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Repositioning of astemizole for malaria
Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). U...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2022
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| _version_ | 1867613176858673153 |
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| access_status_str | Open Access |
| author | Mambwe, Dickson |
| author2 | Chibale, Kelly |
| author_browse | Chibale, Kelly Mambwe, Dickson |
| author_facet | Chibale, Kelly Mambwe, Dickson |
| author_sort | Mambwe, Dickson |
| collection | Thesis |
| description | Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/35849 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:31:58.458Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/35849 Repositioning of astemizole for malaria Mambwe, Dickson Chibale, Kelly chemistry Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date. 2022-02-25T09:27:39Z 2022-02-25T09:27:39Z 2021 2022-02-25T09:27:15Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/35849 eng application/pdf Department of Chemistry Faculty of Science |
| spellingShingle | chemistry Mambwe, Dickson Repositioning of astemizole for malaria |
| thesis_degree_str | Doctoral |
| title | Repositioning of astemizole for malaria |
| title_full | Repositioning of astemizole for malaria |
| title_fullStr | Repositioning of astemizole for malaria |
| title_full_unstemmed | Repositioning of astemizole for malaria |
| title_short | Repositioning of astemizole for malaria |
| title_sort | repositioning of astemizole for malaria |
| topic | chemistry |
| url | http://hdl.handle.net/11427/35849 |
| work_keys_str_mv | AT mambwedickson repositioningofastemizoleformalaria |