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Sci Rep. 2016 May 5;6:25379. doi: 10.1038/srep25379.

PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers.

Author information

1
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2
Division of Preclinical Development, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.

Abstract

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.

PMID:
27147113
PMCID:
PMC4857081
DOI:
10.1038/srep25379
[Indexed for MEDLINE]
Free PMC Article

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