Plasmodium vivax trophozoites insensitive to chloroquine

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Abstract
Background: Plasmodium vivaxis 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 thePlasmodiumspp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminaryin vitroobservations onP. vivaxclinical 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 ofP. vivax.Methods: Thein vitrochloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreservedP. vivaxclinical isolates from Thailand and twoPlasmodium falciparumclones (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.Results: Plasmodium vivaxisolates added to the assay at ring stage had significantly lower median IC50sto chloroquine than the same isolates added at trophozoite stage (median IC5012 nM vs 415 nMp< 0.01). Although only 36% (4/11) of the SYBR Green I assays forP. vivaxwere successful, both microscopy and SYBR Green I assays indicated that onlyP. vivaxtrophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM.Conclusion: Data from this study confirms the diminished sensitivity ofP. vivaxtrophozoites 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 betweenP. vivaxandP. falciparum.