Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia
ARMY INST OF SURGICAL RESEARCH FORT SAM HOUSTON TX
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Novel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies ACTs to treat artemisinin-resistant Plasmodium falciparum malaria. We conducted blinded ex vivo activity testing of fully synthetic OZ78 and OZ277 and semisynthetic artemisone, artemiside, artesunate, and dihydroartemisinin endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200 P. falciparum isolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean GM 50 inhibitory concentrations IC50s were as follows artemisone 2.40 nMartesunate 8.49 nMdihydroartemisinin 11.26 nMartemiside 15.28 nMOZ277 31.25 nMOZ78 755.27 nM. Ex vivo activities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitive P. falciparum W2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolateW2 IC50 susceptibility ratios of2.0. All isolates had P. falciparum chloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides artesunate, dihydroartemisinin, OZ277, and artemisone significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35 prevalence of P. falciparum multidrug resistance gene 1 pfmdr1 amplification and 84.5 occurrence of the pfmdr1 Y184F mutation. GM IC50s for mefloquine, lumefantrine, and endoperoxides artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone correlated with pfmdr1 copy number.
- Medicine and Medical Research