3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Socioeconomic determinants of early health care utilisation and association with malaria hospitalisation among under five years children in Manhiça, Mozambique(2024) Chauque, Alberto AnicetoIntroduction Malaria is one of the significant health problems in the world, and the greatest burden of the disease is concentrated in Africa, which accounts for about 95% of cases. The WHO (World Health Organization) indicates that early seeking for treatment is crucial to avoid worsening the disease and, consequently, death. This work, was evaluated the factors that influence early health care seeking in children under five years old and the effect of early health care seeking on hospitalisations. Methods It was conducted a health facility-based observational longitudinal study where malaria cases were identified in an ongoing surveillance database. Using the first visit for all children that visited a Health Facility with fever and malaria and defined early health care seeking as a visit to a health centre within 48h after the onset of fever. Multilevel logistic regression was used to identify the factors related to early health care seeking and the association between early health care seeking and hospitalisation. Results A total of 66 620 children aged 0 to 15 years were screened. Excluding all children who did not meet the study criteria, ending up with 2 299 children with malaria and fever, but only 1 603 children had demographic information. A kilometre increase in the distance to a health facility reduces the odds of early health care seeking (aOR = 0.89; CI: [0.83-0.95]; p=0.001). Early health care seeking reduces the odds of hospitalization (aOR = 0.56; 95% CI: [0.34 -0.93]; 0.024) and year increase in the year of the visit also increases the odds of hospitalization (aOR = 1.66; 95% CI: [1.41-1.93]; p<0.001). Conclusions Increasing the distance to health facilities reduces the likelihood of early health seeking, whereas early health care reduces the risk of hospitalisation. Maluane and calanga lead the hospitalisation cases in the study area in children with malaria and cases of delay in health-seekingItem Design and synthesis of antifolates as potential antimalarial agents(2024) Butsi, KamogeloMalaria still remains a life threatening disease in many parts of the world. According to the World Health Organisation (WHO) approximately 241 million cases of malaria were reported worldwide in 2020, with Africa being the most affected continent. Prevalence of the disease is attributed to the significant increase in resistance towards currently used chemotherapeutic agents. Therefore, the search for new antimalarial candidates is imperative. In this report, we give progress on the synthesis of novel 2,4- diaminopyrimidine derivatives and their respective activity against Plasmodium falciparum. We have successfully developed a synthetic route towards flexible 2,4- diaminopyrimidine derivatives, which entails the synthesis of these target compounds in five steps starting from commercially available esters. The Sonogashira reaction was the key step employed to functionalise the iodinated pyrimidine ring at the 5- position with a suitable acetylene to form an alkyne intermediate. In this way, a four atom linker was introduced between the heterocyclic ring system and the terminal phenoxy ring. Reduction of the triple bond in the alkyne intermediate by a hydrogenation reaction afforded a library of the desired flexible 2,4-diaminopyrimidine analogues. Of the synthesised compounds, 15 were sent for activity assessment against both wild type and mutant PfDHFR enzymes. They inhibited both PfDHFR enzymes at low nanomolar concentrations. Additionally, these compounds were also tested against the human DHFR to evaluate their selectivity. All tested compounds were selective for PfDHFR over human DHFR. Further assessment on the antiplasmodial activity of these compounds were conducted in vitro in a whole cell P. falciparum assay against the drug sensitive TM4/8.2 strain and the multidrug resistant strain V1S. The tested compounds displayed moderate antiplasmodial activity in the micromolar range with IC50 values of 0.28 – 23.4 µM and 17.`6 – 64.0 µM against the drug sensitive strain and multidrug resistant strain, respectively. Unfortunately, they were mild to highly cytotoxic towards VERO cells. Further interrogation of the selectivity index (SI) indicated that the tested compounds did not display any selectivity for the plasmodial parasite over VERO cells. Abstract iii Therefore, inhibition of the Plasmodium strains is not only due to compounds interacting with the parasite but also cytotoxicity of the compounds on the viability of erythrocyte.Item Synthesis and biological evaluation of pyrimidine and isoquinoline inhibitors as potential antimalarial antifolates and transmission-blocking agents(2024) Somandi, KhonzisizweMalaria continues to be a serious threat, in particular to the African region. According to the World Health Organisation, in 2021, 247 million malaria cases were reported globally of which 95 % and 96 % of malaria related deaths were in the African region. The persistence of the disease, amongst it being difficult to treat and kill, is also attributed to its resistance to currently used antimalarial agents, including class II antifolate drugs such as pyrimethamine, which are used to target the P. falciparum dihydrofolate reductase (PfDHFR) enzyme. However many other drugs have lost activity because of mutations in the active site of the enzyme. The first component of the research described herein has been to synthesise 2,4- diaminopyrimidine analogues that work by disrupting folate metabolism by inhibiting PfDHFR. In a four step synthetic approach we have successfully prepared a series of pyrimidine-2,4-diamines possessing a flexible four atom linker at the 5-position of the pyrimidine ring (in yields of 33-96 %), which could prove advantageous in avoiding clashes with mutant amino acids in the enzyme active site. Enzyme inhibition assays of the compounds have shown successful inhibition of the wild-type (WT) and quadruple mutant (QM) PfDHFR in nM ranges (Ki-WT; 1.27 – 242.72 nM and Ki-QM; 13.01 – 208.23 nM). A moderate antiplasmodial activity in vitro was observed for all compounds assessed against the drug sensitive strain IC50 (TM4/8.2) 0.42 – 28.0 µM and the drug resistant strain IC50(V1S) 3.72 – 53.7 µM. The second component of the research focuses on the synthesis of transmission-blocking analogues that target the sexual stage of the malaria parasite life cycle and work by inhibiting stage IV/V gametocytes which prevents the transmission of the parasite from the human host back to the feeding mosquito. A series of 3-substituted-isoquinolin-1-yl benzamides, derivatives of the hit compound MMV1581558, have been successfully prepared in a synthetic protocol that involves only two steps from relatively simple precursors, in yields ranging between 14 – 68 %. All analogues are undergoing biological assessment against stage IV/V gametocytes and currently we have only received the results of the asexual blood stage activity assay, with most analogues displaying only moderate activity (IC50 1.18 – 7 µM). Additional biological assays are still underwayItem Iron and Malaria(1997-02-07) Van Zyl, Robyn L.Malaria is one of the most devastating infections found in man and the resurgence of drug resistance has prompted the search for novel chemotherapeutic strategies. Clinical observations have exposed the susceptibility of malaria parasites to iron deficiency, thus the metabolism of iron in parasitized erythrocytes could be a potential antimalarial target. In in vitro experiments, the parasites accumulated approximately four times more non-transferrin-bound iron than diferric transferrin. Both forms were accumulated in a concentration- and time-dependent manner, with more iron being associated with the trophozoite stage than the ring stage. The ferric iron chelating agent, desferrioxamine inhibited the uptake of transferrin and non-transferrin-bound iron in a concentration dependent manner. 2,2’-Bipyridyl, a ferrous iron chelating agent also inhibited the uptake of non-transferrin-bound iron, but did not affect the uptake of diferric transferrin. This indicated that the parasite does not accumulate diferric transferrin by transferrin-receptor mediated endocytosis, but rather by a non-specific endocytotic pathway. A large quantity of the accumulated iron was associated with the parasite haemozoin. Desferrioxamine effectively reduced the amount of iron associated with the haemozoin, whilst 2,2’-bipyridyl did not, which indicates that the haemozoin-associated iron is in the ferric state. The parasitized erythrocytes were more susceptible to haemolysis by the haemozoin subunits than the uninfected erythrocytes. The presence of chloroquine and 2,2’-bipyridyl potentiated the haemolysis induced by the subunits, whilst desferrioxamine protected the parasitized erythrocytes. The plasma chelating agents and aminocarboxylate compounds were not as effective in inhibiting parasite growth, as desferrithiocin, bathophenanthroline, desferrioxamine and 2,2’-bipyridyl which avidly chelate iron. The additive interaction between the latter two agents and chloroquine, quinine and pyrimethamine, completely eliminated the malaria infection. As did the combination of two lipophilic ferrous or two hydrophilic ferric iron chelating agents, as well as the combination of a hydrophilic ferric and lipophilic ferrous iron chelating agent. Whilst the combination of hydrophilic ferric and hydrophilic ferrous iron chelating agents antagonised each others antimalarial actions. Variables such as inoculum size, extracellular pH, cation supplementation and stage dependency, all affected the antimalarial activity of the iron chelating agents. Thus, the unique pathways involved in the iron metabolism of P. falciparum-infected erythrocytes, could be potential targets for new antimalarial drugs, which are membrane permeable and avidly chelate iron.Item An investigation of plasmodium falciparum sortilin in trafficking of invasion proteins of the human malaria parasite(2018) Shunmugan, SerenaMalaria is arguably one of the most overwhelming infectious diseases throughout the world's existence. The most virulent parasite, Plasmodium falciparum, has a redundancy of invasion proteins, allowing it to switch between different receptors on the host red blood cell. These invasion proteins are stored in the apical organelles, the rhoptries and micronemes, but very little is known about how newly synthesized proteins are transported to these organelles. The hypothesis in this study was that a common protein is involved in trafficking invasion proteins from the trans-Golgi network and PfSORTILIN was investigated as a potential escorter protein. The CCys domain of PfMAEBL, a rhoptry protein, and the prodomain of PfAMA-l, a microneme protein, have been implicated in trafficking to the apical organelles. These domains and the VPS 10 domain of PfSORTILIN were cloned into expression vectors encoding a GST- or Histag. Recombinant proteins were expressed in E. coli and purified by affinity chromatography on glutathione- or Ni-particles. In vitro binding assays were performed, which showed that PfSORTILIN VPS 10 bound to PfMAEBL ccys but not to the PfAMA-1 prodomain, suggesting that PfSORTILIN is a rhoptry protein escorter and is not involved in microneme trafficking. To identify novel binding partners of PfSORTILIN VPS 10, the protein was biopanned against a P. falciparum phage display library. No binding partners were identified, most likely because the library is not schizont-stage specific, which is when PfSORTILIN and invasion proteins are predominantly expressed. The results from this study were integrated with other studies and a trafficking model for PfMAEBL was proposed. This study enhances our knowledge of trafficking pathways and suggests that PfSORTILIN may serve as a common rhoptry protein escorter.Item Malaria at Chris Hani Baragwanath academic hospital intensive care unit: comparing outcomes between quinine and artesunate therapy(2017) Mathiba, RofhiwaBackground Malaria is a preventable and treatable disease that is a major burden in the African sub-region, accounting for 75% of malaria related deaths globally. Prior to December 2009, quinine has been the therapeutic option of choice for the management of Malaria in our unit. In the non-intensive care unit setting a mortality benefit of artesunate over quinine has been shown by two major trials and thus artesunate is currently therapy of choice for severe malaria. There is paucity of South African data regarding the outcomes of severe malaria patients treated w ith quinine compared to those treated with artesunate in the intensive care unit (ICU). Objectives The aim of this study was to compare the outcomes of patients treated with artesunate versus those treated with quinine, over a four-year period in our ICU. The primary outcome variables were length of stay and mortality, secondary outcomes where hypoglycaemia episodes and neurological outcome as measured by GCS on admission and on discharge. Methods This was a retrospective cohort study of patients with severe malaria treated at Chris Hani Baragwanath Academic Hospital with artesunate or quinine. The study was done in an ICU setting. This included a review of patients treated in the unit from 1st January of 2008 to 31st December 2012. A p value of<0.05 was chosen as a measure of statistical significance. Results The sample consisted of 92 patients. Forty three percent (n=40) received quinine and 57% (n = 52) received artesunate. There was no statistically significant difference between the two drugs in the treatment of severe malaria in our ICU with regards to length of stay (p=0.738), mortality (p=0.246), hypoglycaemia (p= 0.246) and neurological outcome as measured by GCS on admission and discharge (p= 0.357). Conclusion In our intensive care population the difference in outcomes between artesunate and quinine were not statistically significant. Artesunate did not confer an obvious benefit over quinine. Considering the differences in cost, logistical differences associated with the use of the two drugs as well as the emergence of artesunate resistance, we suggest that outcomes of artesunate versus quinine be investigated in other non-endemic regions.Item The effect of terpenes on the life cycle of the malaria parasite(2017) Mustapha, ObaidiyahMalaria is a parasitic infectious disease resulting in high mortality rates especially in sub- Saharan Africa. Vector control and chemoprophylaxis are important aspects in the prevention of malaria. However, due to the emergence of resistance to antimalarial therapies and insecticides as a global issue, new compounds are required to ensure adequate therapy. For centuries, traditional phytomedicines have been used as effective malaria management. African traditional plants are commonly used in South Africa, where the essential oils (EOs) and extracts have been shown to possess promising activity in the control of malaria. As such, the activity of various EOs and essential oil constituents (EOCs) has been investigated on the lifecycle of the parasite. The in vitro parasite lactate dehydrogenase (pLDH) assay determined the antimalarial activity of the EO/EOCs on the asexual stages of the parasite. All five EOs, Artemisia afra, Lippia javanica, Cymbopogon citratus, Cymbopogon nardus and Ocimum basilicum displayed antimalarial activity, with C. citratus (IC50 value: 2.00 x10'5%) displaying the most activity in comparison to the control, quinine (IC50 value 1.71 x10"5%; 0.18 pM). Nine of the 22 selected EOCs displayed antimalarial activity with eucalyptol (IC50 value: 0.37 pM; 6.19 x10~6%) the most active. The sensitivity of the Anopheles vector was assessed by determining the larvicidal activity of the EO/EOCs. Larvicidal activity was displayed by all five EOs and 14 EOCs with LC5o values ranging from 0.001 to 0.047%. The EOCs, c/s-nerolidol and p-cymene displayed the most promising larvicidal activity of all tested EO/EOCs with LC5o values of 0.001 and 0.004%, respectively. When combined these two EOCs interacted in an additive manner (average IFIC: 0.94). It was also determined that the reconstituted crude oils made from the EOCs to replicate the original EO, displayed less larvicidal activities than the original EO. To determine the preliminary toxicological effect of the EO/EOCs, the haemolysis, lipid peroxidation inhibition, tetrazolium and brine shrimp lethality assays were undertaken. Haemolytic activity was not displayed by any of the EO/EOCs, with only O. basilicum and eugenol inhibiting lipid peroxidation. Cellular viability was affected by all five EOs (IC50 values: 2.4 x10"4 - 2.5 x10"1%) and fifteen of the selected EOCs (IC50 values: 0.2 - 72.4 pM). Cymbopogon citratus and C. nardus and ten EOCs possessed Artemia nauplii lethality activity (LC50 values: 6 x10‘7 - 1.4 x10"2%). Varying antimalarial, larvicidal and toxicological properties were observed for the various isomers of nerolidol, geraniol, pinene, linalool, thujone and citronellal. These results showed that the biological activities of the EO/EOCs have the potential to be used as adjuncts in the management of the malaria parasite and vector, as well as the development for novel drugs.Item Atovaquone-Proguanil combination for malaria treatment: a systematic review with meta-analysis(2001) Oduro, Abraham , RexfordBackground: increasing spread of drug resistance among Plasmodium falciparum poses a serious threat to malaria treatment. The situation is complicated not only because new drugs are expensive and slow in development but also because they must be effective, preferably have a novel method of action, with an acceptable level of adverse effects, and be deployed in such a way as to prolong their use.Item Meta-analysis of intermittent treatment with sulfadoxine-pyrimethamine in pregnancy in malaria endemic areas(2002-11-02) Mkopi, Abdallah BakariTo systematically evaluate the efficacy of double dose of sulfadoxine-pyremithamine (SP/SP) treatment in pregnancy in malaria endemic areas. Methods - The relevant articles were retrieved by a computerized search of Medline, Cochrane Review, Pub Med and Google with the following key words, sulfadoxine-pyrimethamine, intermittent, pregnancy, Quasi- experimental studies and Randomised Control Trials. Three reviewers identified only 2 papers meeting the inclusion criteria set for the study. Systematic quantitative review was performed.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.