PROPHYLACTIC ANTIMALARIAL ACTIVITY OF ATOVAQUONE

这是一项双盲、随机、安慰剂对照的评估 阿托瓦酮(广谱)的预防抗疟疾活性 抗原虫药物)在16名健康志愿者中诱导 恶性疟原虫疟疾。这项研究是在一名门诊患者身上进行的 基础上，有三个手臂：a)6名志愿者，每天接受750 mg，qd 从挑战的前一天开始；b)六名志愿者收到一张 挑战前一天250毫克的剂量；以及c)四名志愿者 接受安慰剂治疗。志愿者接受了NF54毒株的挑战 感染按蚊叮咬致恶性疟原虫对氯喹敏感 斯氏蚊子。通过连续采血进行疗效评价 疟疾检查(在三个月内进行了35次) 通过监测感染的症状和体征来预防寄生虫。 培养了寄生虫，它们对阿托瓦酮的敏感性是 下定决心。所有四名安慰剂接受者都出现了寄生虫血症，并 成功地用氯喹治疗。所有12名吸毒者 仍然没有传播中的寄生虫。因此，无论是高剂量还是低剂量 阿托瓦酮提供了有效的预防[95%Cl0.61-1.00；p=0.005]。 然而，在低剂量接受者中，血浆水平在6.5天后下降 挑战(预计恶性疟原虫最早出现在 血液)的浓度已降至远低于 先前研究中的红细胞寄生虫。这表明 生物体在6.5天前被杀死，当时仍在肝脏中。那里 没有证据表明部分治疗反应的形式是 亚临床寄生虫血症或肝期延长。我们的结论是 阿托瓦酮保护非免疫受试者免受蚊子传播 恶性疟疾。此外，证据表明，有一种 抗肝期寄生虫的因果成分。这个额外的维度 抗寄生虫活性的作用消除了需要数周的后- 目前需要用氯喹或甲氟喹进行暴露治疗， 这些药物具有抑制作用，但不是因果作用。 阿托瓦酮作为马拉酮的一种成分，因此提供了一种急需的新的 疟疾化学预防的治疗方法。

This was a double-blinded, randomized, placebo-controlled evaluation of the prophylactic antimalarial activity of atovaquone (a broad spectrum antiprotozoal agent) in sixteen healthy volunteers with induced Plasmodium falciparum malaria. The study was conducted on an outpatient basis, and had three arms: a) six volunteers receiving 750 mg qd starting the day before challenge; b) six volunteers receiving a single dose of 250 mg the day before challenge; and c) four volunteers receiving placebo. Volunteers were challenged with the NF54 strain of chloroquinesensitive P. falciparum, by the bites of infected Anopheles stephensi mosquitoes. Efficacy was evaluated by serial blood examinations (on 35 occasions over a three month period) for malaria parasites and by monitoring for symptoms and signs of infection. Parasites were cultured and their sensitivity to atovaquone was determined. All four placebo recipients developed parasitemia and were successfully treated with chloroquine. All twelve drug recipients remained free of circulating parasites. Thus, both high and low dose atovaquone provided effective prophylaxis [95% Cl 0.61-1.00; p = 0.005]. However, in the low dose recipients, plasma levels by 6.5 days after challenge (the earliest anticipated appearance of P. falciparum in blood) had fallen well below concentrations that failed against erythrocytic parasites in previous studies. This indicates the organisms were killed prior to day 6.5, while still in the liver. There was no evidence for a partial therapeutic response in the form of subclinical parasitemia or a prolonged hepatic phase. We conclude that Atovaquone protects non-immune subjects against mosquito-transmitted falciparum malaria. Furthermore, the evidence indicates there is a causal component against liver stage parasites. This extra dimension of antiparasitic activity eliminates the requirement for weeks of post- exposure therapy currently necessary with chloroquine or mefloquine, which have suppressive, but not causal, antimalarial effects. Atovaquone, as a component of Malarone, thus offers a much-needed new therapeutic approach to malaria chemoprophylaxis.