Current Drug Targets - Volume 15, Issue 2, 2014

The new chemical entity (NCE) has been knocked as novel antidiabetic agent, e.g. Saroglitazar. Saroglitazar is a drug for the treatment of Type II diabetes. Saroglitazar is marketed under the trade name Lipaglyn, developed by the Zydus Cadila. Lipaglyn is the first indigenously developed NCE by any Indian pharmaceutical company, ever. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in June 2013. Lipaglyn is indicated for the patients suffering from diabetes dyslipidemia. It also provides the option of a once-daily oral therapy. Saroglitazar regulates the lipid parameters as well as glycemic control. The present article describes Saroglitazar with its chemical synthesis and patent status with its summary of clinical studies.

Osteoporosis is one of the most serious under-diagnosed and under-treated recessive diseases, leading to increased mortality and morbidity as well as huge economic burden. The fundamental reason for the occurrence of osteoporosis lies in the disequilibrium between bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. Osteoclast-osteoblast communication plays important roles in the maintenance of hemeostasis. In this review, we present the detailed mechanisms of this communication, including modes of diffusible paracrine factors, cell-cell direct contact and cell-bone matrix interaction. We demonstrate that osteoclasts (or osteoblasts) could not only secrete cytokines, growth factors, chemokines and function in a paracrine manner, but also express molecules on their membranes to bind to the receptors on osteoblasts (or osteoclasts) to transduce bidirectional signals. Moreover, growth factors and cytokines deliberated from bone matrix during bone resorption could also regulate the function of both osteoblasts and osteoclasts. This review gives the latest knowledge of communication factors, some of which are emerging as novel therapeutic targets for future development of antiosteoporotic drugs.

Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derived from three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relatively small amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associated with iNOS activity may have detrimental consequences to the cardiovascular system and contribute to hypertension. In this article, we reviewed current literature and found mounting evidence indicating that increased iNOS expression and activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO produced by iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress and endothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete with eNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhanced production of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute to hypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on different animal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosative stress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potential pharmacological target in hypertension.

Influenza neuraminidase (NA) is an important target for designing anti-influenza drugs. By now, three inhibitors, zanamivir, oseltamivir and peramivir have been approved. However, in recent years, the potential threat of influenza pandemics and constant emergence of new drug-resistant influenza virus strains have weaken the defensive role of the current anti-influenza drugs. From another point of view, in this review we focused on some novel NA inhibitors which were mainly derived from natural products that had a variety of structural scaffolds, such as flavonoids, xanthones and diarylheptanoids. Besides interfering the function of NA, some of these compounds also can potently inhibit the replication of influenza virus. It is hoped that these compounds could be the source of leads and provide a guide for discovering new potent anti-influenza virus agents.

Administration of drugs through skin via transdermal route is a non-invasive approach and applicable for systemic delivery but it is not suitable for drugs having higher molecular weight. Various approaches have been used to improve the efficacy of transdermal route such as vesicular system, iontophoresis, microneedles, use of permeation enhancers, etc. Among the several approaches, vesicular delivery is gaining importance in transdermal drug delivery. Transfersomes are one of the vesicular systems and they are best suited for the transdermal delivery of higher molecular weight compounds. Due to the deformable nature of transfersomes, they penetrate into deeper layers of skin, retain their original structure after penetration and finally enter into the systemic circulation. This review focuses mainly on the applications of transfersomes in the field of drug delivery i.e. delivery of analgesics, anti-cancers, proteins and peptides, immunomodulators, steroidal hormones and herbal drugs with increased penetration through skin. In addition, this review also deals with preparation methods available for preparing transfersomes, characterization, mechanism of penetration upon topical application and its kinetic aspects.

Venous thrombosis is a common medical disorder affecting nearly one million Americans each year. This review will focus primarily on the formation of venous thrombosis as well as current and future treatment options. While the full pathophysiology of venous thrombosis is not known, recent evidence points to a role for von Willebrand Factor, platelets, and neutrophils in thrombus formation. Many laboratory and imaging tests may be used for the diagnosis of venous thrombosis (VTE), but risk factor identification and clinical examination should not be overlooked as they are vital in assuring accurate treatment and patient identification. Historically heparin followed by a vitamin K antagonist has been the standard of care for treatment of VTE, but increasing data involving factor Xa inhibitors and direct thrombin inhibitors may mean a shift in first-line therapy in the very near future. Invasive therapies such as catheter-directed thrombolysis have also shown promise in the treatment of venous thrombosis and will likely see increased use in the future.

Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiological phenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. The present review attempts to discuss the currently employed pharmacological agents for the management of neuropathic pain including anti-depressants, anti-convulsants, NMDA receptor antagonists, topical & local anesthetics, and upload analgesics. However, the existing pharmacotherapy has marginal efficacy and significant side effects. The review also gives an insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimental models that include NSAIDs, corticosteroids, ion channel blockers (Ca2+, Na+, K+, and TRP channel); ion exchange modulators (NCE and NHE); ion/molecule transport modulators (NKCC-1 and glycine); receptor modulators (kinin, histamine, 5-HT1A, dopamine, alpha & beta adrenergic, purinergic, excitatory amino acid, sigma, ORL1, endothelin, melanocortin, ephrin and PAR); enzyme inhibitors (cytosolic kinase, metalloproteinase, protease, vasopeptidase, D-amino acid oxidase, fatty acid amide hydrolase, aldose reductase and sorbitol dehydrogenase); other ligands (AGE, RAGEs, neuropeptides, neurotrophic factor, complement cascade, cytokine, glial cell & gap junction, nitrous oxide, growth factor, cell adhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronal cell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.