Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Walzer, Peter D.; Kim, C K; Foy, J; Zhang, J L

doi:10.1128/aac.35.1.158

Cited by 20 publications

(10 citation statements)

References 27 publications

(46 reference statements)

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“…Furazolidone exhibited anti-P. carindi activity in our rat model at doses far higher than those used in humans; therefore, it is unlikely that furazolidone will ever be studied in clinical trials (38). Nevertheless, since thousands of nitrofuran derivatives have been synthesized, further evaluation of these compounds might be productive.…”

Section: Discussionmentioning

confidence: 99%

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Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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Over a 7-year period, we analyzed 261 dose regimens of antimicrobial drugs in the treatment and prevention of Pneumocystis carinii pneumonia in an immunosuppressed rat model. These compounds ranged from drugs in clinical use to newly synthesized agents. Drug efficacy was expressed as the magnitude of the reduction in median P. carinii cyst or nucleus counts on a scale ranging from inactive (<5-fold) to very markedly active (.1,000-fold). The classification system was reproducible and allowed drugs studied at different times to be compared with each other. The system demonstrated a hierarchy of anti-P. carinii activity not only among classes of compounds but also among individual members of a drug class. Sulfonamides, sulfones, and diamidines were the most active agents; some purine nucleosides and nitrofurans also showed promising activity; and most antiparasitic, antifungal, antibacterial, and antiviral drugs were inactive. We conclude that this classification system represents a simple, quantitative method of comparing the activities of antimicrobial drugs against P. carinii. Information gained from this system should be helpful in developing new anti-P. carinii compounds and establishing standard procedures for their evaluation.Over the past decade, there has been a major rise in the number of cases of Pneumocystis carinii pneumonia associated with AIDS. The well-publicized limitations of currently available anti-P. carinii drugs in AIDS patients have emphasized the need for new therapeutic approaches (37). Most drug testing has been performed in an immunosuppressed rat model of pneumocystosis, which accurately predicts activity against human P. carinii. Compounds which have exhibited anti-P. carinii activity in the rat model include antifolate drugs (alone or in combination) such as dihydrofolate reductase (DHFR) inhibitors, sulfonamides, sulfones, and sulfonylureas (7, 9, 12, 14, 16-20, 23, 24, 27, 35, 39, 42, 43); sulfonamides in combination with other drugs (e.g., macrolides) (13); diamidines and related cationic compounds (8,11,21,34,40); 8-aminoquinolones, alone or in combination with other agents (1, 28); purine nucleosides (la, 32, 36); polyamine inhibitors (3, 4); nitrofurans (38); 3-glucan inhibitors (26, 29, 30); hydroxynaphthoquinones (14); fluoroquinolones (2); iron chelators (4); and immunological agents (antibodies, cytokines) (10,31).Although the rat model has been very valuable, evaluation of anti-P. carinii drugs is time-consuming, expensive, and labor intensive; only a few compounds can be tested in a given experiment. Treatment studies have been performed by different experimental protocols and methods of evaluating drug efficacy; this lack of standardization has prevented the results of one investigator from being compared directly with those of another. Little attention has also been devoted to quantitating the reduction in organism burden which can be achieved with different doses of anti-P. carinii drugs. In addition, there have been few published sources of information of the compound...

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Section: Discussionmentioning

confidence: 99%

“…A variety of nitrofuran and nitroimidazole derivatives were evaluated (38). The Merrell-Dow, Cincinnati, Ohio, were administered alone and in combination with other agents, but they showed little anti-P. carinii activity; DFMO was tolerated poorly by the rats (40).…”

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Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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“…(1). The drug has been successfully used in treating multi-resistant typhoid fever in children (2), Pneumocystis carinii pneumonia (3), and in China it has been used in man as an anti-ulcer agent for the last 20 years [reviewed by (4)]. FZ was found to be effective against cysteamine and indomethacin-induced peptic ulcer in rats (5).…”

Section: Introductionmentioning

confidence: 99%

The effect of furazolidone and furaltadone on drug metabolism in rats

Ali

Tanira

Bashir

1996

European Journal of Drug Metabolism and Pharmacokinetics

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This work examines the effect of oral treatment of rats with the nitrofuran drugs furazolidone (FZ) and furaltadone (F) at doses of 100, 200 and 400 mg/kg for 4 days, or F in the drinking water at concentrations of 0.1, 0.2 and 0.4% w/v for 14 days, on drug metabolism in vivo. FZ at doses of 200 and 400 mg/kg, and F at a dose of 400 mg/kg or at a concentration of 0.4% w/v in water depressed growth and prolonged pentobarbitone-induced sleeping time. Treatment also significantly increased the blood concentration of metronidazole when measured 30 and 40 min after metronidazole administration. Administration of tremorine (25 mg/kg, i.p.) to control vehicle-treated rats produced within 2-3 min tremors, piloerection, profuse salivation, defecation urination and chromodacryorrhesis (red tears). The onset of appearance of these signs was delayed to 7-12 min in rats pretreated with FZ or F (100 mg/kg, 4 days) or cimetidine (50 mg/kg, i.p.) given 45 min earlier. Taken together, these results suggest that FZ and F inhibit drug metabolism in rats. Treatment with these nitrofuran drugs may alter the disposition of certain drugs which may be given concomitantly with them.

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“…(i) Treatment. The animal protocol used here has been presented in detail in our earlier reports (20,(38)(39)(40). Most experiments involved the use of 200-to 250-g male Sprague-Dawley rats obtained from Harlan Industries, Madison, Wis., which were latently infected with P. carinii.…”

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“…Assessment of drug activity. As in our earlier reports (20,(38)(39)(40), assessment of drug efficacy was based on analysis of the severity or extent of pneumocystosis in the lungs rather than on animal survival because the rats may die of causes (e.g., drug toxicity, infection with other microorganisms) unrelated to P. carinii. Early deaths occurred mainly in the treatment studies because the rats were already heavily immunosuppressed when the anti-P. carinii drugs were begun.…”

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Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia

Walzer

Foy

Steele

et al. 1992

Antimicrob Agents Chemother

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The efficacy of antifolate, antiviral, and other drugs was compared in an experimental model of pneumocystosis. Sulfamethoxazole (SMX) administered alone in doses of .60 mg/kg/day was highly effective in treatment and prophylaxis. Low (c15 mg/kg/day) doses of SMX showed limited, dose-related antiPneumocystis carinii activity in therapy but were more effective in prophylaxis. The dihydrofolate reductase (DHFR) inhibitors trimethoprim (TMP), pyrimethamine, and trimetrexate exhibited little anti-P. carinii activity when administered alone and did not enhance the efficacy of SMX; the effects of the DHFR inhibitors could not be related to the dose or the concentration in serum. These data suggested that the rat model is an excellent system for studying the anti-P. carinii activity of sulfonamides but is of limited value in studying DHFR inhibitors. The antiviral drugs azidothymidine, dideoxyinosine, inosine pranobex (Isoprinosine), amantadine, and acyclovir displayed little or no activity against P. carinii; however, azidothymidine did not impair the efficacy of SMX or TMP-SMX. These results supported the clinical practice of giving antiviral agents together with antifolate drugs to patients infected with human immunodeficiency virus and suggested that the beneficial effects of antiviral agents on the occurrence of pneumocystosis are due mainly to their effects on the virus or the host immune response. In contrast to the antiviral drugs, 9-deazainosine, a nucleoside analog with antiprotozoal properties, deinonstrated marked activity against P. carinii which was related to dose and route of administration. These data raised the possibility that anti-P. carinii activity is a general property of purine nucleosides Experimental studies of anti-P. carinii drugs have usually been performed in an immunosuppressed rat model of pneumocystosis, which is a reliable predictor of activity against the human form of the disease (10,13,20). In a previous study of antifolate drugs in this model (34), we found that anti-P. carinii activity was a general property of sulfonamides; these compounds were so effective that a doseresponse curve could not be established at the doses used. By contrast, DHFR inhibitors exhibited little anti-P. carinii activity and did not improve the efficacy of the sulfonamides * Corresponding author.or the sulfone dapsone. This lack of synergism differed from the results of previous workers (10,14,15) and raised questions about the value of using the rat model to screen antifolate drugs.In the present study, we have extended these observations by exploring the effect of lower doses of the sulfonamide sulfamethoxazole (SMX) in the therapy of experimental pneumocystosis. We

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Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Cited by 20 publications

References 27 publications

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs

The effect of furazolidone and furaltadone on drug metabolism in rats

Activities of antifolate, antiviral, and other drugs in an immunosuppressed rat model of Pneumocystis carinii pneumonia

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