Abstract
ABSTRACTHigh-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
Highlights
High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax
CQV data for 14 P. falciparum and 5 P. vivax isolates were excluded from the analysis as the CQ-VP combination in one of the drug plate batches failed to pass the internal drug plate quality control (QC)
Our comparative study confirms the ability of four known CQ resistance reversal agents (CQRRAs) to reverse CQ resistance in P. falciparum laboratory strains, and this was apparent in the CQr P. falciparum clinical isolates (Fig. 1)
Summary
High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Whereas CQ resistance in P. falciparum has been well studied, little is known about its mechanisms in P. vivax Candidate markers, such as pvcrt-o and pvmdr, have been investigated; reports about the association between these molecular determinants and in vitro and in vivo CQr phenotypes are conflicting [7,8,9,10]. Primaquine (PQ), an 8-aminoquinoline drug currently used to prevent P. vivax relapses and the radical clearance of gametocytes in falciparum malaria, is the only agent with a demonstrable potential to reverse CQ resistance at clinically relevant concentrations [26, 27]. The antidiarrheal agent loperamide, the calcium channel blocker mibefradil (MF), and the neurokinin 1 (NK1) receptor antagonist L703,606 (L7) have been shown to possess even greater potency than VP for reversal of CQ resistance in P. falciparum [28]
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