Masters Degrees (Clinical Pharmacology)

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Browsing Masters Degrees (Clinical Pharmacology) by browse.metadata.advisor "Decloedt, Eric"

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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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    Evaluation of the effectiveness of dose individualisation to achieve therapeutic vancomycin concentrations
    (Stellenbosch : Stellenbosch University, 2017-12-05) Abulfathi, Ahmed Aliyu; Decloedt, Eric; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
    ENGLISH ABSTRACT: Background The glycopeptide antibiotic vancomycin is used for treatment of methicillin resistant Gram positive cocci. Adequate vancomycin plasma concentrations are related to bacterial cure. However, inter- and intra-patient variability make it difficult to achieve therapeutic vancomycin concentrations. The primary objective of this study was to determine the effectiveness of using computerised therapeutic drug monitoring (TDM) to assist in achieving therapeutic vancomycin concentrations at a tertiary hospital in South Africa. Method This was a 2-period study consisting of a retrospective 1-month observational period followed by a prospective 1-month period where computerised TDM was implemented as an intervention to assist with vancomycin dose individualisation. Prescribers were provided with guidelines on vancomycin dosing and TDM results during both study periods. During the prospective period, all vancomycin TDM results were followed by dose individualisation using computerised TDM. In addition, the area under the-concentration-time curve over minimum inhibitory concentration (AUC/MIC) was calculated to ensure a ratio of ≥400. Results The retrospective study included 77 patients with 292 vancomycin concentrations: 69% (53/77) adult and 31% (24/77) paediatric patients. The prospective study included 80 patients with 217 vancomycin concentrations measured: 69% (55/80) adult and 31% (25/80) paediatric patients. Less vancomycin TDM data were requested during the prospective period with a median (interquartile range) of 2 (1-3) samples per patient compared with 3 (1- 5) during the retrospective period. The odds ratio of achieving therapeutic trough concentrations was 3.63 (95% confidence interval (CI): 1.81 - 7.3) in the prospective period when TDM-adjusted vancomycin dosing and correct TDM procedures were applied. The use of computerised TDM in patients on continuous infusion resulted in 26% improvement in achieving therapeutic vancomycin concentrations in the prospective period (odds ratio 2.96; 95% CI: 1.19 - 7.36). In the prospective period, AUC0-24 was 400 mg·h/L or above in 71% of occasions. Conclusion The correct use of computerised TDM results in a higher frequency of therapeutic vancomycin concentrations in a middle income setting. Trough vancomycin concentrations alone correlate poorly with AUC0-24. Achieving therapeutic vancomycin concentration may strengthen antibiotic stewardship and save on TDM resources.
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    Pharmacology and intraocular pressure relationship of topical and systemic paracetamol in the adult New Zealand White Rabbit Eye
    (Stellenbosch : Stellenbosch University, 2022-02) Anderson, Sean Glen; Decloedt, Eric; Meyer, David; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.
    ENGLISH ABSTRACT: Background The main modifiable risk factor in open-angle glaucoma is the increased intraocular pressure (IOP). The primary goal of therapy is to lower IOP in order to slow, or even halt disease progression. Paracetamol has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. Endocannabinoid stimulation is now thought to be one of the proposed mechanism of actions of paracetamol and a proposed mechanism by which it lowers IOP. Paracetamol is metabolised to N-arachidonoylaminophenol (AM404) in the brain and spinal cord tissue. In vivo studies found that AM404 significantly increases and prolongs the pharmacological effect of exogenous anandamide, which in turn decreases IOP. Small randomised controlled trials of oral and intravenous (IV) paracetamol demonstrated intraocular lowering properties in humans. This project aims to describe the pharmacokinetics of topical and IV paracetamol and to determine its effect on IOP in the adult New Zealand White Rabbit. Study design and methodology A randomised control trial was conducted using IV and topical 1% paracetamol as well as topical 1% AM404. The study was divided into three separate protocols: Protocol 1: To study the corneal penetration properties of topical 1% paracetamol. Protocol 2: To study the ocular pharmacokinetics and IOP pharmacodynamics after an immediate dose of IV 1% paracetamol. Protocol 3: To study the ocular pharmacokinetics and IOP pharmacodynamics of topical 1% paracetamol, 1% AM404 and 1% paracetamol/AM404 combined. Each protocol utilised paired eye and two-eye design experiments. IOP measurements were done at different time intervals using the Icare Pro© tonometer depending on the experiment. Samples for concentration measurements were taken from the serum, aqueous humour (AH) and the vitreous, while the analysis was done using ultra-performance liquid chromatography, coupled to tandem high-definition mass spectrometry (UPLC-MS/MS). Results Protocol 1 Pharmacokinetics: The mean (95% CI) concentration of paracetamol detected in the AH was 4.09 ppm (3.18 to 5.00) at 2 hours and 0.92 ppm (0.60 to 1.24) at 4 hours after an immediate dose of topical 1% paracetamol. Protocol 2 Pharmacokinetics The mean (95% CI) highest paracetamol concentration detected was 14.99 ppm (11.73 – 18.25); 5.99 ppm (5.42 to 6.56) and 4.64 ppm (3.24 to 6.04) at 30 minutes post-dosing in the serum, AH and vitreous respectively. The serum concentration was 31.04 ppm when extrapolating back to 0 minutes. Based on the area under the curve (AUCt0-inf), the vitreous showed the greatest paracetamol exposure (2587.78 min⋅μg/mL) followed by the serum (1323.21 min⋅μg/mL) and the AH (796.25 min⋅μg/mL). The half-life (t1/2) and clearance of the vitreous, AH and serum was 368.20 min, 41.32 mL/min; 74.10 min, 126.37 mL/min and 29.10 min, 76.05 mL/min, respectively. Pharmacodynamics The mean (95% CI) change in IOP from baseline for the left and right eye was +0.30 mmHg (-0.69 to 1.28) at 30 minutes, -0.39 mmHg (-1.26 to 0.48) at 60 minutes, +0.98 mmHg (-1.29 to 3.24) at 90 minutes and -0.78 mmHg (-2.40 to 0.84) at 120 minutes post-dosing. Protocol 3 Pharmacokinetics Half-hourly topical 1% paracetamol had a median (IQR) cumulative AH concentration of 13.0 ppm (13.60) after a 4 hour dosing interval, while hourly topical 1% paracetamol had an AH concentration of 3.60 ppm (4.85). Cumulative mean (95% CI) AH concentrations of paracetamol after half-hourly topical drug application at 4 hours were 0.66 ppm (0.45 to 0.87) for paracetamol/AM404 combined, 0.08 ppm (0.04 to 0.12) for AM404 only and 0.79 ppm (0.52 to 2.17) for paracetamol only. AM404 was detected in the AH of one rabbit receiving paracetamol only eye drops where the recorded level was 0.008 ppm. Pharmacodynamics The integral IOP, defined as the integral of IOP change from baseline over time and calculated as an AUC was -5.1 mmHg⋅hr (95% CI, -10 to 0.41) for the control, -7.5 mmHg⋅hr (95% CI, - 14 to -1.1) for half-hourly topical 1% paracetamol and -4.4 mmHg⋅hr (95% CI, -14 to 5.5) for hourly topical 1% paracetamol over a 4-hour period. When comparing topical paracetamol with topical AM404, the integral IOP was -2.3 mmHg⋅hr (95% CI, -5.9 to 1.3) for the control, -2.0 mmHg⋅hr (95% CI, -5.6 to 1.7) for half-hourly topical 1% AM404, -1.7 mmHg⋅hr (95% CI, -4.5 to 1.2) for half-hourly topical 1% paracetamol and - 3.2 mmHg⋅hr (95% CI, -5.4 to -0.96) for half-hourly topical 1% paracetamol/AM404 combined. Conclusion Paracetamol, but not its metabolite AM404, penetrated the multi-layered cornea via passive diffusion in a dose-dependent fashion. AM404 was measured in the AH, which indicates potential breakdown of paracetamol into AM404 within the ocular tissues. We found a diurnal pattern with IOP lowest in the morning and highest in the afternoon. Additionally, IOP showed marked fluctuations over short periods. Using the integral IOP, it was found that there was a tendency to cause a lowering of IOP over time at higher concentrations of paracetamol in the AH, although this was not found to be significant. Topical AM404 did not show any significant IOP lowering effect.