title: Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria.
abstract: 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.
authors.affiliation: Division of Pharmacology, University of Cape Town, Cape Town, South Africa. frakudz@hotmail.com
authors.forename: Fraction K
authors.initials: FK
authors.lastname: Dzinjalamala
authors.forename: Allan
authors.initials: A
authors.lastname: Macheso
authors.forename: James G
authors.initials: JG
authors.lastname: Kublin
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Karen I
authors.initials: KI
authors.lastname: Barnes
authors.forename: Malcom E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
mesh_terms: D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005492:Folic Acid / Q000097:blood*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008295:Malawi; D008297:Male; D016017:Odds Ratio; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D013413:Sulfadoxine; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine