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SENSITIVITY TO ANTIFOLATES AND GENETIC ANALYSIS OF PLASMODIUM VIVAX ISOLATES FROM THAILAND

We investigated the association between the Plasmodium vivax dihydrofolate reductase (Pvdhfrtas) and the P. vivax dihydropteroate synthase (Pvdhps) genotype and in vitro sensitivity to the antifolates pyrimethamine, WR99210, chlorcycloguanil, sulfadoxine, and dapsone. Drug responses of 32 P. vivax isolates were assessed in two in vitro systems: schizont maturation inhibition and a yeast expression system. The geometric mean of 50% inhibition concentration (IC₅₀) values for pyrimethamine, chlorcycloguanil, WR99210, sulfadoxine, and dapsone were 85 ± 88, 784 ± 662, 95 ± 87, 2,424 ± 2,784, and 1,625 ± 1,801 nM, respectively, for the schizont maturation assay. Five different Pvdhfr alleles and four Pvdhps alleles were observed: 26 of 32 quadruple mutant alleles of Pvdhfr (F57I,L/S58R/T61M/S117T), four triple mutants (S58R/T61M/S117T, K49C/S58R/S117N), and two double mutant isolates (S58R/S117N). All isolates carried Pvdhps 585V. Twenty four isolates carried double mutant Pvdhps (A383G/A553G), six an additional mutation, S382A,C/A383G/A553G, and two a single mutation, A383G. Increasing geometric mean IC₅₀ values were observed with increased number of Pvdhfr mutations from double to quadruple. Results suggest that quadruple mutant alleles confer decreased sensitivity to pyrimethamine but retain sensitivity to WR99210.

Received December 6, 2006. Accepted for publication February 11, 2007.

Acknowledgments: We thank the patients who participated in this study and the staff of the Mae Sot General Hospital and Section 4, Vector Borne Disease Control, Mae Sot District, Tak Province for their kind assistance during blood sample collection. We also thank Dr. David Jacobus (Jacobus Pharmaceutical, Inc.) for the gift of the drugs used in the studies and for his thoughtful comments on the manuscript.

Financial support: This work was supported by Thailand Research Fund for the scholarship of The Royal Golden Jubilee Ph.D. program and National Institutes of Health grant AI 55604 to Carol Hopkins Sibley.

^* Address correspondence to Carol Hopkins Sibley, Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065. E-mail: sibley{at}u.washington.edu

Authors’ addresses: Kanchana Rungsihirunrat and Kesara Na-Bangchang, Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand. Mathirut Mungthin, Department of Parasitology, Phramongkutklao College of Medicine, Bangkok, Thailand. Vivian N. Hawkins and Carol Hopkins Sibley, Department of Genome Sciences, University of Washington, Seattle, WA 98195-5065.

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