Gbotosho G O, Ogundahunsi O A, Happi C T, Kyle D E, Gerena L, Milhous W K, Sowunmi A, Oduola A M J, Salako L A
Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
Ann Trop Med Parasitol. 2006 Oct;100(7):571-8. doi: 10.1179/136485906X118486.
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.
已开发出一种基于半自动微量稀释技术的体外模型，用于筛选可能在临床上用于逆转氯喹耐药性的化合物。该模型最初用于测试恶性疟原虫克隆W2对氯喹（CQ）的敏感性。然后，该模型用于研究四种耐药性逆转剂（维拉帕米、地昔帕明、氯苯那敏和异丙嗪，浓度均为1微摩尔）中的每一种在有无α1酸性糖蛋白（AGP）存在的情况下，在病理生理浓度（1.25克/升）的培养基中对该寄生虫对CQ敏感性的影响。在没有AGP的情况下，每种耐药性逆转剂都将CQ的半数抑制浓度从约94纳克/毫升的基线值降低了82%-97%。然而，在有AGP的情况下，大多数耐药性逆转剂的效果要小得多。CQ、耐药性逆转剂和AGP之间似乎存在竞争性相互作用。如果要在体外筛选出临床有效的耐药性逆转剂，显然需要阐明CQ、耐药性逆转剂、AGP和其他血浆蛋白之间的结合动力学。
