Thangavel Mahalingam Vijayakumar

Novel drug targets in clinical development for heart failure

BackgroundHeart Failure continues to be a leading cause of mortality and morbidity worldwide. The dismal prognosis of patients in acute heart failure (AHF) can be altered only by exploring novel drug molecules. Although the treatment for chronic heart failure (CHF) has seen remarkable progress, there is still a need to develop molecules that could improve the long-term survival outcomes.PurposeTo review the drug targets for acute and chronic heart failure and the molecules acting on these targets.MethodsThe article discusses on the mechanism of how the potential drug targets can be modulated to alter the pathophysiological processes in heart failure. Current evidence on molecules acting on these targets has also been described from published literature using the PubMed and Clinical Trials.gov databases.ResultsSome of the molecules that are currently being explored for AHF includeomecamtiv mecarbil which activates cardiac myosin ATPase, istaroxime an ionotropicagent that activates SERCA2a pump activity, ularitide and carperitide which are ANP(atrial natriuretic peptide) analogues and recombinant relaxin. Some of the targets forCHF include stabilization of ryanodine receptors, renin inhibition, neprilysin inhibition, neuregulins and SERCA2a gene therapy.ConclusionClinical trials in heart failure must be designed to minimize the risk of “drug failures.” Nevertheless, it is hoped that in the days to come, drugs with superior efficacy and safety will eventually be produced from the surge of molecules that are in the pipeline.

WITHDRAWN: Assessment of serum leptin and resistin levels in association with the metabolic risk factors of pre- and post-menopausal rural women in South India

OBJECTIVES Menopausal status is related with weight gain, abnormal lipid and glucose metabolism leading to metabolic syndrome susceptibility. The aim of this study is to determine circulating serum leptin and resistin levels and to correlate these levels in relationship with the metabolic factors in pre- and post-menopausal women. METHODS A cross-sectional study has been carried out for 34 subjects who were in post-menopause and 31 subjects who had regular menstruation in south Indian rural women. Anthropometric indices, blood pressure, fasting blood sugar (FBS), fasting lipid profile, fasting leptin and resistin levels were measured. RESULTS In a total of 65 subjects, the mean age of pre-menopausal group was 38.65±6.21 and that of post-menopausal group was 55.32±6.32. Fasting serum leptin level was increased considerably in post-menopausal women when compared to pre-menopausal women (P=0.018). Resistin has no significant relationship with metabolic factors except Body Mass Index (BMI) in both the groups. Triglycerides and FBS were lower in pre-menopausal group when compared to post-menopausal group (P<0.001). Leptin was well correlated with BMI in pre-menopausal women (r(2)=0.7120, P<0.0001) as well as post-menopausal women (r(2)=0.2470, P=0.0028). Leptin also had significant correlation with FBS in both pre (r(2)=0.1373, P=0.0402) and post-menopausal women (r(2)=0.2141, P=0.0401). Systolic blood pressure was positively associated with the leptin levels in post-menopausal women (P<0.001). CONCLUSION Leptin was found to have significant association with metabolic factors when compared to resistin in pre- and post-menopausal women and there is no doubt that association of BMI and FBS elevates the level of leptin in both the category.

Safety, Efficacy, and Bioavailability of Fixed-Dose Combinations in Type 2 Diabetes Mellitus: A Systematic Updated Review

Purpose Type 2 diabetes mellitus (T2DM) is a multifactorial disease characterized by insulin resistance. As time progresses, monotherapy often does not provide effective glycemic control, generating the need for an add-on therapy. Hence, multiple oral hypoglycemic agents formulated as a single-dose form called fixed-dose combinations (FDCs) play an essential role in glycemic control. The purpose of this systematic review is to appraise the recently published evidence on the safety, efficacy, and bioavailability of FDCs. Methods A comprehensive literature search of PUBMED, Scopus, ScienceDirect.com, ProQuest, SpringerLink, clintrials.gov, Embase, and EBSCO using the key words FDCs, combination therapy, T2DM management, and add-on therapy was conducted. Studies on the safety profile/tolerability, efficacy, and bioavailability of various FDCs of oral hypoglycemic agents were preferred. Findings The systematic review of all the publications suggests that FDCs of oral hypoglycemic agents (OHAs) significantly reduce HbA1c and fasting plasma glucose values, thereby efficiently reducing hyperglycemia in patients in whom monotherapy fails. FDCs are the bioequivalent of the concomitant drugs administered as individual components. Improved adherence to FDCs and the absence of serious adverse drug reactions compared with dual therapy play an important role in decreasing the incidence of hyperglycemia in patients with T2DM. Implications From this updated review, it was found that metformin was the most widely used component of FDCs with other OHAs. Studies on the safety and efficacy of newly approved OHAs such as sodium glucose cotransporter inhibitors were limited. An increasing number of randomized trials on the safety and efficacy of newly emerging FDCs suggests that they would be better treatment options for T2DM patients.

Comparative assessment of methylcobalamin and ascorbic acid on cognitive function in post-menopausal women - A randomized, double-blind trial

Introduction A decline in cognitive function occurs as women progress through the menopausal transition. Objective The present study was designed to compare the effect of Methylcobalamin and Ascorbic Acid on Cognitive Function in post-menopausal women. Methods A randomized, double-blind trial was conducted in postmenopausal women with mild to moderate cognitive dysfunction. Eligible 56 subjects were randomized, the effect of ascorbic acid (500 mg OD) and methylcobalamin (50 mcg OD) was compared after 12 weeks of treatment. MMSE Questionnaire was used to assess the cognitive function, and β-amyloid42 was estimated in serum by enzyme-linked immunosorbent assay (ELISA). Results In MMSE score, delayed verbal recall (P = 0.027), naming (P = 0.042) and repetition (P = 0.031) scores were significantly improved in ascorbic acid group when compared to baseline. The β-amyloid42 level was decreased significantly in subjects receiving ascorbic acid (P = 0.04) when compared to Methylcobalamin group (P = 0.31). The inverse relationship between β-amyloid42 levels and the MMSE score was found in ascorbic acid treatment (r = 0.6324, P = 0.0004). Conclusion Based on MMSE and β-amyloid42 results, ascorbic acid showed improvement in cognitive function among post-menopausal women when compared to methylcobalamin supplement.

Effect of Dioscorea bulbifera and its Major Bioactive Compound, Diosgenin on CYP450 Mediated Drug Metabolism

Cytochrome P450 (CYP450) inhibition by the bioactive molecules of herbs leading to greater potential for toxicity of co-administered drugs. Diosgenin is an important bioactive steroidal sapogenin from Dioscorea bulbifera belonging to the triterpene group and is of great interest to the pharmaceutical industry. The purpose of this study was, to find whether D. bulbifera and Diosgenin influences the effect on rat CYP450 enzymes and its important isoforms (CYP3A4, CYP2D6) by using high through put screening. CYP450-CO Complex assay was performed in rat pooled liver microsomes to calculate percentage inhibition of test samples on CYP450. IC values were determined by fluorometric assays of CYP3A4 and CYP2D6. Mode of inhibition of Diosgenin on these CYPs were further assessed by molecular docking studies with the Glide (Schrodinger Inc. U.S.A.). In CYP450 inhibition assay, the inhibitory potential of herb extract (40.44±1.28 %) was found to be less than positive control (72.08±1.96 %). In fluorometric assay, herb extract exhibited higher IC values (96.21 ± 1.32 to 180.42±0.12 µg/ml) when compared to positive inhibitors and lower than Diosgenin (172.54±0.52 to 201.86±1.49 µg/ml) on CYP3A4 and CYP2D6. Based on the inhibitory potential, test substances exhibited very less interaction capacity, thereby leading to less significant herb-drug interaction with co-administered drugs.Further clinical studies are required to fully assess the safety of Diosgenin in terms of CYP450.