Characterisation of Mefloquine accumulation in Plasmodium falciparum

 

Show simple item record

dc.contributor.advisor Smith, Peter en_ZA
dc.contributor.advisor Folb, Peter I en_ZA
dc.contributor.author Walden, Jason C en_ZA
dc.date.accessioned 2014-10-18T06:00:02Z
dc.date.available 2014-10-18T06:00:02Z
dc.date.issued 2003 en_ZA
dc.identifier.citation Walden, J. 2003. Characterisation of Mefloquine accumulation in Plasmodium falciparum. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/8601
dc.description Includes bibliographical references (leaves 165-180). en_ZA
dc.description.abstract 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. en_ZA
dc.language.iso eng en_ZA
dc.subject.other Pharmacology en_ZA
dc.title Characterisation of Mefloquine accumulation in Plasmodium falciparum en_ZA
dc.type Doctoral Thesis
uct.type.publication Research en_ZA
uct.type.resource Thesis en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Clinical Pharmacology en_ZA
dc.type.qualificationlevel Doctoral
dc.type.qualificationname PhD en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Walden, 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/11427/8601 en_ZA
dc.identifier.chicagocitation Walden, 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/11427/8601 en_ZA
dc.identifier.vancouvercitation Walden 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/11427/8601 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


Files in this item

This item appears in the following Collection(s)

Show simple item record