Inhibitors of folic acid synthesis were compared alone and in different combinations in the therapy of pneumocystosis in immunosuppressed rats. Sulfonamides (sulfamethoxazole, sulfadiazine, and sulfadoxine) and sulfones (dapsone) used alone were very active against Pneumocystis carinii, as judged by histologic examination of the lungs and by organism quantitation. Improved efficacy could not be demonstrated by the addition of an inhibitor of dihydrofolate reductase to the regin1en. Dihydrofolate reductase inhibitors (trimethoprim, diaveridine, and pyrimethamine) used alone were ineffective against P. carinii. All drugs were well tolerated except pyrimethamine, which caused bone marrow depression; folinic acid ameliorated this adverse reaction but did not interfere with P. carinii treatment. These data have potential clinical implications but need to be interpreted with caution and in light of other systems of P. carinii drug evaluation.
Cationic compounds used in the treatment of veterinary African trypanosomiasis have structural properties similar to those of pentamidine, which has been used in the therapy of human trypanosomiasis and infection with Pneumocystis carinii. We have compared the activities of these drugs and other antimicrobial agents in an immunosuppressed rat model of P. carinii pneumonia. Diminazene, imidocarb, amicarbalide, quinapyramine, and isometamidium showed efficacy greater than or equal to that of pentamidine in the therapy of P. carinji infection, whereas ethidium and methylglyoxal bis(guanylhydrazone) were only slightly active against the organism. Diminazene and pentamidine also exhibited comparable efficacy in P. carinii prophylaxis. aLDifluoromethylornithine (DFMO), a polyamine inhibitor, was ineffective therapy when used alone and did not improve the effectiveness of pentamidine or diminazene. Quinine, quinidine, quinacrine, chlorpromazine, spiramycin, Pentostam, Astiban, dehydroemetine, ampicillin, gentamicin, chloramphenicol, and spectinomycin also showed little or no activity against the organism. Thus, in this model anti-P. carinii activity appears to be a common property of veterinary cationic trypanocidal compounds. This should be important in studying structure-activity relationships and in developing new drugs for the treatment of P. carinii infection in humans.Since the discovery of the acquired immunodeficiency syndrome (AIDS) in 1981 (13, 26), the incidence of Pneumocystis carinji pneumonia in this country has increased dramatically. P. carinii is the most frequent opportunistic pathogen in AIDS, occurring in over 60% of cases (10). The problems of treatment of P. carinii infection in AIDS (e.g., the high rate of relapse and adverse drug reactions) have emphasized the need to develop new forms of therapy (12,14,24,39).Drug development for P. carinii has generally been empiric because of a lack of knowledge about the metabolic pathways of the organism. An alternative approach would be to explore compounds which are related to drugs currently in use for the treatment of P. carinii infection. Pentamidine isethionate, one of the principal anti-P. carinii drugs, is a diamidine originally introduced for human clinical use over 40 years ago for the treatment of African trypanosotniasis (32). We wondered whether other old cationic quaternary ammonium compounds with structural properties similar to those of pentamidine, which have been used in the therapy of veterinary African trypanosomiasis, might have activity against P. carinii. Support for this hypothesis can be found in reports which have shown anti-P. carinji activity with hydroxystilbamidine, a diamidine, and with the structurally unrelated antitrypanosomal drugs a-difluromethylornithine (DFMO) and 9-deazinosine (4, 11, 28).Experimental systems for anti-P. carinii drug evaluation have mainly consisted of immunosuppressed animals. Rats administered corticosteroids for 6 to 8 weeks spontaneously develop P. carinii pneumonia with histologic features identic...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.