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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.
AuthorsSivicha Krudsood, Mallika Imwong, Polrat Wilairatana, Sasithon Pukrittayakamee, Apichart Nonprasert, Georges Snounou, Nicholas J White, Sornchai Looareesuwan
JournalTransactions of the Royal Society of Tropical Medicine and Hygiene (Trans R Soc Trop Med Hyg) Vol. 99 Issue 2 Pg. 142-9 (Feb 2005) ISSN: 0035-9203 [Print] England
PMID15607340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimalarials
  • Artemisinins
  • Sesquiterpenes
  • Artesunate
  • Dapsone
  • Tetrahydrofolate Dehydrogenase
  • Dihydropteroate Synthase
  • Proguanil
Topics
  • Adolescent
  • Adult
  • Animals
  • Antimalarials (adverse effects, therapeutic use)
  • Artemisinins (adverse effects, therapeutic use)
  • Artesunate
  • Dapsone (adverse effects, therapeutic use)
  • Dihydropteroate Synthase (genetics)
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Humans
  • Malaria, Falciparum (drug therapy, genetics)
  • Male
  • Middle Aged
  • Mutation
  • Plasmodium falciparum (genetics)
  • Proguanil (therapeutic use)
  • Prospective Studies
  • Recurrence
  • Sesquiterpenes (adverse effects, therapeutic use)
  • Tetrahydrofolate Dehydrogenase (genetics)
  • Treatment Outcome

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