Characterisation of Mefloquine accumulation in Plasmodium falciparum

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dc.contributor.advisorSmith, Peteren_ZA
dc.contributor.advisorFolb, Peter Ien_ZA
dc.contributor.authorWalden, Jason Cen_ZA
dc.date.accessioned2014-10-18T06:00:02Z
dc.date.available2014-10-18T06:00:02Z
dc.date.issued2003en_ZA
dc.descriptionIncludes bibliographical references (leaves 165-180).en_ZA
dc.description.abstractMefloquine has been in use for over twenty years and still very little is known about its interaction with Plasmodium falciparum. In 1979, Fitch er al carried out the only other published extensive investigation of mefloquine accumulation, but were not able to demonstrate energy dependent uptake. They later indicated that an energy requirement may be being masked by mefloquine’s ability to bind membrane phospholipids to a large extent (Chevli & Fitch, 1982).Until now no energy requirement for mefloquine accumulation has been uncovered. This thesis investigates the relationship between chloroquine and mefloquine resistance, and characterizes the mechanism of mefloquine accumulation in Plasmodium falciparum. Conditions were established that enabled the amplification of the parasites' contribution to overall mefloquine accumulation in the parasitised erythrocyte. It was found that mefloquine accumulation is stimulated by glucose and is inhibited by the glycolysis inhibitor, iodoacetate, and also by incubation at low temperature. Mefloquine accumulation was also found to be partly dependent on the pH gradient between the acidic food vacuole and the external medium. It has also been determined that mefloquine-resistant Plasmodium falciparum accumulate approximately half the amount of mefloquine than do mefloquine-sensitive parasites. It has been shown that the accumulation of both chloroquine and mefloquine have two components, a high affinity saturable component and a low affinity non-saturable component (Fitch et aI., 1979; Fitch et al., 1974; Bray et al., 1998). The saturable component has been well characterized, but until now the non-saturable component has not been identified. This thesis shows that chloroquine and mefloquine adsorption to synthetic β-haematin and pure isolated haemozoin is non-saturable. It is proposed that the malaria pigment is responsible for the low affinity, non-saturable component of chloroquine and mefloquine accumulation. The effect of chloroquine, mefloquine and artemisinin on haemoglobin levels in parasitised erythrocytes was also measured. Chloroquine caused a buildup in haemoglobin and mefloquine caused a decrease in haemoglobin levels. This adds weight to previously published work (Famin & Ginsburg, 2002) suggesting that chloroquine prevents the degradation of haemoglobin, while mefloquine inhibits the endocytosis of haemoglobin.en_ZA
dc.identifier.apacitationWalden, J. C. (2003). <i>Characterisation of Mefloquine accumulation in Plasmodium falciparum</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology. Retrieved from http://hdl.handle.net/11427/8601en_ZA
dc.identifier.chicagocitationWalden, Jason C. <i>"Characterisation of Mefloquine accumulation in Plasmodium falciparum."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2003. http://hdl.handle.net/11427/8601en_ZA
dc.identifier.citationWalden, J. 2003. Characterisation of Mefloquine accumulation in Plasmodium falciparum. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Walden, Jason C AB - Mefloquine has been in use for over twenty years and still very little is known about its interaction with Plasmodium falciparum. In 1979, Fitch er al carried out the only other published extensive investigation of mefloquine accumulation, but were not able to demonstrate energy dependent uptake. They later indicated that an energy requirement may be being masked by mefloquine’s ability to bind membrane phospholipids to a large extent (Chevli & Fitch, 1982).Until now no energy requirement for mefloquine accumulation has been uncovered. This thesis investigates the relationship between chloroquine and mefloquine resistance, and characterizes the mechanism of mefloquine accumulation in Plasmodium falciparum. Conditions were established that enabled the amplification of the parasites' contribution to overall mefloquine accumulation in the parasitised erythrocyte. It was found that mefloquine accumulation is stimulated by glucose and is inhibited by the glycolysis inhibitor, iodoacetate, and also by incubation at low temperature. Mefloquine accumulation was also found to be partly dependent on the pH gradient between the acidic food vacuole and the external medium. It has also been determined that mefloquine-resistant Plasmodium falciparum accumulate approximately half the amount of mefloquine than do mefloquine-sensitive parasites. It has been shown that the accumulation of both chloroquine and mefloquine have two components, a high affinity saturable component and a low affinity non-saturable component (Fitch et aI., 1979; Fitch et al., 1974; Bray et al., 1998). The saturable component has been well characterized, but until now the non-saturable component has not been identified. This thesis shows that chloroquine and mefloquine adsorption to synthetic β-haematin and pure isolated haemozoin is non-saturable. It is proposed that the malaria pigment is responsible for the low affinity, non-saturable component of chloroquine and mefloquine accumulation. The effect of chloroquine, mefloquine and artemisinin on haemoglobin levels in parasitised erythrocytes was also measured. Chloroquine caused a buildup in haemoglobin and mefloquine caused a decrease in haemoglobin levels. This adds weight to previously published work (Famin & Ginsburg, 2002) suggesting that chloroquine prevents the degradation of haemoglobin, while mefloquine inhibits the endocytosis of haemoglobin. DA - 2003 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2003 T1 - Characterisation of Mefloquine accumulation in Plasmodium falciparum TI - Characterisation of Mefloquine accumulation in Plasmodium falciparum UR - http://hdl.handle.net/11427/8601 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/8601
dc.identifier.vancouvercitationWalden JC. Characterisation of Mefloquine accumulation in Plasmodium falciparum. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Clinical Pharmacology, 2003 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/8601en_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.otherPharmacologyen_ZA
dc.titleCharacterisation of Mefloquine accumulation in Plasmodium falciparumen_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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