Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro

Transactions of the Royal Society of Tropical Medicine and Hygiene
Mita M ThaparAnders Björkman

Abstract

Synergistic interaction between atovaquone and proguanil has been suggested as the reason for the effectiveness of Malarone. The pharmacodynamic interactions among atovaquone, proguanil and its metabolite cycloguanil were investigated in 4 Plasmodium falciparum parasite strains by culture assays in vitro. The response parameters were determined and 2 statistical methods, log-concentration/response probit method and sum of fractional inhibitory concentrations (sigmaFIC) method, were used to analyse the experimental data. Within therapeutically relevant concentration ratios, the combination of atovaquone and proguanil showed mean sigmaFICs of 0.37 at EC50 (50% effective concentrations) and 0.13 at EC90, indicating high synergism. The combination of atovaquone and cycloguanil yielded corresponding mean sigmaFICs of 3.70 and 2.11, indicating antagonism. The EC50 and EC90 values for proguanil alone were not influenced by RPMI-1640 medium with low concentrations of paraaminobenzoic acid and folic acid (LPLF culture medium), whereas the EC50 and EC90 values for cycloguanil were more than 10 times lower in LPLF medium than in normal RPMI-1640 medium. This confirms the hypothesis that proguanil may act on another target than dihydrofola...Continue Reading

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Citations

Nov 30, 2006·Wiener klinische Wochenschrift·Carola LütgendorfWalther H Wernsdorfer
Nov 20, 2004·Transactions of the Royal Society of Tropical Medicine and Hygiene·Mita M ThaparAnders Björkman
Nov 30, 2005·Transactions of the Royal Society of Tropical Medicine and Hygiene·M D Matsika-ClaquinA Talarmin
Dec 27, 2005·Antimicrobial Agents and Chemotherapy·Karin Seifert, Simon L Croft
Jan 1, 2007·Wiener klinische Wochenschrift·Bettina ExnerWalther H Wernsdorfer
Jan 26, 2016·PLoS Computational Biology·C Brandon OgbunugaforDaniel L Hartl
Mar 9, 2012·Clinical Pharmacology and Therapeutics·M CellaO Della Pasqua
May 10, 2019·Communications Biology·Tina S Skinner-AdamsKatherine T Andrews
Sep 1, 2009·Expert Review of Clinical Pharmacology·Kesara Na-Bangchang
Mar 9, 2012·Clinical Pharmacology and Therapeutics·M CellaO Della Pasqua
Jan 12, 2020·Communications Biology·Tina S Skinner-AdamsKatherine T Andrews
Aug 8, 2021·European Journal of Medicinal Chemistry·Oleksandr GrytsaiRachid Benhida

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