Hoshen M B, Na-Bangchang K, Stein W D, Ginsburg H
Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
Parasitology. 2000 Sep;121 ( Pt 3):237-46. doi: 10.1017/s0031182099006332.
Although artesunate, one of the potent derivatives of the qinghaosu family of drugs for treating falciparum malaria, is already in use in the field, its therapeutic protocol has only been developed empirically by hit-or-miss. A pharmacokinetic-pharmacodynamic (PK-PD) model, required for creating such a protocol, is not straightforward. Artesunate presents extremely fast pharmacokinetics. As a result the stage specificity of its action must be treated explicitly. Also, use of standard PK-PD modelling fails to explain the clinical results. Our PK-PD modelling of its activity leads us to the postulation of the existence of a novel effect: a small fraction of the parasites, as a result of chemotherapeutic pressure, become cytostatic, or 'dormant'. At this stage, the parasite cycle is halted, making them unsusceptible to further dosing until wakening. This slows down the antimalarial activity of the drug, entailing either many frequent doses or an extended period of treatment and surveillance. Based on our modelling, we suggest a method for deciding on rational models of chemotherapy against falciparum malaria.
尽管青蒿琥酯作为青蒿素类药物治疗恶性疟的有效衍生物之一已在临床应用，但它的治疗方案只是通过反复试验经验性地制定出来的。创建这样一个方案所需的药代动力学 - 药效学（PK - PD）模型并非易事。青蒿琥酯具有极快的药代动力学特性。因此，必须明确考虑其作用的阶段特异性。此外，使用标准的PK - PD模型无法解释临床结果。我们对其活性的PK - PD建模使我们推测存在一种新的效应：由于化疗压力，一小部分寄生虫会变成细胞静止状态，即“休眠”。在此阶段，寄生虫周期停止，使其在苏醒之前对进一步给药不敏感。这减缓了药物的抗疟活性，需要频繁给药或延长治疗及监测时间。基于我们的建模，我们提出了一种确定针对恶性疟化疗合理模型的方法。
