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Plasmodium vivax trophozoites insensitive to chloroquine

DOI: 10.1186/1475-2875-7-94

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Abstract:

The 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.Plasmodium 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.Data 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.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. In response to this oxidative threat, Plasmodium spp. cross-link free haem monomers to form an inert polymer known as haemozoin or malaria pigment. It is generally thought that the catalytic activity of haem polymerase is the primary target of chloroquine [1,2]. The majority of studies on the mechanism of chloroquine have used in vitro cultures of Plasmodium falciparum as a model. 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 maxim

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