Molecular insights into human transmembrane protease serine-2 (TMPS2) inhibitors against SARS-CoV2: homology modelling, molecular dynamics, and docking studies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which caused novel corona virus disease-2019 (COVID-19) pandemic, necessitated a global demand for studies related to genes and enzymes of SARS-CoV2. SARS-CoV2 infection depends on the host cell Angiotensin-Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease-2 (TMPRSS2), where the virus uses ACE2 for entry and TMPRSS2 for S protein priming. The TMPRSS2 gene encodes a Transmembrane Protease Serine-2 protein (TMPS2) that belongs to the serine protease family. There is no crystal structure available for TMPS2, therefore, a homology model was required to establish a putative 3D structure for the enzyme. A homology model was constructed using SWISS-MODEL and evaluations were performed through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). Molecular dynamics simulations were employed to investigate the stability of the constructed model. Docking of TMPS2 inhibitors, camostat, nafamostat, gabexate, and sivelestat, using Molecular Operating Environment (MOE) software, into the constructed model was performed and the protein-ligand complexes were subjected to MD simulations and computational binding affinity calculations. These in silico studies determined the tertiary structure of TMPS2 amino acid sequence and predicted how ligands bind to the model, which is important for drug development for the prevention and treatment of COVID-19

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Effect of superplasticizers on the hydration kinetic and mechanical properties of Portland cement pastes

Hydration of ordinary Portland cement in the presence of two different types of superplasticizers namely sodium lignosulfonate (LS) and naphthalene sulfonate-formaldehyde condensate (NSF) was studied using different experimental techniques. Superplasticized ordinary Portland cement pastes were prepared using the values of standard water of consistency with different additions of each type of superplasticizers used. Pastes were hydrated for different time intervals under normal curing conditions. The results reveal that both superplasticizers increase the workability and reduce the standard water of consistency. This results in an improvement in the mechanical properties of superplasticized cement pastes at all ages of the hydration–hardening process. Naphthalene sulfonate-formaldehyde condensate was found to have the higher efficiency in improving the mechanical properties of the hardened pastes than that of sodium lignosulfonate superplasticizer

Repercussions of pathway inhibition response of Panaxginseng fractions ameliorate cardiac dysfunction in hypertensive model rats

This study examined the preventive and therapeutic benefits of various Panax ginseng fractions against NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension in rats. Rats injected with L-NAME plus vehicle exhibited persistently elevated SBP, serum concentrations of the cardiac injury biomarkers creatine kinase (CK), CK-MB, and troponin, total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), and interleukin (IL)-6, but lower high-density lipoprotein (HDL) compared to the vehicle control group. Furthermore, L-NAME disrupted the normal histological structure and function of rat cardiac tissue. All ginseng fractions and losartan restored SBP to a normal level, reversed the changes in CK, CK-MB, troponin, total cholesterol, TG, HDL, and LDH, and preserved normal myocardial histology, with the WGF demonstrating the greatest cardioprotective and antihypertensive effects. Compounds within multiple ginseng fractions, but especially the aqueous fraction, possess potent and effective antihypertensive, antilipidemic, anti-inflammatory, and cardioprotective properties

Chitosan and sodium alginate—Based bioadhesive vaginal tablets

Metronidazole was formulated in mucoadhesive vaginal tablets by directly compressing the natural cationic polymer chitosan, loosely cross-linked with glutaraldehyde, together with sodium alginate with or ine cellulose (MCC). Sodium carboxymethylcellulose (CMC) was added to some of the formulations. The drug content in tablets was 20%. Drug dissolution rate studies from tablets were carried out in buffer pH 4.8 and distilled water. Swelling indices and adhesion forces were also measured for all formulations. The formula (FIII) containing 6% chitosan, 24% sodium alginate, 30% sodium CMC, and 20% MCC showed adequate release properties in both media and gave lower values of swelling index compared with the other examined formulations. FIII also proved to have good adhesion properties with minimum applied weights. Moreover, its release properties (% dissolution efficiency, DE) in buffer pH 4.8, as well as release mechanism (n values), were negligibly affected by aging. Thus, this formula may be considered a good candidate for vaginal mucoadhesive dosage forms