Repetitive dosing of artemisinin and quinine against Plasmodium falciparum in vitro: A simulation of the in vivo pharmacokinetics
Repetitive dosing of artemisinin and quinine against Plasmodium falciparum in vitro: A simulation of the in vivo pharmacokinetics
复制标题
DOI：
10.1016/s0001-706x(96)00565-7
复制
发表时间：
1997-04-30
期刊：
影响因子：
2.7
通讯作者：
Bjorkman, A
中科院分区：
文献类型：
--
作者：
Bwijo, B;Alin, MH;Bjorkman, A
将恶性疟原虫（F32）分别暴露于青蒿素和奎宁3和4 h，每日1次或2次，连续3、5或7 d。在峰值之间，寄生虫暴露于谷浓度。还评估了持续药物暴露以进行比较。在药物暴露后，将培养物延长至30天的观察期，以评估药物暴露后残留寄生虫的活力。对于青蒿素，生长抑制需要3 x 10（-8）M的临界阈值浓度。每天给药两次，持续至少5天也很关键。将药物暴露持续时间延长至7天进一步提高了疗效。对于奎宁，结果则完全不同。疗效的浓度依赖性更为渐进。另一方面，每日一次给药似乎与每日两次给药几乎一样有效，即使在10（-5）M峰浓度下暴露3天后也可获得自由基清除。如果持续时间延长至7天，10（-6）M的浓度提供了相同的效果。体外自由基清除所需的游离未结合药物的估计浓度与体内临床疗效所需的经验浓度之间有很强的相似性。这表明，如果体外系统适于模拟体内药代动力学，则体外模型代表了用于估计药物疗效和药效学的适当模型。(C)1997年Elsevier Science B.V.
Plasmodium falciparum (F32) parasites were exposed to artemisinin and quinine for 3 and 4 h, respectively, once or twice daily and for 3, 5 or 7 days. Between the peaks the parasites were exposed to trough concentrations. Continuous drug exposure was also assessed for comparison. After drug exposure, the cultures were extended for an observation period of up to 30 days to assess the viability of the parasites remaining after drug exposure.For artemisinin, a critical threshold concentration of 3 x 10(-8) M was required for growth inhibition. Dosing twice daily for at least 5 days was also critical. Prolonging the duration of drug exposure to 7 days further increased the efficacy. For quinine the results were quite different. The concentration dependency of the efficacy was more gradual. On the other hand dosing once daily appeared to be nearly as effective as twice daily and radical clearance was obtained even after 3 days of exposure at peak concentrations of 10(-5) M. A concentration of 10(-6) M provided the same effect if the duration was extended to 7 days.There was a strong similarity between estimated concentrations of free unbound drug required for radical clearance in vitro and those empirically required for clinical efficacy in vivo. This suggests that the in vitro model represents an appropriate model for estimating drug efficacy and pharmacodynamics if the in vitro system is adapted to simulate in vivo pharmacokinetics. (C) 1997 Elsevier Science B.V.