Verdier F, Pussard E
INSERM U13, Institut de Médecine et d'Epidémiologie Africaines et Tropicales, Paris, France.
Med Trop (Mars). 1995;55(4 Suppl):27-32.
Modulating agents that circumvent the Plasmodium falciparum resistance to antimalarials are components without any intrinsic antimalarial activity but able, in association with a standard antimalarial drug, to restore the sensitivity of Plasmodium falciparum to this drug. Two hypotheses are forwarded about their possible mechanisms of action : the mechanisms involving the inhibition of the drug efflux and the mechanisms involving the inhibition of antimalarial drug metabolic degradation. None of these mechanisms is able to alone explain the effect of all modulating agents. The future use prospects of these compounds are limited by their in vivo toxicity. That relevant to the calcium channels blockers seems to be circumvented by the use of dextro-enantiomers. A toxicity relevant to a possible accumulation of the antimalarial in healthy, non target cells must be also suspected. Moreover the use of these agents evidences a socio-economic problem : a complete new development of the association (antimalaria plus modulatin drugs) is needed and that, in developing countries. Nevertheless, the agents modulating the Plasmodium falciparum resistance are a new approach for the treatment of resistant malaria which might give a recrudescence of activity to the old antimalarials as chloroquine.
能够规避恶性疟原虫对抗疟药耐药性的调节剂是一类本身没有任何抗疟活性，但与标准抗疟药物联合使用时能够恢复恶性疟原虫对该药物敏感性的成分。关于其可能的作用机制提出了两种假说：一种是涉及抑制药物外排的机制，另一种是涉及抑制抗疟药物代谢降解的机制。这些机制都无法单独解释所有调节剂的作用效果。这些化合物的未来应用前景受到其体内毒性的限制。使用右旋对映体似乎可以规避与钙通道阻滞剂相关的毒性。还必须怀疑与抗疟药在健康非靶细胞中可能蓄积相关的毒性。此外，这些药物的使用还凸显了一个社会经济问题：在发展中国家，需要对抗疟药与调节剂联合用药进行全新研发。尽管如此，调节恶性疟原虫耐药性的药物是治疗耐药疟疾的一种新方法，可能会使氯喹等老一代抗疟药重新恢复活性。
