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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphisms to predict quinine in vitro sensitivity or clinical effectiveness in Uganda.
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Limited ability of Plasmodium falciparum pfcrt, pfmdr1, and pfnhe1 polymorphisms to predict quinine in vitro sensitivity or clinical effectiveness in Uganda.

机译：恶性疟原虫pfcrt，pfmdr1和pfnhe1多态性在乌干达预测奎宁体外敏感性或临床有效性的能力有限。

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Quinine is a standard drug for treating severe malaria in Africa, and it is also increasingly used to treat uncomplicated disease. However, failures of quinine therapy are common, and it is unknown if failures in Africa are due to drug resistance. Recent studies have identified associations between in vitro quinine sensitivity and polymorphisms in genes encoding putative transporters, including well-described polymorphisms in pfcrt and pfmdr1 and varied numbers of DNNND or DDNHNDNHNND repeats in microsatellite 4760 (ms4760) of the predicted sodium-hydrogen exchanger, pfnhe1. To better characterize mediators of quinine response, we assessed associations between genetic polymorphisms, in vitro quinine sensitivity, and quinine treatment responses in Kampala, Uganda. Among 172 fresh clinical isolates tested in vitro, decreasing sensitivity to quinine was associated with accumulation of pfmdr1 mutations at codons 86, 184, and 1246. Nearly all parasites had pfcrt 76T, preventing analysis of associations with this mutation. pfnhe1 ms4760 was highly polymorphic. Parasites with 2 copies of either ms4760 repeat showed modest decreases in quinine sensitivity compared to those with 1 or >/=3 repeats, but the differences were not statistically significant. None of the above polymorphisms predicted treatment failure among 66 subjects treated with quinine for uncomplicated malaria. Our data suggest that quinine sensitivity is a complex trait and that known polymorphisms in pfcrt, pfmdr1, and pfnhe1, while associated with quinine sensitivity, are not robust markers for quinine resistance.
机译：奎宁是治疗非洲严重疟疾的标准药物，并且也越来越多地用于治疗简单的疾病。然而，奎宁治疗失败很普遍，非洲失败是否是由于耐药性尚不清楚。最近的研究已经确定了体外奎宁敏感性与编码推定转运蛋白的基因中的多态性之间的关联，包括在pfcrt和pfmdr1中描述得很好的多态性，以及在预测的钠氢交换器pfnhe1的微卫星4760（ms4760）中DNNND或DDNHNDNHNND重复数目的变化。 。为了更好地表征奎宁反应的介体，我们在乌干达坎帕拉评估了遗传多态性，体外奎宁敏感性和奎宁治疗反应之间的关联。在172个体外测试的新鲜临床分离株中，对奎宁的敏感性降低与pfmdr1突变在86、184和1246位密码子上的积累有关。几乎所有寄生虫均具有pfcrt 76T，从而阻止了与该突变相关的分析。 pfnhe1 ms4760是高度多态的。与具有1个重复或> / = 3个重复的寄生虫相比，具有2个拷贝的ms4760重复的寄生虫显示奎宁敏感性适度降低，但差异无统计学意义。上述多态性均未预测在用奎宁治疗的单纯性疟疾的66名受试者中治疗失败。我们的数据表明，奎宁敏感性是一个复杂的特征，pfcrt，pfmdr1和pfnhe1中已知的多态性虽然与奎宁敏感性相关，但并不是奎宁抗性的可靠标记。

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