Pharmacogenetics and Adverse Events in the Use of Fluoropyrimidine in a Cohort of Cancer Patients on Standard of Care Treatment in Zimbabwe.

Fluoropyrimidines are commonly used in the treatment of colorectal cancer. They are, however, associated with adverse events (AEs), of which gastrointestinal, myelosuppression and palmar-plantar erythrodysesthesia are the most common. Clinical guidelines are used for fluoropyrimidine dosing based on dihydropyrimidine dehydrogenase (DPYD) genetic polymorphism and have been shown to reduce these AEs in patients of European ancestry. This study aimed to evaluate, for the first time, the clinical applicability of these guidelines in a cohort of cancer patients on fluoropyrimidine standard of care treatment in Zimbabwe. DNA was extracted from whole blood and used for DPYD genotyping. Adverse events were monitored for six months using the Common Terminology Criteria for AEs (CTCAE) v.5.0. None of the 150 genotyped patients was a carrier of any of the pathogenic variants (DPYD*2A, DPYD*13, rs67376798, or rs75017182). However, severe AEs were high (36%) compared to those reported in the literature from other populations. There was a statistically significant association between BSA (p = 0.0074) and BMI (p = 0.0001) with severe global AEs. This study has shown the absence of the currently known actionable DPYD variants in the Zimbabwean cancer patient cohort. Therefore, the current pathogenic variants in the guidelines might not be feasible for all populations hence the call for modification of the current DPYD guidelines to include minority populations for the benefit of all diverse patients.

Computational study of the therapeutic potentials of a new series of imidazole derivatives against SARS-CoV-2.

Owing to the urgent need for therapeutic interventions against the SARS-coronavirus 2 (SARS-CoV-2) pandemic, we employed an in silico approach to evaluate the SARS-CoV-2 inhibitory potential of newly synthesized imidazoles. The inhibitory potentials of the compounds against SARS-CoV-2 drug targets - main protease (Mpro), spike protein (Spro) and RNA-dependent RNA polymerase (RdRp) were investigated through molecular docking analysis. The binding free energy of the protein-ligand complexes were estimated, pharmacophore models were generated and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the compounds were determined. The compounds displayed various levels of binding affinities for the SARS-CoV-2 drug targets. Bisimidazole C2 scored highest against all the targets, with its aromatic rings including the two imidazole groups contributing to the binding. Among the phenyl-substituted 1H-imidazoles, C9 scored highest against all targets. C11 scored highest against Spro and C12 against Mpro and RdRp among the thiophene-imidazoles. The compounds interacted with HIS 41 - CYS 145 and GLU 288 - ASP 289 - GLU 290 of Mpro, ASN 501 of Spro receptor binding motif and some active site amino acids of RdRp. These novel imidazole compounds could be further developed as drug candidates against SARS-CoV-2 following lead optimization and experimental studies.

Neisseria gonorrhoeae Antimicrobial Resistance: Past to Present to Future.

Neisseria gonorrhoeae (gonococcus) is a Gram-negative bacterium that causes gonorrhoea-a sexually transmitted disease. This gonococcus has progressively developed resistance to most of the available antimicrobials. Only a few countries around the world have been able to run extensive surveillance programmes on gonococcal infection and antimicrobial resistance, raising a global concern. Thus, this review focuses on the mechanisms of resistance to recommended antimicrobials in the past and present time. The approaches by the scientific community in the development of novel technologies such as whole-genome sequencing to predict antimicrobial resistance, track gonococcal transmission, as well as, introduce new therapeutics like Solithromycin, Zoliflodacin, and Gepotidacin were also discussed.