Current Drug Targets (v.15, #2)

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

Communication Factors-Promising Targets in Osteoporosis Treatment by Yan Zhang, Peijun Liu, Juan Li, Kun Li, Yue Teng, Xiang Wang, Xu Li (156-163).
Osteoporosis is one of the most serious under-diagnosed and under-treated recessive diseases, leading to increasedmortality and morbidity as well as huge economic burden. The fundamental reason for the occurrence of osteoporosislies 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 directcontact 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 tobind to the receptors on osteoblasts (or osteoclasts) to transduce bidirectional signals. Moreover, growth factors and cytokinesdeliberated 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 therapeutictargets for future development of antiosteoporotic drugs.

Inducible Nitric Oxide Synthase as a Possible Target in Hypertension by Gustavo H. Oliveira-Paula, Riccardo Lacchini, Jose E. Tanus-Santos (164-174).
Nitric oxide (NO) is an important vasodilator produced by vascular endothelium. Its enzymatic formation is derivedfrom three different synthases: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) synthases. While relativelysmall amounts of NO produced by eNOS are important to cardiovascular homeostasis, high NO levels produced associatedwith 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 expressionand activity contribute to the pathogenesis of hypertension and its complications. Excessive amounts of NO producedby iNOS up-regulation can react with superoxide anions forming peroxynitrite, thereby promoting nitrosative stress andendothelial dysfunction. In addition, abnormal iNOS activity can up-regulate arginase activity, allowing it to compete witheNOS for L-arginine, thereby resulting in reduced NO bioavailability. This may also lead to eNOS uncoupling with enhancedproduction of superoxide anions instead of NO. All these alterations mediated by iNOS apparently contribute tohypertension and its complications. We also reviewed current evidence showing the effects of iNOS inhibitors on differentanimal models of hypertension. iNOS inhibition apparently exerts antihypertensive effects, decreases oxidative and nitrosativestress, and improves vascular function. Together, these studies highlight the possibility that iNOS is a potentialpharmacological 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 influenzapandemics and constant emergence of new drug-resistant influenza virus strains have weaken the defensive role of thecurrent anti-influenza drugs. From another point of view, in this review we focused on some novel NA inhibitors whichwere 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 replicationof influenza virus. It is hoped that these compounds could be the source of leads and provide a guide for discovering newpotent anti-influenza virus agents.

Administration of drugs through skin via transdermal route is a non-invasive approach and applicable for systemicdelivery but it is not suitable for drugs having higher molecular weight. Various approaches have been used to improvethe 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. Transfersomesare one of the vesicular systems and they are best suited for the transdermal delivery of higher molecular weightcompounds. Due to the deformable nature of transfersomes, they penetrate into deeper layers of skin, retain their originalstructure after penetration and finally enter into the systemic circulation. This review focuses mainly on the applications oftransfersomes 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 withpreparation methods available for preparing transfersomes, characterization, mechanism of penetration upon topical applicationand its kinetic aspects.

Pathophysiology and Pharmacologic Treatment of Venous Thromboembolism by Jonathan Bain, Douglas R. Oyler, Susan S. Smyth, Tracy E. Macaulay (199-209).
Venous thrombosis is a common medical disorder affecting nearly one million Americans each year. This reviewwill focus primarily on the formation of venous thrombosis as well as current and future treatment options. While thefull 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 venousthrombosis (VTE), but risk factor identification and clinical examination should not be overlooked as they are vital in assuringaccurate treatment and patient identification. Historically heparin followed by a vitamin K antagonist has been thestandard of care for treatment of VTE, but increasing data involving factor Xa inhibitors and direct thrombin inhibitorsmay mean a shift in first-line therapy in the very near future. Invasive therapies such as catheter-directed thrombolysishave also shown promise in the treatment of venous thrombosis and will likely see increased use in the future.

Drug Therapy of Neuropathic Pain: Current Developments and Future Perspectives by Arunachalam Muthuraman, Nirmal Singh, Amteshwar Singh Jaggi, Muthusamy Ramesh (210-253).
Understanding mechanism of neuropathic pain is too complex and involves both peripheral and central pathophysiologicalphenomenon. Accordingly the treatment of neuropathic pain is also very complex and is unsatisfactory. Thepresent review attempts to discuss the currently employed pharmacological agents for the management of neuropathicpain 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 givesan insight into various pharmacological agents with potential neuropathic pain attenuating properties in experimentalmodels that include NSAIDs, corticosteroids, ion channel blockers (Ca2+, Na+, K+, and TRP channel); ion exchangemodulators (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 acidoxidase, 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, celladhesion molecule and neuronal sprouting molecule). Moreover, some advanced therapeutic approaches such as neuronalcell transplantation, stem cell therapy, anti-sense oligonucleotide and recombinant therapy have also been dicussed.