Eastman Richard T, Khine Pwint, Huang Ruili, Thomas Craig J, Su Xin-Zhuan
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Division of Preclinical Development, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Sci Rep. 2016 May 5;6:25379. doi: 10.1038/srep25379.
Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen. Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Here we investigated the parasite responses to dihydroartemisinin (DHA) and various Ca(2+) and Na(+) channel blockers and showed positively correlated responses between DHA and several channel blockers, suggesting potential shared transport pathways or mode of action. Additionally, we demonstrated that PfCRT and PfMDR1 could also significantly modulate the pharmacodynamic interactions of the compounds and that the interactions were influenced by the parasite genetic backgrounds. These results provide important information for better understanding of drug resistance and for assessing the overall impact of drug resistance markers on parasite response to ACTs.
在疟疾流行地区，恶性疟原虫有症状无性阶段的治疗几乎完全依赖于青蒿素（ART）联合疗法（ACTs）。ACTs将青蒿素或其衍生物与一种长效辅助药物联合使用，以在典型的三天疗程中最大限度地提高疗效。此前，实验室和临床研究均已证明，常见的耐药性决定因素——恶性疟原虫氯喹抗性转运蛋白（PfCRT）和多药抗性转运蛋白（PfMDR1）——可调节对许多当前抗疟药物和化合物的敏感性。在此，我们研究了疟原虫对双氢青蒿素（DHA）以及各种钙（Ca2+）和钠（Na+）通道阻滞剂的反应，结果显示DHA与几种通道阻滞剂之间存在正相关反应，这表明可能存在共同的转运途径或作用方式。此外，我们还证明PfCRT和PfMDR1也可显著调节这些化合物的药效学相互作用，且这种相互作用受疟原虫遗传背景的影响。这些结果为更好地理解耐药性以及评估耐药性标志物对疟原虫对ACTs反应的总体影响提供了重要信息。
