Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs demands a continuous effort to develop new antima larial agents. In this quest, the identification of antimalarial effects of drugs already in use for other therapies represents an attractive approach with potentially rapid clinical application. We have found that the extens ively used antimycotic drug clotrimazole (CLT) effectively and rapidly inhi bited parasite growth in five different strains of P. falciparum, in vitro, irrespective of their chloroquine sensitivity. The concentrations for 50% inhibition (IC50), assessed by parasite incorporation of [H-3]hypoxanthine, were between 0.2 and 1.1 mu M. CLT concentrations of 2 mu M and above caus ed a sharp decline in parasitemia, complete inhibition of parasite replicat ion, and destruction of parasites and host cells within a single intraeryth rocytic asexual cycle (approximate to 48 hr). These concentrations are with in the plasma levels known to be attained in humans after oral administrati on of the drug. The effects were associated with distinct morphological cha nges, Transient exposure of ring-stage parasites to 2.5 mu M CLT for a peri od of 12 hr caused a delay in development in a fraction of parasites that r everted to normal after drug removal; 24-hr exposure to the same concentrat ion caused total destruction of parasites and parasitized cells. Chloroquin e antagonized the effects of CLT whereas mefloquine was synergistic. The pr esent study suggests that CLT holds much promise as an antimalarial agent a nd that it is suitable for a clinical study in P. falciparum malaria.