Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects
Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects
复制标题
DOI：
10.1002/cpt.1716
复制
发表时间：
2019-12-27
影响因子：
6.7
通讯作者：
Tarning, Joel
中科院分区：
文献类型：
--
作者：
Kobylinski, Kevin C.;Jittamala, Podjanee;Tarning, Joel
大规模使用抗疟药物和伊维菌素被认为是消灭疟疾的潜在加速剂。评价了伊维菌素、双氢青蒿素-哌喹和伯氨喹联合用药的安全性、耐受性、药代动力学和蚊虫致死作用。伊维菌素和双氢青蒿素-哌喹联合给药导致伊维菌素浓度增加，所有受试者的蚊子致死效应相应增加。当与伊维菌素联合给药时，哌喹暴露量也增加，但心电图QT间期延长并未增加。1例受试者出现一过性肝功能损害。伊维菌素对蚊子的致死作用大于先前对东南亚主要疟疾媒介的预测。大劣按蚊和微小按蚊的死亡率大幅增加（20倍和35倍，分别增加）时，在志愿者的血液伊维菌素给药后，在体外伊维菌素加标的血液相比，喂养。这表明存在伊维菌素代谢物，可产生蚊子致死作用。有必要进一步研究这种加速消灭疟疾的综合办法。
Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics, and mosquito-lethal effects of combinations of ivermectin, dihydroartemisinin-piperaquine, and primaquine were evaluated. Coadministration of ivermectin and dihydroartemisinin-piperaquine resulted in increased ivermectin concentrations with corresponding increases in mosquito-lethal effect across all subjects. Exposure to piperaquine was also increased when coadministered with ivermectin, but electrocardiograph QT-interval prolongation was not increased. One subject had transiently impaired liver function. Ivermectin mosquito-lethal effect was greater than predicted previously against the major Southeast Asian malaria vectors. Both Anopheles dirus and Anopheles minimus mosquito mortality was increased substantially (20-fold and 35-fold increase, respectively) when feeding on volunteer blood after ivermectin administration compared with in vitro ivermectin-spiked blood. This suggests the presence of ivermectin metabolites that impart mosquito-lethal effects. Further studies of this combined approach to accelerate malaria elimination are warranted.