Mutations in dhfr in Plasmodium falciparum infections selected by chlorproguanil-dapsone treatment.
Treatment with the novel antifolate drug combination chlorproguanil-dapsone effectively cleared asymptomatic Plasmodium falciparum infections in 246 (93.5%) of 263 children in the Usambara Mountains of Tanzania during the course of a 2-week follow-up. Samples from 71 recurrent infections, collected over a 9-week follow-up, showed selection for parasites with the triple mutant Ile(51)-Arg(59)-Asn(108) in dihydrofolate reductase. There was no selection for mutations in dihydropteroate synthetase, the target enzyme of dapsone. Search for complete identity in the highly polymorphic genes coding for merozoite surface proteins 1 and 2 in parasite samples collected before and after treatment indicated that the majority of recurrent parasitemias were new infections. These observations on selection in Tanzania and the lack of selection reported from a less endemic area suggest that the active metabolite of chlorproguanil, which has a short half-life in the blood, may persist in the liver, where it exerts selective pressure on growing preerythrocytic stages.
Item Type | Article |
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Keywords | Animal, Antimalarials/*therapeutic use, Child, Child, Preschool, Chloroguanide/*therapeutic use, Comparative Study, Dapsone/*therapeutic use, Dihydropteroate Synthase/genetics, Drug Therapy, Combination, Follow-Up Studies, Genes, Protozoan, Human, Infant, Malaria, Falciparum/*drug therapy/enzymology, Merozoite Surface Protein 1/analysis, Mutation, Parasitemia, Plasmodium falciparum/enzymology/*genetics, Support, Non-U.S. Gov't, Tanzania, Tetrahydrofolate Dehydrogenase/*genetics |
ISI | 179392800024 |
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