Artemisinin resistance in Plasmodium falciparum malaria.
Artemisinin resistance in Plasmodium falciparum malaria.
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DOI：
10.1056/nejmoa0808859
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发表时间：
2009-07-30
期刊：
影响因子：
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通讯作者：
White NJ
中科院分区：
文献类型：
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作者：
Dondorp AM;Nosten F;Yi P;Das D;Phyo AP;Tarning J;Lwin KM;Ariey F;Hanpithakpong W;Lee SJ;Ringwald P;Silamut K;Imwong M;Chotivanich K;Lim P;Herdman T;An SS;Yeung S;Singhasivanon P;Day NP;Lindegardh N;Socheat D;White NJ
青蒿素类复方疗法是所有地方病国家推荐的治疗恶性疟疾的第一线疗法。最近有人担心，在泰国-柬埔寨边境，这种疗法的疗效已经下降，历史上这是一个新出现的抗疟药物耐药性的地方。在两项开放标签、随机试验中，我们比较了柬埔寨西部拜林和泰国西北部旺帕两种治疗方法对无并发症恶性疟疾的疗效：口服青蒿琥酯，剂量为每天每公斤体重2毫克，持续7天，和青蒿琥酯，剂量为每天每公斤体重4毫克，持续3天，然后是两次剂量的甲氟喹，共25毫克/千克。我们评估了体外和体内恶性疟原虫的易感性，青蒿琥酯的药代动力学和耐药的分子标志物。我们在两个地点各研究了40名患者。拜林和王帕的总体中位寄生虫清除时间分别为84小时（四分位距，60 - 96）和48小时（四分位距，36 - 66）（P<0.001）。Pailin组20例接受青蒿琥酯单药治疗的患者中有6例（30%）复发，20例接受青蒿琥酯-甲氟喹治疗的患者中有1例（5%）复发，而Wang Pha组分别为20例中的2例（10%）和20例中的1例（5%）（P = 0.31）。这些显著不同的寄生虫学应答不能用年龄、青蒿琥酯或双氢青蒿素药代动力学、同位素体外敏感性试验结果或恶性疟原虫耐药性的假定分子相关性（编码多药耐药蛋白[PfMDR 1]的基因突变或扩增或编码肌质内质网钙ATP酶6 [PfSERCA]的基因突变）来解释。不良事件轻微，两个治疗组之间无显著差异。与泰国西北部相比，柬埔寨西部的恶性疟原虫对青蒿琥酯的体内敏感性降低。耐药性的特征是体内寄生虫清除缓慢，而常规体外敏感性试验没有相应的降低。迫切需要遏制措施。（ClinicalTrials.gov编号，NCT 00493363和当前对照试验编号，ISRCTN 64835265。）
Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai–Cambodian border, historically a site of emerging antimalarial-drug resistance. In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)