Bwijo B, Hassan Alin M, Abbas N, Eriksson O, Björkman A
Department of Immunology, Microbiology, Pathology and Infectious Diseases, Karolinska Institutet, Huddinge University Hospital, Sweden.
Acta Trop. 1997 Apr 30;65(1):11-22. doi: 10.1016/s0001-706x(96)00565-7.
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.
恶性疟原虫（F32）寄生虫分别暴露于青蒿素和奎宁中3小时和4小时，每天给药一次或两次，持续3天、5天或7天。在药物浓度峰值之间，寄生虫暴露于谷浓度。还评估了持续药物暴露以作比较。药物暴露后，将培养物延长长达30天的观察期，以评估药物暴露后剩余寄生虫的活力。对于青蒿素，生长抑制所需的临界阈值浓度为3×10⁻⁸ M。每天给药两次至少5天也很关键。将药物暴露时间延长至7天可进一步提高疗效。对于奎宁，结果则大不相同。疗效的浓度依赖性更为渐进。另一方面，每天给药一次似乎与每天给药两次几乎同样有效，即使在峰值浓度为10⁻⁵ M的情况下暴露3天后也能实现根治性清除。如果将暴露时间延长至7天，10⁻⁶ M的浓度也能产生相同的效果。体外根治性清除所需的游离未结合药物估计浓度与体内临床疗效所需的经验浓度之间存在很强的相似性。这表明，如果体外系统经过调整以模拟体内药代动力学，那么体外模型是评估药物疗效和药效学的合适模型。
