AJTMH Transactions of the Royal Society of Tropical Medicine and Hygiene
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Am. J. Trop. Med. Hyg., 50(2), 1994, pp. 200-205
Copyright © 1994 by The American Society of Tropical Medicine and Hygiene

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In Vitro Activity of Bisquinoline WR268,668 Against African Clones and Isolates of Plasmodium falciparum

Leonardo K. Basco, Steven L. Andersen, Wilbur K. Milhous, Jacques Le Bras AND Jonathan L. Vennerstrom
Centre National de Reference pour la Chimiosensibilite du Paludisme, Institut de Medecine et d'Epidemiologie Tropicales, Laboratoire de Parasitologie, Hopital Bichat-Claude Bernard, Paris, France; Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, District of Columbia: College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska

The in vitro activity of a new bisquinoline, WR268,668, was determined against chloroquine-susceptible and chloroquine-resistant African clones and isolates of Plasmodium falciparum using an isotopic semimicro drug susceptibility assay. The chloroquine-resistant clone (mean 50% inhibitory concentration [IC50] = 61.2 nM) was 11 times less susceptible to WR268,668 than the chloroquine-susceptible clone (IC50 = 5.75 nM). A similar result was obtained with fresh clinical isolates, with the chloroquine-susceptible isolates (IC50 = 5.36 nM, n = 11) being significantly (P < 0.05) more susceptible to WR268,668 than the chloroquine-resistant isolates (IC50 = 16.1 nM, n = 18). The compound WR268,668 exhibited a high activity against some moderately chloroquine-resistant isolates. There was a significant positive correlation between the in vitro responses to chloroquine and WR268,668 (r = 0.904, P < 0.05). Combinations of WR268,668 and desipramine, a chloroquine efflux inhibitor, showed that resistance to WR268,668 can be reversed against the chloroquine-resistant clone and that desipramine has no effect on the activity of WR268,668 against the chloroquine-susceptible clone. The results of the study indicate the presence of cross-resistance between chloroquine and WR268,668, and suggest that the basis of resistance to WR268,668 may be similar to that of other 4-aminoquinolines.




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