3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Gene variant screening for biomarkers significant for effective ARV therapy with a focus on tenofovir nephrotoxicity(2018) Tshabalala, Elizabeth SibongileRecent South African studies report an increase in hospital admissions due to adverse drug reactions (ADRs), including to tenofovir disoproxil fumarate (TDF). Pharmacogenetic studies conducted in African populations have reported notable differences compared to other populations in variants associated with ADRs, including TDF-induced nephrotoxicity (clinically manifesting as acute kidney injury (AKI)), warranting their further investigation in local populations. The aim of this study was to identify variants in eight TDF implicated ADME genes and to select a subset of SNPs for a genetic association study for TDF-associated nephrotoxicity. Using next generation sequencing (NGS) to screen a cohort of 40 HIV-infected patients of Bantuspeaking origin, 275 variants were identified, including three loss of function and 40 novel variants. Based on allele frequency information (MAF>0.1) and prior association with ADRs, nine polymorphisms within five genes were prioritised for genotyping. This was done in cases presenting with AKI following TDF treatment (n=53) and in controls of similar ethnic origin not presenting with AKI (n=84). The cohort was genotyped using TaqMan® assays. A case-control association study was performed with genotypes, alleles and haplotypes using tests. Suggestive associations were detected for the ABCC2 1249A allele (p=0.02) and ABCC2 haplotypes AAC and AAT (p=0.02 and 0.03 respectively) and TDF induced AKI. The ABCC2 GTT haplotype (p=0.02) appeared to be protective of TDF induced AKI. However, the observed associations were not deemed to be significant following corrections for multiple testing. A limitation of the study was its relatively low power because of the small sample size. Therefore, findings from this work will need to be replicated in more suitably powered cohorts. Despite this, we observed evidence that suggests the potential influence of a subset of ABCC2 variants on TDFinduced AKI.Item Knowledge, attitudes and practices of nurses and pharmacists towards adverse drug reaction reporting in the Private Sector(2018) Bogolubova, SophiaBackground: Pharmacovigilance is an important tool not only in protecting patients from potentially harmful effects of medicines, but it plays a role in providing good quality of care and monitoring efficacy of drug products within a population. Spontaneous reporting is a system of reporting adverse drug reactions (ADRs) practiced worldwide as part of the WHO Programme for International Drug Monitoring. Unfortunately, the major drawback of this system is the underreporting of ADRs. Methodology: A cross-sectional questionnaire-based survey was conducted amongst pharmacists and nurses in six private hospitals in Gauteng. A pre-designed and structured multiple choice questionnaire containing 20 close-ended questions was used to assess demographics (four questions), knowledge (six questions), attitudes (five questions) and practices (five questions) of participants. E-mail and manual questionnaires were provided to target as many nurses and pharmacists as possible. Electronic responses were captured as they were submitted, while manual responses were collected by the principle investigator from a contact person identified within each hospital. The data obtained was analysed using appropriate statistical analysis through Microsoft Excel 2010 and Google Forms software. Results: A total of 233 healthcare professionals participated in the study. Although three quarters of participants believed ADR reporting to be important, most had received no previous pharmacovigilance training and did not know how to report an ADR. 87.1% of participants believed that all ADRs should be reported, with 75.5% of participants believing they would report all ADRs they encountered in the future provided they had sufficient training and knowledge. The major factors discouraging participants from reporting was a lack of awareness with respect to the process of reporting as well as a lack of access to the ADR reporting form. Conclusion: This study indicates that the majority of participants require further training regarding ADR reporting. Although the knowledge of most participants was acceptable, the transition into practice needs to be improved.Item Evaluating the knowledge, attitudes and practices of healthcare workers towards adverse drug reaction reporting in a Public Tertiary Hospital(2018) Gordhon, YashmayBackground Spontaneous reporting of adverse drug reactions (ADRs) is a method of monitoring the safety of drugs post-marketing, providing a way to discover new, rare or unnoticed ADRs. Despite its importance, there is widespread underreporting of ADRs by health care professionals in South Africa. Objectives The study assessed the knowledge, attitudes and practices (KAP) of health care professionals on ADR reporting at a public hospital. Methods The questionnaire consisted of 21 questions (5 demographics; 7 knowledge; 1 attitude; 7 practices of the participant). Hard copies of the questionnaire were completed by doctors, nurses and pharmacists. The results were captured on Microsoft Excel™, and imported onto Stata® 14 to conduct Pearson chi-squared and Fishers tests. Results 297 health care professionals (87.87%) responded to the questionnaire. 50.17% had knowledge of reporting, and pharmacists were the most likely professionals to know how to report (82.61%) (p< 0.001). 96.88% of participants who had previously received ADR training knew how to report ADRs. 90.24% stated they would report an ADR based on the seriousness of the reaction. Lack of knowledge; managing the patient being more important than reporting; and reporting being time-consuming were some discouraging factors. 58.59% of participants had encountered an ADR before but only 16.50% had reported (p< 0.001). Conclusions Doctors, nurses and pharmacists were aware of the presence of ADRs, but were unlikely to report them. Health care professionals should be made aware of the benefits of reporting, and perhaps a culture of reporting can be adopted given an awareness of pharmacovigilance.Item Addressing cancer treatment in an African setting: a bioinformatics analysis of pharmacogemically relevant varients(2018) Da Rocha, JorgeCancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are severe and expensive, and often cause adverse-drug-reactions (ADRs). These may be attributed to variants in genes that encode proteins involved in key drug pathways. Most pharmacogenomics (PGx) research has been done in populations of European, Asian and African-American ancestry, with sparse data from African populations. Thirteen genes linked with ADRs to medicines used for treating major cancer types were identified: ABCB1, DPYD, TYMS, CYP19A1, GSTP1, CYP1B1, CYP3A4, CYP3A5, ESR1, CYP2D6, SLC19A1 and XRCC1/5. Public domain wholegenome-sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess eight African populations. Functional annotation was performed with a series of bioinformatics-based scoring tools to assess potential likelihood of deleterious impact. Variants of high likelihood of deleterious impact, including some novel variants were identified. These novel variants, however, are rare and require further validation. Two key African specific variants were identified: the CYP3A5 frameshift variant, rs41303343, which is highly likely to knockout gene function, and the CYP2D6 missense variant rs59421388, which was scored highly likely deleterious by all tools. Both variants are common in Africans, at frequencies above 10%, but lack clinical investigation into their PGx impact. For missense variants with known PGx effects, such as CYP2D6 - rs1065852 and DPYD - rs2297595, African frequencies are significantly distinct from global populations (p < 1x10-4) (with rs1065852 less common, and rs2297595 more common in Africans respectively). There is also variation within Africa, with the rs1065852 A allele being more common in West Africans, while the rs2297595 C allele is more common in East Africans. These data indicate that guidelines for cancer drug safety based on African data is essential for use in Africa, and novel region-specific guidelines should be developed to ensure that Africans could benefit for a personalized medicine approach.