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Studies on the 2,4-Diamino-6-Substituted Quinazolines

III. The Capacity of Sulfadiazine to Enhance the Activities of WR-158,122 and WR-159,412 Against Infections with Various Drug-Susceptible and Drug-Resistant Strains of Plasmodium Falciparum and Plasmodium Vivax in Owl Monkeys^*

Previous studies showed: 1) that the activities of the 2,4-diamino-6-substituted quinazolines, WR-158,122 and WR-159,412, against Plasmodium falciparum and Plasmodium vivax infections in owl monkeys, were seriously impaired when infecting strains were pyrimethamine-resistant; and 2) that primary treatment failure with either agent led frequently to emergence of parasites resistant to these derivatives. Taking advantage of the potencies of WR-158,122 and WR-159,412 as dihydroflic acid reductase inhibitors, the current studies were aimed at determining whether the above liabilities could be reduced to manageable levels or eliminated by concomitant administration of a -aminobenzoic acid inhibitor such as sulfadiazine. Application of these combinations prevented emergence of parasites resistant to WR-158,122 or WR-159,412, but did not abolish the differences in effectiveness of either compound against infections with pyrimethamine-susceptible and pyrimethamine-resistant strains; however, activities against infections with either susceptible or resistant strains were enhanced markedly. With WR-158,122, this enhancement ranged from greater than 7-fold to 75-fold; with WR-159,412, it ranged from greater than 5-fold to 13-fold. Maximal increases in activity were attained with a remarkably small dose of sulfadiazine, 5.0 mg per kg of body weight daily. With this augmentation of activity, acceptably small doses of WR-158,122 regularly cured infections with even the most highly pyrimethamine-resistant strain.

Accepted for publication March 10, 1979.

^* The experimental components of this report were supported by contract DADA 17-69-C-9104 between the U.S. Army Medical Research and Development Command and Southern Research Institute. Manuscript preparation was supported in part by the above contract and in part by Southern Research Institute. This is contribution number 1533 from the Army Research Program on Malaria.

Address reprint requests to: L. H. Schmidt, Kettering-Meyer Laboratory, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35205.