minocycline hydrochloride, also known as minocycline (structure), is a broad spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic. It is primarily used to treat acne and other skin infections as well as lyme disease. It may be used to treat certain strains of MRSA infection and disease caused by drug resistant Acinetobacter. Its also used in DMARD (Disease-Modifying Anti-Rheumatic Drug) for RA. 

Now, Johns Hopkins scientists have found that this safe and inexpensive antibiotic (minocycline),   effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating. 

As per the claim by the researchers, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy).  Though HART is really effective in keeping down active replication, minocycline is another arm of defense against the virus. 

Dr. Janice Clements lead researcher claims that,  unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. and  minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS. 

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. Interestingly the same researchers earlier found that  minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.  

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV. Researchers conclude that,  this new understanding about minocyline's effects on a T cell  might help to find even more drugs that target its signaling pathways.

At Johns Hopkins and elsewhere, scientists are now testing whether giving HIV patients minocycline benefits them, let us hope for the positive results....

Ref : http://www.usnews.com/science/articles/2010/03/26/existing-antibiotic-might-help-keep-wraps-on-aids-virus.html

Salsalate may be useful for the treatment of patients with type 2 diabetes .....

We know that Salsalate (see structure; source Drugs.com)  is a  non-steroidal anti-inflammatory drug (NSAID) belonging to salicylates. It is used in the treatment of Osteo Arthritis and  Rheumatoid Arthritis. 

Now researchers from Harvard Medical School, lead by Dr. Allison Goldfine, have come up with interesting finding, i.e., Salsalate may be useful for the treatment of patients with type 2 diabetes as well. In a three-month trial of people with type 2 diabetes ,  those who took the drug showed significantly improved blood glucose levels. 

Starting off, the patients all had levels of hemoglobin A1C (a standard measurement that reflects blood sugar levels over several months) in the range of 7.0 to 9.5%. A significant number of those who took salsalate saw this number drop by 0.5%, a result that is in the range of several recently released diabetes therapeutics. Other tests related to glucose levels also showed substantial improvement.  

Overall the drug appeared to be safe and to be tolerated well by patients. The study included 108 individuals, aged from 18 to 75 years, at 17 clinical sites around the United States. Patients were randomly divided into four; three groups were each given differing amounts of salsalate in three daily doses, while the fourth received placebos. All patients continued with their current regimes for managing diabetes.

Though these preliminary findings  suggests  that,   salsalate may provide an effective, safe and inexpensive new avenue for diabetes treatment, however the researchers  want to complete the ongoing  additional studies so that they can further substantiate their claim........

Ref : March 16 in the Annals of Internal Medicine

Serotonin-Specific Reuptake Inhibitor (SSRIs) as antiinflammatory agents?

We know that Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.  Now researchers from Brighton and Sussex Medical School (BSMS) in the UK, lead by Dr. Sandra Sacre have come up with an interesting findings, i.e., two SSRIs fluoxetine &  citalopram significantly inhibited disease progression of collagen-induced arthritis (CIA) in mice. As per the claim by the researchers both SSRIs exhibited antiinflammatory effects and may provide drug development opportunities for arthritic conditions such as rheumatoid arthritis (RA).

Prior studies (of SSRIs)  have shown that patients with depression,  who respond to treatment with SSRIs display a reduction in cytokine levels (signals that can induce inflammation), suggesting a connection between SSRIs and the immune system. 

In the current study, researchers used a CIA mouse model due to the similarities to human RA, including synovitis, bone erosion and pannus formation. At the onset of arthritis, mice were treated daily for 7 days with a dose of 10 or 25 mg/kg of fluoxetine and 25 mg/kg of citalopram. At the lower dose of fluoxetine the mice showed a small reduction in the clinical score (a combined measure of redness, swelling and joint mobility/deformity) and a slower increase in paw swelling. At a dose of 25 mg/kg, fluoxetine halted disease progression and no further elevation was noted in the clinical score or paw swelling.

Researchers observed reduced inflammation, reduced cartilage and bone erosion, and a preservation of the joint structure in the mice treated with a higher dose of fluoxetine.  Citalopram was not as effective as fluoxetine at inhibiting disease progression in this model. 

They  also observed a decrease in cytokine production from cultures of human RA synovial joint tissues that were treated with SSRIs.  Toll-like receptors (TLRs) are strong activators of immune cells leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram. 

Researchers conclude that SSRIs effectively target TLRs contributing to inflammation and could provide therapeutic benefit in RA, they are not ideal candidates to progress into clinical trials (from the data, the  effective inhibition of RA requires levels of the drugs higher than the safe therapeutic dosages.) The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of RA in the future..... 

Ref : http://www3.interscience.wiley.com/journal/123235497/abstract

Celecoxib reduces the risk of common skin cancer in humans.....

We know that Celecoxib   is a non-steroidal anti-inflammatory drug (NSAID)  used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. It is marketed by Pfizer. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

Researchers from UC-San Francisco and Children's Hospital Oakland,  (Dr. Tang was was an assistant professor at UC-San Francisco and Children’s Hospital Oakland  when the trial was conducted) have come up with very interesting results for the same drug. The drug can reduce the risk of a common skin cancer in humans. Though celecoxib, is associated with an increased risk of heart attack and stroke in some people, it's possible that topical application could have a safer, protective effect for people prone to developing the cancers, called basal cell carcinomas, the researcher believes.

For the current research, Tang and her colleagues capitalized on a previous finding suggesting that celecoxib, a NSAID, can inhibit the development of a different kind of skin cancer, squamous cell carcinoma, in mice. They wondered if the drug, sold by the pharmaceutical company Pfizer under the brand names Celebrex and Onsenal, would have a similar effect on the more common basal cell carcinoma.

Celecoxib is thought to work to prevent or slow cancer growth by interfering with the action of an enzyme called Cox-2, which causes tissue inflammation (pro inflammator). Celecoxib has both pain-killing (analgesic) and anti-inflammatory properties. Chronic inflammation has long been associated with the development of many types of cancer, and celecoxib has been shown in clinical trials to reduce the incidence of colon cancer in people with a genetic predisposition to the disease.

Interestingly, researchers stopped the clinical trials in 2003 (from 2001) when the study lead to high risk  of heart attack and stroke in patients taking a different NSAID. (Rofecoxib,  Vioxx by  Merck & Co. was withdrawn from the market by Merck in 2004  and Tang's trial was discontinued that year in response to ongoing concerns about long-term treatment with Cox-2 inhibitors). At that time, most participants had received about two years of drug treatment. No patient died or suffered adverse cardiovascular events due to their participation in the trial. Although drug treatment had been discontinued, the researchers continued to monitor basal cell carcinoma formation in people who had received the drug or placebo for an additional year to complete the three-year study. They found that, although both groups continued to develop new cancers during the study, oral celecoxib treatment decreased the growth of skin tumors by about 50 percent as compared to placebo in participants who entered the trial with 15 or fewer basal cell carcinomas. Celecoxib treatment also reduced the overall tumor burden in the  group of patients (where in the carcinomas are removed upon diagnosis in most people).

Now the lead researcher Dr. Tang is continuing her focus on skin cancer prevention at Stanford. She's currently investigating whether it's possible to develop a topical formulation of the drug that can be applied directly to the skin to achieve a similar protective effect without associated cardiovascular risk. Hope she will get positive results via topical formulation .....

In my opinion  its really a great achievement.We know that compounds with selective inhibitors of 5-LO (Lipoxygenase) and COX (Cyclooxegenase, that too COX-II) will be  the best NSAIDs without any ulcerogenecity, its good see that the  same compounds can be used to treat skin cancer....

Ref : http://med.stanford.edu/ism/2010/january/tang.html

Methotrexate & Ocrelizumab combination a new hope for RA patients....

In recent days, I have seen many researchers are trying the combination of existing drugs in combination with a monoclonal antibodies for many diseases like cancer, rheumatoid arthritis and are successful too. As synthetic chemist I was interested in knowing about these monoclonal antibodies and found some interesting info, which I am sharing herewith...

About monoclonal antibodies :

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given almost any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab.

The invention is generally accredited to Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975; who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. In 1988 Greg Winter (Nat Rev Cancer 2001;1:118-129) and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. Interestingly, many monoclinical antibodies have been tried for rheumatoid arthritis, chrohn's disease and as anticancer agents.

Many monoclonal antibodies like infliximab, etanercept and adalimumab were tried for the rheumatoid arthritis now its interseting to note that Genentech and Biogen Idec reported positive outcome from ocrelizumab ( humanized anti-CD20) -MTX (Methotrexate - see the structure : this drug is a part of DMARD treatment meant for RA patients) combination study in RA. The results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis. Hope patients suffering from RA and those are not responding will breathe a sigh of relief in the days to come...

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487

CCII capsules offer safe and effective treatment for rheumatoid arthritis

Chicken collagen can provide relief from rheumatoid arthritis (RA) symptoms. A randomised, controlled trial, published in BioMed Central's open access journal Arthritis Research & Therapy, has found that Chicken type II collagen (CCII), a protein extracted from the cartilage of chicken breast, is a safe and effective treatment for RA.

More....CCII capsules offer safe and effective treatment for rheumatoid arthritis

Minocycline for stroke patients?

Minocycline hydrochloride, also known as minocycline (right structure), is a broad spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bactriostatic antibiotic. As a result of its long half-life it generally has serum levels 2-4 times that of most other tetracyclines (150 mg giving 16 times the activity levels compared to 250 mg of tetracycline at 24–48 hours). It is primarily used to treat acne and other skin infections. Apart from the antibacterial activity, 'minocycline' is recognized as a DMARD (Disease-Modifying Anti-Rheumatic Drug) by the American College of Rheumatology, which recommends its use as a treatment for mild rheumatoid arthritis.

A recent study by the Dr. Cesar V. Borlongan (University of South Florida, USA) has lead to some interesting result, i.e., minocycline can be used to treat the stroke patients !. As per the claim by the researchers this drug might be a better option, when compared with the thrombolytic agent tPA (the only effective drug for acute ischemic stroke) and more over only 2 % of ischemic stroke patients benefit from this treatment due to its limited therapeutic window.

During a stroke, a clot prevents blood flow to parts of the brain, which can have wide ranging short-term and long-term implications. This study recorded the effect of intravenous minocycline in both isolated neurons and animal models after a stroke had been experimentally induced. At low doses it was found to have a neuroprotective effect on neurons by reducing apoptosis of neuronal cells and ameliorating behavioral deficits caused by stroke. The safety and therapeutic efficacy of low dose minocycline and its robust neuroprotective effects during acute ischemic stroke make it an appealing drug candidate for stroke therapy claims the researchers. Congrats for this interesting finding...

Ref : http://www.biomedcentral.com/1471-2202/10/126/abstract

Podophyllotoxin in American Mayapple ?

A common plant called American mayapple (see the picture) may soon offer an alternative to an Asian cousin that's been harvested almost to extinction because of its anti-cancer properties. The near-extinct Asian plant, Podophyllyum emodi, produces podophyllotoxin (see the structure), a compound used in manufacturing etoposide, the active ingredient in a drug used for treating lung and testicular cancer. Podophyllyum emodi is a cousin of the common mayapple, sometimes considered a weed, found in the United States.

Podophyllotoxin and its derivatives are used in several commercially available pharmaceutical products such as the anticancer drugs etoposide, teniposide, and etopophos, which are used in the treatment of small-cell lung cancer, lymphoblastic leukemia, testicular cancer, and brain tumors. Podophyllotixin derivatives are also used for the treatment of psoriasis and malaria, and some are being tested for the treatment of rheumatoid arthritis. Currently, podophyllotoxin is produced commercially using the roots and rhizomes of Indian mayapple, an endangered species harvested from the wild in India, Pakistan, Nepal, and China.

Now the researchers from the US, found that mayapple colonies in the eastern part of the United States can be used for the development of high podophyllotoxin cultivars, which could subsequently provide the base for commercial production of podophyllotoxin in the United States.

Ref : http://hortsci.ashspublications.org/cgi/content/abstract/44/2/349

Masitinib - a relief for arthritis patients ....

I know the sufferings of arthritis patients closely, (as my mother-in-law is having the problem) it makes patients' life miserable. Though there are a few drugs for the treatment, but are inadequate for patients suffering from active rheumatoid arthritis (RA) especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is need of the hour. In that aspect clinical trials of Mastineb, 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-thiazolyl] amino] phenyl]benzamide carried out by Alain Moussey et. al., is of great importance.

The study evaluates the safety and efficacy of Masitinib, a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.

We also know that, the orally bioavailable mesylate salt of masatinib, a multi-targeted protein tyrosine kinase inhibitor with potential antineoplastic activity selectively binds to and inhibits both the wild-type and mutated forms of the stem cell factor receptor (c-Kit; SCFR); platelet-derived growth factor receptor (PDGFR); fibroblast growth factor receptor 3 (FGFR3); and, to a lesser extent, focal adhesion kinase (FAK). As a consequence, tumor cell proliferation may be inhibited in cancer cell types that overexpress these receptor tyrosine kinases (RTKs), clinical trials also reported.

As per the conclusions by the authors, treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. Congrats for the group...

Simponi the first biologic therapy to be approved for rheumatologic diseases !

We did know about the three 3 TNF inhinitors (namely-Infliximab, Etanercept and Adalimumab), the last still to be approved by US.

Like Infliximab and Etanercept, Adalimumab binds to TNFα preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein. TNFα inactivation has proven to be important in down regulating the inflammatory reactions associated with autoimmune diseases. As of 2008 adalimumab has been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis.

Humira (brand name is an abbreviation of "Human Monoclonal Antibody in Rheumatoid Arthritis") is marketed in both preloaded 0.8 ml syringes and also in preloaded pen devices (called Humira Pen), both injected subcutaneously, typically by the patient at home. It cannot be administered orally, because the digestive system would destroy the drug. But its now the turn of Golimumab, a new fully human monoclonal antibody. Being a fully human MAb directed against TNF, Golimumab resembles Adalimumab (Humira, Abbott), which was the first such product to reach the market. Now the Canadian government has approved Golimumab along with ‘methotrexate’ for the treatment of three forms of Rheumatiod arthritis (Rheumatoid Arthritis, Ankylosing Spondylitis & Psoriatic Arthritis) and more over making this treatment the first biologic therapy to be approved.

With this approval in Canada, Simponi (Golimumb), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms in adult patients with moderately to severely active RA; reducing signs and symptoms in adult patients with moderately to severely active PsA, alone or in combination with MTX; and reducing signs and symptoms in adult patients with active AS who have had an inadequate response to conventional therapies. More...

Genetic basis of psoriasis revealed.....

As we know psoriasis, an autoimmune disease that occurs when the body's immune cells mistakenly attack the skin, is becoming more problematic with nearly 10 to 30 percent of patients (an estimated 7 million people suffer from psoriasis in US) with psoriasis develop psoriatic arthritis. which occurs when inflammation attacks the joints, causing pain and disability. Thanks to Dr. Anne Bowcock, a professor of genetics at Washington University School of Medicine in St. Louisand and his group have made significant gains in understanding the genetic basis of psoriasis, a chronic skin condition that can be debilitating in some patients.

This basic understanding of psoriasis is of significance becoz of the fact that, now one will be able target treatments to psoriasis patients based on the genetic alterations that have contributed to their disease. The two groups (Bowcock and her colleagues in Spain) found that the absence of two skin genes - LCE3B and LCE3C - increases the risk of psoriasis.

Both genes normally are activated after an injury to the skin. The researches suspect the absence of the genes could lead to an inappropriate immune response, which may cause the inflammation that is a hallmark of the disease. Until now, all of the genes linked to psoriasis have been involved in the immune system. But psoriasis is a disease of the immune system and the skin, and it makes sense that we would eventually find genes in the skin that are involved in the disease.

Though the new variants uncovered by the researchers each make only a small contribution to the overall genetic risk of the psoriasis, its a good beginning. This finding is important, because newly discovered variants have been associated with other inflammatory diseases such as Crohn's disease and autoimmune diseases like rheumatoid arthritis and lupus. Hope additional studies will help to tease apart the ways in which these diseases are connected at the level of DNA and this information will also aid in the search for more targeted drugs that can zero in on particular genetic defects that cause the diseases. More....

For Psoriasis picture, see the slide no., 4 of slide show of skin problems.