This may be the first product to directly treat gastroparesis by restoring gastrointestinal nitric oxide synthase, thereby increasing stomach motility and improving blood glucose control. Synvista Therapeutics, Inc. announced the publication of preclinical data demonstrating the ability of its compound, alagebrium, to reduce serum levels of advanced glycated end-products (AGEs) and restore neuronal nitric oxide synthase (nNOS) activity in rats with diabetes. Loss of gastrointestinal nNOS activity is one of the major putative mechanisms for the development of diabetic complications involving the gut including gastroparesis and intestinal dysfunction and has been the subject of both intense investigation and thorough review. Diabetic gastroparesis is a motility disorder in which the stomach takes too long to empty its contents. It is a disease of significant unmet medical need, as no pharmaceutical products are approved for the treatment of this condition, which afflicts over one million type 1 and type 2 diabetic patients in the U.S. and many more worldwide.
Pankaj J. Pasricha, M.D., Ph.D., Professor and Chief, Division of Gastroenterology & Hepatology at Stanford University School of Medicine, and colleagues; from the University of Texas Medical Branch authored the paper, which was published in the October 2007 issue of Neurogastroenterology and Motility. Dr. Pasricha is also Chairman of the NIH-funded Diabetic Gastroparesis Consortium, which has a mandate to better characterize the underlying biology and develop therapeutic interventions for patients with diabetic gastroparesis.
In this study, Dr. Pasricha examined the expression of duodenal nNOS and the role of AGE and RAGE (receptor for AGEs) signaling in an in vivo model of diabetes. He used two drugs aminoguanidine, a well characterized inhibitor of AGE formation, and alagebrium, a novel compound that acts as an AGE-crosslink breaker. The study showed that diabetes resulted in an accumulation of serum AGEs and that there was a 50% reduction in myenteric nNOS expression which was reversible by either aminoguanidine or alagebrium. This is the first reported evidence for the potential importance of AGE signaling in the pathogenesis of enteric neuropathy. In this study, late administration of alagebrium reduced serum AGEs to control levels and also restored nNOS levels. Further studies will be needed to understand the mode of action of alagebrium, however, the results of the study suggest that countering the AGE-RAGE signaling pathway may be a major target for diabetes related gastrointestinal complications, particularly those that arise from reduction of nNOS expression.
"I am quite enthused by the observation that alagebrium may preserve nNOS activity, which would allow it to advance as a leading candidate for clinical development in the fight against this challenging disease," said Dr. Pasricha.
Patients with diabetes commonly experience gastric and intestinal dysfunction, however, the mechanism of how this happens is not well understood. The term diabetic enteropathy is often used to explain the disturbance in bowel function such as chronic diarrhea which occurs in 15% or more diabetics. A role for decreased nNOS expression has been suggested as a possible cause for the diarrhea however how diabetes causes such changes in nNOS expression levels is unknown. Dr. Raj Kumar will continue to work on how glycation of nNOS affects its structure and function.
"Dr. Pasricha’s ground breaking work may be the first step in providing treatment for gastrointestinal disorders resulting from diabetes," said Noah Berkowitz, M.D., Ph. D. President and Chief Executive Officer of Synvista. "We look forward to future research efforts to further elucidate the role of AGEs in gastrointestinal complications including diabetic intestinal dysfunction, diabetic enteropathy and diabetic gastroparesis and the role that alagebrium may play in those disease."
Nature Clinical Practice Gastroenterology & Hepatology 4, 336 – 346 (01 Jun 2007) Review, Pankaj J. Pasricha, M.D., Ph.D., Professor of Neuroscience & Cell Biology and Biomedical Engineering at the University of Texas Medical Branch
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