Curtis J, Maxwell C A, Msuya F H M, Mkongewa S, Alloueche A, Warhurst D C
London School of Hygiene and Tropical Medicine, London, United Kingdom.
J Infect Dis. 2002 Dec 15;186(12):1861-4. doi: 10.1086/345765. Epub 2002 Nov 15.
Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.
在坦桑尼亚乌桑巴拉山脉的263名儿童中，使用新型抗叶酸药物组合氯胍-氨苯砜进行治疗，在为期2周的随访过程中，有效地清除了246名（93.5%）儿童的无症状恶性疟原虫感染。在为期9周的随访中收集的71例复发性感染样本显示，二氢叶酸还原酶中具有三重突变Ile(51)-Arg(59)-Asn(108)的寄生虫被选择出来。对氨苯砜的靶酶二氢蝶酸合酶的突变没有选择作用。在治疗前后收集的寄生虫样本中，对编码裂殖子表面蛋白1和2的高度多态性基因进行完全同一性搜索表明，大多数复发性寄生虫血症是新感染。在坦桑尼亚关于选择作用的这些观察结果以及在一个疟疾流行程度较低地区报告的缺乏选择作用的情况表明，氯胍的活性代谢物在血液中的半衰期较短，但可能在肝脏中持续存在，在肝脏中它对生长中的前体红细胞阶段施加选择压力。
