In Vitro Activity of Artemisinin in Combination with Clotrimazole or Heat-treated Amphotericin B against Plasmodium falciparum

Abstract

Currently available artemisinin-based combination therapies (ACTs) for malaria are inadequate. There remains an enormous unmet need for alternate artemisinin-based combination therapies. One of the fastest methods to identify promising artemisinin-based combination therapies is to look for synergistic or additive antimalarial interaction between artemisinin and an alternate drug against P. falciparum in vitro. Amphotericin B and clotrimazole are known drugs for treatment of human fungal infections. We repurposed clotrimazole or heat-treated amphotericin B in fixed ratio combination with artemisinin for antimalarial properties. Isobologram results show synergistic/additive interaction in both of the cases at therapeutically safe concentrations. Artemisinin, clotrimazole, and their synergistic combinations also decrease hemozoin production in parasitized erythrocytes. New permeation pathways induced in infected cells remain unaffected by drug combinations as indicated by sorbitol lysis. It would be interesting to extend the studies' in vivo system.

Evaluation of anti-leishmanial activity of artemisinin combined with amphotericin B or miltefosine in <i>Leishmania donovani</i> 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.…”

Effect of Amphotericin B on Parasitemia and Survival of <i>Plasmodium Berghei</i>-infected Mice

“…As a matter of fact, administration of amphotericin B has indeed been suggested to positively influence the course of malaria [33][34][35][36], an effect, however, attributed to lysis of host erythrocytes in the trophozoite stage of Plasmodium falciparum [36] rather than to accelerated eryptosis.…”

HIV Protease Inhibitors, Indinavir or Nelfinavir, Augment Antimalarial Action of Artemisinin in vitro

“…The Σ FIC < 1 represents synergism, Σ FIC ≥ 1 and < 2 represents additive interaction, Σ FIC ≥ 2 and < 4 represents slight antagonism, whereas Σ FIC ≥ 4 represents marked antagonism. [15][16][17] The isobolograms obtained from fixed ratio combinations against two strains of P. falciparum are presented in Figure 1 . The points appearing below the additive line of concentration 1 and 6 represent synergism (Σ FIC < 1).…”

“…14, 15 The first and the last ratio of these six preparations had the artemisinin and antiretroviral drug alone at a concentration approximately 8× their respective IC 50 value against a particular parasite strain. Further dilutions of these combinations have been described in plate preparation elsewhere.…”

“…Further dilutions of these combinations have been described in plate preparation elsewhere. 14,15 After 48 hours, thin blood film slides from each triplicate experimental well and from control were prepared separately for counting the parasitemia. The fractional inhibitory concentration (FIC) for each drug in triplicate for six fixed-dose ratios was calculated by the following formula: FIC = Concentration of drug in combination to produce IC 50 Concentration of drug alone required to produce IC 50…”