Clinical Pharmacology
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Browsing Clinical Pharmacology by browse.metadata.advisor "Reuter, Helmuth"
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- ItemAccuracy Optimization of anti-TB Drug Assays using Protein Evaluation in Calibration Curves during Pharmacokinetics Quality Assurance(Stellenbosch : Stellenbosch University, 2021-12) Vallie, Sarfaraaz; Stander, Marietjie; Reuter, Helmuth; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. Medicine: Clinical Pharmacology.ENGLISH ABSTRACT: Quality assurance of drug assaying is an important aspect in clinical testing. Accuracy is important to ensure correct bio-analytical results by constructing calibration curves that took blood matrix interferences into consideration. I have adhered to the United States of America Food and Drug Administration (FDA) call for improved accuracy in bio-equivalence, bio-availability and administering of narrow therapeutic indexed drugs. Significant different plasma levels were observed in clinical trials for the occasional hyperproteinemia (an increase in protein concentration in the bloodstream) and hypoproteinemia (lower-than normal levels of protein in the blood) patients this includes disease-related hyperalbuminemia (an increased concentration of albumin in the blood) and hypoalbuminemia (a deficit of albumin in the blood) patients. This research supported a modeled approach for accuracy improvements by including the patients‘ plasma protein levels using a combined calibration curve (protein evaluation calibrations curves – PROTECC-PKTM). Levels of albumin were classified as marked hypoalbuminemia (<2.5 g/dL), mild hypoalbuminemia (2.5-3.5 g/dL), normal albumin (3.5-4.5 g/dL), and hyperalbuminemia (>4.5 g/dL). This research was specifically important for drugs with a narrow therapeutic index. The rifampicin method was developed, validated and the concentration calibration curve of rifampicin with and without plasma was assessed. The limit of detection for rifampicin with and without plasma was 0.189 μg/ml ± 0.082 and 0.080 μg/ml ± 0.053 μg/ml respectively (LOD ± mean standard diviation). The limit of quantification of rifampicin with and without plasma was 0.573 μg/ml ± 0.082μg/ml and 0.243 μg/ml ± 0.053μg/ml respectively (LOQ ± mean standard diviation). The r2 for rifampicin was 0.9971 without plasma and 0.9852 with plasma present. A novel analytical method for determination of the % protein content present in blood plasma was performed using the Karl Fischer Titration process. Results indicated deviation in % protein of blood plasma for patients compared to literature values of about 8 %. Using the data obtained, the PROTECC-PKTM curves indicated that the relative accuracy differed by a minimum of 0.1% for low binding affinity drugs and a maximum of more than 20% for drugs with moderate binding affinities. The relative accuracy of the anti TB drugs was supported by computational modelling and thermodynamic analytical methods for each drug during multiple drug co-administration regimens. This study focused on the drug binding affinity that affects the extrapolation of the patient‘s sample drug concentration from the slope of LCMS calibration curve. The binding constants calculated from fluorescence spectroscopy data were as follows: rifampicin 5.379 x 102 M-1 (moderate affinity), isoniazid 9.285 M-1 (low affinity), 25-desacetyl rifampicin 3.156 M-1 (low affinity), ethambutol 3.443 M-1 (low affinity) and pyrazinamide 3.076 X 102 M-1 (moderate affinity). These drugs Gibbs free energies for these drugs indicated spontaneous binding reactions. Rifampicin, a non-polar weak acid with a higher affinity, showed the most stable complex formation with human serum albumin (HSA) compared to soluble isoniazid. This is because isoniazid in its ionized form can be easily excreted in the urine resulting in low levels of detection. This will affect the bioavailability and accuracy of the assay levels for patients experiencing hyper and hypoalbuminemia with related competition and induction processes of the enzymes. These complications are apparent where a larger number of patients are involved in clinical trials, bioequivalence and bioavailability studies with varying protein levels that may be more crucial for drugs with a narrow therapeutic index.
- ItemA cross-sectional study to investigate the knowledge, attitudes, and current practices of pharmacovigilance, among medical doctors and pharmacists in South Africa(Stellenbosch : Stellenbosch University, 2021-12) Rikhotso, Nyeleti Portia; Page, Carine; Reuter, Helmuth; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.Background: Pharmacovigilance pertains to activities aimed at monitoring medicines for related safety concerns, thereby ensuring patient safety and wellbeing. The primary method of pharmacovigilance is spontaneous reporting of adverse drug reactions (ADRs). ADRs have a socio-economic impact when they are not reported and mitigated appropriately. This impact is even more apparent in low-to-middle income countries (LMICs), an economic category encompassing all African countries. The World Health Organisation (WHO) has developed a global pharmacovigilance database (Vigibase®) for countries which are members of the Programme for International Drug Monitoring (PIDM), which includes many African countries. ADR reporting levels however remains low across Africa. This is also true for South Africa, despite being the first African country to become a member of the PIDM in 1992. Therefore, this research study was conducted to investigate the knowledge, attitudes, and practices of pharmacovigilance among medical doctors and pharmacists in South Africa. The aim of this study is to investigate the factors influencing the low adverse drug reporting levels by healthcare professionals in South Africa. Methodology: A cross-sectional survey was conducted in the form of a knowledge, attitudes, and practices (KAP) study design. The targeted sample population was 384 study participants. The questionnaire consisted of closed-ended questions, designed to assess the demographics, knowledge, attitudes, practices of healthcare professionals nationally. The survey also served to obtain suggestions from healthcare professionals to improve ADR reporting in SA. An online survey was created in the survey platform, SurveyMonkey® and the e-link to the survey was shared with the South African Medical Association (SAMA) and the South African Clinical Research Association (SACRA), two professional associations hosting memberships of registered medical doctors and pharmacists in South Africa. Both associations distributed the e-link to their members via email. The obtained data was analysed using IBM SPSS® Statistics version 27. Results: A total of 325 responses were received, accounting for 85% of the target sample population. Most (252; 77.5%) of the study participants on this study received an average score for their knowledge on pharmacovigilance, despite extremely low reported levels (91;28%) of training. Most of the respondents (269; 82.8%,) thought that awareness regarding pharmacovigilance in their professional environment is inadequate. Although the majority (310; 95.4%) of respondents agreed that ADR reporting is their professional obligation, (119; 36.6%) had never seen a reporting form and only (172; 52.9%) had ever participated in ADR reporting. The major factors discouraging respondents from participating in ADR reporting were lack of knowledge on the reporting process and lack of access to the ADR reporting form. The topmost suggestions selected by the respondents to improve ADR reporting in South Africa were to include pharmacovigilance training in the undergraduate curricula of South African universities (266; 81.8%) as well as implementation of on-line or telephonic reporting platforms (235; 72.3%). Conclusion: This study indicates that there is an average level of knowledge of pharmacovigilance amongst medical doctors and pharmacists in South Africa and that they mostly have a positive attitude towards pharmacovigilance. However, this does not translate into acceptable levels of participation in ADR reporting, most likely due to inadequate pharmacovigilance training provided to medical doctors and pharmacists in South Africa.
- ItemDevelopment of a direct ADR reporting tool for patients to address under-reporting of ADRs to the National Pharmacovigilance Unit in South Africa(Stellenbosch : Stellenbosch University, 2022-12) Maluleke, Tirhani Lineth; Page, Carine; Allen, Elizabeth; Reuter, Helmuth; Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology.ENGLISH ABSTRACT: High standards of public health can be achieved through efficient and safe utilisation of healthcare products and the continuous monitoring thereof. Pharmacovigilance (PV), defined as the science and activities relating to the monitoring of adverse reactions associated with all medicines, is however hampered by the global under-reporting of adverse drug reactions (ADRs) by healthcare professionals. Several countries have successfully incorporated direct patient reporting into their PV system as a means of addressing the under-reporting challenge. Innovative ADR reporting tools have the potential to enable PV systems through increasing signal detection, assessment, understanding and prevention of adverse effects. Whilst the proof-of-concept of such tools have been promising, the use thereof by patients and consumers with access to the South African healthcare system has not been tested. The aim of the current study is to develop an ADR reporting tool for use by consumers in reporting ADRs to address under-reporting in South Africa. The design of the current study and the development of a patient/consumer ADR reporting tool precedes the adoption and implementation of the Med Safety Mobile Application as an online Adverse Event Following Immunisation (AEFI) reporting tool by the South African Health Products Regulatory Authority (SAHPRA) in 2021. If it had not been for the outbreak of the COVID-19 pandemic in 2020 and the immediate need for AEFI reporting tools following the global roll-out of immunisation programmes shortly thereafter by the World Health Organisation (WHO), National Health Departments and Regulators around the globe, this study would have been one of the first to have investigated direct consumer reporting on a larger scale in South Africa. The standard South African Health Products Regulatory Authority (SAHPRA) Yellow Form was used as a frame reference for designing an online-based consumer ADR reporting tool, which is compatible with a mobile application and a paper-based version. Validation and reliability testing of the tool was carried out in two stages: A content validation by healthcare professionals determined whether the content of the tool is appropriate and relevant for the designed purpose of ADR reporting by consumers/patients and face validation by consumers evaluated the usability of the tool in terms of readability, how clear/easy to follow the instructions and/or provide the required information. The developed and tested ADR reporting tool consists of five main elements: consumer’s details, consumer’s medical history, ADR details, suspected medicine(s), and reporter details. All items included received a majority inter-agreement rating of over 80% each as relevant to include in the tool, except for the reporter initials, the batch number and expiry date of the suspected medicine. Using the McNemar Chi-square test, the test and re-test responses of face validation showed no significant difference in responses across all items in the ADR reporting tool. Feasibility testing to assess the ease with which the ADR reporting tool could be used, how practical it is to access the tool and submit the report through it was carried out over a period of 1 year and 3 months. Participants were recruited from twelve healthcare centres and through social media, and they have completed and submitted ADR reports via online tool. A total of 348 reports were received with female consumers contributing 58.3% most of which were from those aged 31- 40 years (22.5%). These were associated with birth control medicines, the fourth highest suspected medicines reported (13.5%) with all reported ADRs listed as expected in the respective package inserts. Hydrochlorothiazide (52.17%) and enalapril (27.54%) were the most frequently suspected medicines within the antihypertensive class. All suspected medicines had well-established safety profiles, except for a lamivudine, tenofovir disoproxil fumarate and dolutegravir fixed-dose combination, nine reports related to investigational medicinal products and twenty-three suspected medicines which could not be identified. Expectedness of reported ADRs was confirmed in 73.9% of the suspected medicines, with dose reduction in 3.4%, treatment changed in 1.8% and treatment stopped in 6.9% of the consumers. A total of 5.3% of suspected medicines could not be verified as the names could not be recognised. Only two reports were received from healthcare professionals with the completeness and terminology used being similar to those of non-healthcare professionals. Reported terms produced 63.4% ‘exact matches’ from the MedDRA search, 8.7% were from ‘contains search’ results and terms used from ‘lexicant variant’ results amounted to 2.5%. Over 25% of the reported terms could not be found in the MedDRA database and therefore an alternative term was used. The high response rate in this study as well as the manner in which the consumers completed the ADR reports demonstrates their understanding and feasibility of using the tool to consistently submit ADR reports whose information would enable causality assessment over time, which will also boost the local PV system. However, the use of English only in the study limited participation of consumers who cannot use and/or understand the language. There was also no measure on the readability index conducted and causality assessment was not carried out. With consumer reporting being relatively new in South Africa, this study can be used as a basis to assess and improve on the newly introduced SAHPRA ADR reporting tools. Further studies are needed to assess the interest, understanding and factors influencing consumers to report ADRs.
- ItemDrug repurposing and optimisation to improve tuberculosis treatment(Stellenbosch : Stellenbosch University, 2021-03) Abulfathi, Ahmed Aliyu; Svensson, Elin M.; Reuter, Helmuth; Diacon, Andreas H.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.ENGLISH ABSTRACT: Tuberculosis, a leading infectious cause of mortality, morbidity, and reduced quality of life with loss of income, remains a huge public health burden particularly in resource-limited settings. The golden thread throughout this dissertation, was improving tuberculosis treatment through repurposing and optimisation of existing medicines. For that purpose, we sought to improve our understanding of the pharmacokinetics and pharmacodynamics of selected anti-tuberculosis drugs.
- ItemExploring and identifying the indigenous healers of madwaleni and their relationship with ethnobotany and healthcare(Stellenbosch : Stellenbosch University, 2019-04) May, Thandokazi; Mji, Gubela; Reuter, Helmuth; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.Rationale: The use of indigenous medicine is widely known in South Africa. In fact, it is estimated that 80-85% of black South Africans consult with indigenous healers in both rural and urban communities (Moshabela, et al., 2016). Despite increased academic interest in indigenous health knowledge (IHK) in the country, there is still interest in studies that are aimed at documenting the indigenous practitioners as well as their herbs and plants. Suggestions have been made to fill this knowledge gap by conducting ethnobotanical surveys of the plants used by indigenous healers as well as to identify who are these healers that use these plants. Aim and Objectives: The main aim and objective of this study was to explore and identify the indigenous healers of the Madwaleni, including the illnesses these healers manage, and which herbs are used to treat each illness. Other objectives were to: catalogue the ethnobotanical diversity used by these healers, and to identify the precise botanical environment that these herbs grow as well as the relationship these healers have with these environments. Lastly, the study explores the relationship between indigenous healers and the biomedical health care system in the area. Method: This is a descriptive, ethnographic study that used qualitative methods of data collection. The data was collected through participant observation, where participants took part in interviews and Focus Group Discussions (FGDs). There were 37 participants and key stakeholders, 30 being practitioners of indigenous medicine, 5 being biomedical health professionals, and 2 being traditional leaders. Both in-depth interviews and FGDs were used to collect data, totalling up to 6 interviews and 15 FGDs. Life stories were documented as part of exploring methods that could be used in the reconciliation process. The plants used by the indigenous healers of the area were documented transcriptionally and photographically. Findings: • The indigenous healers of Madwaleni can be categorized in five categories: (1) amaGqirha (indigenous doctors) and (2) amaXhwele (herbalists), (3) elite older Xhosa women and (4) amaTola (older elite men), and (5) abaThandazeli (faith healers). Intersectionality and partnerships between these groups of healers was welcomed and encouraged, although some unresolved tensions exist between the healers due differences in philosophy and practice. • The relationships between the individual, the community, the natural environment and the ancestral spirits all play a pivotal role in maintaining health in Madwaleni. Therefore, health is attained when the complete balance between mind, body and soul is achieved through the maintenance of solid relationships between all members of society, including the ancestors and the natural environment. When sickness results because of rifts in these relationships, indigenous medicinal plants must be administered to treat the illness and to regain the normal state of health. These plants are believed to be imbued with the spiritually healing powers of the natural environments in which they grow. Consequently, indigenous amaBomvana medicines have not only a healing function, but also have an apotropaic spiritually protective function. • Tensions continue to dominate the landscape between indigenous health knowledge and Western knowledge in Madwaleni. Biomedical professionals in the area cite the lack of empirical evidence for the pharmacological functions of indigenous medicines as the reason behind their refusal to accept IHK as a valid health system. Conclusion: Considering the cultural understanding of well-being and the determinants of health, the amaBomvana prefer to utilize diverse health management strategies when it comes to managing and treating illness. The health strategies of the amaBomvana people are exceptional and have the potential to help unlock some of the medical challenges of the modern world. The existence and endurance of various indigenous healers and their IHK strategies in the face of the threat of biomedicine is attestation to this. There exists a lot of unresolved tension between the various groups of healers in the area, due to differences in ethnomedical practice and philosophy. Before a partnership can be formed with the biomedical field, the indigenous healers themselves would need to share and acknowledge each other without taking any position of superiority over each other. The unresolved relationship between biomedicine and the indigenous health system creates spaces of confusion for the patients of Madwaleni, often resulting in bad health decision making and mismanagement of disease. A reconciliation process model is recommended by the study in order to repair this.
- ItemVenomous spider bites in south africa: epidemiology and clinical features(Stellenbosch : Stellenbosch University, 2019-04) Du Plessis, Catharina Elizabeth; Reuter, Helmuth; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: Clinical Pharmacology.Introduction: Worldwide the number of spider bite calls to poison centres comprises less than 2.5% of calls. Only a small proportion of spiders cause serious envenomation in humans. The known medically important spiders of South Africa include the Latrodectus (button), Cheiracanthium (sac) and Loxosceles (violin) species. The button spiders can cause neurotoxicity called latrodectism while violin and sac spider bites can cause necrotic skin lesions. The clinical syndrome of latrodectism is well defined and an effective antivenom is available. The diagnosis of necrotic arachnidism on the other hand is more difficult, especially if the spider bite is not painful. The necrotic skin lesions are not specific and have a wide differential diagnosis. Aim: The main aim of the study was to perform a retrospective assessment of poison centre data regarding spider bites from January 2005 to December 2017 and to develop an algorithm for the diagnosis of spider bites. Results: From a total of 83 974 calls, 1917 (2.3%) were related to suspected spider bites. The majority of these calls were from the Western Cape Province. The majority of bites occurred during the warmer months of the year, peaking in January and February. Adults were involved more frequently than children, 1497 versus 420, respectively. In 138 (48.6%) of the 284 reported button spider bites, the spider was positively identified. Of these, 80 (28.1%) patients were treated with antivenom. The most common clinical features were generalised pain (n = 89, 31.3%), muscle pain and cramps (n = 88, 31.0%) and sweating (n = 58, 20.4%). In the cytotoxic spider group only 5 spiders were positively identified. In the majority of calls the spider was not seen or could not be identified (n = 1301, 68%). Discussion: The number of spider bite calls to poison centres are low when compared to the total number of calls received. Bites usually involved adults and occurred mostly during the warmer months of the year. There has not been a single death associated with spider bites. In terms of a Poison Information Centre helpline data collection suggested categories for the diagnosis of spider bites include definite, probable and unlikely. Based on the clinical presentation it is possible to diagnose neurotoxic spider bites caused by button spiders with confidence and advise the use of the antivenom when indicated. A positive response to the antivenom supports the presumed diagnosis. It is more difficult to diagnose cytotoxic spider bites and the majority reported skin lesions are unlikely to be caused by spiders. We have developed a diagnostic algorithm that incorporates the most important clinical features and the distribution of spiders to assist with the diagnosis. Conclusion: In the majority of spider bites it is unlikely that serious effects will develop, however the early identification of a spider as well as the recognition of a clinical syndrome associated with certain spider bites, would assure safe and effective treatment. The helpline data is insufficient to fully describe necrotic arachnidism and further prospective studies are warranted.