1,2-Difunctionalization of Aryne with Sulfenamide and Organohalide: Mild and Metal-Free Access to S-(o-Halo)aryl Sulfilimine.

A mild and metal-free approach has been developed for 1,2-difunctionalization of aryne using sulfenamides as a nucleophile and a halogen source (CX4) as an electrophile to synthesize S-(o-halo)aryl sulfilimines. The late-stage functionalizations of halide handles via Suzuki-Miyaura and Buchwald-Hartwig reactions exhibit the synthetic utilities of the products. The chemoselectivity, regioselectivity, rapidity, and use of economical CCl4 are the advantages of this protocol.

Fixed-Dose Combination of Dapagliflozin + Sitagliptin + Metformin in Patients with Type 2 Diabetes Poorly Controlled with Metformin: Phase 3, Randomized Comparison with Dual Combinations.

INTRODUCTION: This study compared efficacy and safety of triple drug fixed-dose combination (FDC) of dapagliflozin (DAPA) + sitagliptin (SITA) + metformin (MET) extended release (ER) with SITA + MET sustained release (SR) and DAPA + MET ER in patients with type 2 diabetes poorly controlled with metformin. METHODS: This phase 3, randomized, open-label, active-controlled study included adult patients with glycated hemoglobin (HbA1c) ≥ 8% (64 mmol/mol) and ≤ 11% (97 mmol/mol), randomized in 1:1:1 ratio to receive either FDC of DAPA + SITA + MET ER (10 mg + 100 mg + 1000 mg) tablets once daily (n = 137) or co-administration of SITA + MET SR (100 mg + 1000 mg) tablets once daily (n = 139) or FDC of DAPA + MET ER (10 mg + 1000 mg) tablets once daily (n = 139). Primary endpoint was mean change in HbA1c from baseline to week 16. RESULTS: Mean baseline HbA1c was approximately 9% (75 mmol/mol) in each treatment group. At week 16, adjusted mean reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER (- 1.73% [- 19.0 mmol/mol]) compared to SITA + MET SR (- 1.28% [- 14.1 mmol/mol]; difference of - 0.46% [- 5.1 mmol/mol], p < 0.001) and DAPA + MET ER (- 1.33% [- 14.6 mmol/mol]; difference - 0.4% [4.4 mmol/mol], p < 0.001). Similarly, at week 12, reduction in HbA1c from baseline was significantly greater with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0006) and DAPA + MET ER (p = 0.0276). At week 16, DAPA + SITA + MET ER showed significant reduction in postprandial blood glucose compared to DAPA + MET ER (p = 0.0394) and significant reduction in fasting blood glucose with DAPA + SITA + MET ER compared to SITA + MET SR (p = 0.0226). The proportion of patients achieving HbA1c < 7.0% (53 mmol/mol) at week 16 was significantly higher with DAPA + SITA + MET ER (38.5%) versus SITA + MET SR (12.8%) (p < 0.001) and DAPA + MET ER (21.3%) (p = 0.0023). All study medications were well tolerated. CONCLUSION: Triple FDC of DAPA + SITA + MET ER tablets once daily was significantly better in achieving glycemic control versus dual combination once daily in patients with type 2 diabetes poorly controlled with metformin without any significant safety concerns. TRIAL REGISTRATION: CTRI/2021/11/038176, registered on 22 November 2021.

Type 2 diabetes is a progressive disease in which the risks of microvascular and macrovascular complications and mortality are strongly associated with hyperglycemia. Achieving glycemic control remains the main goal of treatment to prevent these complications. Estimates in 2019 showed that 77 million individuals had diabetes in India, which is expected to rise over 134 million by 2045. Considering the progressive nature of the disease, many guidelines recommend use of dual or triple drug therapy based on glycated hemoglobin (HbA1c) level. Use of fixed-dose combination (FDC) helps to improve therapy compliance and can provide optimum therapeutic benefits. Mechanisms of action of dipeptidyl peptidase 4 (DPP4) and sodium­glucose cotransporter 2 (SGLT2) inhibitors are complementary to that of metformin with low risk of hypoglycemia. Studies have shown beneficial effects of adding both DPP4 inhibitors and SGLT2 inhibitors after metformin monotherapy. This phase 3 study was designed to assess efficacy and safety of triple FDC of dapagliflozin + sitagliptin + metformin extended release in comparison with combipack of sitagliptin + metformin sustained release and FDC of dapagliflozin + metformin ER in patients with type 2 diabetes inadequately controlled with metformin monotherapy. The study demonstrated superiority of triple FDC of dapagliflozin + sitagliptin + metformin ER over dual combinations in terms of reduction in HbA1c and percentage of patients achieving target HbA1c at the end of week 16. The current study provides evidence for considering triple FDC of dapagliflozin + sitagliptin + metformin ER as an alternative option with minimal risk of hypoglycemia and weight gain, while considering oral triple-combination therapy for patients to achieve their glycemic target.

Mild and Metal-Free Protocol toward the Synthesis of Triarylmethanes by Reactions of (Hetero)Arylboronic Acids and ortho-Hydroxyarylaldehydes.

Herein, we have reported a metal-free, mild, and novel protocol for the synthesis of various triarylmethanes (TRAMs) in moderate to good yields via the reactions of aryl boronic acids and ortho-hydroxyarylaldehydes in the presence of stoichiometric amounts of Et3N in dichloroethane at 80 °C. Additionally, the synthetic utilities of few synthesized TRAMs were proven by carrying out bromination on the -OH-containing aryl part and followed by functionalization of bromine through a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with arylboronic acids in good yields. The -OH group was also alkylated and arylated through simple alkylation and Chan-Lam reaction, respectively.

Patterns and predictive factors of long-lasting insecticidal net usage in a previously high malaria endemic area in Sri Lanka: a cross-sectional survey.

BACKGROUND: Long-lasting insecticidal nets (LLINs) have been widely distributed in Sri Lanka for malaria control. Their effectiveness depends on proper utilisation and maintenance at the household level. METHODS: A cross-sectional study was performed to examine the patterns and predictive factors of LLIN maintenance and use in Anuradhapura district. Data was collected and analysed from 530 LLIN-owning households, selected by a multi-stage cluster sampling technique. Multivariable logistic regression identified factors associated with proper maintenance at the household level. Hierarchical linear modelling identified factors associated with LLIN use the previous night. RESULTS: Almost 75% (377/504) of households had used all their LLINs the previous night, while 82.9% (418/504) had used at least one. Only 3.2% (15/474) were maintaining the LLIN in such a way as to maximise its insecticidal efficacy. Six variables were significantly associated (p<0.05) with use the previous night: more residents, fewer plain nets, reporting practical benefits of LLINs, conical shape, newer nets and lack of side effects. Two variables were significantly associated with proper maintenance: increasing level of education and taking safety precautions while washing. CONCLUSIONS: Results suggest LLIN practices could improve in settings of low malaria transmission if distribution programmes took into account recipient preferences, promoted LLIN use over plain nets, and emphasised the techniques and significance of proper net maintenance.

A rare case of mucormycosis of median sternotomy wound caused by Rhizopus arrhizus.

We describe a case of mucormycosis of median sternotomy wound caused by Rhizopus arrhizus . The patient, a known diabetic and a case of coronary artery disease underwent coronary artery bypass surgery. In the postoperative period, patient developed infection of the median sternotomy wound, from which R. arrhizus was isolated on culture. Patient succumbed in spite of being treated with surgical debridement and amphotericin B. To the best of our knowledge, this is the first reported case of mucormycosis of median sternotomy wound from India.

Possible mechanisms of hypotension produced 70% alcoholic extract of Terminalia arjuna (L.) in anaesthetized dogs.

BACKGROUND: The bark of Terminalia arjuna L. (Combretaceae) is used in Ayurveda since ancient times for the treatment of cardiac disorders. Previous laboratory investigations have demonstrated the use of the bark in cardiovascular complications. The present study was aimed to find the effect of 70% alcoholic extract of Terminalia arjuna on anaesthetized dog blood pressure and probable site of action. METHODS: Six dogs were anaesthetized with intraperitoneal injection of thiopental sodium and the blood pressure of each dog (n = 6) was measured from the left common carotid artery connected to a mercury manometer on kymograph. The femoral vein was cannulated for administration of drug solutions. The extract of T. arjuna (dissolved in propylene glycol) in the dose range of 5 to 15 mg/kg were administered intravenously in a pilot study and the dose (6 mg/kg) which produced appreciable hypotension was selected for further studies. RESULTS: Intravenous administration of T. arjuna produced dose-dependent hypotension in anaesthetized dogs. The hypotension produced by 6 mg/kg dose of the extract was blocked by propranolol but not by atropine or mepyramine maleate. This indicates that muscarinic or histaminergic mechanisms are not likely to be involved in the hypotension produced by the extract. The blockade by propranolol of the hypotension produced by T. arjuna indicates that the extract might contain active compound(s) possessing adrenergic beta2-receptor agonist action and/or that act directly on the heart muscle. CONCLUSION: The results indicated the likely involvement of peripheral mechanism for hypotension produced by the 70% alcoholic extract of Terminalia arjuna and lends support for the claims of its traditional usage in cardiovascular disorders.