Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand
Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand
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DOI：
10.4269/ajtmh.1996.54.62
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发表时间：
1996-01-01
影响因子：
3.3
通讯作者：
Canfield, CJ
中科院分区：
文献类型：
--
作者：
Looareesuwan, S;Viravan, C;Canfield, CJ
在东南亚许多地区，恶性疟原虫疟疾的治疗仍然是一个问题，因为它对几乎所有现有的抗疟疾药物都具有多重耐药性。阿托伐醌是一种具有广谱抗原虫活性的新型羟基萘醌类药物。我们最近在曼谷热带病医院对317名疟疾患者进行了一系列剂量范围研究，评估了阿托伐醌的抗疟疾活性。最初，这种药物是单独使用的。单独使用阿托伐醌在所有患者中产生了令人满意的初始临床反应；平均清除寄生虫和发热时间分别为62和53小时。然而，无论治疗时间长短，总治愈率约为67%。对患者治疗前和复发时的寄生虫体外敏感性研究表明，复发寄生虫对阿托伐酮的敏感性明显降低。为了提高治愈率，阿托伐酮与其他具有抗疟活性的药物合用。选择普罗胍和四环素是由于实验室证据的增强；选择强力霉素是因为它的半衰期比四环素长。虽然乙胺嘧啶没有显示与阿托伐酮增强的实验室证据，但它被选为二氢叶酸还原酶的替代抑制剂，其半衰期比原胍长。这些药物组合的临床研究证实了实验室结果，即原胍、四环素和强力霉素的治愈率显著提高；乙胺嘧啶仅显示出微小的改善。Proguanil后来被选为首选的药物合作伙伴，因为它有长期的安全记录，并且可以在孕妇和儿童中使用。在104例恶性疟疾患者中，阿托伐醌加普罗胍治疗3-7天，101例治愈，几乎没有不良副作用。阿托伐醌联合普罗胍对消除间日疟原虫红细胞型也有效，但大多数患者出现寄生虫病复发。
The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphthoquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 317 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr, respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquone in the recrudescent parasites, To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of potentiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethamine did not show laboratory evidence of potentiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycycline; pyrimethamine showed only minimal improvement. Proguanil was subsequently selected as the preferred drug partner because of its long record of safety and the ability to use the drug in pregnant women and children. Of the 104 patients with falciparum malaria treated with atovaquone plus proguanil for 3-7 days, 101 were cured and had virtually no adverse side effects. The combination of atovaquone and proguanil also was effective in eliminating erythrocytic forms of P. vivax, but parasitemia recurred in most patients.