Thapar Mita M, Gil Jose P, Björkman Anders
Department of Medicine, Infectious Diseases Unit, Malaria Research Laboratory, M9/02, Karolinska University Hospital, Karolinska Institute, SE 171-76 Stockholm, Sweden.
Trans R Soc Trop Med Hyg. 2005 Jan;99(1):62-70. doi: 10.1016/j.trstmh.2004.01.016.
We studied the viability of Plasmodium falciparum parasites reappearing in long-term cultures after repetitive exposure to atovaquone and proguanil. Parasites (F32 and FCR3) exposed to 100-5000 nM atovaquone for 96 hours were reduced to <5% of initial parasitaemia but recrudesced after 9-15 days. Also, parasites exposed to 1000 nM atovaquone for 48, 72, 96 and 144 hours recrudesced after 9, 14, 21 and 23 days respectively. Immediately after removal of the drug, only 1-3 schizonts per 10000 red blood cells were found consistently, apparently unable to produce trophozoites and thus, possibly, adopting a "dormant state". Parasites (F32 and FCR3) exposed to 500 nM atovaquone for 72 hours reappeared after 14 days. These recrudescing parasites were then re-exposed and suppressed by atovaquone in three consecutive follow-up experiments. They reappeared after 12, 11 and 9 days respectively. No known point mutations in cytochrome b gene (cytb), associated with atovaquone resistance, were detected in any recrudescing parasites. Finally, parasites (F32) exposed to various concentrations of atovaquone and proguanil in combination for 72 hours reappeared after 9-17 days. The baseline susceptibilities of the parasites to individual drugs were similar before and after recrudescence in all experiments.
我们研究了恶性疟原虫在反复暴露于阿托伐醌和氯胍后在长期培养物中重新出现的活力。暴露于100 - 5000 nM阿托伐醌96小时的疟原虫（F32和FCR3）减少至初始寄生虫血症的<5%，但在9 - 15天后复发。此外，暴露于1000 nM阿托伐醌48、72、96和144小时的疟原虫分别在9、14、21和23天后复发。药物去除后立即发现，每10000个红细胞中始终只有1 - 3个裂殖体，显然无法产生滋养体，因此可能处于“休眠状态”。暴露于500 nM阿托伐醌72小时的疟原虫（F32和FCR3）在14天后重新出现。然后在连续三次后续实验中，将这些复发的疟原虫重新暴露并被阿托伐醌抑制。它们分别在12、11和9天后重新出现。在任何复发的疟原虫中均未检测到与阿托伐醌耐药性相关的细胞色素b基因（cytb）的已知点突变。最后，暴露于不同浓度阿托伐醌和氯胍组合72小时的疟原虫（F32）在9 - 17天后重新出现。在所有实验中，疟原虫复发前后对单一药物的基线敏感性相似。
