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Apart from all the gloominess, the COVID-19 Pandemic has a silver lining of bringing a renaissance as Ayurveda and integrated medicine are becoming a choice for acute as well as infective diseases. Here we report outcomes of a preliminary work, the randomized controlled trial (CTRI/2021/02/031256) of Madhav Rasayan Plus, an Ayurveda formulation as adjuvant in moderate COVID-19 patients. Madhav Rasayan Plus is a herbomineral formulation beneficial for respiratory, coagulative and other systemic complements of COVID-19. Forty patients with moderate COVID-19 disease were included in two parallel groups (n = 20/group). The Intervention group (Treatment) received Madhav Rasayan Plus tablets (250 mg) twice a day for 15 days, along with standard care (SOC), while the control group received SOC alone. The intervention group significantly improved symptoms of COVID-19 like cough, breathlessness, fatigue and gastric disturbances. There was also statistically significant reduction in inflammatory markers like CRP and Ferritin. Tissue level markers like creatinine phosphokinase and NT- Pro BNP were found restored after treatment. The requirement of supplemental oxygen in the control group (6 days) was reduced by 2.5 times compared to the intervention group (2.4 days). There was also reduced hospital stay and reduced requirement of ICU in comparison with the control group. Also, the indices of fatigue severity score, disturbed sleep cycle score and quality of life revealed better and holistic recovery in the intervention group. This study reveals that COVID-19 and such infective diseases with vital complications can be better dealt with integrated management as immunomodulation and protection of tissues and vital organs are strengths of Ayurveda., Competing Interests: Dr. Sameer Jamadagni, Dr. Prasad Pandkar and Dr. Girish Shirke and Dr. Shailesh Malekar are consultants at Shri Vishwavati Chikitsalaya and Research center, and were involved in basic and literary research work about formulation. Dr Tushar Saundankar also associated with Shri Vishwavati Chikitsalaya and Research center., (© 2022 The Authors.)

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25 , which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae , compound 25 , and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1 H )-ones, exemplified by 34 , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that 34 occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.

Raloxifene hydrochloride (RLX) shows poor bioavailability (<2%), high inter-patient variability and extensive gut metabolism (>90%). The objective of this study was to develop nanostructured lipid carriers (NLCs) for RLX to enhance its bioavailability. The NLC formulations were produced with glyceryl tribehenate and oleic acid. The particle characteristics, entrapment efficiency (EE), differential scanning calorimetry (DSC), in vitro drug release, oral bioavailability (in rats) and stability studies were performed. The optimized nanoparticles were 120 ± 3 nm in size with positive zeta potential (14.4 ± 0.5 mV); % EE was over 90% with the drug loading of 5%. The RLX exists in an amorphous form in the lipid matrix. The optimized RLX-NLC formulation showed sustained release in vitro. The RLX-NLC significantly (p < 0.05) enhanced oral bioavailability 3.19-fold as compared to RLX-free suspension in female Wistar rats. The RLX-NLC can potentially enhance the oral bioavailability of RLX. It can also improve the storage stability., Competing Interests: The authors declare no conflict of interest.

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

Raloxifene HCl (RLX) shows low oral bioavailability (<2%) in humans due to poor aqueous solubility and extensive (>90%) metabolism in gut. Lipid nanoparticles (SLN) with glyceryl tribehenate were designed to enhance drug's oral bioavailability. Box-Bhenken design was used to optimize manufacturing conditions. Optimized SLN had particle size of 167±3nm and high encapsulation efficiency (>92%). Oral bioavailability of RLX from SLN was improved by 3.24 folds compared to free RLX in female Wistar rats. Both clathrin and caveolae mediated endocytosis pathways were involved in the uptake of SLN. Lymphatic transport inhibitor, cycloheximide significantly reduced oral bioavailability of SLN., (Copyright © 2013 Elsevier B.V. All rights reserved.)