Adovelande J, Delèze J, Schrével J
Laboratoire de Biologie Parasitaire et Chimiothérapie, CNRS ERS 156, Muséum National d'Histoire Naturelle, Paris, France.
Biochem Pharmacol. 1998 Feb 15;55(4):433-40. doi: 10.1016/s0006-2952(97)00482-6.
This study describes the synergistic interaction of two calcium channel blockers, verapamil (VR) and SR33557 or fantofarone (SR), in reversing chloroquine resistance in Plasmodium falciparum, the causative agent of human malaria. The two calcium channel blockers exhibited an intrinsic antimalarial activity at 10 and 1 microM for verapamil and fantofarone, respectively. Isobolograms revealed that chloroquine and verapamil, and chloroquine and fantofarone, acted synergistically against chloroquine-resistant strains of P. falciparum. When used at subinhibitory concentrations, verapamil appeared 2 to 3 times more potent than fantofarone in reversing chloroquine resistance. Indeed, verapamil completely reversed the chloroquine resistance in P. falciparum, while fantofarone did so only partially. In the highly chloroquine-resistant strain FcB1, VR and SR acted synergistically to reverse CQ resistance, and the concentrations of VR used in these combinations could be reduced 10- or 100-fold (e.g. 100 nM and 10 nM) those required when this drug was used alone. In the moderately chloroquine-resistant strain K1, a combination of VR and SR for CQ resistance reversal allowed us to reduce the concentration of these chemosensitizers 1000- and 100-fold, respectively. The maximum tolerable plasma level beyond which side-effects occurred when using verapamil is 2.5 microM. Thus, the approach described, which allowed us to lower the doses of chemosensitizers, could well prevent toxic effects in humans and enlighten the advantages of polychemotherapy.
本研究描述了两种钙通道阻滞剂维拉帕米（VR）和SR33557或泛托法隆（SR）在逆转恶性疟原虫（人类疟疾的病原体）氯喹抗性方面的协同相互作用。这两种钙通道阻滞剂分别在10 μM和1 μM时对维拉帕米和泛托法隆表现出内在抗疟活性。等效线图显示，氯喹与维拉帕米以及氯喹与泛托法隆对恶性疟原虫的氯喹抗性菌株具有协同作用。当以亚抑制浓度使用时，维拉帕米在逆转氯喹抗性方面的效力似乎比泛托法隆高2至3倍。实际上，维拉帕米完全逆转了恶性疟原虫的氯喹抗性，而泛托法隆仅部分逆转。在高度氯喹抗性菌株FcB1中，VR和SR协同作用以逆转氯喹抗性，并且这些组合中使用的VR浓度可以降低10倍或100倍（例如100 nM和10 nM），而单独使用该药物时所需的浓度。在中度氯喹抗性菌株K1中，VR和SR联合用于逆转氯喹抗性使我们能够分别将这些化学增敏剂的浓度降低1000倍和100倍。使用维拉帕米时出现副作用的最大可耐受血浆水平为2.5 μM。因此，所描述的方法使我们能够降低化学增敏剂的剂量，很可能预防对人类的毒性作用，并揭示联合化疗的优势。
