Chemotherapeutic properties of prominent nitrofurans

Chamberlain, R. E.

doi:10.1093/jac/2.4.325

Cited by 81 publications

(22 citation statements)

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“…The antimicrobial properties of furazolidone and other nitrofuran compounds are related to the 5-nitro group on the furan ring, whereas the chemical characteristics, toxicity, and clinical use are due mainly to the side chain at the 2-position (4,20,25,29,31 (39). Whether the active form of furazolidone against P. carinii is the parent compound or some metabolite is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…These drugs are nitrofurans and hence represent a class of compounds which are unrelated to currently available anti-P. carinii agents. At least 3,500 nitrofuran derivatives have been synthesized, but only a select few have been developed for clinical use (4). Perhaps investigation of some of these compounds would lead to the development of new analogs with improved efficacy and less toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrofurans possess broad antimicrobial properties, including activity against trypanosomes (4,20,25,26,29,31). Our rationale for testing them against P. carinii was based on the following considerations.…”

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Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Walzer

Kim

Foy

et al. 1991

Antimicrob Agents Chemother

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Furazolidone and nitrofurantoin, oral nitrofuran derivatives with broad-spectrum antimicrobial properties already in clinical use, were compared for activity against Pneumocystis carinii in an immunosuppressed rat model of P. carinii pneumonia. Furazolidone exhibited only slight activity as a prophylactic agent but was moderately effective in the therapy of pneumocystosis. The median histologic score and organism count fell from 4+ and and their toxic effects on the rats will probably discourage investigation of this drug in the treatment of pneumocystosis in humans. Nevertheless, since many nitrofurans have been synthesized, further exploration of this class of compounds might be helpful in developing new anti-P. carinii agents or in studying structureactivity relationships.Pneumocystis carinii is a leading cause of pneumonia in immunosuppressed patients. The incidence of pneumocystosis has increased markedly over the past decade in association with the emergence of AIDS (34). Treatment of P. carinii pneumonia in AIDS patients has been hindered by a high frequency of recurrence and of toxic reactions to antimicrobial drugs. Anti-P. carinii compounds currently in clinical use include inhibitors of dihydrofolate reductase (e.g., trimethoprim [TMP], trimetrexate), sulfonamides (sulfamethoxazole [SMX]), and sulfones (dapsone); diamidines (pentamidine isethionate); polyamine inhibitors (adifluromethylornithine); and the combination of clindamycin and primaquine (2,11,13,21,27).Our laboratory has been engaged in developing new forms of P. carinii therapy for the past several years (8,15,35,36). Drug selection has been hampered by the lack of knowledge about the metabolic pathways of the organism. Studies are conducted in an animal model in which rats given corticosteroids spontaneously develop pneumocystosis by a process of reactivation of latent infection. Although this system permits evaluation of relatively few compounds, it has been a reliable predictor of drug activity in humans (10, 12).Here we report our experience with two nitrofuran derivatives, furazolidone and nitrofurantoin. Nitrofurans possess broad antimicrobial properties, including activity against trypanosomes (4,20,25,26,29,31). Our rationale for testing them against P. carinii was based on the following considerations. First, several classes of drugs (e.g., diamidines, polyamine inhibitors, purine nucleosides) with antitrypanosomal properties have been shown to be effective against P. carinii, although the specific mechanisms of action are unknown (8,21,28,36). Second, since furazolidone and nitrofurantoin are oral preparations and are already in clinical use, they would be much easier to develop as anti-P. carinii drugs than would unlicensed compounds with poorly * Corresponding author. understood pharmacokinetic properties or toxicological profiles. MATERIALS AND METHODSExperimental design. (i) Treatment. The animal protocol that we used has been described in detail previously (15,(35)(36)(37). In brief, adult male Sprague-Dawley rats (Harlan I...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Walzer

Kim

Foy

et al. 1991

Antimicrob Agents Chemother

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“…The high fluid flow rate in the small intestine in cholera (19) may cause capsules to discharge their contents in the lower small intestine. In the absence of any significant absorption and enterohepatic circulation of furazolidone (6), adequate intraluminal concentrations of drug may not be achieved in the duodenum and upper jejunum, where cholera infection exerts its strongest effects (1,12,13,15). Pierce et al (17) reported that furazolidone administered in tablet form to adults with cholera was effective in reducing duration of diarrhea and volume of stool but was less effective than tetracycline in shortening the period of vibrio excretion.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a single dose of furazolidone for treatment of cholera in children

Rabbani

Butler

Shahrier

et al. 1991

Antimicrob Agents Chemother

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To test the efficacy and safety of furazolidone given as a single dose for childhood cholera, a randomized double-blind placebo-controlled trial was carried out among 118 culture-positive dehydrated children with diarrhea. Patients were randomly assigned to one of four groups to receive medication orally in liquid suspension: furazolidone at 7 mg/kg/day once, furazolidone at 7 mg/kg/day divided into four doses for 3 days, placebo once, or placebo for 3 days. After 12 patients with furazolidone-resistant infections were excluded from the analysis of efficacy, it was determined that both groups treated with furazolidone showed significantly higher rates of bacteriologic success (stool cultures negative for Vibrio cholerae on days 2 to 4 after start of therapy) and clinical success (cessation of diarrhea within 72 h after start of therapy) than corresponding placebo groups (P < 0.001). There were no significant differences between responses to the 3-day and single-dose regimens of furazolidone, but there was a trend toward better clinical responses in patients who received furazolidone for 3 days. No patient treated with furazolidone dropped out because of side effects. These results indicate that furazolidone, given as either a single dose or divided doses for 3 days, is effective treatment for childhood cholera.Cholera is an acute illness caused by an enterotoxin produced by Vibrio cholerae that have colonized in the small bowel. In its most severe form, there is rapid loss of fluid and electrolytes from the gastrointestinal tract, resulting in hypovolemic shock, metabolic acidosis, and, if untreated, death (20). Cholera remains one of the diarrheal diseases with significant mortality in many developing countries (4). Fluid replacement is the most important component of therapy. While antibiotics are not essential to the treatment of the disease, they do shorten the duration of excretion of vibrios, the duration and volume of diarrhea, and the amount of fluid replacement required (5). Tetracycline is the antibiotic of choice for the treatment of cholera, and consideration of alternative drugs has been confined to the treatment of pregnant women and children for whom tetracycline was contraindicated because it stains developing teeth (8). Additionally, in areas such as Bangladesh, where multiply antibiotic-resistant V. cholerae have emerged, an alternative treatment must be considered (11).Furazolidone is effective in the treatment of cholera when given in multiple doses or single daily doses for 3 to 7 days (7,8,14,17 Treatment and clinical observations. After selection for the study, patients were allocated to one of four treatment groups according to a computer-generated list of random numbers. The treatments consisted of liquid suspensions of (i) furazolidone (7 mg/kg/day) given as a single dose on day 1, (ii) placebo liquid suspension given as a single dose on day 1, (iii) furazolidone (7 mg/kg/day) given in four equal daily doses on days 1, 2, and 3, and (iv) placebo liquid suspension given in four equal dai...

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“…Nitrofurazone (5-nitro-2-furaldehyde semicarbazone; NF), a broad-spectrum antibiotic, has been widely used in human and veterinary medicine, either systemically or topically [1][2][3] . Toxic effects of NF have been described, including convulsive seizures, testicular degeneration, and degenerative arthropathy in rodents 4,5 .…”

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confidence: 99%

Nitrofurazone at a High Dose Induces Hepatocyte and Adrenal Necrosis in Rats

Ito¹,

Takeuchi²,

Nii³

et al. 2004

J Toxicol Pathol

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Nitrofurazone (NF), a well-known testicular toxicant, was given to rats at 500 mg/kg to characterize its effects on the liver and adrenal gland. Marked degenerative or necrotic changes were seen in the adrenal gland, and, to a lesser extent, in the liver. The adrenal gland displayed coagulative necrosis involving the cortex, especially the zonae fasciculata and reticularis, which was apparent as early as at 1.5 h postdose and had spread to the whole area by 3 h. Hepatic changes became clear at 3 h, but the degree and the extent of the lesion were far less than in the adrenal gland. The lesions consisted of foci of hepatocyte degeneration and necrosis, which were exacerbated by diethyl maleate (DEM), a hepatic glutathione-depleting agent. The results suggest that NF induces changes possibly by a mechanism which involves free radical production. (J Toxicol Pathol 2004; 17: 59-61)

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Chemotherapeutic properties of prominent nitrofurans

Cited by 81 publications

References 0 publications

Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia

Efficacy of a single dose of furazolidone for treatment of cholera in children

Nitrofurazone at a High Dose Induces Hepatocyte and Adrenal Necrosis in Rats

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