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The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria
Although several dozen different compounds are able to transiently alter chloroquine resistance via chemosensitisation, the phenomenon has never evolved beyond laboratory practice as a result of in vivo difficulties. Chemosensitising compounds either need to be administered at doses which are toxic...
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| Format: | Thesis |
| Language: | English |
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Division of Clinical Pharmacology
2015
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| _version_ | 1867613330731958272 |
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| access_status_str | Open Access |
| author | Taylor, Dale |
| author2 | Smith, Peter |
| author_browse | Smith, Peter Taylor, Dale |
| author_facet | Smith, Peter Taylor, Dale |
| author_sort | Taylor, Dale |
| collection | Thesis |
| description | Although several dozen different compounds are able to transiently alter chloroquine resistance via chemosensitisation, the phenomenon has never evolved beyond laboratory practice as a result of in vivo difficulties. Chemosensitising compounds either need to be administered at doses which are toxic to the host in order to reverse resistance, or the drug is so highly bound to serum proteins that there is an insufficient circulating quantity available to restore sensitivity. Nine chemosensitisers were evaluated in vitro against several resistant isolates of the malaria parasite in order to develop a cocktail treatment of three compounds which could reverse resistance additively or synergistically when used at low doses with chloroquine. This would bypass any toxicity issues which might arise from the use of a high dose of a single agent. Six of the chemosensitisers were selected for combination into six different cocktails which were tested in vitro. Each cocktail contained one antidepressant, one antihistamine and one antipsychotic. Low doses of each drug were able to alter resistance to a small extent singly and in combination; this was shown by determining the effect of drugs and cocktails on both chloroquine transport using radiolabelled chloroquine, and chloroquine efficacy using the lactate dehydrogenase assay for parasite viability. The reversal activity was shown to be additive in the cocktail treatments and not synergistic, and was highly dose-dependent. There was no direct correlation between the change in chloroquine transport and the extent of resistance reversal. The chemosensitisers' effect on chloroquine transport was evaluated in a mouse model of malaria and shown to be similar to that seen against cultured human parasites; following this, the cocktails were tested for efficacy in mice infected with chloroquine-resistant malaria. Five of the six cocktails were able to significantly alter parasite survival in the mice in conjunction with a low dose of chloroquine. Drug levels in the mice were quantified via mass spectrometry and liquid chromatography in order to correlate the efficacy data. One of the compounds in the failed treatment was shown to circulate at low levels in the animals and this is possibly why that treatment, although effective in vitro, did not yield a result in vivo. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/14394 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:34:25.395Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | Division of Clinical Pharmacology |
| publisherStr | Division of Clinical Pharmacology |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/14394 The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria Taylor, Dale Smith, Peter Clinical Pharmacology Although several dozen different compounds are able to transiently alter chloroquine resistance via chemosensitisation, the phenomenon has never evolved beyond laboratory practice as a result of in vivo difficulties. Chemosensitising compounds either need to be administered at doses which are toxic to the host in order to reverse resistance, or the drug is so highly bound to serum proteins that there is an insufficient circulating quantity available to restore sensitivity. Nine chemosensitisers were evaluated in vitro against several resistant isolates of the malaria parasite in order to develop a cocktail treatment of three compounds which could reverse resistance additively or synergistically when used at low doses with chloroquine. This would bypass any toxicity issues which might arise from the use of a high dose of a single agent. Six of the chemosensitisers were selected for combination into six different cocktails which were tested in vitro. Each cocktail contained one antidepressant, one antihistamine and one antipsychotic. Low doses of each drug were able to alter resistance to a small extent singly and in combination; this was shown by determining the effect of drugs and cocktails on both chloroquine transport using radiolabelled chloroquine, and chloroquine efficacy using the lactate dehydrogenase assay for parasite viability. The reversal activity was shown to be additive in the cocktail treatments and not synergistic, and was highly dose-dependent. There was no direct correlation between the change in chloroquine transport and the extent of resistance reversal. The chemosensitisers' effect on chloroquine transport was evaluated in a mouse model of malaria and shown to be similar to that seen against cultured human parasites; following this, the cocktails were tested for efficacy in mice infected with chloroquine-resistant malaria. Five of the six cocktails were able to significantly alter parasite survival in the mice in conjunction with a low dose of chloroquine. Drug levels in the mice were quantified via mass spectrometry and liquid chromatography in order to correlate the efficacy data. One of the compounds in the failed treatment was shown to circulate at low levels in the animals and this is possibly why that treatment, although effective in vitro, did not yield a result in vivo. 2015-10-28T05:36:03Z 2015-10-28T05:36:03Z 2012 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/14394 eng application/pdf Division of Clinical Pharmacology Faculty of Health Sciences University of Cape Town |
| spellingShingle | Clinical Pharmacology Taylor, Dale The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| thesis_degree_str | Doctoral |
| title | The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| title_full | The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| title_fullStr | The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| title_full_unstemmed | The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| title_short | The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria |
| title_sort | use of combinations of chemosensitisers to reverse chloroquine resistance in mice infected with malaria |
| topic | Clinical Pharmacology |
| url | http://hdl.handle.net/11427/14394 |
| work_keys_str_mv | AT taylordale theuseofcombinationsofchemosensitiserstoreversechloroquineresistanceinmiceinfectedwithmalaria AT taylordale useofcombinationsofchemosensitiserstoreversechloroquineresistanceinmiceinfectedwithmalaria |