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Folate antagonizes the antimalarial action of sulfadoxine-pyrimethamine (SP) in vitro, but its role in vivo is not well understood. We measured blood folate concentrations and SP therapeutic outcomes in Malawian children. Children with late treatment failure and those with adequate clinical and parasitologic responses had similar demographic characteristics, prevalence of parasite mutations conferring resistance to SP, and blood concentrations of anti-malarial drugs following treatment. However, a higher folate concentration was associated with late treatment failure. Patients from a low malaria transmission site had higher blood folate concentrations than those in a higher transmission site (mean ± SEM = 39 ± 9.3 ng/mL versus 29 ± 10 ng/mL; P < 0.0001), and there was a higher rate of late treatment failure in the low transmission area (54.4% versus 40.2%; P = 0.010). This study also provides the first evidence of the independent role of physiologic folate concentrations in in vivo SP therapeutic efficacy, and the critical role of pyrimethamine concentrations in the therapeutic efficacy of SP when one controls physiologic folate levels and the frequency of critical dihydrofolate reductase/dihydropteroate synthase mutations.
Received July 7, 2004. Accepted for publication November 1, 2004.
Acknowledgments: We thank the children of Dedza and Mangochi, G. Gamadzi (Laboratory technician, Lilongwe Central Hospital, Lilongwe, Malawi), and the clinical staff who supported this study in various ways.
Financial support: Funding for the study reported in this paper was provided in part by the World Health Organization/Multilateral Initiative on Malaria/Tropical Disease Research Task Force on Malaria Research Capability Strengthening in Africa grant (Allan Macheso, Principal Investigator, grant number 980041), National Institutes of Health grant R01AI44824 to Christopher V. Plowe, and the Department of Pharmacology of the University of Cape Town.
Authors’ addresses: Fraction K. Dzinjalamala, Karen I. Barnes, and Peter J. Smith, Division of Pharmacology, University of Cape Town, Cape Town, South Africa, E-mails: frakudz{at}hotmail.com, kbarnes{at}uctgsh1.uct.ac.za, and psmith{at}uctgsh1.uct.ac.za. Allan Macheso, Management Sciences for Health, Lilongwe, Malawi, E-mail: amacheso{at}msh.org. James G. Kublin, Division of Community Health, Malawi College of Medicine, Blantyre, Malawi, E-mail: jameskublin{at}merck.com. Terrie E. Taylor, Department of Community Health, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824-1316, E-mail: taylort{at}msu.edu. Malcom E. Molyneux, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi, E-mail: mmolyneux{at}malawi.net. Christopher V. Plowe, Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201-1509, E-mail: cplowe{at}medicine.umaryland.edu.
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