Pharmacokinetic influences of selected phytochemical compounds from herbal medicine used by HIV- positive patients on drugs-metabolising proteins of HIV-1 protease inhibitor drugs.

Doctoral Degree. University of KwaZulu-Natal, Durban.Introduction: Sub-Saharan Africa has the highest incidence of HIV/AIDS and AIDS-related deaths in the world. Although there is currently no cure for the disease, significant progress has been made in developing antiretroviral drugs (ARVs) that can inhibit disease progression. However, despite the availability of these ARVs, HIV-positive patients use traditional herbal medicines (THMs) either alone or simultaneously with conventional ARVs. This simultaneous usage may cause serious adverse effects due to herb-drug interactions, although there are also possible positive effects such as the enhanced bioavailability of the ARVs or possible antiviral activity. Aim: These potential interactions prompted this study which examined the pharmacokinetic properties and influences of selected phytochemical compounds (PCs) commonly found in THMs on drug-metabolising proteins involved in the metabolism of protease inhibitor drugs (PIs) as well as their potential as inhibitors of HIV-1 protease. Method: The potential inhibitory activities of fifteen PCs (Epigallocatechin gallate (EGCG), Fisetin (FST), Ellagic acid (EGA), Cholesta-4,6-dien-3-ol (CHD), Lanosteol (LNT), Benzyl Isothiocyanate (BIT), Gallic acid, (GA), Isosteviol (IST), Stigmasterol (STG), Phthalic acid (PTA), Naringenin (NGN), Kaempferol-7-glucoside (K7G), Luteolin (LUT), Geranin (GER), Apigenin (APG)) against the South African sub-type C HIV-1 protease enzyme and PIs’ drug-metabolizing proteins were investigated, using molecular dynamic (in-silico) techniques. Furthermore, an in vitro evaluation of the cytotoxicity assays, cell viability profiles and modulatory influences of the most promising antiviral PCs on the mRNA and protein expressions of the drug-metabolising proteins in two human cell lines (liver (HepG2) and kidney (HEK293)) was carried out. Result: Four of the fifteen PCs (EGCG, K7G, LUT and EGA) were predicted to be potential inhibitors of HIV-1 protease, as well as inhibitors of cytochrome P450 3A4 (CYP3A4) and Pglycoprotein P-gp/ABCB1. Results from the in vitro study showed that these four PCs were not toxic to HepG2 cells at their IC50 (50% cell viability) and IC20 (80% cell viability). ATP (adenosine triphosphate) levels increased at IC20, with no significant change at IC50. In addition, no significant change in LDH (lactate dehydrogenase) was seen (with the exception of LUT).In the HepG2 cells, ABCB1 protein expression (western blot) decreased overall. While all PCs decreased CYP3A4 protein expression at IC20, (with the exception of LUT) xxv protein expression increased at IC50. mRNA levels were decreased for EGCG and K7G at IC20. InHEK293 cells, all PCs were non-toxic. ATP concentrations were similar to the control except for EGCG which decreased at IC20, and K7G which increased at IC50. LDH concentration decreased when exposed to the PCs at IC20, but a significant (p < 0.05) increase was recorded in LUT IC50. ABCB1 protein expression increased at both IC20 and IC50 concentrations, although LUT and EGA mRNA expression decreased at IC50. The decreased protein activities of CYP3A4 in K7G IC50 and LUT IC20 correlates with increased intracellular ATP. Conclusion: The study therefore suggests that EGCG, K7G, LUT and EGA could decrease the biotransformation of drugs, and eventually increase drug plasma concentrations in the systemic circulation. These natural compounds that can serve as inhibitors of drugmetabolizing proteins and the HIV-1 protease enzymecould be useful in the treatment of HIV-1

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Molecular Dynamics Study on Selected Bioactive Phytochemicals as Potential Inhibitors of HIV-1 Subtype C Protease

Acquired immunodeficiency syndrome (AIDS), one of the deadliest global diseases, is caused by the Human Immunodeficiency Virus (HIV). To date, there are no known conventional drugs that can cure HIV/AIDS, and this has prompted continuous scientific efforts in the search for novel and potent anti-HIV therapies. In this study, molecular dynamics simulation (MDS) and computational techniques were employed to investigate the inhibitory potential of bioactive compounds from selected South African indigenous plants against HIV-1 subtype C protease (HIVpro). Of the eight compounds (CMG, MA, UA, CA, BA, UAA, OAA and OA) evaluated, only six (CMG (−9.9 kcal/mol), MA (−9.3 kcal/mol), CA (−9.0 kcal/mol), BA (−8.3 kcal/mol), UAA (−8.5 kcal/mol), and OA (−8.6 kcal/mol)) showed favourable activities against HIVpro and binding landscapes like the reference FDA-approved drugs, Lopinavir (LPV) and Darunavir (DRV), with CMG and MA having the highest binding affinities. Using the structural analysis (root-mean-square deviation (RMSD), fluctuation (RMSF), and radius of gyration (RoG) of the bound complexes with HIVpro after 350 ns, structural evidence was observed, indicating that the six compounds are potential lead candidates for inhibiting HIVpro. This finding was further corroborated by the structural analysis of the enzyme–ligand complexe systems, where structural mechanisms of stability, flexibility, and compactness of the study metabolites were established following binding with HIVpro. Furthermore, the ligand interaction plots revealed that the metabolites interacted hydrophobically with the active site amino residues, with identification of other key residues implicated in HIVpro inhibition for drug design. Overall, this is the first computational report on the anti-HIV-1 activities of CMG and MA, with efforts on their in vitro and in vivo evaluations underway. Judging by the binding affinity, the degree of stability, and compactness of the lead metabolites (CMG, MA, CA, BA, OA, and UAA), they could be concomitantly explored with conventional HIVpro inhibitors in enhancing their therapeutic activities against the HIV-1 serotype