Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring,Maryland 20910, USA.
Clin Infect Dis. 2012 Jan 15;54(2):232-9. doi: 10.1093/cid/cir770. Epub 2011 Nov 3.
We conducted a randomized, placebo-controlled, double-blind trial to establish the efficacy of atovaquone-proguanil to prevent malaria with the goal of simulating weekly dosing in a human Plasmodium falciparum challenge model.
Thirty volunteers randomly received 1 of the following dose regimens: (1) 250 milligrams of atovaquone and 100 milligrams of proguanil (250/100 milligrams) 1 day prior to infectious mosquito challenge (day -1), (2) 250/100 milligrams on day 4 after challenge, (3) 250/100 milligrams on day -7, (4) 500 milligrams of atovaquone and 200 milligrams of proguanil (500/200 milligrams) on day -7 or, (5) 1000 milligrams of atovaquone and 400 milligrams of proguanil (1000/400 milligrams) on day -7. All regimens included matching placebo such that all volunteers received identical pill numbers. Six volunteers served as open-label infectivity controls. Volunteers underwent mosquito sporozoite challenge with P. falciparum 3D7 strain. Follow-up consisted of serial microscopy and close clinical monitoring for 90 days.
Six of 6 infectivity controls developed parasitemia as expected. Two of 5 evaluable volunteers receiving 250/100 milligrams 7 days prior to challenge and 1 of 6 volunteers receiving 1000/400 milligrams 7 days prior to challenge were microscopically diagnosed with malaria. All other volunteers were protected. Atovaquone exposure (area under the curve) during liver stage development was low in 2 of 3 volunteers with prophylactic failure (423 and 199 ng/mL × days compared with a mean for protected volunteers of 1903 ng/mL × days), as was peak concentration (165 and 81 ng/mL compared with a mean of 594 ng/mL in volunteers with prophylactic success). Elimination half-life was short in volunteers with prophylactic failure (2.4, 2.0, and 3.3 days compared with a mean of 4.1 days in volunteers with prophylactic success).
Single-dose atovaquone-proguanil provides effective malaria chemoprophylaxis against P. falciparum challenge at dosing intervals supportive of weekly dosing. Postexposure prophylaxis 4 days after challenge was 100% effective.
我们进行了一项随机、安慰剂对照、双盲试验，以确定阿托伐醌-普罗喹胺预防疟疾的疗效，目的是在人类疟原虫感染模型中模拟每周给药。
30 名志愿者随机接受以下 1 种剂量方案之一：（1）在感染性蚊子挑战前 1 天（-1 天）给予 250 毫克阿托伐醌和 100 毫克普罗喹胺（250/100 毫克），（2）在挑战后第 4 天给予 250/100 毫克，（3）在-7 天给予 250/100 毫克，（4）在-7 天给予 500 毫克阿托伐醌和 200 毫克普罗喹胺（500/200 毫克），或（5）在-7 天给予 1000 毫克阿托伐醌和 400 毫克普罗喹胺（1000/400 毫克）。所有方案均包括匹配的安慰剂，以使所有志愿者接受相同数量的药丸。6 名志愿者作为开放性感染性对照。志愿者接受 P. falciparum 3D7 株的疟原虫孢子虫挑战。随访包括连续显微镜检查和 90 天的密切临床监测。
6 名感染性对照中的 6 名按预期出现了寄生虫血症。5 名可评估志愿者中的 2 名在挑战前 7 天接受 250/100 毫克，6 名志愿者中的 1 名在挑战前 7 天接受 1000/400 毫克，经显微镜诊断患有疟疾。所有其他志愿者均得到保护。2 名预防失败的志愿者（423 和 199 ng/mL×天，而保护志愿者的平均值为 1903 ng/mL×天）和 1 名预防成功的志愿者（165 和 81 ng/mL，而保护志愿者的平均值为 594 ng/mL）的阿托伐醌暴露（曲线下面积）较低。峰浓度（165 和 81 ng/mL，而预防成功志愿者的平均值为 594 ng/mL）也较低。预防失败的志愿者的消除半衰期较短（2.4、2.0 和 3.3 天，而预防成功的志愿者的平均值为 4.1 天）。
单剂量阿托伐醌-普罗喹胺在支持每周给药的给药间隔内提供了针对疟原虫感染的有效疟疾化学预防。挑战后 4 天的暴露后预防 100%有效。
