Immunogenicity and safety of two quadrivalent influenza vaccines in healthy adult and elderly participants in India - A phase III, active-controlled, randomized clinical study

Background This study was conducted to compare the immunogenicity and safety profile of two quadrivalent influenza vaccines (QIVs) in healthy adults (18–60 years) and elderly (>61 years) participants. Method This phase III study was conducted from March 2018 to April 2018 across 12 sites in India. In this randomized, observer-blind, active-controlled study, 480 participants were randomized to receive a single dose of test vaccine (subunit, inactivated influenza vaccine; Influvac® Tetra, Abbott) (n = 240) or reference vaccine (split virion, inactivated influenza vaccine; VaxiFlu-4, Zydus Cadilla Healthcare) (n = 240). The primary objective was to describe and compare the immunogenicity of each vaccination group based on hemagglutination inhibition (HI) assay seroprotection and seroconversion rates, and geometric mean fold increase (GMFI) against four vaccine strains in two age groups. Safety and reactogenicity were also compared for the vaccines in both the age groups. Results The pre- and post-vaccination HI titers for both the vaccines were comparable. The GMFI varied from 4.3 – 22.7 in the test and 3.7–21.6 in the reference vaccine group. The seroprotection rates were >90% for the A-strains and ranged between >43% and <60% for B-strains for both the vaccines. Seroconversion rates varied between 41.4% and 78.8%. Overall, the reported adverse events (AEs) for both the vaccines were <1% and comparable. Reported local and systemic reactions were comparable. Conclusion Influvac® Tetra elicited an adequate immune response with a favorable safety profile which was comparable with the reference vaccine. (Clinical trial registry number: CTRI/2018/02/012222

Community and anti-poverty targeting

anti-poverty targeting, community, inequality, local public good, D31, D63, D74, Z13,

Efficacy and safety of fixed dose combination of Sitagliptin, metformin, and pioglitazone in type 2 Diabetes (IMPACT study): a randomized controlled trial

Abstract Background Due to the progressive decline in β-cell function, it is often necessary to utilize multiple agents with complementary mechanisms of action to address various facets and achieve glycemic control. Thus, this study aimed to evaluate the efficacy and safety of a fixed-dose combination (FDC) of metformin/sitagliptin/pioglitazone (MSP) therapy vs. metformin/sitagliptin (MS) in type 2 diabetes mellitus (T2DM). Methods In this phase 3, multicenter, double-blind study, patients with T2DM who exhibited inadequate glycemic control with HbA1c of 8.0–11.0% while taking ≥1500 mg/day metformin for at least 6 weeks were randomized to receive either FDC of MSP (1000/100/15 mg) or MS (1000/100 mg) per day for 24 weeks. The primary outcome measure was the change in HbA1c, and secondary outcomes included changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight from baseline to 24 weeks along with safety and tolerability. Results Among the 236 patients randomized, 207 (87.71%) successfully completed the study. All baseline characteristics were comparable between the FDC of MSP and MS groups. There was a subsequent significant reduction of HbA1c in FDC of MSP (− 1.64) vs. MS (− 1.32); between groups was [− 0.32% (95% CI, − 0.59, − 0.05)], P = 0.0208. Similar reductions were found in FPG [− 13.2 mg/dL (95% CI, − 22.86, − 3.71)], P = 0.0068, and PPG [− 20.83 mg/dL (95% CI, − 34.11, − 7.55)], P = 0.0023. There were no significant changes in body weight. A total of 27 adverse effects (AEs) and one severe AE were reported, none of which were related to the study drug. Conclusion The FDC of MSP demonstrated significant efficacy in managing glycemic indices and could serve as a valuable tool for physicians in the management of Indian patients with T2DM. Trial registration Clinical Trials Registry of India, CTRI/2021/10/037461

Design, Synthesis of Novel, Potent, Selective, Orally Bioavailable Adenosine A_2A Receptor Antagonists and Their Biological Evaluation

Our initial structure–activity relationship studies on 7-methoxy-4-morpholino-benzothiazole derivatives featured by aryloxy-2-methylpropanamide moieties at the 2-position led to identification of compound <b>25</b> as a potent and selective A_2A adenosine receptor (A_2AAdoR) antagonist with reasonable ADME and pharmacokinetic properties. However, poor intrinsic solubility and low to moderate oral bioavailability made this series unsuitable for further development. Further optimization using structure-based drug design approach resulted in discovery of potent and selective adenosine A_2A receptor antagonists bearing substituted 1-methylcyclohexyl-carboxamide groups at position 2 of the benzothiazole scaffold and endowed with better solubility and oral bioavailability. Compounds <b>41</b> and <b>49</b> demonstrated a number of positive attributes with respect to in vitro ADME properties. Both compounds displayed good pharmacokinetic properties with 63% and 61% oral bioavailability, respectively, in rat. Further, compound <b>49</b> displayed oral efficacy in 6-OHDA lesioned rat model of Parkinson diseases

Discovery of Potent and Selective A_2A Antagonists with Efficacy in Animal Models of Parkinson’s Disease and Depression

Adenosine A_2A receptor (A_2AAdoR) antagonism is a nondopaminergic approach to Parkinson’s disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A_2AAdoR antagonists. We herein described a novel series of [1,2,4]­triazolo­[5,1-<i>f</i>]­purin-2-one derivatives that displays functional antagonism of the A_2A receptor with a high degree of selectivity over A₁, A_2B, and A₃ receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound <b>33</b>. Compound <b>33</b> endowed with satisfactory <i>in vitro</i> and <i>in vivo</i> pharmacokinetics properties. Compound <b>33</b> demonstrated robust oral efficacies in two commonly used models of Parkinson’s disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models)