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Antimicrobial Agents and Chemotherapy, November 2001, p. 3171-3174, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3171-3174.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Reversal of Chloroquine Resistance in Plasmodium falciparum Using Combinations of Chemosensitizers

Donelly A. van Schalkwyk, Jason C. Walden, and Peter J. Smith*

Department of Pharmacology, University of Cape Town, Observatory 7925, South Africa

Received 23 February 2001/Returned for modification 25 June 2001/Accepted 30 July 2001

Research into chloroquine resistance reversal in Plasmodium falciparum has revealed a widespread range of functionally and structurally diverse chemosensitizers. However, nearly all of these chemosensitizers reverse resistance optimally only at concentrations that are toxic to humans. Verapamil, desipramine, and trifluoperazine were shown to potentiate chloroquine accumulation in a chloroquine-resistant (CQr) strain of P. falciparum, while progesterone, ivermectin, and cyclosporin A were not shown to potentiate chloroquine accumulation. The simultaneous use of two or even three of these chemosensitizers at concentrations within their therapeutic ranges in humans displayed an additive effect in potentiating chloroquine accumulation in the CQr strain. The levels of resistance reversal achieved with these multiple combinations were comparable to those achieved with high concentrations of the single agents used to enhance the activity of chloroquine. No chemosensitizer, 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 chemosensitizers at concentrations not toxic to humans could effectively reverse chloroquine resistance without the marked toxicity from the use of a single agent at high concentrations. This cocktail of chemosensitizers may serve as a viable treatment to restore the efficacy of chloroquine in patients with malaria.

* Corresponding author. Mailing address: Department of Pharmacology, University of Cape Town Medical School, Anzio Rd., Observatory 7925, South Africa. Phone: 27 21 406-6289. Fax: 27 21 448-1989. E-mail: psmith{at}uctgshl.uct.ac.za.

Antimicrobial Agents and Chemotherapy, November 2001, p. 3171-3174, Vol. 45, No. 11
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.11.3171-3174.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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