Experimental drug shows promise in mice with multiple sclerosis

An experimental drug originally identified in a National Cancer Institute library of chemical compounds as a potential therapy for brain and basal cell cancers improves the symptoms of mice with a form of the debilitating neurological disorder multiple sclerosis (MS), according to new research from NYU Langone Medical Center.

The experimental drug employed by the NYU Langone team of neuroscientists is called GANT61. It blocks the action of a key protein, Gli1, which is involved in so-called sonic hedgehog signaling, a biological pathway closely tied to neural stem cell development and the growth of some cancers, and whose signaling is raised in tissue samples taken from brain lesions in patients with MS.

A report describing the findings is being published in the journal Nature online Sept. 30.

In the study, mice with chemically damaged brain myelin were given daily doses of GANT61 for one month. Results showed that mice that received the drug had 50 percent more myelin at the end of treatment than did untreated mice. Myelin is the nerve-protecting sheath whose degradation is a principal cause of MS.

Experimental drug shows promise in mice with multiple sclerosis

Psoriasis Drug May Help Treat Type 1 Diabetes: Report - Drugs.com MedNews

In continuation of my update on alefacept (Amevive)

A drug formerly used to treat the skin condition psoriasis shows promise in treating type 1 diabetes, according to a new study.

Both psoriasis and type 1 diabetes are autoimmune disorders. The drug alefacept (Amevive) is an immune-suppressing drug that was used to treat psoriasis but was withdrawn by its manufacturer in 2011. The drug maker, Astellas Pharma U.S., said at the time that "business needs" led to its decision to pull the drug from the market.

The new study included 49 type 1 diabetes patients at 14 medical centers in the United States. Thirty-three of the patients received weekly injections of alefacept for 12 weeks, followed by a break of 12 weeks and then another 12 weekly doses of the drug. Sixteen patients received a placebo on the same schedule.

The clinical trial's main outcome was a measure of how well the pancreas could secrete insulin in response to food, two hours after eating. Using this measure, the researchers found no significant differences between the two groups of patients. 

Ref : http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70111-6/abstract

Psoriasis Drug May Help Treat Type 1 Diabetes: Report  

Reformulated Copaxone Meets Goals........

Teva Pharmaceutical Industries Ltd. said that a new version of its multiple sclerosis drug Copaxone met its goals in a late-stage clinical trial.....

We know that, COPAXONE is the brand name for glatiramer acetate (formerly known as copolymer-1). Glatiramer acetate, the active ingredient of COPAXONE (glatiramer acetate) , consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000 – 9,000 daltons. Glatiramer acetate is identified by specific antibodies.

Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:

(Glu, Ala, Lys, Tyr)_x•xCH₃COOH

(C₅H₉NO₄•C₃H₇NO₂•C₆H₁₄N₂O₂•C₉H₁₁NO₃)_x•xC₂H₄O₂

CAS - 147245-92-9

COPAXONE (glatiramer acetate) is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 1 mL of solution contains 20 mg of glatiramer acetate and 40 mg of mannitol. The pH range of the solution is approximately 5.5 to 7.0. The  biological activity of COPAXONE (glatiramer acetate) is determined by its ability to block the induction of experimental autoimmune encephalomyelitis (EAE) in mice.

Reformulated Copaxone Meets Goals | News | Drug Discovery and Development Magazine

Crocin for multiple sclerosis?

Medical researchers at the University of Alberta have discovered that an active ingredient in the Persian spice saffron may be a potential treatment for diseases involving neuroinflammation, such as multiple sclerosis. Researchers found there is a compound in saffron, known as crocin (see the structure below), that exerts a protective effect in brain cell cultures and other models of MS. It prevented damage to cells that make myelin in the brain.

Lead researcher  Power said. "Myelin is insulation around nerves. MS is characterized by inflamed brain cells that have lost this protective insulation, which ultimately leads to neurodegeneration.......

More......

Biogen’s Multiple Sclerosis pill succeeds at a late phase clinical trial

Biogen Idec Inc. has reported success in a late stage clinical trial of its oral multiple sclerosis drug BG-12 (see below structure), a competitor's of Teva Pharmaceutical Industries’ Laquinimod. A 240-milligram dose of BG-12 administered two or three times a day significantly reduced the proportion of patients who relapsed by 49% and 50%, respectively, after two years compared with a placebo....

Company adds that, in addition to significantly reducing ARR, BG-12 met all secondary relapse and MRI endpoints for both dose regimens.....

Ref : http://www.biogenidec.com/PRESS_RELEASE_DETAILS.aspx?ID=5981&ReqId=1621631 

Teriflunomide drug reduces relapse rate of people with MS

 In continuation of my update on  Teriflunomide
A new oral drug has been shown in a large international clinical trial to significantly reduce the relapse rate of people with multiple sclerosis and to slow the progression of the disease.

More....

FDA approves fingolimod drug for multiple sclerosis...

Fingolimod (see structure), a drug modified from a fungus  (Isaria sinclairii), a structural analogue of sphingosine and gets phosphorylated by sphingosine kinases in the cell originally found in Asian wasps, prevents autoimmune attacks by trapping white blood cells in the body's lymph nodes. Two large Phase III clinical studies published in February found that fingolimod was at least twice as effective in preventing MS attacks when compared to placebo or current treatments. 

Research on additional uses for fingolimod continues at the University of Chicago, including a new clinical trial in patients with progressive MS, for which there are no available treatments. With fingolimod adding to the recent boom of new MS therapies, and with a number of clinical trials for new therapies in progress, patients should be sure to seek out an experienced MS center for their care.

As per the claim by the lead researcher, Anthony Reder, MD, Professor of Neurology at the University of Chicago Medical Center,  fingolimod is first oral medication for multiple sclerosis was approved  by the Food & Drug Administration. He also claims that'

"We have six drugs right now, and they all involve injections. So the convenience alone of a pill is a major change in how we treat MS."

Hope people suffering from MS, (A chronic, neurologic disorder, which affects roughly 400,000 Americans and 2.5 million people around the world.  MS can cause issues with walking and movement, fatigue, weakness, pain, and loss of vision. Patients with relapsing-remitting MS suffer from intermittent and unpredictable immune system attacks that can damage the brain, spinal cord, and eyes) breathe a sigh of relief..

More..

FDAs approval of fampridine-SR for multiple sclerosis...

In continuation of my  update on MS, I found this info useful to share with. Multiple sclerosis (MS, also also known as disseminated sclerosis or encephalomyelitis disseminata) is a disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. Disease onset usually occurs in young adults, and it is more common in females. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin.

In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. The name multiple sclerosis refers to scars (scleroses, better known as plaques or lesions) in the white matter of the brain and spinal cord, which is mainly composed of myelin. (see, picture, source : URMC).

Now FDA has approved fampridine-SR (see structure, source : chemspider),  for the treatment of multiple sclerosis. Most interesting part of the research lies in the fact that Researchers at the University of Rochester Medical Center (URMC) have been evaluating the effects of the drug in MS for more than 10 years- it is the first medication shown to enhance some neurological functions in people with the disease and I think their efforts helped pave the way for action by the FDA.

Researchers at URMC helped develop the study protocols and lead the clinical trials  that demonstrated consistently improved mobility - timed walking speed- in more than a third of patients with MS. This is the first instance in which a drug for multiple sclerosis was found to improve function lost as a result of the disease. Goodman and his colleagues published the results of a Phase 3 clinical trial of the drug in the journal Lancet. Fampridine-SR is being developed by Acorda Therapeutics and marketed under the name Ampyra. The company submitted a new drug application to the FDA in February 2009. An expert advisory panel recommended approval of the drug in October and that recommendation was adopted by the FDA on 23. January 2010.

As per the claim by the researchers, fampridine improves the transmission of signals in the central nervous system of some multiple sclerosis patients by blocking potassium ion channels in nerve cells and restoring signal conduction( have covered an article in the same lines).

The authors claim that, 35% of patients taking the drug were responders who consistently improved their walking speed by an average of about 25%. While walking was the primary measure, patients also reported that they could walk farther distances, climb stairs better, and stay on their feet longer. Except for the mild seizure, at the FDA approved dosage, the drug is safe. Hope, people with MS will have some sort of relief......

Ref : http://www.urmc.rochester.edu/news/story/index.cfm?id=2744

Cladribine-the first oral disease-modifying multiple sclerosis therapy ?

In my earlier blog, I have mentioned about the NDA (new drug application) of this drug Cladribine as drug to treat Multiple Sclerosis.  Now as per the report by Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that a recent "refuse to file" (RTF) letter issued by the FDA regarding Merck Serono's oral cladribine has heightened the competition between oral cladribine and its primary competitor, Novartis/Mitsubishi Tanabe's FTY-720 (fingolimod), to be the first oral disease-modifying multiple sclerosis therapy to reach the market in the United States.

Although oral cladribine's first-to-market advantage over FTY-720 will be reduced as a result of a likely delay to market caused by the FDA's action, oral cladribine is still expected to launch in the U.S. in 2010 while FTY-720 remains on track to launch in early 2011. .....

Ref : http://www.decisionresources.com/News-and-Events/Press-Releases/Multiple-Sclerosis-010510

A potassium channel blocker to restore nerve function in patients with spinal cord injuries..

The experimental compound, 4-aminopyridine-3-methyl hydroxide, has been shown to restore function to damaged axons, slender fibers that extend from nerve cells and transmit electrical impulses in the spinal cord.

The researchers subjected spinal cord tissue to stresses that mimic what happens in a compression injury, which stretches nerves. Then they treated the damaged axons with 4-aminopyridine-3-methyl hydroxide. The same drug is used primarily as a research tool and also to manage symptoms of multiple sclerosis.

The axons of each nerve are sheathed in a thick insulating lipid layer, called myelin, which enables the transmission of signals without short circuiting, much like the insulation surrounding electrical wires. Spinal cord trauma damages the myelin sheath, exposing "fast potassium channels" that are embedded in the axons and are critical for transmitting nerve impulses.

The researchers also discovered that 4-aminopyridine-3-methyl hydroxide is a "potassium channel blocker," using a sophistic laboratory technique called "patch clamp" to measure signal conduction. Findings confirmed that the compound prevents the exposed channels from leaking electrical current and enhances nerve conduction in segments of the damaged spinal cord. The compound could make it possible to sidestep spinal cord damage by enabling axons to transmit signals as though they were still sheathed in myelin.

As per the claim by the researchers, the new compound is about 10 times more potent than 4-aminopyridine, meaning lower doses can be used to reduce the likelihood of serious side effects. Because myelin also is damaged in multiple sclerosis, the same drug might be used to restore nerve function in people stricken with the disease. Hope in the days to come patients suffering from Multiple sclerosis and spinal cord injuries will breathe a sigh of relief...

Ref : J Neurophysiol (November 18, 2009). doi:10.1152/jn.00154.2009.

Imatinib for the treatment of Scleroderma ?

We know that Imatinib (its mesylate salt, Novartis) is a drug used to treat certain types of cancer. It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other cancers. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

More over the discovery of this compound itself is interesting & its one drug obtained via, High Throughput Screening (HTS). Chemists used a HTS of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib. More interesting part of this drug is a recent discovery, i.e., GLEEVEC^® (imatinib mesylate) can be used to treat Scleroderma. As per the claim by the researchers, until now no drug has been shown to be effective in treating scleroderma in a clinical trial. Several years ago, a small study provided some evidence that a chemotherapy drug called cyclophosphamide may help scleroderma patients, but the benefit was minimal and this drug causes side effects including infertility and secondary cancers.

The investigators reported an interim analysis of their results, although the study is ongoing. At one year, the investigators saw a 23 percent improvement in skin scores. The researchers also saw an improvement in forced vital capacity scores by 9.6 percent and diffusion capacity scores by 11 percent in the 18 patients who had completed one year of treatment. The lung function data was really exciting,” Dr. Spiera said. “In patients with scleroderma, you usually see lung function tests getting worse over time, and if doctors try a therapy for a year and a patient doesn’t get any worse, we get pretty excited. What is amazing to me in this study is that we actually saw improvements in both lung function tests. Congrats for this remarkable achievement.....

Ref : http://www.hss.edu/newsroom_drug-provide-treatment-scleroderma.asp

Retinoic acid may provide relief for ulcerative colitis !

We know that Retinoic acid is the oxidized form of Vitamin A. It functions in determining position along embryonic anterior/posterior axis in chordates. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages. Retinoic acid acts by binding to heterodimers of the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), which then bind to retinoic acid response elements (RAREs) in the regulatory regions of direct targets (including Hox genes), thereby activating gene transcription.

Recently when I was reading a paper, found this interesting fact that is "retinoic acid, could be a beneficial treatment for people suffering from ulcerative colitis and other irritable bowel diseases. Specifically the researchers found that retinoic acid helps suppress out-of-control inflammation, which is a hallmark of active ulcerative colitis.

Pharmaceutical strategies based on this research may offer a promising alternative to the current approaches of managing immune diseases including, IBD, arthritis, multiple sclerosis, and so on, Aiping Bai, a researcher involved in the work from Nanchang University in Nanchang City, China claimed.

The studies ultimately found that treatment with retinoic acid reduced the inflammation in the colon by increasing the expression of FOXP3, a gene involved with immune system responses, as well as decreasing the expression of IL-17, a cytokine believed to cause inflammation. Because many experts believe that IL-17 directly relates to the uncontrolled inflammation seen in ulcerative colitis and irritable bowel disease, the discovery that retinoic acid reduces IL-17's ability to cause inflammation could accelerate the development of treatments for these chronic diseases.

Ref : http://www.jleukbio.org/cgi/content/abstract/86/4/959?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Aiping+Bai&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

NDA of Cladribine as a drug for Multiple Sclerosis !

When I was working with Innovasynth Technologies, Khopoli, I worked in the field of "antisense drugs" and as the company has tie up with many MNCs (working with these class of compounds) I had many times interacted with Serono, Pharmaceuticals (US) for some of the intermediates (oligonucleotides). When I read this article, I am happy there are many drugs still to be established as antisense drugs and more over this NDA (new drug application) is something to cherish.

We know that 2-chlorodeoxyadenosine, Cladribine (Leustatin) is drug used to treat hairy cell leukemia (leukemic reticuloendotheliosis).

As a purine analog, it is a synthetic anticancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.

Though it has been used to treat leukemic reticuloendotheliosis, other activities like B cell leukemias and lymphomas, such as mantle cell lymphoma are still to be established. Now EMD Serono has applied for this NDA with FDA. As per the claim by the company, Cladribine Tablets has the potential to be the first orally administered disease-modifying therapy available for people living with relapsing MS, as all disease-modifying therapies currently approved for the treatment of MS are parenteral therapies. Hope FDA will approve the drug and will help many patients with relapsing forms of multiple scleorosis will have a relief in the days to come..

Ref : http://www.emdserono.com/cmg.emdserono_us/en/images/Cladribine%20Tablets%20FDA%20Submission%20FINAL%20US%20FINAL_tcm115_44365.pdf