title: The effects of alpha1-acid glycoprotein on the reversal of chloroquine resistance in Plasmodium falciparum.
abstract: An in-vitro model based on the semi-automated microdilution technique has been developed for selecting compounds that might be used clinically for the reversal of chloroquine resistance. This was used initially to test the susceptibility of Plasmodium falciparum clone W2 to chloroquine (CQ). The model was then employed to investigate the effects of each of four resistance-reversing agents (verapamil, desipramine, chlorpheniramine and promethazine, at 1 microM) on this parasite's susceptibility to CQ, with and without alpha(1)-acid glycoprotein (AGP), at a patho-physiological concentration (1.25 g/litre), in the culture medium. In the absence of AGP, each of the resistance-reversing agents reduced the median inhibitory concentrations of CQ by 82%-97%, from a baseline value of about 94 ng/ml. In the presence of AGP, however, most of the resistance-reversing agents had much less effect. There appears to be competitive interaction between CQ, the resistance-reversing agents and AGP. The binding kinetics between CQ, resistance-reversing agents, AGP and other plasma proteins will clearly need to elucidated if clinically effective resistance-reversing agents are to be selected in vitro.
authors.affiliation: Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria. sgbot@skannet.com
authors.forename: G O
authors.initials: GO
authors.lastname: Gbotosho
authors.forename: O A
authors.initials: OA
authors.lastname: Ogundahunsi
authors.forename: C T
authors.initials: CT
authors.lastname: Happi
authors.forename: D E
authors.initials: DE
authors.lastname: Kyle
authors.forename: L
authors.initials: L
authors.lastname: Gerena
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
authors.forename: A
authors.initials: A
authors.lastname: Sowunmi
authors.forename: A M J
authors.initials: AM
authors.lastname: Oduola
authors.forename: L A
authors.initials: LA
authors.lastname: Salako
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D002744:Chlorpheniramine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004351:Drug Resistance / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D009961:Orosomucoid / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011398:Promethazine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D009961:Orosomucoid; D002744:Chlorpheniramine; D002738:Chloroquine; D014700:Verapamil; D011398:Promethazine; D003891:Desipramine