AIM: The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools. BACKGROUND: Warfarin, a commonly used anticoagulant drug, is influenced by cytochrome P450 (CYP) enzymes, particularly CYP2C9. MLAs have been identified to have great potential in personalized therapy. OBJECTIVE: The purpose of the study was to evaluate MLAs in predicting the critical outcomes of warfarin therapy and validate the key predictor genotyping variable using bioinformatics tools. METHODS: An observational study was conducted on adults receiving warfarin. Allele discrimination method was used for estimating the single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and CYP4F2. MLAs were used for identifying the significant genetic and clinical variables in predicting the poor anticoagulation status (ACS) and stable warfarin dose. Advanced computational methods (SNPs' deleteriousness and impact on protein destabilization, molecular dockings, and 200ns molecular dynamics simulations) were employed for examining the influence of CYP2C9 SNPs on structure and function. RESULTS: Machine learning algorithms revealed CYP2C9 to be the most important predictor for both outcomes compared to the classical methods. Computational validation confirmed the altered structural activity, stability, and impaired functions of protein products of CYP2C9 SNPs. Molecular docking and dynamics simulations revealed significant conformational changes with mutations R144C and I359L in CYP2C9. CONCLUSION: We evaluated various MLAs in predicting the critical outcome measures associated with warfarin and observed CYP2C9 as the most critical predictor variable. The results of our study provide insight into the molecular basis of warfarin and the CYP2C9 gene. A prospective study validating the MLAs is urgently needed.

BACKGROUND: Catalpol, one of the main bioactive components isolated from Rehmannia glutinosa, was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate. OBJECTIVE: This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [3H]catalpol in rats. METHODS: Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q- Extractive plus MS. RESULTS: The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median Tmax of 0.75 h and an arithmetic mean half-life (t1/2) of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drug-related substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [3H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems. CONCLUSIONS: Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.

One of the key factors contributing to mortality and morbidity globally is infectious ailments. According to recent statistics from WHO, amplified antimicrobial resistance occurrence among bacteria signifies the utmost threat to global public health. Bacteria have developed various strategies to resist antimicrobials, including enzymatic inactivation of antibiotics, drug efflux, modifications of the antibiotic molecule or chemical alteration of the antibiotic, limited drug uptake, etc. Furthermore, the inefficiency of antimicrobial drugs against resistant bacteria due to low solubility, instability, and associated side effects augments challenges to combat these resistant pathogens. This has attracted the attention of researchers to create nano-delivery and targeting techniques. This review presents an overview of antimicrobial resistance (AMR), its various subtypes, as well as mechanisms involved in AMR. This review also describes current strategies and applications of various nanocarriers, including nanoparticles, liposomes, lipid-based nanoparticles, micelles, and polymeric nanoparticles.

INTRODUCTION: The present study has compiled the prevalence of polypharmacy worldwide and assessed the prevalence of polypharmacy in different populations, including community-dwelling individuals, hospitalized patients, and institutionalized patients. METHODS: This systematic review was conducted and reported according to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A systematic search of electronic databases, including PubMed, Web of Science, and Scielo, was performed in March 2021 without any date and language restrictions. Combinations of the following keywords were used for the search strategy: polypharmacy OR multiple medications OR multiple medicines OR multiple drug AND prevalence. Based on the search and inclusion criteria, two hundred and eight studies (73,076,167 individuals) were selected for inclusion in the systematic review. It was observed that there is a wide variation in the prevalence of polypharmacy between studies. RESULTS: The prevalence of polypharmacy was found to be 30.2%, 61.7%, and 56.9% for community-dwelling individuals, hospitalized patients, and institutionalized patients, respectively. CONCLUSION: Based on the analyses, this systematic review has demonstrated a wide variation in the prevalence of polypharmacy between studies and countries and a high prevalence of polypharmacy in institutionalized and hospitalized patients.

BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β-unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites. OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST. METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer. RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor. CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).