Abstract
BackgroundPlasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax.MethodsThe in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27) was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment.ResultsPlasmodium vivax isolates added to the assay at ring stage had significantly lower median IC50s to chloroquine than the same isolates added at trophozoite stage (median IC50 12 nM vs 415 nM p < 0.01). Although only 36% (4/11) of the SYBR Green I assays for P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM.ConclusionData from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum.
Highlights
Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine
P. vivax ring stage and P. falciparum ring and trophozoite stage treatments were all sensitive to chloroquine concentrations as low as 100 nM (Figures 1 and 2)
All of the P. falciparum SYBR Green I assay were successful (6/6) and the derived IC50s were similar to the microscopic method
Summary
Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. The stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax. Plasmodium spp. derive most of their nutritional requirements from the digestion of host erythrocyte haemoglobin This catabolic process results in the release of toxic free haem. Despite some controversy regarding the stage specificity of chloroquine [3,4], most agree it is active against the P. falciparum trophozoite stage, when haemoglobin catabolism is maximal [5,6]. Ex vivo studies on clinical P. vivax isolates suggest that, in contrast to P. falciparum, chloroquine has little effect on the trophozoite stage. The objective of this study was to better understand the stage specific action of chloroquine against P. vivax using synchronous cryopreserved isolates and a uniform drug exposure time
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