+publisher:"Stellenbosch University" +contributor:("Rosenkranz, Bernd")

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Stellenbosch University

1. Fouche, Desire. Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.

Degree: MScMedSc, Medicine, 2012, Stellenbosch University

URL: http://hdl.handle.net/10019.1/20079

► 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… (more)

▼ 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… Advisors/Committee Members: Rosenkranz, Bernd, Stellenbosch University. Faculty of Health Sciences. Dept. of Medicine. Pharmacology..

Subjects/Keywords: Pharmacology; Drug resistance

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APA (6^th Edition):

Fouche, D. (2012). Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/20079

Chicago Manual of Style (16^th Edition):

Fouche, Desire. “Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.” 2012. Masters Thesis, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/20079.

MLA Handbook (7^th Edition):

Fouche, Desire. “Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients.” 2012. Web. 11 Apr 2021.

Vancouver:

Fouche D. Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. [Internet] [Masters thesis]. Stellenbosch University; 2012. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/20079.

Council of Science Editors:

Fouche D. Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients. [Masters Thesis]. Stellenbosch University; 2012. Available from: http://hdl.handle.net/10019.1/20079

Stellenbosch University

2. Matsebula-Myeni, Zinhle. Investigating the effect of interventional programmes in combatting inappropriate use of antibiotics in managing and treating acute gastroenteritis in children younger than five years at the Raleigh Fitkin Memorial Hospital in ESwatini.

Degree: MSc, Medicine, 2019, Stellenbosch University

URL: http://hdl.handle.net/10019.1/106224

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ENGLISH ABSTRACT: Patients at the Raleigh Fitkin Memorial Hospital, ESwatini, especially children diagnosed with acute gastroenteritis, are mostly prescribed with antibiotics. Previous data suggest that inappropriate use of antibiotics results in higher antibiotic resistance, extended hospitalisation and increased medication costs. Antibiotic stewardship programmes and clinical practice guidelines can reduce the inappropriate use of antibiotics and improve patient outcomes. Despite increased theoretical awareness of the benefits of antibiotic stewardship programmes, none have been established in ESwatini, and limited comprehensive studies have evaluated their effect in paediatric settings globally. The knowledge, attitude and practices on antibiotic use and resistance have not been determined at the Raleigh Fitkin Memorial Hospital. An 18-month, single-centre process improvement study, comprising a six-month pre-intervention phase, a preparatory period of six months and a six-month intervention phase, was conducted at the Raleigh Fitkin Memorial Hospital to assess the effectiveness of a multifaceted intervention in combatting the inappropriate use of antibiotics and improving the management of acute gastroenteritis and its comorbidities in children aged less than five years. The intervention included the establishment of an antibiotic stewardship programme and the implementation of clinical practice guidelines related to the diagnosis, treatment and management of acute gastroenteritis and its associated comorbidities. Two hundred and thirteen patients participated in the study, with 87 patients in the pre-intervention phase and 126 in the intervention phase. Knowledge, attitude and practices of healthcare professionals were investigated by conducting a survey before and after the intervention phase. An improvement in the appropriateness of antibiotics use was observed in the intervention phase. A decrease in duration of hospitalisation, cost of antibiotics and mortality was observed. During the intervention phase, deaths were observed where severe acute malnutrition was present as comorbidity to acute gastroenteritis, whereas various causes of death were observed during the pre-intervention phase. Most recommendations by the antibiotic stewardship programme team were adopted during the intervention phase. An improvement in knowledge, attitude and practices on antibiotic use and resistance was observed after the intervention phase. The study demonstrates that an antibiotic stewardship programme can improve the appropriate use of antibiotics in children, with limited adverse effects. Clinical practice guidelines play a vital role in providing guidance to prescribers and harmonising therapies. Antibiotic stewardship programmes can improve healthcare professionals’ knowledge, attitude and practices on the appropriate use of antibiotics, and a decrease in antibiotic resistance.

AFRIKAANSE OPSOMMING: Pasiënte by die Raleigh Fitkin Memorial-hospitaal in ESwatini, veral kinders wat gediagnoseer is met akute…

Advisors/Committee Members: Rosenkranz, Bernd, Reuter, Helmuth, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology..

Subjects/Keywords: Antibiotics; Gastroenteritis – Acute; Gastroenteritis in children; Raleigh Fitkin Memorial Hospital; ESwatini; UCTD

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APA (6^th Edition):

Matsebula-Myeni, Z. (2019). Investigating the effect of interventional programmes in combatting inappropriate use of antibiotics in managing and treating acute gastroenteritis in children younger than five years at the Raleigh Fitkin Memorial Hospital in ESwatini. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/106224

Chicago Manual of Style (16^th Edition):

Matsebula-Myeni, Zinhle. “Investigating the effect of interventional programmes in combatting inappropriate use of antibiotics in managing and treating acute gastroenteritis in children younger than five years at the Raleigh Fitkin Memorial Hospital in ESwatini.” 2019. Masters Thesis, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/106224.

MLA Handbook (7^th Edition):

Vancouver:

Matsebula-Myeni Z. Investigating the effect of interventional programmes in combatting inappropriate use of antibiotics in managing and treating acute gastroenteritis in children younger than five years at the Raleigh Fitkin Memorial Hospital in ESwatini. [Internet] [Masters thesis]. Stellenbosch University; 2019. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/106224.

Council of Science Editors:

Matsebula-Myeni Z. Investigating the effect of interventional programmes in combatting inappropriate use of antibiotics in managing and treating acute gastroenteritis in children younger than five years at the Raleigh Fitkin Memorial Hospital in ESwatini. [Masters Thesis]. Stellenbosch University; 2019. Available from: http://hdl.handle.net/10019.1/106224

Stellenbosch University

3. White, Charlize. Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach.

Degree: MSc, Medicine, 2016, Stellenbosch University

URL: http://hdl.handle.net/10019.1/98593

► 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… (more)

▼ 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,… Advisors/Committee Members: Rosenkranz, Bernd, Bouic, Patrick, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology..

Subjects/Keywords: Cytochrome P-450; UCTD; Drug-herb interactions

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

White, C. (2016). Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/98593

Chicago Manual of Style (16^th Edition):

White, Charlize. “Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach.” 2016. Masters Thesis, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/98593.

MLA Handbook (7^th Edition):

White, Charlize. “Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach.” 2016. Web. 11 Apr 2021.

Vancouver:

White C. Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach. [Internet] [Masters thesis]. Stellenbosch University; 2016. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/98593.

Council of Science Editors:

White C. Inhibitory effect of selected herbal supplements on CYP450-mediated metabolism : an in vitro approach. [Masters Thesis]. Stellenbosch University; 2016. Available from: http://hdl.handle.net/10019.1/98593

Stellenbosch University

4. Kumar, Saneesh. Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies.

Degree: PhD, Medicine, 2018, Stellenbosch University

URL: http://hdl.handle.net/10019.1/105081

► Introduction Traditional, complementary and alternative medicines have been used to treat various health conditions. The use of such medicines among HIV/AIDS and TB patients in… (more)

▼ Introduction Traditional, complementary and alternative medicines have been used to treat various health conditions. The use of such medicines among HIV/AIDS and TB patients in sub- Saharan Africa has increased considerably, and within this context, questions have been raised about the medical use of herbs or extracts as treatment alternatives without adequate clinical testing and without monitoring of adverse effects once on the market. Furthermore, potential herb-drug interactions (HDI) have been predicted based on the pharmacological and pharmacokinetic properties of prescription medications and the phytoconstituents within the herbs. This study investigated the potential of six popular African herbs consumed by HIV/AIDS and TB patients, viz., Withania somnifera, Glycyrrhiza glabra, Astragalus membranaceus, Inula helenium, Althaea officinalis and Ocimum basilicum, to inhibit the cytochrome P450 enzyme CYP2B6 and the esterase-mediated metabolism pathway of rifampicin and their ability to induce CYP3A4 and CYP2B6. The study was undertaken in four phases: (1) qualitative assessment of various classes of phytocompounds present in each herbal extract by biochemical phytoprofiling, (2) study of the potential inhibitory effects of the extracts on cytochrome CYP2B6 and on the metabolism pathway of rifampicin to 25-O-desacetyl rifampicin by in vitro assays using human liver microsomes (HLM), (3) analysis of the potential inducing effects of the herbal extracts on mRNA expression of CYP2B6 and CYP3A4 in HepG2 cell lines, using reverse transcription polymerase chain reaction (RT-PCR) and agarose gel electrophoresis (AGE), and (4) fingerprint analysis, identification and relative quantification of the major phytoconstituents present in each extract and prediction of compounds which may cause HDI by liquid chromatography-mass spectrometry coupled with photo diode array detection (LC-MS/PDA). Methods Dried roots of Withania somnifera, Glycyrrhiza glabra, Astragalus membranaceus, Inula helenium, Althaea officinalis and dried leaves and inflorescence of Ocimum basilicum were obtained from Pharma Germania, South Africa. Aqueous, methanol, ethanol and ethyl acetate extracts were prepared and analysed using biochemical tests to identify the presence of various classes of phytocompounds. HLM assays were conducted to evaluate the inhibitory potential of each extract on the CYP2B6-mediated metabolism of efavirenz to 8-Hydroxy efavirenz, and the biotransformation of rifampicin to 25-O-desacetyl rifampicin. The protocol included the incubation of the herbal extract, HLM, co-factors and substrates in phosphate buffer for 30 min at 37 °C, termination of reaction and HPLC analysis of the supernatant from the centrifuged assay sample (at 245 nm for efavirenz and its metabolite, and 254 nm for rifampicin and its metabolite). The half-maximal inhibitory concentrations (IC50) for the active extracts were calculated based on the percentage of remaining activity relative to the control. Time-dependent… Advisors/Committee Members: Rosenkranz, Bernd, Bouic, Patrick, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.

Subjects/Keywords: Herb-drug interaction; UCTD; Liver – Microsomes; Alternative medicine – HIV patients; Traditional medicine – Africa; Metabolism – Effect of drugs on; TB patients

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kumar, S. (2018). Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies. (Doctoral Dissertation). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/105081

Chicago Manual of Style (16^th Edition):

Kumar, Saneesh. “Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies.” 2018. Doctoral Dissertation, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/105081.

MLA Handbook (7^th Edition):

Kumar, Saneesh. “Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies.” 2018. Web. 11 Apr 2021.

Vancouver:

Kumar S. Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies. [Internet] [Doctoral dissertation]. Stellenbosch University; 2018. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/105081.

Council of Science Editors:

Kumar S. Pharmacokinetic Herb-Drug Interactions involving african traditional medicines - fingerprint analysis and in vitro metabolism studies. [Doctoral Dissertation]. Stellenbosch University; 2018. Available from: http://hdl.handle.net/10019.1/105081

Stellenbosch University

5. Awortwe, Charles. Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS.

Degree: DMed, Medicine, 2015, Stellenbosch University

URL: http://hdl.handle.net/10019.1/96796

► 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… (more)

▼ 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.… Advisors/Committee Members: Rosenkranz, Bernd, Bouic, Patrick J., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Clinical Pharmacology..

Subjects/Keywords: Pharmacokinetics; Herbs – Therapeutic use; HIV infections – Treatment; AIDS (Disease) – Treatment; UCTD

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APA (6^th Edition):

Awortwe, C. (2015). Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS. (Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/96796

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Awortwe, Charles. “Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS.” 2015. Thesis, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/96796.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Awortwe, Charles. “Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS.” 2015. Web. 11 Apr 2021.

Vancouver:

Awortwe C. Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS. [Internet] [Thesis]. Stellenbosch University; 2015. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/96796.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Awortwe C. Pharmacokinetic herb-drug interaction study of selected traditional medicines used as complementary and alternative medicine (CAM) for HIV/AIDS. [Thesis]. Stellenbosch University; 2015. Available from: http://hdl.handle.net/10019.1/96796

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Stellenbosch University

6. Flepisi, Thabile Brian. Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy.

Degree: PhD, Medicine, 2015, Stellenbosch University

URL: http://hdl.handle.net/10019.1/97798

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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… (more)

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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.

AFRIKAANSE OPSOMMING: INLEIDING: Versteurde immuun meganisme speel ‘n kritiese rol in die patogenese van Non-Hodgkin limfoom (NHL), soos aangedui deur verhoogde tempo van NHL onder MIV+ pasiënte [De Roos et al., 2012; Mellgren et al., 2012]. DOELWITTE: Om te bepaal indien biomerkers van B-, T-sel aktivering en inflammasie verhoog is in MIV+NHL pasiënte; en indien kART hul uitdrukking beinvloed. METODE: Die uitdrukking van CD8+CD38 en FoxP3 was bepaal deur vloei sitometrie; die serum konsentrasies van sirkulerende sCD20, sCD27, sCD30 en sCD44 was bepaal deur ensiem gekoppelde immuno sorbant toets (ELISA); en die serum konsentrasies van sirkulerende IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 en TNF-α bepaal was deur meso-skaal ondekking (MSD) toets in 141 deelnemers bestaande uit MIV positiewe NHL (MIV+NHL); MIV negatiewe NHL (NHL), kombinasie antiretrovirale behandeling MIV+…

Advisors/Committee Members: Rosenkranz, Bernd, Bouic, Patrick J., Sissolak, Gerhard, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology..

Subjects/Keywords: Biochemical markers; Lymphomas; Antirheumatic agents; AIDS (Disease) – Treatment; UCTD

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Flepisi, T. B. (2015). Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy. (Doctoral Dissertation). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/97798

Chicago Manual of Style (16^th Edition):

Flepisi, Thabile Brian. “Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy.” 2015. Doctoral Dissertation, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/97798.

MLA Handbook (7^th Edition):

Flepisi, Thabile Brian. “Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy.” 2015. Web. 11 Apr 2021.

Vancouver:

Flepisi TB. Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy. [Internet] [Doctoral dissertation]. Stellenbosch University; 2015. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/97798.

Council of Science Editors:

Flepisi TB. Biomarkers of HIV associated malignancies and of drug interaction between anti-retrovirals (ARVs) and chemotherapy. [Doctoral Dissertation]. Stellenbosch University; 2015. Available from: http://hdl.handle.net/10019.1/97798

Stellenbosch University

7. Fasinu, Pius Sedowhe. In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential.

Degree: PhD, Medicine, 2013, Stellenbosch University

URL: http://hdl.handle.net/10019.1/85850

► ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical… (more)

▼ ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical risks in the concomitant administration of herbal products and prescription medicine is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes and transport proteins. The aim of this study was to investigate the potential of the crude extracts of popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes and transport proteins through in vitro assessment. Methods Medicinal herbs were obtained from traditional medical practitioners and 15 were selected for this study. The selected herbal products were extracted and incubated with human liver microsomes to monitor the following reactions as markers for the metabolic activities of the respective CYP: phenacetin O-deethylation (CYP1A2), diclofenac 4‟-hydroxylation (CYP2C9), S-mephenytoin 4‟- hydroxylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In addition, the influence of Lessertia frutescens (formerly Sutherlandia frutescens) and Hypoxis hemerocallidea was investigated on more isozymes: coumarin 7-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), paclitaxel 6α-hydroxylation (CYP2C8), bufuralol 1‟-hydroxylation (CYP2D6), chlorzoxazone 6- hydroxylation (CYP2E1) and midazolam 1‟-hydroxylation (CYP3A4/5). The generation of the CYPspecific substrates/metabolites were monitored and quantified with the aid of LC-MS/MS. The metabolic clearance of midazolam using cryopreserved hepatocytes was monitored in the presence of Lessertia frutescens and Hypoxis hemerocallidea. The potential of both to inhibit human ATP-binding cassette (ABC) transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells overexpressing human breast cancer resistant protein (BCRP) and human P-glycoprotein (P-gp), respectively. Similarly, the potential for interactions with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) was assessed using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively. Results Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (methanolic extract), Hypoxis hemerocallidea, Spirostachys africana and Lessertia frutescens (aqueous extract), in ascending order of potency demonstrated strong inhibition of CYP1A2 activity (IC50 = 1-100 g/mL). Similarly, Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana and Pentanisia prunelloides inhibited CYP2C9 with IC50 less than 100 g/mL. The following demonstrated strong inhibition of CYP2C19 with IC50 values less than 100 g/mL: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens and Zantedeschia aethiopica. CYP3A4 was inhibited by Lessertia frutescens, Hypoxis… Advisors/Committee Members: Rosenkranz, Bernd, Bouic, Patrick J., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology..

Subjects/Keywords: Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fasinu, P. S. (2013). In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential. (Doctoral Dissertation). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/85850

Chicago Manual of Style (16^th Edition):

Fasinu, Pius Sedowhe. “In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential.” 2013. Doctoral Dissertation, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/85850.

MLA Handbook (7^th Edition):

Fasinu, Pius Sedowhe. “In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential.” 2013. Web. 11 Apr 2021.

Vancouver:

Fasinu PS. In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential. [Internet] [Doctoral dissertation]. Stellenbosch University; 2013. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/85850.

Council of Science Editors:

Fasinu PS. In vitro assessment of some traditional medications used in South Africa for pharmacokinetics drug interaction potential. [Doctoral Dissertation]. Stellenbosch University; 2013. Available from: http://hdl.handle.net/10019.1/85850

Stellenbosch University

8. Makiwane, Memela MacDonald. Adverse drug reactions in paediatric in-patients in a South African tertiary hospital.

Degree: MSc, Medicine, 2017, Stellenbosch University

URL: http://hdl.handle.net/10019.1/102625

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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… (more)

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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.

AFRIKAANSE OPSOMMING: Geen opsomming

Masters

Advisors/Committee Members: Decloedt, Eric, Rosenkranz, Bernd, Kruger, Mariana, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology..

Subjects/Keywords: Off-label drug use – Complications; Drugs – Side effects; Children – Drug use; Children – Hospital care – South Africa; Cancer in children – Chemotherapy – Complications

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Makiwane, M. M. (2017). Adverse drug reactions in paediatric in-patients in a South African tertiary hospital. (Masters Thesis). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/102625

Chicago Manual of Style (16^th Edition):

Makiwane, Memela MacDonald. “Adverse drug reactions in paediatric in-patients in a South African tertiary hospital.” 2017. Masters Thesis, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/102625.

MLA Handbook (7^th Edition):

Makiwane, Memela MacDonald. “Adverse drug reactions in paediatric in-patients in a South African tertiary hospital.” 2017. Web. 11 Apr 2021.

Vancouver:

Makiwane MM. Adverse drug reactions in paediatric in-patients in a South African tertiary hospital. [Internet] [Masters thesis]. Stellenbosch University; 2017. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/102625.

Council of Science Editors:

Makiwane MM. Adverse drug reactions in paediatric in-patients in a South African tertiary hospital. [Masters Thesis]. Stellenbosch University; 2017. Available from: http://hdl.handle.net/10019.1/102625

Stellenbosch University

9. Innes, Steven Eugene Vere. Lipoatrophy in HIV-infected children on antiretroviral therapy.

Degree: PhD, Paediatrics and Child Health, 2013, Stellenbosch University

URL: http://hdl.handle.net/10019.1/79864

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Bibliography

ENGLISH ABSTRACT: Introduction: Lipoatrophy is a common adverse effect of stavudine and this effect is strongly dose-dependent. Stavudine remains the most commonly used paediatric… (more)

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Bibliography

ENGLISH ABSTRACT: Introduction: Lipoatrophy is a common adverse effect of stavudine and this effect is strongly dose-dependent. Stavudine remains the most commonly used paediatric antiretroviral drug in sub-Saharan Africa, yet when the current study began in 2009, the prevalence and severity of lipoatrophy in children on antiretroviral therapy in sub-Saharan Africa had never been studied. The development of lipoatrophy may have serious and far-reaching consequences for patients and their families. The off-label stavudine dosing method, prescribed to children whose caregivers do not have access to a refrigerator, in which the contents of an adult capsule is mixed into tap water, has potential for over-dosing or under-dosing. In addition, children on stavudine continue to be exposed to a disproportionately high dose out of line with the reduced adult dose. Aims: 1. a) To investigate the prevalence and risk factors for lipoatrophy in HIV-infected children in Southern Africa b) To identify a simple anthropometric screening tool to detect early lipoatrophy in children 2. To validate the off-label stavudine dosing method prescribed to children whose caregivers do not have access to a refrigerator, with a view to reducing the recommended dose and thereby the side-effects. Methods: 1. a) We recruited pre-pubertal children on antiretroviral therapy from a family HIV clinic in our facility. Lipoatrophy was identified by two experienced paediatric HIV clinicians using a standardized grading scale. A dietician performed dietary assessment and anthropometric measurements. Previous antiretroviral exposures were recorded. A subset of recruits received Dual-Energy X-ray Absorbtiometry scanning. b) Anthropometric measurements in children with and without lipoatrophy were compared using multivariate linear regression adjusting for age and gender. The most discerning anthropometric variables underwent Receiver Operating Characteristic curve analysis to identify the most appropriate diagnostic cut-off. 2. a) Accuracy of the standard off-label stavudine dosing method was investigated using high-performance liquid chromatography to recover active drug from solutions made up using the prescribed method. This was compared to the stated drug content of the capsules. b) Bioavailability was investigated by performing a randomized crossover pharmacokinetic study wherein healthy HIV-seronegative adult volunteers received one of two generic stavudine capsule formulations, either intact or mixed in water using the prescribed method. Plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Results: 1. a) Prevalence of lipoatrophy was 36%, and incidence was 12% per person-year. Adjusted odds ratio for developing lipoatrophy was 1.9 (CI: 1.3–2.9) for each additional year of accumulated exposure to standard-dose stavudine. b) Baseline biceps skin-fold thickness correlated well with maximum lipoatrophy grading score at any site, giving a partial correlation coefficient of 0.33…

Advisors/Committee Members: Cotton, Mark Fredric, Rosenkranz, Bernd, Rabie, Helena, Zollner, Ekkehard Werner, Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health..

Subjects/Keywords: Pediatrics; Dissertations – Pediatrics; Lipoatrophy – HIV-positive children – Risk factors; HIV positive children – Treatment; Antiretroviral agents – Risk factors; Stavudine – Therapeutic use; Pediatrics and Child Health

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Innes, S. E. V. (2013). Lipoatrophy in HIV-infected children on antiretroviral therapy. (Doctoral Dissertation). Stellenbosch University. Retrieved from http://hdl.handle.net/10019.1/79864

Chicago Manual of Style (16^th Edition):

Innes, Steven Eugene Vere. “Lipoatrophy in HIV-infected children on antiretroviral therapy.” 2013. Doctoral Dissertation, Stellenbosch University. Accessed April 11, 2021. http://hdl.handle.net/10019.1/79864.

MLA Handbook (7^th Edition):

Innes, Steven Eugene Vere. “Lipoatrophy in HIV-infected children on antiretroviral therapy.” 2013. Web. 11 Apr 2021.

Vancouver:

Innes SEV. Lipoatrophy in HIV-infected children on antiretroviral therapy. [Internet] [Doctoral dissertation]. Stellenbosch University; 2013. [cited 2021 Apr 11]. Available from: http://hdl.handle.net/10019.1/79864.

Council of Science Editors:

Innes SEV. Lipoatrophy in HIV-infected children on antiretroviral therapy. [Doctoral Dissertation]. Stellenbosch University; 2013. Available from: http://hdl.handle.net/10019.1/79864

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