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首页> 外文期刊>Antimicrobial agents and chemotherapy. >A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum
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A Dynamic Stress Model Explains the Delayed Drug Effect in Artemisinin Treatment of Plasmodium falciparum

机译：动态应力模型解释了疟原虫治疗疟原虫的延迟药物作用

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Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria, particularly in light of developing resistance to partner drugs. Improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential for the optimization of dosing regimens and the development of strategies to prolong the life span of current first-line treatment options. Recent short-drug-pulse in vitro experiments have shown that the parasite killing rate depends not only on drug concentration but also the exposure time, challenging the standard pharmacokinetic-pharmacodynamic (PK-PD) paradigm in which the killing rate depends only on drug concentration. Here, we introduce a dynamic stress model of parasite killing and show through application to 3D7 laboratory strain viability data that the inclusion of a time-dependent parasite stress response dramatically improves the model's explanatory power compared to that of a traditional PK-PD model. Our model demonstrates that the previously reported hypersensitivity of early-ring-stage parasites of the 3D7 strain to dihydroartemisinin compared to other parasite stages is due primarily to a faster development of stress rather than a higher maximum achievable killing rate. We also perform in vivo simulations using the dynamic stress model and demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions for in vivo parasite clearance. Given the important role that PK-PD models play in the design of clinical trials for the evaluation of alternative drug dosing regimens, our novel model will contribute to the further development and improvement of antimalarial therapies.
机译：青蒿素抵抗构成对疟疾控制计划持续成功的重大威胁，特别是鉴于对合作伙伴药物的抗性的抗性。改善我们对蒿属素蛋白的毒品法以及抵抗表现方式的理解，对于优化给药方案以及延长当前一线治疗方案的寿命的策略的发展至关重要。近期的短药脉冲在体外实验表明，寄生虫杀伤率不仅取决于药物浓度，还取决于暴露时间，挑战标准药代动力学药物动力学（PK-PD）范式，其中杀伤率仅取决于药物浓度。在这里，我们介绍了寄生虫杀戮的动态应力模型，并通过应用于3D7实验室应变的活力数据，其中包含时间依赖的寄生虫应力反应显着提高了与传统PK-PD模型相比的模型的解释功率。我们的模型表明，与其他寄生虫阶段相比，先前报道了3D7菌株的早期环阶段寄生虫的超敏反应主要是由于应力的更快地发展而不是最大的可实现杀伤率。我们还使用动态应力模型进行体内模拟，并证明在体外观察到的青蒿素作用的复杂时间特征对体内寄生虫清除的预测产生了重大影响。鉴于PK-PD模型在临床试验设计中发挥的重要作用，用于评估替代药物给药方案的评估，我们的新型模型将有助于进一步发展和改善抗疟疗法。

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