New Class of Drugs for Treating Epileptic Seizures....

A chemical compound called Galanin,  that boosts the action of a molecule normally produced in the brain may provide the starting point for a new line of therapies for the treatment of epileptic seizures, according to a new study by scientists at "The Scripps Researcher Institute".

"This compound really provides a new angle for developing drugs to treat seizures," says Scripps Research Assistant Professor Xiaoying Lu..

Galanin is a peptide, a fragment of a protein, produced in the brain to regulate a variety of functions, such as pain, memory, addition, mood, and appetite. In the late 1990s, researchers discovered that galanin is also a potent anticonvulsant.

Recent research suggests that when seizures occur the brain steps up production of galanin, possibly as a way to protect itself against the seizures. As a result, mice engineered to lack galanin are more susceptible to developing seizures.

Because galanin seems to play a role in reducing seizures, several groups of researchers, including those at Scripps Research, have been working to develop drugs that target the galanin system. The first category of such compounds consists of synthetic molecules that mimic galanin's functions (called agonists) and include Galnon, developed by Bartfai's group. Galnon and other galanin agonists have been shown to act as anticonvulsants when given to animals that were rendered prone to developing seizures. But these agonists have several drawbacks as potential therapeutic agents. For one thing, because Galnon acts relativly broadly, it may have unwanted side effects.

Interestingly, now Lu, Roberts, Bartfai, and colleagues at Scripps Research have now designed a compound that targets the galanin system but, unlike the previous agonists, is more selective in its action. The compound, dubbed CYM2503, binds to one of the three receptors for galanin on nerve cells, the galanin receptor type 2 (GalR2). On its own, CYM2503 has no effect on GalR2, but when galanin also binds to the receptor, CYM2503 boosts galanin's function.

The researchers tested the effects of CYM2503 on mice and rats that had received a chemical causing them to have seizures. The animals that received CYM2503 took longer to get the seizures and, when they did, the seizures lasted for a shorter time. Most importantly, when the researchers looked at the animals after 24 hours, the rats that had been treated with CYM2503 had a dramatically higher survival rate than those that had not.

This mechanism of action, modifying a receptor's function, is common to many successful drugs that have been developed for the treatment of a number of conditions, including epilepsy, hyperparathyroidism, and AIDS, but not yet for drug candidates targeting galanin system.

Because CYM2503 only works when galanin, a natural molecule, is also present, the researchers predict it will have fewer side effects than drugs that work on their own. This study provides the first evidence that modulating the GalR2 receptor is an effective strategy for treating seizures, thus opening the door for the development of drugs that target this mechanism.

"It is a double breakthrough" . "The compound is a first new mode-of-action anticonvulsant and it represents a new mechanism of molecular action." Also based on the known functions of the GalR2 receptors, it may also work in treating depression and in protecting the brain from damage," says Lu...

Ref : http://www.scripps.edu/news/press/20100728.html

Valproic Acid Shown to Halt Vision Loss in Patients With Retinitis Pigmentosa...

Researchers at the University of Massachusetts Medical School (UMMS) believe, they may have found a new treatment for retinitis pigmentosa (RP), a severe neurodegenerative disease of the retina that ultimately results in blindness. One of the more common retinal degenerative diseases, RP is caused by the death of photoreceptor cells. RP typically manifests in young adulthood as night blindness or a loss of peripheral vision and in many cases progresses to legal blindness by age 40. Dr. Shalesh Kaushal,  chair of ophthalmology and associate professor of ophthalmology and cell biology at UMMS, and his team, describe a potential new therapeutic link between valproic acid and RP, which could have tremendous benefits for patients suffering from the disease. In a retrospective study, valproic acid -  approved by the FDA to reduce seizures, treat migraines and manage bipolar disorder -- appeared to have an effect in halting vision loss in patients with RP and in many cases resulted in an improved field of vision. Results from this study, in conjunction with prior in vitro data, suggest valproic acid may be an effective treatment for photoreceptor loss associated with RP.

UMass Medical School will be the coordinating site for a $2.1 million, three-year clinical trial funded by the Foundation Fighting Blindness/National Neurovision Research Institute quantifying the potential of valproic acid as a treatment for RP. The clinical trials will build upon Kaushal's work in the retrospective study in which patients were treated off-label with doses of valproic acid ranging from 500mg to 750mg per day over the course of two to six months. Treated at a time when patients normally experience rapid vision loss as a result of RP, five of the seven patients in the study experienced improvement in their field of vision.

"Inflammation and cell death are key components of RP," said Kaushal. "It appears the valproic acid protects photoreceptor cells from this. If our observations can be further substantiated by randomized clinical trials then low dose valproic acid could have tremendous potential to help the thousands of people suffering from RP."

Dr. Kaushal and colleagues, having previously demonstrated the use of the small molecule, retinoid, as a pharmacological agent capable of increasing the yield of properly folded RP rhodopsins, began screening other small molecules for similar attributes. Because of its already known qualities as a potent inhibitor of the inflammatory response pathway and cell death, valproic acid was believed to have a unique profile making it a potential candidate as a retinal disease treatment...

Ref : http://www.umassmed.edu/VALPROIC_ACID_SHOWN_TO_HALT_VISION_LOSS_IN_PATIENTS.aspx

Carbamazepine Reduces Hepatic Fibrosis.....

We know that Carbamazepine (CBZ see structure), is an  anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. It is also used off-label for a variety of indications, including attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, paroxysmal extreme pain disorder, and post-traumatic stress disorder.

Now researchers from University of Pittsburgh School of Medicine, have come up with interesting finding about this drug, i.e., the liver scarring of α1-antitrypsin (AT) deficiency, the most common genetic cause for which children undergo liver transplantation, might be reversed or prevented with carbamazepine.  The disease, which affects 1 in 3,000 live births, a gene mutation leads to an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to aggregation. As per the claim by the researchers these aggregates of ATZ accumulate in the liver cells and eventually lead to scarring, or fibrosis, of the organ and set the stage for tumor development. The disease sometimes doesn't show itself until adulthood, when the liver starts to fail due to cirrhosis or cancer.

Encouraged by the fact that carbamazepine could enhance a natural cellular pathway called autophagy  or self-digestion, researchers thought that  it might be able to rid the cells of the toxic aggregated ATZ. For the study researchers treated an ATZ cell line with carbamazepine. They found that carbamazepine did indeed cause a marked decrease in ATZ because the abnormal proteins were degraded more quickly via autophagy, and so they did another experiment in a mouse model of AT deficiency.

The most amazing finding,  as per the claim by the researchers is  that the drug reversed the fibrosis in the livers of the mice and after two weeks of treatment the liver tissue resembled that of a healthy mouse...

The ability of carbamazepine and drugs like it to "soup up" the cell's autophagy machinery might have value in other disorders ― such as Alzheimer's disease, Huntington's disease and Parkinsonism ― that are thought to be caused by toxic effects of protein clumping in the brain. Dr. Perlmutter and his colleagues are now exploring these possibilities in preclinical studies. ....

Ref : http://www.sciencemag.org/cgi/content/abstract/science.1190354v1

Talampanel has potential to slow the muscle weakening that comes with amyotrophic lateral sclerosis (ALS)...

Talampanel (strutcure, source:ChemSpider), (8R)-7-Acetyl-5-  (4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine  is a drug used to treat epilepsy. Now researchers from Johns Hopkins and Indiana University, have found interesting activity of the same anticonvulsant drug, i.e., the drug has potential to slow the muscle weakening that comes with amyotrophic lateral sclerosis (ALS)  . The researchers after completing a Phase II clinical trial-an early, small-scale test to show if the drug works and continues to be safe. As per the claim by the researchers,  the drug talampanel showed some ability to slow the loss of major daily life activities such as speaking, walking and dressing that typically slip away as the disease progresses. Interestingly the drug  has the anti-anxiety and  muscle relaxing activity too (work in the brain and spinal cord).

The trial in 59 volunteers with ALS - also called Lou Gehrig's disease - showed that talampanel can be safe for patients with the disease and that any recorded side effects are tolerable.  Phase II trials are designed to show on a small scale if a drug is safe and if it works. So the present trial included ways to measure the drug's benefits, which came across as clear, if not statistically significant. The research demonstrates that talampanel appears able to slow the progression of disabling ALS symptoms. Though the effect isn't overwhelming at the dosage of medicine used in this early, very small trial and the researchers claims that  having promising human data is reason enough to keep it in the drug pipeline where they can really find out where it stands for patient.

With the exception of riluzole, the single FDA-approved drug for the disease, there's no other treatment to slow or stop it. Riluzole can extend life only modestly and hasn't been shown to slow ALS symptoms. so the need for better therapy is real. Hope in the days to come people with ALS symptoms will have a better drug...

Ref : http://www.hopkinsmedicine.org/Press_releases/2010/01_04a_10.html