The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria

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dc.contributor.advisorSmith, Peteren_ZA
dc.contributor.authorTaylor, Daleen_ZA
dc.date.accessioned2015-10-28T05:36:03Z
dc.date.available2015-10-28T05:36:03Z
dc.date.issued2012en_ZA
dc.description.abstractAlthough 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.en_ZA
dc.identifier.apacitationTaylor, D. (2012). <i>The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology. Retrieved from http://hdl.handle.net/11427/14394en_ZA
dc.identifier.chicagocitationTaylor, Dale. <i>"The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2012. http://hdl.handle.net/11427/14394en_ZA
dc.identifier.citationTaylor, D. 2012. The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Taylor, Dale AB - 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. DA - 2012 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2012 T1 - The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria TI - The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria UR - http://hdl.handle.net/11427/14394 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/14394
dc.identifier.vancouvercitationTaylor D. The Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malaria. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2012 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/14394en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDivision of Clinical Pharmacologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherClinical Pharmacologyen_ZA
dc.titleThe Use of Combinations of Chemosensitisers to Reverse Chloroquine Resistance in Mice infected with Malariaen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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