Adoption of the World Health Organization access, watch reserve index to evaluate and monitor the use of antibiotics at a tertiary care hospital in India.

Background: The World Health Organization classification of antibiotics classifies key antibiotics into access, watch, and reserve (AWaRe) categories. Categorization provides a novel metrics called "AWaRe index" to study and monitor antibiotic consumption globally and within the same setting over time. Aim: The aim of this study is to compare the use of antibiotics in 2 years using the AWaRe index tool. Materials and Methods: A retrospective study was conducted in SMS Hospital, Jaipur to collect data regarding total antibiotics consumed between January 2017 and December 2018 from drug distribution centers in hospital premises using the AWaRe classification. Data were then compared on yearly basis. Results: In 2017, 53.31% of antibiotics consumed belonged to access, 40.09% to watch, and 3.40% to reserve category, respectively, as compared to 41.21%, 46.94%, and 8.15%, respectively, in 2018. Conclusion: Increased use of watch (17%) and reserve antibiotics (140%) over 1 year with the same infection scenario in a similar setting indicates resistance in evolution.

Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947.

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

Students' perception regarding pedagogy, andragogy, and heutagogy as teaching-learning methods in undergraduate medical education.

INTRODUCTION: Medical education is tricky to imbibe and difficult to apply. Various teaching-learning (TL) methods have been tried from time to time to enhance the proficiency of students. The aim was to assess the students' perception toward three different TL methods (pedagogy, andragogy, and heutagogy) in medical education. MATERIALS AND METHODS: A comparative experimentalquestionnaire-based study was done on population of second-year MBBS students of SMS Medical College, Jaipur, in October 2019. They were taught topic of anticancer drugs using pedagogy, andragogy, and heutagogy methods. Then, their opinion regarding these methods was collected and evaluated. The reliability of the questionnaire was ascertained by Cronbach's alpha value which turned out to be 0.89. The data collected were analyzed statistically using one-way Analysis of Variance (ANOVA) and Principal Component Analysis (PCA). RESULTS: The results showed that all these methods differ significantly from each other as the P < 0.05 considering 5% as level of significance. PCA revealed that andragogy and heutagogy were found to be most effective in this study. CONCLUSION: Competency-based andragogy and capability-based heutagogy are more effective TL methods than didactic lecture-based pedagogy for MBBS undergraduate students.

A novel series of indazole-/indole-based glucagon receptor antagonists.

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.

Evaluation of Glycemia Control Achieved by Glargine and Lispro Versus Detemir and Aspart Insulin Regimes in Type 2 Diabetics Undergoing Surgery.

There is paucity of scientific literature regarding the clinical outcome of long lasting basal insulin and rapid acting mealtime insulin regimes in surgical situations although employed in non-surgical situations. This study has evaluated the clinical outcome of two subcutaneous split-mixed Glargine+Lispro and Detemir+Aspart insulin regimes in type 2 diabetics undergoing surgery.

Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective ß3 adrenergic receptor agonists for the treatment of overactive bladder.

A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.

Isolated collagenoma on the scalp: a rare presentation.

Connective tissue nevi of the skin are benign hamartomatous lesions consisting predominantly of one of the components of the extracellular matrix comprising of collagen, elastin or glycosaminoglycans type. Connective tissue nevi may be solitary or multiple, sporadic or inherited. Collagenomas are asymptomatic and usually occurs over upper trunk, arms, back, thighs and soles. We, hereby report a young boy with collagenoma over the scalp, a rare site.

Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human ß3 adrenergic receptor agonists.

A novel class of human ß(3)-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed ß(3)-AR agonists. As observed, many of the ß(3)-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human ß(3) functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N-C bond of the ethanolamine. Compound 39 exhibited excellent functional ß(3) agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new ß(3)-AR agonists containing the pyrrolidine moiety.

Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles.

A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

Glycaemic control in type 2 diabetes mellitus patients undergoing major surgery: comparison of three subcutaneous insulin regimens.

Pre-operative glucose control with subcutaneous insulin in non-urgent situations is logical and well accepted. But the best regimen amongst the many available ones of insulin administration during peroperative period during major surgery is uncertain. We compared three subcutaneous insulin regimens for pre-operative glucose control in type 2 diabetes mellitus (T2DM) patients. One hundred and seventy-two T2DM patients hospitalised for major surgeries were enrolled in the study. Pre-operative glycaemic control was achieved with one of the following regimens: (1) Premix 30/70 insulin (R/N-0-R/N). (2) R + NPH; basal-bolus regular and NPH insulin (R-R-R/N). (3) R + G; basal-bolus regular and glargine insulin (R-R-R-G) [G: glargine insulin; N: neutral protamine hagedorn insulin; R: regular insulin]. Insulin doses were adjusted to achieve fasting and postmeal glucose values respectively <120 and <180 mg/dl. Intra-operative management included glucose insulin potassium solution. Postoperatively, patients were switched back to the same insulin regimen that they received pre-operatively. These regimens were compared for following parameters. (1) Time to achieve glycaemic target. (2) Total daily insulin dose. (3) Incidence of hypo- and severe hyperglycaemia. (4) Complications like renal failure, infection, etc. (5) in hospital mortality. R + G regimen was associated with lesser dose of insulin (29.53 +/- 9.83 versus 35.67 +/- 12.19 and 37.42 +/- 13.5 unit respectively for regimen 2 and 1, p < 0.005), lesser time to achieve glycaemic target (6.75 +/- 3.25 versus 7.37 +/- 7.47 and 8.23 +/- 6.04 days, p > 0.05), lower incidence of hypoglycaemia (10.53 versus 14.81 and 30.00%, p < 0.02) and severe hyperglycaemia (5.26 versus 29.63 and 8.33%, p < 0.005). Incidence of infection (10.53 versus 18.52 and 15.00%, p > 0.05), renal complications (10.53 versus 11.11 and 15.00%, p > 0.05) and mortality (5.26 versus 14.81 and 15.00%, p > 0.05) were lower with this regimen, but the difference was not statistically significant. Premix 30/70 and R + NPH regimens were comparable for most parameters but hypoglycaemia and severe hyperglycaemia were more frequent respectively with premix 30/70 and R + NPH regimens. In contrast to the popular perception about the risk of hypoglycaemia with long acting insulins, insulin analogue glargine was found to be better than NPH insulin in basal bolus regimens in achieving better glycaemic control with fewer incidence of hypoglycaemia.

The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection.

A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.

A recombinant 63-kDa form of Bacillus anthracis protective antigen produced in the yeast Saccharomyces cerevisiae provides protection in rabbit and primate inhalational challenge models of anthrax infection.

Infection by Bacillus anthracis is preventable by prophylactic vaccination with several naturally derived and recombinant vaccine preparations. Existing data suggests that protection is mediated by antibodies directed against the protective antigen (PA) component of the anthrax toxin complex. PA is an 83-kDa protein cleaved in vivo to yield a biologically active 63-kDa protein. In an effort to evaluate the potential of yeast as an expression system for the production of recombinant PA, and to determine if the yeast-purified rPA63 can protect from a lethal inhalational challenge, the sequence of the 63-kDa form of PA was codon-optimized and expressed in the yeast Saccharomyces cerevisiae. Highly purified rPA63 isolated from Saccharomyces under denaturing conditions demonstrated reduced biological activity in a macrophage-killing assay compared to non-denatured rPA83 purified from Escherichia coli. Rabbits and non-human primates (NHP) immunized with rPA63 and later challenged with a lethal dose of B. anthracis spores were generally protected from infection. These results indicate that epitopes present in the 63-kDa from of PA can protect rabbits and non-human primates from a lethal spore challenge, and further suggest that a fully functional rPA63 is not required in order to provide these epitopes.

A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects.

Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 +/- 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a KDB of 81 +/- 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagon-induced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo.