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 dihydrofolic 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 rho-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 remarkedly 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.
D000818:Animals; D001029:Aotus trivirgatus; D004338:Drug Combinations; D004352:Drug Resistance, Microbial; D005260:Female; D000882:Haplorhini; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D011739:Pyrimethamine; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013411:Sulfadiazine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D004338:Drug Combinations; D011799:Quinazolines; D013411:Sulfadiazine; C012685:WR 158122; C021135:WR 159412; D011739:Pyrimethamine