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Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics

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The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine‐sensitive (F32) strain of Plasmodium falciparum. A method of repetitive dosing and extending the culture observation period to 28–30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from 10−8 to 10−5 m, mefloquine from 3×10−9 to 10−5 mand their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug‐dosing duration was 3 days.

Neither artemisinin nor mefloquine alone provided radical clearance of P. falciparum, even when maximum concentrations (10−5 m) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo, this effect was clearly synergistic (P=0.016)

Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC‐values for the individual compounds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single‐drug treatment.
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Keywords: Plasmodium falciparum; artemisinin; combinations; in vitro; malaria; mefloquine

Document Type: Original Article

Affiliations: 1: Division of Infectious Diseases, Karolinska Institutet, Huddinge, Sweden, 2: Division of Infectious Diseases, Karolinska Institutet, Danderyd, Sweden, 3: Institute of Specific Prophylaxis & Tropical Medicine, University of Vienna, Vienna, Austria

Publication date: May 1, 1997

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