乙胺嘧啶、环氯胍及其他抗疟药物对恶性疟原虫非洲分离株和克隆株的体外活性

In vitro activity of pyrimethamine, cycloguanil, and other antimalarial drugs against African isolates and clones of Plasmodium falciparum.

作者信息

Basco L K, Ramiliarisoa O, Le Bras J

机构信息

Centre National de Reference pour la Chimiosensibilite du Paludisme, Hopital Bichat-Claude Bernard, Paris, France.

出版信息

Am J Trop Med Hyg. 1994 Feb;50(2):193-9. doi: 10.4269/ajtmh.1994.50.193.

DOI:10.4269/ajtmh.1994.50.193

PMID:8116812

Abstract

The in vitro activity of two dihydrofolate reductase (DHFR) inhibitors, pyrimethamine and cycloguanil, was evaluated against African clones and isolates of Plasmodium falciparum using an isotopic, semimicro drug susceptibility test. Three susceptibility levels (susceptible, intermediate, and resistant) were observed in the response of culture-adapted clones and strains to pyrimethamine (50% inhibitory concentration [IC50]) < 100, 100-2,000, and > 2,000 nM) and cycloguanil (IC50 < 50, 50-500, and > 500 nM). Based on these susceptibility levels, 73 and 68 of 96 fresh clinical isolates were susceptible to pyrimethamine (mean IC50 15.4 nM) and cycloguanil (mean IC50 11.1 nM), respectively. Thirteen and 18 isolates were resistant to pyrimethamine (mean IC50 9,440 nM) and cycloguanil (mean IC50 2,030 nM), respectively. A highly significant positive correlation was found between pyrimethamine and cycloguanil (r = 0.786), indicating in vitro cross-resistance between these antifolates. The spread of resistance to one of the DHFR inhibitors in Africa may compromise the utility of the other DHFR inhibitor.

摘要

使用同位素半微量药物敏感性试验，评估了两种二氢叶酸还原酶（DHFR）抑制剂乙胺嘧啶和环氯胍对恶性疟原虫非洲克隆株和分离株的体外活性。在适应培养的克隆株和菌株对乙胺嘧啶（50%抑制浓度[IC50]<100、100 - 2000和>2000 nM）和环氯胍（IC50<50、50 - 500和>500 nM）的反应中观察到三种敏感性水平（敏感、中等和耐药）。基于这些敏感性水平，96份新鲜临床分离株中分别有73份和68份对乙胺嘧啶（平均IC50 15.4 nM）和环氯胍（平均IC50 11.1 nM）敏感。分别有13份和18份分离株对乙胺嘧啶（平均IC50 9440 nM）和环氯胍（平均IC50 2030 nM）耐药。乙胺嘧啶和环氯胍之间存在高度显著的正相关（r = 0.786），表明这些抗叶酸药物之间存在体外交叉耐药性。在非洲，对其中一种DHFR抑制剂耐药性的传播可能会损害另一种DHFR抑制剂的效用。