Publication: Artesunate-dapsone-proguanil treatment of falciparum malaria: Genotypic determinants of therapeutic response
Issued Date
2005-02-01
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ISSN
00359203
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2-s2.0-11144323302
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Mahidol University
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SCOPUS
Bibliographic Citation
Transactions of the Royal Society of Tropical Medicine and Hygiene. Vol.99, No.2 (2005), 142-149
Suggested Citation
Sivicha Krudsood, Mallika Imwong, Polrat Wilairatana, Sasithon Pukrittayakamee, Apichart Nonprasert, Georges Snounou, Nicholas J. White, Sornchai Looareesuwan Artesunate-dapsone-proguanil treatment of falciparum malaria: Genotypic determinants of therapeutic response. Transactions of the Royal Society of Tropical Medicine and Hygiene. Vol.99, No.2 (2005), 142-149. doi:10.1016/j.trstmh.2004.07.001 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/16611
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Title
Artesunate-dapsone-proguanil treatment of falciparum malaria: Genotypic determinants of therapeutic response
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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 2.5 mg/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 anti-malarial activity of the biguanide-dapsone combination, but this is insufficient for infections with parasites carrying the highly antifol-resistant Pfdhfr I164L mutation. © 2004 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.