Clinical Pharmacology

Permanent URI for this community

https://scholar.sun.ac.za/handle/10019.1/164
This division was known as Pharmacology until 27 June 2013.

Browse

Browsing Clinical Pharmacology by Subject "AIDS (Disease) -- Treatment"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy
    (Stellenbosch : Stellenbosch University, 2015-12) Flepisi, Thabile Brian; Rosenkranz, Bernd; Bouic, Patrick J. D.; Sissolak, Gerhard; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
    ENGLISH ABSTRACT: INTRODUCTION: Altered immune mechanisms play a critical role in the pathogenesis of Non-Hodgkin lymphoma (NHL), as evidenced by increased rates of NHL among HIV+ patients [De Roos et al., 2012; Mellgren et al., 2012]. AIMS: To determine whether biomarkers of B-, T-cell activation, and inflammation are elevated in HIV+NHL patients; and whether cART influences their expression. METHODS: The expression of CD8+CD38 and FoxP3 were determined by flow cytometry; the serum concentrations of circulating sCD20, sCD23, sCD27, sCD30 and sCD44 were determined by enzyme linked immunosorbent assay (ELISA); and the serum concentrations of circulating IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α were determined by meso-scale discovery (MSD) assay in 141 participants consisting of HIV positive NHL (HIV+NHL), HIV negative NHL (NHL); combination antiretroviral treated HIV+ (HIV+ cART), treatment naive HIV+ (cART-naïve HIV+) patients; and healthy controls. RESULTS: HIV+NHL patients had higher serum concentrations of sCD20 (p<0.0001 and p=0.0359), sCD23 (p=0.0192 and p<0.0001), sCD30 (p=0.0052 and p<0.0001), sCD44 (p=0.0014 and p<0.0001), and IL-4 (p=0.0234 and p=0.03360); and lower expression of FoxP3 (p<0.0001 and p=0.0171) as compared to NHL and HIV+ cART patients. As compared to NHL patients, the serum concentrations of IL-2 (p=0.0115), and TNF-α (p=0.0258) were higher in HIV+NHL patients, while those of IL-1β (p=0.0039) were significantly lower. HIV+NHL patients had higher expression of CD8+CD38 (p=0.0104), serum concentrations of IFN-γ (p=0.0085), and IL-6 (p=0.0265); and lower serum concentrations of IL-12p70 (p=0.0012) than HIV+ cART patients. As compared to controls, NHL had higher concentrationsof all biomarkers investigated except FoxP3 expression. As compared to HIV+ cART and controls, cART-naïve HIV+ patients had higher concentrations of all biomarkers investigated except sCD23 and FoxP3 expression. CONCLUSION: Biomarkers of chronic B- and T-cell activation and inflammation are up-regulated in HIV+NHL and the untreated HIV+ state. cART decreases immune activation and inflammation.
  • Thumbnail Image
    Item
    Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS
    (Stellenbosch : Stellenbosch University, 2015-03) Awortwe, Charles; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology.
    ENGLISH ABSTRACT: Introduction The increasing intake of traditional medicines among HIV/AIDS patients in sub-Saharan Africa needs urgent consideration by clinicians and other healthcare providers since the safety of such medications are unknown. The pharmacokinetic parameters - Absorption, Distribution, Metabolism and Elimination (ADME) play important role in the safety evaluation of drugs, thus implicating drug metabolizing enzymes and transporters as critical indicators for herb-drug interactions. The objective of this study was to evaluate the risk potential of seven herbal medicines commonly consumed by HIV/AIDS patients for drug interactions applying in vitro models. In this study, inhibition and induction effects of the herbal medicines on cytochrome P450s (CYPs) 1A2, 2C9, 2C19, 2D6 and 3A4 as well as P-glycoprotein (P-gp) were investigated. Methods Herbal medicines – Lessertia frutescens, Hypoxis hemerocallidea, Kalanchoe integra and Taraxacum officinale were sourced from Medico Herbs, South Africa were identified by experts from Compton Herbarium, South African National Biodiversity Institute, Cape Town. Moringa oleifera, Echinacea purpurea and Kalanchoe crenata were obtained from the repository of the National Centre for Natural Product Research (NCNPR), University of Mississippi, USA. Reversible inhibitory effect of aqueous and methanol herbal extracts were evaluated in recombinant CYPs applying the fluorescent metabolites at specified excitation/emission wavelengths; CYP1A2 (3-cyano-7-hydroxycoumarin (CHC); 405/460 nm), CYP2C9, CYP2C19 and CYP3A4 (7-hydroxy-4-(trifluoromethyl)-coumarin (HFC); 405/535 nm) and CYP2D6 (7-hydroxy-4-(aminomethyl)-coumarin (HAMC); 390/460 nm). Comparative studies in human liver microsomes (HLM) and recombinant CYPs were conducted to investigate the inhibitory effect of methanol herbal extracts and fractions on 6β testosterone hydroxylation activity. Time dependent inhibitory (TDI) effect of the herbal extracts were evaluated applying the IC50 shift fold, normalized ratio and the NADPH-, time- and concentration-dependent approaches. Influence of herbal extracts on metabolic clearance of testosterone was assessed in both HLM and human hepatocytes. The effects of each herbal extract on expression of CYP1A2, CYP3A4 and MDR1 genes were evaluated in activated human pregnane X receptor (PXR) co-transfected HepG2 cells. Finally, the inhibitory effect of herbal extracts on P-gp was assessed using the calcein-acetoxymethyl ester (calcein-AM) uptake and the digoxin radiolabelled substrates in MDCKII-MDRI cells. Results The aqueous extracts of Moringa oleifera, Kalanchoe integra, Kalanchoe crenata, Echinacea purpurea and Lessertia frutescens demonstrated high risk of in vivo inhibition on CYPs 3A4 and 1A2 with Cmax/Ki >1.0. Methanol extracts of these herbal medicines also indicated potential risk of reversible drug interaction. The methanol extracts of M. oleifera, K. crenata and L. frutescens showed strong TDI effect on CYP3A4 with IC50 shift fold >1.5 and normalised ratio <0.7. Moringa oleifera intermediately reduced intrinsic clearance of testosterone in human hepatocytes (2 ≤ AUC ratio ≤ 5) when scaled up to humans. Methanol extracts of Echinacea purpurea up-regulated the expression of CYP1A2, CYP3A4 and MDR1 genes in activated PXR. Kalanchoe crenata and Echinacea purpurea indicated strong inhibition on P-gp by reducing transport of digoxin across hMDR1-MDCKII cell monolayer from basolateral to apical with IC50 values of 18.24 ± 2.52 μg/mL and 24.47 ± 4.97 μg/mL, respectively. Conclusion The herbal medicines especially M. oleifera, K. integra and E. purpurea have the potential to cause herb-drug interaction in vivo if sufficient hepatic concentration is achieved in humans.