In Vitro Interactions of Artemisinin with Atovaquone, Quinine, and Mefloquine againstPlasmodium falciparum

Abstract

The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (⌺FICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC 50 The evolution and spread of multidrug-resistant Plasmodium falciparum malaria have prompted the need to use combinations of antimalarial drugs, preferably drugs with different modes of action, in order to increase drug efficacy and to potentially reduce the possibility of the development of resistance to either compound. Artemisinin and its derivatives are highly effective compounds against multidrug-resistant P. falciparum, with consistently rapid clearance of parasites and fever in patients with malaria (14). However, in monotherapy with artemisinin and its derivatives, a relatively long treatment course of 5 to 7 days is required; such a treatment course entails the risk of poor compliance and high recrudescence rates (8). Artemisinin therefore needs to be combined with a partner drug with a longer elimination half-life (t 1/2 ) in order to reduce the risk of recrudescence.In areas with multidrug resistance, i.e., mainly parts of Southeast Asia, the efficacy of mefloquine (as monotherapy) is compromised. Nevertheless, mefloquine and artesunate were found to be synergistic both in vivo and in vitro, and this combination is now widely recommended for clinical use in Southeast Asia (13,20,29). However, there is a need for drugs that can be alternative partners to artemisinin, especially in areas where malaria transmission is intensive and where the persistence of subinhibitory concentrations of mefloquine (elimination t 1/2 , 3 weeks) for long periods entails a high risk of selection of resistant parasite populations (25).Quinine, a quinoline methanol like mefloquine, represents one potential partner drug to artemisinin. There is relatively little resistance to the drug worldwide, and it has a t 1/2 of 9 to 18 h. There is yet little in vitro information and practically no in vivo data on the interactive profile of artemisinin and quinine.Atovaquone, a hydroxynaphthoquinone with a t 1/2 of 52 to 80 h, is a newly introduced antimalarial drug with a novel mode of action. It is well tolerated and active against both chloroquine-sensitive and -resistant strains of P. falciparum, but it should not be used alone for treatment or prophylaxis of malaria. It is formulated as a fixed combination with proguanil since the two drugs have shown a high degree of synergism both in vivo and in vitro (4,16,27). One in vitro study has been performed with the combination of artemisinin and atovaquone, but the results were inconclusive (4).The present study was conducted to assess poten...

Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

“…This suggests that at high concentrations ATV could have an alternative mode of action against resistant parasites compared to its mode of action at lower concentrations lethal to ATV-sensitive parasites. Using the checkerboard technique, Gupta et al (11) reported an indifferent interaction and a synergistic interaction (obtained from IC 50 s and IC 90 s, respectively) between artemisinin and ATV in ATV-sensitive parasite lines. Although the investigators claimed an indifferent interaction, all the points on the isobologram lay above the line of indifference, which would be consistent with our results and those of Canfield et al (2).…”

The in vitro anti-plasmodial and in vivo anti-malarial efficacy of combinations of some medicinal plants used traditionally for treatment of malaria by the Meru community in Kenya

“…In this system: SFIC < 1 denotes synergism, 1 < SFIC < 2 denotes additive interaction, while SFIC ≥ 2 denotes antagonism (Gupta et al, 2002).…”

Evaluation of anti-leishmanial activity of artemisinin combined with amphotericin B or miltefosine in &lt;i&gt;Leishmania donovani&lt;/i&gt; promastigotes

“…The sum FIC (ΣFIC) value for each of the six combinations was determined to classify the drug-drug interaction [16][17][18] as ΣFIC=FIC (artemisinin)+FIC (amphotericin B) or FIC (miltefosine) where ΣFIC <1 represented synergism, ΣFIC ≥1, but <2 represented additive interaction and ΣFIC ≥2 indicated antagonism.…”