PROPHYLACTIC ANTIMALARIAL ACTIVITY OF ATOVAQUONE

阿托伐醌的预防性抗疟活性

• 批准号: 6275514
• 负责人: Theresa A Shapiro
• 金额: $ 2.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6275514
• 关键词: Plasmodium falciparum; antimalarial agents; atovaquone; chemoprevention; clinical research; clinical trials; drug screening /evaluation; human subject; human therapy evaluation; malaria

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.

这是一项双盲、随机、安慰剂对照的评价， 阿托伐醌（广谱 抗原虫剂）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病人身上进行的。 基础上，并有三组：a）6名志愿者接受750 mg qd 从激发前一天开始; B）六名志愿者接受单次 激发前一天250 mg剂量;和c）4名志愿者 接受安慰剂。 志愿者用NF 54菌株进行攻击。 氯喹敏感的恶性疟原虫，通过感染的按蚊叮咬 斯蒂芬蚊子。 通过连续采血评价疗效 疟疾检查（三个月内35次） 寄生虫和监测感染的症状和体征。 寄生虫培养，其对阿托伐醌的敏感性为 测定 所有四名安慰剂接受者都出现了寄生虫血症， 用氯喹成功治愈 所有12名吸毒者 仍然没有循环的寄生虫。 因此，高剂量和低剂量 阿托伐醌提供了有效的预防[95% CI 0.61-1.00; p = 0.005]。 然而，在低剂量接受者中， 挑战（最早预期出现的恶性疟原虫， 血液）的浓度远远低于未能 红细胞寄生虫在以前的研究。 这表明 在第6.5天之前杀死仍在肝脏中的微生物。 那里 没有证据表明部分治疗反应， 形式 亚临床寄生虫血症或肝期延长。 我们的结论是 阿托伐醌保护非免疫受试者免受蚊子传播的 恶性疟疾 此外，有证据表明， 致病成分对肝脏阶段寄生虫。 这个额外的维度 的抗寄生虫活性消除了数周的后， 目前需要用氯喹或甲氟喹进行暴露疗法， 其具有抑制性而非因果性的抗疟疾作用。 阿托伐醌作为马拉隆的一种成分，因此提供了一种急需的新的 疟疾化学预防的治疗方法。