Masters Degrees (Clinical Pharmacology)

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Browsing Masters Degrees (Clinical Pharmacology) by browse.metadata.advisor "Rosenkranz, Bernd"

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    Adverse drug reactions in paediatric in-patients in a South African tertiary hospital
    (Stellenbosch : Stellenbosch University, 2017-12) Makiwane, Memela MacDonald; Decloedt, Eric; Rosenkranz, Bernd; Kruger, Mariana; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.
    ENGLISH SUMMARY: Purpose: Paediatric patients have more adverse drug reaction (ADR) rates than adults due to off-label use of medicines and the prevalence data of ADRs in Sub-Saharan African children is limited. The aim was to describe the prevalence and nature of ADRs in paediatric (≤ 16 years old) in-patients at a tertiary hospital in South Africa. Methods: We conducted a prospective study of paediatric in-patients to identify suspected ADRs. Children had to be admitted for at least 24 hours during the 3-month study period (1 December 2015 to 29 February 2016). The data collected included age, sex, diagnosis and medicines received. We assessed causality using the 10-question Naranjo probability scale and classified severity using the Hartwig severity scale. Results: We found that 18.4% (52/282) of patients had 61 ADRs. The median age of patients with ADRs was 1.4 years (interquartile range (IQR): 0.5 – 5.3 years). ADR was the reason for admission in a third of the patients (31%; 16/52). Paediatric oncology patients suffered the majority of the ADRs (56.5%; 13/23), followed by HIV-infected patients on antiretroviral therapy (ART) (42.9%; 9/21) and tuberculosis (TB) patients (17.5%; 7/40). HIV-TB coinfected patients also experienced a high 30.8% (4/13) rate of ADRs. The majority of the ADRs were moderate 45.9% (28/61), while 42.6% (26/61) were mild, and 11.5% severe ADRs (7/61). These ADRs range from severe neutropaenia 4.9% (3/61) and drug induced liver injury (DILI) 4.9% (3/61) to mild cutaneous rashes 13.1% (8/61). There were no fatal ADRs, while 13.1% (8/61) ADRs were considered life threatening; 27.9% (17/61) necessitated and/or prolonged hospitalisation and 31.1% (19/61) resulted in persistent or significant disability or incapacity. Thirty eight percent of ADRs (23/61) were predictable. Paediatric oncology patients on chemotherapy were 7 times more likely to have ADR(s) than other patient groups [OR 7.3 (3.0 – 17.9), p < 0.01]. More ADRs were associated with chemotherapy 44.3% (27/61) and antimicrobials 42.6% (26/61), while the other miscellaneous medicine classes were associated with 34.4% (21/61) of the recorded ADRs. Conclusion: The prevalence of ADRs was 18.4% and in 31% the ADR was the reason for admission. The ADRs in paediatric oncology patients were expected, but of note nearly half the HIV-infected patients (43%) suffered an ADR.
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    Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients
    (Stellenbosch : Stellenbosch University, 2012-03) Fouche, Desire; Rosenkranz, Bernd; Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology.
    ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which makes them highly susceptible for opportunistic infections, requiring additional treatment. Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A great potential for drug-drug interactions (DDIs) between fluconazole and antiretrovirals (ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common metabolic pathways. The outcome may result in the development of adverse drug reactions or drug resistance and treatment failure. Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients diagnosed with cryptococcal meningitis or oropharyngeal candidiasis. Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region. Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse sampling design was used and corresponding ARV serum concentrations were determined by established HPLC and GC methods. Fluconazole serum concentrations were determined by a newly developed HPLC method. Patient characteristics, concomitant medications, clinical test data and ARV serum concentrations were included in a NONMEM generated, onecompartment, open pharmacometric model with first order elimination to detect any drugdrug interactions between fluconazole and the studied ARVs. The secondary outcome was to establish which patient characteristics influence ARV pharmacokinetics. Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67 nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz clearance was correlated with race and concomitant use of rifampicin. No significant covariates were established in the nevirapine model. In the lopinavir model, concomitant use of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin were identified as significant covariates. Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in clearance), which has not been previously described in the South African context. Although gender was not a significant covariate in the nevirapine model, female patients tended to have higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different effects on CYP isoenzymes. The exact contributing factor of each drug in the ultimate decrease in lopinavir clearance (46.4%) can therefore not be established. Conclusions: Given the limitations of the sample size in the present study, no statistical significant effect of fluconazole on the pharmacokinetics of the investigated ARVs could be demonstrated. A retrospective analysis of the data showed various co-factors that influence the pharmacokinetics of the investigated ARVs. This data needs to be confirmed in a prospective study as the identified covariates are appropriate in the management of HIVinfected patients in the South African context.
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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.