3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Acceptability of Malaria raid diagnostic test among health workers in Kintampo North municipality, Ghana(2017) Anaba, MichaelBackground: Research suggests that treatment of malaria is not evidenced based resulting in malaria parasites becoming resistant to antimalarial drugs. WHO recommends a malaria rapid diagnostic test (mRDT) for implementing the policy of test-based management of malaria to avoid inaccurate diagnosis and misuse of antimalarial drugs. Ghana adopted the “Test-Before Treat” guideline to facilitate the diagnosis for malaria with mRDT. However, Health Workers (HWs) still treat half of febrile patients with negative malaria results with antimalarial drugs suggesting limited or lack of acceptability of the intervention. This study sought to measure the level of mRDT acceptability and examine its associated determinants among HWs in the Kintampo North Municipality (KNM) of Ghana. Methods: This study employed a cross-sectional study design from February to April, 2017. Data on mRDT acceptability, its determinants and user characteristics were collected from 110 HWs in KNM involved in malaria management. The survey tool was based on two frameworks – the Technology Acceptance Model (TAM) and Normalization Process Theory (NPT). The latter proposed coherence, collective action, cognitive participation and reflexive monitoring as determinants for the implementation of the health intervention. A composite acceptability score was computed from a 21-item questionnaire for each respondent. Composite scores were also computed for the key determinants as well as median and inter quartile ranges. The respondents were divided into three equal groups (tertiles) for ordered logistic regression to examine the relationship between acceptability and its determinants. Results: The median acceptability score was 84 with interquartile range of 68-103. About 34% of HWs were in the low acceptability tertile, while 37% and 29% were in the moderate and high acceptability tertiles respectively. In the unadjusted model, determinants relating to each of the constructs of the adapted conceptual framework were identified, with a the clarity ii over the scope and boundaries of mRDT (coherence); variable investment in mRDT (cognitive participation); availability of resources, skills and training to deliver mRDT (collective action), improved reflection and feedback on the HW role in mRDT implementation and its impact (reflexive monitoring), rural HWs and HWs with three and above years’ experience positively influenced acceptability of mRDT. In the adjusted model, improved coherence, cognitive participation, working in rural facilities, community health officers and HWs with three and above years of experience were associated with high acceptability of mRDT. Whilst improved reflexive monitoring negatively influenced acceptability of mRDT. Conclusion: To successfully implement mRDT for test based management of malaria, HWs need to be equipped, resourced individually as well as the social or organizational context within which they work. In addition, programme implementers and policy makers must consider the roles of HWs and the how mRDT fit with their existing skill-sets. Furthermore, supervision and technical support of HWs is essential to facilitate transition to test based management with mRDT.Item The effect of 7-chloroquinoline derivatives on the life cycle of the malaria parasite(2017) Kathrada, FatimaWith the widespread resistance to current antimalarials and the great burden of malaria, the aim of this study was to determine the antimalarial activity of novel derivatives against the Plasmodium falciparum NF54 strain alone and in combination with quinine using the pLDH assay. The derivatives were designed such that they maintained the core chloroquinoline structure with known antimalarial activity with the addition of further scaffolds with a different mechanism of action in an attempt to produce compounds with good antimalarial activity with a lower probability of developing resistance. The twenty-seven 7-chloroquinolin-4-yl piperazine-1-yl acetamide (CQPA) derivatives and the nine 4-((7-chloroquinolin-4-yl) piperazine-1-yl) pyrrolidin-2-yl) methanone (CQPPM) derivatives all possessed antimalarial activity with 4 and 8 derivatives from each class respectively showed inhibitory activity below 10 µM. The most active derivative from each set of derivatives, CQPA-26 and CQPPM-9 displayed good antimalarial activity with IC50 values of 1.29 µM and 1.42 µM, respectively compared to the standard antimalarial, quinine (IC50: 0.18 µM). The two most active derivatives displayed drug-like properties with favourable ionisation properties to confirm its ability to accumulate in the parasites’ digestive vacuole. In combination with quinine, these derivatives displayed synergistic and additive interactions, respectively. Morphological studies were carried out over a period of 48 hours to identify which parasite stage was most sensitive to the most active derivative from each class of derivatives. Both derivatives proved to show similar schizonticidal activity as the standard quinine with a lag in progression from the trophozoite stage. The inability to induce haemolysis indicated that the derivatives acted against the parasite and not the host red blood cell (<1% lysis), conferring a good safety profile. The low toxic nature of the derivatives was further demonstrated with the minimal toxicity towards human embryonic kidney epithelial cells and no effect on Artemia fransiscana brine shrimp viability (<5% lethality). Although the cyclopropyl and methyl substituted derivatives displayed good activity towards the intra-erythrocytic parasite, all the derivatives lacked larvicidal activity towards Anopheles arabiensis (mortality range: 0 - 5%). The derivatives showed no effect on the morphological structure of the Artemia fransiscana brine shrimp and the An. arabiensis larvae. This study highlights the good antimalarial activity of these derivatives coupled with a favourable safety profile as antimalarial agents and not larvicides. The introduction of less bulky side chains proved to show a greater antimalarial activity against Plasmodium falciparum.Item Retrospective outcomes and cost analysis of antimalarial treatment in HIV-infected patients in a tertiary hospital setting in Soweto, South Africa(2017) Dandare, Murtala MuhammadMalaria is the most lethal parasitic infection globally, with a high mortality rate in sub-Saharan Africa. Imported malaria continues to cause life-threatening illness among non-immune antimalarial treatment and outcomes and performed a costs analysis among HIV-infected patients with malaria at Chris Hani Baragwanath Academi. [Abbreviated Abstract. Open document to view full version]Item Amantadine as an antimalarial(1996) Evans, Sandra GailAmantadine is used clinically to treat influenza. A viral infections and Parkinsons's disease. The lysosomotropio nature of funantadine suggested potential as an antimalarial. The aim of this study was to determine and characterise the antimalarial activity of amantadine. [Abbreviated Abstract. Open document to view full version]Item Synthesis and characterization of spirooxindole derivatives as potential antimalarial agents(2017) Butsi, Kamogelo RosinahSpirooxindoles are an important class of spirocycles in organic and medicinal chemistry. They are characterised by a spiro-ring fused with the oxindole scaffold and have a wide range of biological activity. We are particularly interested in spirooxindoles because of their antimalarial activity. Malaria is a major health problem in many parts of the world and the burden caused by the disease is still of great concern. In 2015 alone, an estimated 438 000 deaths due to malaria were reported across the world, with 90% of the deaths occurring in Africa. The increase in drug resistance to currently used antimalarial agents has rendered most of them ineffective, thereby contributing to the high mortality rates. As a result, there is a need for the development of new effective antimalarial agents. In the search for a new class of antimalarial chemotypes, cipargamin, introduced as NITD609 by norvatis in 2010 was synthesised. This compound is a novel synthetic antimalarial candidate, with an IC50 of ~1 nM against P. falciparum strains, including multi drug-resistant strains. Previously in our laboratory, several spirooxindole derivatives were synthesised using an imino Diels-Alder reaction, also known as the Povarov reaction. Of all the compounds synthesised, only those derived from a para-substituted aniline displayed activity in the low micromolar range (~5μM) against P. falciparum in vitro. In this project, we aimed to further explore the antimalarial activity of these compounds by designing and synthesising ring-opened analogues. The analogues were successfully synthesised by a Grignard addition reaction using N-Boc protected arylimines as electrophiles. Despite several attempts, we were unable to remove the Boc-protecting group in the final step. The second series of compounds we aimed to synthesise were ring closed analogues lacking one aromatic ring. The compounds were synthesised starting from an imine condensation reaction between benzyl protected isatin with para-substituted 2-allyanilines. The 2-allylanilines were prepared by subjecting N-allylanilines to an aza-Cope rearrangement. The arylimines prepared were then subjected to a nucleophilic Grignard addition reaction with commercially available vinylmagnesium bromide to yield the intermediate necessary for the ring closure step. Unfortunately, the nucleophilic addition reaction was unsuccessful. The ring-closure step is very crucial during the synthetic route as it gives rise to the desired ring closed analogues via ring-closing metathesis. Although we were unable to reach the final step in the synthesis of ring-closed analogues, some progress was made in developing methodology for the synthesis of these analogues. The synthesised ring-opened analogues were screened for antimalarial activity against P. falciparum in vitro. Six hit compounds were identified from the series of compounds tested with tert-butyl 3-(2,4-dichlorophenethyl)-2-oxo-3-(p-tolylamino)indoline-1-carboxylate 60 being the most active compound in the series with an IC50 value of 0.60 nM against the FCR 3 Strain. In general, compounds derived from p-toluidine displayed the most potent activity.