Reversal of chloroquine resistance in Plasmodium falciparum using combinations of chemosensitizers

Research into chloroquine resistance reversal in Plasmodium falciparum has revealed a widespread range of functionally and structurally diverse chemos ensitizers. However, nearly all of these chemosensitizers reverse resistanc e optimally only at concentrations that are toxic to humans. Verapamil, des ipramine, and trifluoperazine were shown to potentiate chloroquine accumula tion in a chloroquine-resistant (CQ(r)) strain of P. falciparum, while prog esterone, ivermectin, and cyclosporin A were not shown to potentiate chloro quine accumulation. The simultaneous use of two or even three of these chem osensitizers at concentrations within their therapeutic ranges in humans di splayed an additive effect in potentiating chloroquine accumulation in the CQ(r) strain. The levels of resistance reversal achieved with these multipl e combinations were comparable to those achieved with high concentrations o f the single agents used to enhance the activity of chloroquine. No chemose nsitizer, whether used singly or in combination, potentiated any change in chloroquine accumulation or a shift in the 50% inhibitory concentration for the chloroquine-sensitive strain. The use of combinations of chemosensitiz ers at concentrations not toxic to humans could effectively reverse chloroq uine resistance without the marked toxicity from the use of a single agent at high concentrations. This cocktail of chemosensitizers may serve as a vi able treatment to restore the efficacy of chloroquine in patients with mala ria.