Antimalarial drug resistance and combination chemotherapy
Antimalarial drug resistance and combination chemotherapy
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DOI：
10.1098/rstb.1999.0426
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发表时间：
1999-04-29
影响因子：
6.3
通讯作者：
White, N
中科院分区：
文献类型：
--
作者：
White, N
抗疟药物耐药性的发展时，自然发生的寄生虫突变体的敏感性降低，选择，然后传播。单点突变导致敏感性显著降低的药物尤其脆弱。低清除率和浅浓度-效应关系增加了选择的机会。使用不具有相同耐药机制的抗疟药组合将减少选择的机会，因为耐药突变体存活的机会是单个药物的每个寄生虫突变率乘以感染中暴露于药物的寄生虫数量的乘积。青蒿素衍生物是特别有效的组合伙伴，因为（i）它们是非常活跃的抗疟药，每个无性周期使寄生虫生物量减少多达10 000倍;（ii）它们降低疟疾传播性;和（iii）尚未报道对这些药物的耐药性。在治疗中不再单独使用抗疟药物，而是始终使用与青蒿素或其衍生物之一的组合，这是有充分理由的。
Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10 000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.