title: Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum.
abstract: A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquone-sensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.
authors.affiliation: ITD, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. quinton.fivelman@lshtm.ac.uk
authors.forename: Quinton L
authors.initials: QL
authors.lastname: Fivelman
authors.forename: Ipemida S
authors.initials: IS
authors.lastname: Adagu
authors.forename: David C
authors.initials: DC
authors.lastname: Warhurst
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D053626:Atovaquone; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004351:Drug Resistance; D004357:Drug Synergism; D009285:Naphthoquinones / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D002727:Proguanil / Q000494:pharmacology*; D015203:Reproducibility of Results; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D009285:Naphthoquinones; D012717:Sesquiterpenes; C039060:artenimol; D002727:Proguanil; D053626:Atovaquone