ABSTRACT Citalopram, is an extremely potent inhibitor of neuronal serotonin reuptake. It is structurally unrelated to other antidepressants, but it contains the chemical features associated with reversal of drug resistance and exhibits minimal cardiotoxic side effects and fewer of the anticholinergic and adrenolytic side effects associated with other psychotropic agents. Sensitivity tests to citalopram alone and in combination with chloroquine were performed against chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum and Plasmodium chabaudi. Citalopram alone showed intrinsic activity against the chloroquine-resistant strains of P. falciparum (IC 50 ϭ 1.51 Ϯ .6 M) but only limited activity against the chloroquine-sensitive strain (IC 50 ϭ 33.27 Ϯ 5.87 M) and no activity in vivo. The interaction of chloroquine and citalopram in vitro resulted in a synergistic response in the chloroquineresistant strain but there was no interaction between the drugs in the chloroquine-sensitive strain-a pattern found with other reversal agents. Citalopram enhanced chloroquine susceptibility in both strains of P. chabaudi, however, the potentiating effect was seen at lower doses in the chloroquine-resistant strain. The results of this study suggest that citalopram may have potential as a chemosensitizer in Plasmodium infections on the basis of the low toxicity of citalopram at concentrations potentiating chloroquine activity both in vitro and in vivo. Malaria is a significant source of global morbidity and mortality. Despite the development of new antimalarial agents such as mefloquine, halofantrine and the artemisins, chloroquine remains the drug of choice for the treatment of uncomplicated Plasmodium falciparum malaria infections, due to its low cost, rapid onset of action and its low toxicity. However, the efficacy of chloroquine has diminished due to the emergence and prevalence of chloroquine-resistant strains of P. falciparum (Wensdorfer and Payne, 1991). The rapid development and spread of resistance to chloroquine and other antimalarials, and the tremendous cost of drug development has emphasized the necessity to optimize the use of existing antimalarial agents A number of adjunct drugs have been identified from a wide variety of chemical classes including calcium-channel blockers Citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3dihydroisobenzofuran-5-carbonite), is an extremely potent inhibitor of neuronal serotonin reuptake The low toxicity coupled with the chemical similarity to chemosensitizers (resistance reversal agents) prompted us to investigate the chemosensitizing effect of citalopram in Plasmodium. In this study, we screened citalopram for chloroquine potentiating activity in chloroquine-resistant and chloroquine sensitive-parasites; both in vitro against P. falciparum and in a rodent malaria model (Plasmodium chabaudi). Methods Effect of Citalopram in Vitro Parasites. Two well-characterized isolates of P. falciparum were used for the drug assays. The chloroquine-resistant FCR-3 strain (IC 50 ϳ 150 nM) (donated by J. Freese, Research in diseases of the Tropical Environment, Durban, South Africa) and the chloroquine
