Masters Degrees (Clinical Pharmacology)

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Browsing Masters Degrees (Clinical Pharmacology) by browse.metadata.advisor "Bouic, Patrick J. D."

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    Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach
    (Stellenbosch : Stellenbosch University, 2016-03) White, Charlize; Rosenkranz, Bernd; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology.
    ENGLISH ABSTRACT: INTRODUCTION Herbal products are popularly used as complementary and alternative medicines to treat a variety of conditions. Often patients use them in conjunction with conventional medicines. Herbal products contain many pharmacologically active phytochemicals that may interfere with the absorption, distribution, metabolism, and elimination of medicines. This interaction can lead to an increase of the plasma concentrations of other medicines to toxic levels, or to their decrease below therapeutic levels, resulting in lack of efficacy. The liver cytochrome P450 (CYP) enzymes are responsible for the metabolism of a large majority of medicines. In order to provide more information on the potential interaction between African herbal medicines and conventional medicines, the present study has investigated the inhibition of selected CYP enzymes by three popular South African medicinal plants, Buchu, African ginger, and Warburgia salutaris. METHODS Buchu capsules, African ginger, and Warburgia salutaris tablets were obtained in a local pharmacy. 60% methanol/water extracts were prepared and analysed by GC-MS to reveal the composition of the volatile components of each product. Fluorogenic inhibition assays were conducted using Vivid® recombinant CYP screening kits according to the manufacturer’s protocol. This protocol included the pre-incubation of herbal extracts, recombinant CYP isoform and cofactor solution. The metabolic reaction was initiated by the addition of CYP-specific substrate and NADP+; the solution was incubated for 30 minutes at 37°C, after which fluorescence was measured using a microplate reader. The percentage remaining activity was calculated and used to determine the IC50 values of each herbal product. Time - dependent inhibition (TDI) was evaluated using the normalized ratio, NADP+-, concentration -, and time - dependent approaches. RESULTS The GC-MS analysis revealed monoterpenes, sesquiterpenes, and alkane hydrocarbons in the volatile component. Warburgia salutaris, African ginger, and Buchu inhibited CYP2C19 with IC50 values of 5.88 μg/ml, 32.38 μg/ml, and 53.52 μg/ml, respectively. Likewise, the IC50 values of 5.64 μg/ml, 1.09 μg/ml, and > 100 μg/ml were obtained for inhibition of CYP3A4 by Warburgia salutaris, African ginger, and Buchu, respectively. Using the normalized ratio, Warburgia salutaris and African ginger showed time- and concentration - dependent inhibition of CYP1A2, and Buchu showed intermediate TDI effects that were not concentration dependent. All three extracts showed TDI of CYP3A4; the inhibition displayed by Buchu and Warburgia salutaris was NADP+ dependent. African ginger was the only extract to show NADP+ dependent inhibition of CYP1A2. A kinetic TDI assay Stellenbosch University https://scholar.sun.ac.za iii showed that the IC50 value of African ginger decreased over time, indicating TDI. Warburgia salutaris was not a time-dependent inhibitor of CYP3A4, and Buchu may have a limited time-dependent inhibitory effect. CONCLUSION Warburgia salutaris, African ginger, and Buchu have the potential to cause clinically relevant herb-drug interaction, if sufficient concentrations are achieved in vivo. Further studies are needed to confirm this finding.
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    Pharmacokinetics and dosing rationale of Para-Aminosalicylic acid in children and the evaluation of the in vitro metabolism of Ethionamide, Terizidone and Para-aminosalicylic acid
    (Stellenbosch : Stellenbosch University, 2012-03) Liwa, Anthony Cuthbert; Bouic, Patrick J. D.; Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology.
    ENGLISH ABSTRACT: BACKGROUND: The emergence of mycobacterium tuberculosis resistance to first line drugs has renewed interest in second-line anti-tuberculosis drugs. Generally, Paraaminosalicylic acid (PAS) is less potent and frequently more toxic than the first line drugs. Furthermore, the pharmacokinetics of PAS in children has not been well characterized. AIMS: The aims of the present study were (1) to determine the pharmacokinetics of PAS in pediatric patients, (2) to describe the discrepancy between children and adult pharmacokinetics and the appropriate dosing regimen of PAS and (3) to investigate the potential of the second-line anti-tuberculosis drugs PAS, terizidone and ethionamide (often used as first-line drug in children) to inhibit the catalytic activities of CYP450 1A2 and 2C9. PATIENTS: Twenty two patients with drug resistant tuberculosis were included in the study. Ten patients were children with mean age of 4.2 years (range: 1 to 12 years). Twelve patients were adults with mean age of 31.3 years (range: 18 to 53). 4 children (40%) and 4 adults (33.3%) were HIV positive and were on ART. METHODS: Children received 75 mg/kg twice daily on the first visit and after two weeks they received 150 mg/kg once. Adults received a standard 4 g twice daily. Blood samples were taken at different time points after the dose. In the additional study, the inhibitory effects of PAS, ethionamide and terizidone on phenacetin O-deethylation, a marker substrate of CYP1A2 and diclofenac 4’-hydroxylation, a marker substrate of CYP2C9, were studied using human liver microsomes. RESULTS: For the 75 mg/kg dose, the mean AUC was 233.3 =g•h/ml and the mean CL was 10.4 l/h/kg. The mean of the observed Cmax of the drug was 45.4 =g/ml and the mean Tmax was 4.8 hrs. For the 150 mg/kg dose, the mean AUC of PAS was 277.9 =g•h/ml and the mean CL was 47.1 l/h/kg. The mean of the observed Cmax of the drug was 56.5 =g/ml and the mean Tmax was 4.8 hrs. On the first visit the mean AUC was 368 =g•h/ml and the mean CL was 13.2 l/h/kg. The mean of the observed Cmax of PAS was 51.3 =g/ml and the mean Tmax was 5.2 hrs. On the second visit the mean AUC was 230 =g•h/ml and the mean CL was 23.9 l/h/kg. The mean of the observed Cmax of PAS was 37.6 =g/ml and the mean Tmax was 5.2 hrs. The comparisons between pharmacokinetics profile of PAS and patients characteristics e.g. age, indicated no statistically significant differences between children (both treatment regimens) and adult patients as well as HIV positive and negative patients. In the in vitro study, all drugs demonstrated no inhibition potency towards the investigated CYP450 enzymes. CONCLUSIONS:The dose of 75 mg/kg twice daily in children appears to be appropriate to achieve serum concentration above the PAS minimum inhibitory concentration of approximately 1 =g/ml. PAS, ethionamide and terizidone are unlikely to affect the metabolism of concomitantly administered medications that are metabolized by either CYP450 1A2 and/or 2C9 isoenzymes.