Ram Kumar Mishra

Potential role of Rho kinase inhibitors in combating diabetes-related complications including diabetic neuropathy--a review.

The worldwide epidemic scale of diabetes mellitus has been underestimated for a long time. Currently every 10 seconds one patient dies of diabetes-related pathologies. Given the high risk and prevalence of secondary complications as well as individual predisposition to target organ injury, diabetes is one of the major risk factors for various organ and tissue dysfunctions including nerves. The present review outlines the role of Rho Kinase (ROCK) in various diabetic indications: diabetic neuropathy, erectile dysfunction, cardiomyopathy, sexual dysfunction, nephropathy, cardiomyopathy, retinopathy, cerebro-vascular disease and cystopathy. We found that ROCK is involved in various pathophysiological mechanisms, leading to a number of unique diabetic complications. Recent studies have indicated an increasing interest in the use of ROCK inhibitors like Y-27632, H1152 and fasudil not only for the treatment of diabetic neuropathy, but also for the treatment of sexual dysfunction, cardiomyopathy and other diabetic complications. The pathophysiological mechanism has been extensively analyzed and the current status of ROCK inhibitors has been discussed in the review.

Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain

Glutamate is the most widely distributed and a major excitatory neurotransmitter in the CNS. It has been found to play a critical role in various physiological functions in which increased glutamate or its subsequent stimulation is thought to have a role in pathophysiological mechanism of various CNS diseases like epilepsy, stroke, depression and pain. Early attempts to develop glutamatergic antagonists failed in clinical studies due to nonselective or competitive antagonism and have a lot of safety issues like loss of cognitive functions, psychomimetic effect and sedation. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. At present, there are very few effective therapies for neuropathic pain. The current approach includes targeting specific or alternate binding sites of glutamate receptors, resulting in reduced CNS liabilities. Targeting the glutamatergic system shows a better efficacy and fewer side effects, compared with classical drugs for the treatment of neuropathic pain. This review discusses the various targets on glutamatergic system, which includes the receptors, transporters and enzymes, for the treatment of neuropathic pain and their advantages over classical glutamatergic antagonists. The review also highlights the newer drugs in clinical trials for neuropathic pain.

Design of novel rho kinase inhibitors using energy based pharmacophore modeling, shape-based screening, in silico virtual screening, and biological evaluation.

Rho-associated protein kinase (ROCK) plays a key role in regulating a variety of cellular processes, and dysregulation of ROCK signaling or expression is implicated in numerous diseases and infections. ROCK proteins have therefore emerged as validated targets for therapeutic intervention in various pathophysiological conditions such as diabetes-related complications or hepatitis C-associated pathogenesis. In this study, we report on the design and identification of novel ROCK inhibitors utilizing energy based pharmacophores and shape-based approaches. The most potent compound 8 exhibited an IC50 value of 1.5 μM against ROCK kinase activity and inhibited methymercury-induced neurotoxicity of IMR-32 cells at GI50 value of 0.27 μM. Notably, differential scanning fluorometric analysis revealed that ROCK protein complexed with compound 8 with enhanced stability relative to Fasudil, a validated nanomolar range ROCK inhibitor. Furthermore, all compounds exhibited ≥96 μM CC50 (50% cytotoxicity) in Huh7 hepatoma cells, while 6 compounds displayed anti-HCV activity in HCV replicon cells. The identified lead thus constitutes a prototypical molecule for further optimization and development as anti-ROCK inhibitor.

Diffuse panbronchiolitis cases in India: An update

Sir, Diffuse panbronchiolitis (DPB) is an inflammatory lung disease, first identified in 1969. It is well recognized in East Asian countries such as Japan, China, and Korea.[1] The name was proposed to distinguish it from chronic bronchiolitis. “Diffuse” refers to “presence of lesions through both the lungs” and “pan” refers to “inflammation in all layers of bronchioles.” At the time of discovery, DPB had poor prognosis because of recurrent respiratory infections leading to respiratory failure. In the years following the initial description of the DPB in Japan, cases were also identified in other parts of Asia including China and Taiwan. Clinicians across the world became aware of this disease during early 1980s. Over years, DPB cases have been reported from across the globe, thus giving it a recognition of distinct clinical entity. The prognosis of DPB significantly improved after introduction of long‐term, low dose of erythromycin therapy in 1985.[2]