title: Artesunate-dapsone-proguanil treatment of falciparum malaria: genotypic determinants of therapeutic response.
abstract: The combination of chlorproguanil and dapsone is being considered as an alternative antimalarial to sulfadoxine-pyrimethamine in Africa, because of its greater efficacy against resistant parasites, and its shorter half-lives, which exert less selective pressure for the emergence of resistance. A triple artesunate-chlorproguanil-dapsone combination is under development. In a previous study of relatively low-dose chlorproguanil-dapsone in multidrug-resistant falciparum malaria in Thailand failure rates were high. Proguanil is inexpensive, widely available and very similar to chlorproguanil. The safety and efficacy of artesunate-dapsone-proguanil (artesunate 4 mg/kg, dapsone 2.5mg/kg, proguanil 8 mg/kg daily for three days), was studied prospectively in 48 Thai adult patients with acute falciparum malaria followed daily for 28 days. Eleven of these had a recrudescence of their infection. Genotyping of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) indicated that the Pfdhfr I164L mutation was the main determinant of therapeutic outcome; all 11 failures carried this mutation (failure rate 11/37; 30%) whereas none of the 11 infections with 'wild type' 164 genotypes failed. The addition of artesunate considerably augments the antimalarial activity of the biguanide-dapsone combination, but this is insufficient for infections with parasites carrying the highly antifol-resistant Pfdhfr I164L mutation.
authors.affiliation: Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.
authors.forename: Sivicha
authors.initials: S
authors.lastname: Krudsood
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Polrat
authors.initials: P
authors.lastname: Wilairatana
authors.forename: Sasithon
authors.initials: S
authors.lastname: Pukrittayakamee
authors.forename: Apichart
authors.initials: A
authors.lastname: Nonprasert
authors.forename: Georges
authors.initials: G
authors.lastname: Snounou
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Sornchai
authors.initials: S
authors.lastname: Looareesuwan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000009:adverse effects / Q000627:therapeutic use*; D037621:Artemisinins / Q000009:adverse effects / Q000627:therapeutic use*; D000077332:Artesunate; D003622:Dapsone / Q000009:adverse effects / Q000627:therapeutic use*; D004094:Dihydropteroate Synthase / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010963:Plasmodium falciparum / Q000235:genetics; D002727:Proguanil / Q000627:therapeutic use*; D011446:Prospective Studies; D012008:Recurrence; D012717:Sesquiterpenes / Q000009:adverse effects / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D002727:Proguanil