Sowunmi A, Oduola A M
Department of Pharmacology and Therapeutics and Postgraduate Institute for Medical Research and Training, University of Ibadan, Nigeria.
Eur J Clin Pharmacol. 1998 May;54(3):221-6. doi: 10.1007/s002280050449.
Severe malaria is increasingly treated with artemether and sulfadoxine-pyrimethamine, but their effects on the viability of Plasmodium falciparum ex vivo following therapeutic doses, and the relationship between conventional indices of therapeutic response and parasite viability, have not been evaluated. We assessed these parameters in children with severe non-cerebral falciparum malaria.
Between May and August 1995, 17 children with severe non-cerebral malaria were randomized to receive therapeutic doses of artemether or sulfadoxine-pyrimethamine. Parasitemia quantification and withdrawal of blood culture of P. falciparum in vitro were done before and at specific intervals after drug administration. Therapeutic indices of response were determined by the conventional method. The corresponding viability estimates ex vivo were derived for each drug and compared with conventional therapeutic indices.
Artemether produced a significantly more rapid reduction of parasitemia and fever than sulfadoxine-pyrimethamine. Resistance to sulfadoxine-pyrimethamine was present in three out of seven patients (RI, RII and RIII) and was readily detectable by the functional viability estimate ex vivo. Ex vivo, functional reduction of parasite viability was significant 8 or 12 h after administration of artemether, with no functionally viable parasites 30 h after administration. In contrast, functional viability in isolates sensitive to sulfadoxine-pyrimethamine became significant by 16-20 h after drug administration and viable parasites were still evident after 36 h in some isolates. Indices of therapeutic response estimated by the conventional methods, i.e., time to 50% or 90% reduction of parasitemia and parasite clearance time, were significantly higher than those derived from the corresponding functional viability estimates ex vivo for each drug. There was correlation between some of the two sets of parameters.
These data suggest the rapid and relatively broad stage effects of artemether when compared with sulfadoxine-pyrimethamine on P. falciparum asexual forms. Estimation of parasite viability indices ex vivo permits comparison of the relative speed of antimalarial drug action.
蒿甲醚和磺胺多辛-乙胺嘧啶越来越多地用于治疗重症疟疾，但尚未评估其治疗剂量对恶性疟原虫体外生存能力的影响，以及治疗反应的传统指标与寄生虫生存能力之间的关系。我们在患有严重非脑型恶性疟疾的儿童中评估了这些参数。
1995年5月至8月期间，17名患有严重非脑型疟疾的儿童被随机分配接受蒿甲醚或磺胺多辛-乙胺嘧啶的治疗剂量。在给药前及给药后的特定时间间隔，对疟原虫血症进行定量，并进行恶性疟原虫的体外血培养。通过传统方法确定治疗反应指标。对每种药物的相应体外生存能力估计值进行推导，并与传统治疗指标进行比较。
与磺胺多辛-乙胺嘧啶相比，蒿甲醚能更迅速地降低疟原虫血症和体温。7名患者中有3名（RI型、RII型和RIII型）对磺胺多辛-乙胺嘧啶耐药，通过体外功能生存能力估计很容易检测到。体外实验中，给药后8或12小时，蒿甲醚对寄生虫生存能力的功能降低显著，给药30小时后无功能存活的寄生虫。相比之下，对磺胺多辛-乙胺嘧啶敏感的分离株在给药后16至20小时功能生存能力开始显著，在某些分离株中36小时后仍有存活的寄生虫。通过传统方法估计的治疗反应指标，即疟原虫血症降低50%或90%的时间以及寄生虫清除时间，显著高于每种药物相应的体外功能生存能力估计值。两组参数之间存在一定相关性。
这些数据表明，与磺胺多辛-乙胺嘧啶相比，蒿甲醚对恶性疟原虫无性体具有快速且相对广泛的阶段效应。体外寄生虫生存能力指标的估计允许比较抗疟药物作用的相对速度。
