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PubMed1992

Potentiation of alkylating chemotherapy by dual function nitrofurans in multi-cell spheroids and solid tumors.

The cytotoxicity and chemosensitizing potential of four dual function nitrofurans was determined in human HT-29 multi-cell spheroids and rodent KHT sarcoma solid tumors. Spheroids were treated with a range of doses of the bioreductive drugs for a period of up to 48 h and the extent of cell kill was assessed at various times after treatment. Cytotoxicity was determined using a clonogenic cell-survival assay. The results demonstrated that two of the nitrofurans were even more toxic to spheroid cells than was the potent bioreductive nitroimidazole aziridine RSU 1069. The dose of the nitrofuran which, after a 24-h exposure, led to a survival value between 0.5 and 1.0, then was chosen for subsequent studies aimed at assessing the ability of these agents to potentiate the efficacy of the nitrosourea CCNU. Exposure to this chemotherapeutic agent was for a period of 1 h. The results indicated that all four dual function nitrofurans enhanced the cell killing of the conventional chemotherapeutic agent by factors ranging from 1.1 to 1.7. Subsequent studies evaluated the therapeutic benefit of combining these bioreductive agents and CCNU in KHT sarcoma-bearing C3H/HeJ mice. The nitrofurans were administered i.p. 0.5 h prior to the chemotherapy and tumor response was assessed by measuring the survival of clonogenic KHT cells 22-24 h after treatment. Normal tissue toxicity was determined using a bone marrow stem cell (CFU-GM) assay. Combining these bioreductive agents with CCNU increased the tumor cell kill by factors of 1.2 to 1.7.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase.

Lipoamide dehydrogenase (LipDH), trypanothione reductase (TR), and glutathione reductase (GR) catalyze the NAD(P)H-dependent reduction of disulfide substrates. TR occurs exclusively in trypanosomatids which lack a GR. Besides their physiological reactions, the flavoenzymes catalyze the single-electron reduction of nitrofurans with the concomitant generation of superoxide anions. Here, we report on the interaction of clinically used antimicrobial nitrofurans with LipDH and TR from Trypanosoma cruzi, the causative agent of Chagas' disease (South American trypanosomiasis), in comparison to mammalian LipDH and GR. The compounds were studied as inhibitors and as subversive substrates of the enzymes. None of the nitrofurans inhibited LipDH, although they did interfere with the disulfide reduction of TR and GR. When the compounds were studied as substrates, T. cruzi LipDH showed a high rate of nitrofuran reduction and was even more efficient than its mammalian counterpart. Several derivatives were also effective subversive substrates of TR, but the respective reaction with human GR was negligible. Nifuroxazide, nifuroxime, and nifurprazine proved to be the most promising derivatives since they were redox-cycled by both T. cruzi LipDH and TR and had pronounced antiparasitic effects in cultures of T. cruzi and Trypanosoma brucei. The results suggest that those nitrofuran derivatives which interact with both parasite flavoenzymes should be revisited as trypanocidal drugs.

Animals↗
PubMed2003

Preparation of stable isotope-labeled 2-nitrobenzaldehyde derivatives of four metabolites of nitrofuran antibiotics and their comprehensive characterization by UV, MS, and NMR techniques.

A convenient method is presented for the preparation of the carbon-13-labeled 2-nitrobenzaldehyde derivatives of the nitrofuran metabolites 3-amino-2-oxazolidinone (AOZ), semicarbazide (SC), 1-aminohydantoin (AH), and 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), with the purpose of using them as internal standards for the quantification of trace levels of nitrofuran residues by liquid chromatography-tandem mass spectrometry in foods of animal origin. The synthesis encompasses the nitration of [1,2,3,4,5,6-(13)C(6)]toluene prior to chromyl compound-mediated oxidation of the methyl group into the corresponding aldehyde. The four metabolites of nitrofuran antibiotics were derivatized independently with the resulting ring-labeled 2-nitrobenzaldehyde (NBA) to obtain the target compounds. Both the isotopically enriched and native substances were used to perform a comprehensive fragmentation study by electrospray ionization (ESI) collision-induced dissociation (CID) mass spectrometry (MS). Full characterization of the nitrofuran derivatives was accomplished with ultraviolet (UV) and exhaustive nuclear magnetic resonance (NMR) analysis. A major advantage of the described procedure is that it can be extended to the preparation of other carbon-13-labeled derivatives of metabolites of nitrofuran antibiotics.

Anti-Bacterial Agents↗
PubMed2003

Evaluation of treatment and prophylaxis with nitrofurans and comparison with alternative antimicrobial agents in experimental Salmonella enterica Serovar enteritidis infection in chicks.

The ability of the nitrofuran antimicrobial agents furazolidone and furaltadone to prevent, reduce or eliminate Salmonella enterica serovar enteritidis PT4 infection in artificially challenged day-old chicks was evaluated. Treating the birds with the nitrofurans failed to eliminate established infections with either furazolidone-resistant (FzR) or furazolidone-sensitive (FzS) strains. Simultaneous administration of the nitrofurans to day-old chicks challenged with FzS failed to prevent infection but reduced colonization significantly (p<0.05) compared to unmedicated controls. No reduction of colonization occurred with FzR. Challenging birds with FzS and simultaneous dosing with nitrofurans for 1 week, followed by a second week of continued treatment, resulted in an increase in the level of colonization in the second week rather than a decrease. Dosing with the nitrofurans (200 ppm) for 1 week prior to challenge with FzS and continued medication for a further week prevented colonization of the caecum, liver and spleen. However, cessation of dosing at the time of challenge with salmonella resulted in colonization. Chloramphenicol and tetracycline at concentrations of 200 ppm were both independently capable of preventing colonization by salmonella. Sulphadiazine initially reduced colonization but failed to eliminate the infection. Only when furazolidone was combined with chloramphenicol or when sulphadiazine was combined with trimethoprim, and the combined drugs were administered concurrently with the challenge, was colonization prevented.

Animals↗
PubMed2005

Depletion of four nitrofuran antibiotics and their tissue-bound metabolites in porcine tissues and determination using LC-MS/MS and HPLC-UV.

Depletion of the nitrofuran antibiotics furazolidone, furaltadone, nitrofurantoin and nitrofurazone and their tissue-bound metabolites AOZ, AMOZ, AHD and SEM from pig muscle, liver and kidney tissues is described. Groups of pigs were given feed medicated with one of the nitrofuran drugs at a therapeutic concentration (400?mg?kg(-1)) for ten days. Animals were slaughtered at intervals and tissue samples collected for analysis for six weeks following withdrawal of medicated feed. These samples were analysed both for parent nitrofurans (using LC-MS/MS and HPLC-UV), and for tissue-bound metabolites (using LC-MS/MS). The parent drugs were detectable only sporadically and only in pigs subjected to no withdrawal period whatsoever. This confirms the instability of the four major nitrofuran antibiotics in edible tissues. In contrast, the metabolites accumulated to high concentrations in tissues (ppm levels) and had depletion half lives of between 5.5 and 15.5 days. The metabolites of all four drugs were still readily detectable in tissues six weeks after cessation of treatment. This emphasizes the benefits of monitoring for the stable metabolites of the nitrofurans.

Animals↗
PubMed2005

Comparative genotoxic evaluation of 2-furylethylenes and 5-nitrofurans by using the comet assay in TK6 cells.

The genotoxicity of three 2-furylethylene derivatives and four 5-nitrofurans was evaluated by using the comet assay in human lymphoblastoid cultured TK6 cells. The 2-furylethylene derivatives were 2-furyl-1-nitroethene, 1-(5-bromofur-2-yl)-2-nitroethene and 1-(5-bromofur-2-yl)-2-bromo-2-nitroethene, while the 5-nitrofurans were nitrofurantoin, nitrofurazone, furazolidone and 5-nitro-2-furanacrolein. The treatments lasted for 3 h in the absence of metabolic activation. No genotoxic effects were observed for two of the 2-furylethylene compounds, while the derivative 1-(5-bromofur-2-yl)-2-nitroethene showed a statistically significant response mainly at the highest concentration tested; this effect was considered biologically relevant and the compound was classified as slightly genotoxic. On the other hand, for the classical 5-nitrofurans tested there is a tendency towards a dose-related increase of the DNA damage in the comet assay and the observed increases for the parameters analysed (Olive tail moment, tail % DNA and tail length) were significant for all compounds. Then, the four 5-nitrofurans tested were considered genotoxic. These results show that the position of the nitro group influences the genotoxicity of the assayed compounds. Thus, in this comet assay, the 2-furylethylene derivatives having the nitro group attached outside the furan ring appear to be much less genotoxic than the 5-nitrofurans.

Cell Line, Tumor↗
PubMed1984

[Combined action of nitrofuran preparations and bile acids on staphylococci].

The effect of cholic, glycocholic and deoxycholic bile acids on the antimicrobial activity of furacin, furadonin, furagin and furoxone was studied with the use of collection strains and fresh isolates of staphylococci. The method of dilutions in liquid media was used. Cholic and glycocholic acids lowered the MIC of furacin, furadonin, furoxone and furagin with respect to the collection strains by 4-16, 5, 4-6 and 22-37 times, respectively. The potentiating effect of deoxycholic acid on the nitrofuran drugs was even more pronounced. Thus, when the nitrofurans were used in combination with deoxycholic acid, their MIC dropped by 16-114 times. A significant increase in the antimicrobial activity of the nitrofurans under the effect of the bile acids was also observed with respect to the fresh isolates of Staphylococcus, while it was somewhat lower. The subbacteriostatic doses of cholic, glycocholic and deoxycholic bile acids also increased the bactericidal effect of the nitrofuran drugs. The minimum bactericidal concentrations (MBC) of furacin, furoxone, furadonin and furagin decreased from 12.5, 2.08, 25.0 and 1.82 to 0.78, 0.26, 2.34 and 0.032 micrograms/ml, respectively. The most pronounced decrease in the MBC was observed under the effect of deoxycholic acid. Therefore, the bile acids potentiated the nitrofuran antistaphylococcal activity. The combinations of deoxycholic acid with furagin or furoxone were the most effective.

Bile Acids and Salts↗
PubMed1980

Mutagenicity of nitrofuran drugs in bacterial systems.

The mutagenic activity of 5 nitrofuran drugs (furadantin, furoxon, furacin, benzazon VII and lampit) was tested on strains Salmonella typhimurium TA 100, TA 1535, TA 1438 and Escherichia coli WP2 uvrA+ and WP2 wrA. All nitrofurans tested has a marked mutagenic effect on strain TA 100 and, partially, on strain TA 1535 except for furoxon which was strongly toxic for this strain. No significant mutagenic effects of the drugs were observed with strain TA 1538. With the exception of lympit, all drugs exerted a mutagenic action on E coli WP2 vwA but no on WP2 uvA+ which has an intact excision repair system. The only drug exerting a mutagenic effect on the latter strain was furoxon. All five nitrofurans exhibited a positive repair test. The results support the notion that the nitrofuran mutagens under study induce single base substitutions.

Chemistry↗
PubMed2006

Advantages of LC-MS-MS compared to LC-MS for the determination of nitrofuran residues in honey.

In the framework of developing analyses for exogenous contaminants in food matrices such as honey, we have compared data obtained by high-performance liquid chromatography coupled with mass spectrometry (LC-MS) to those provided by high-performance liquid chromatography and tandem mass spectrometry (LC-MS-MS). Initial results obtained with LC-MS showed that the technique lacked selectivity, which is why the method was validated by LC-MS-MS. This method involves a solid-phase extraction (SPE) of nitrofuran metabolites and nitrofuran parent drugs, a derivatization by 2-nitrobenzaldehyde for 17 h, and finally a clean-up by SPE. The data obtained show that the limits of detection varied between 0.2 and 0.6 microg kg(-1) for the metabolites and between 1 and 2 microg kg(-1) for nitrofuran parent drugs. The method was applied to different flower honeys. The results showed that nitrofurans (used as antibiotics) are consistently present in this matrix, the predominant compound being furazolidone. Figure Working bees.

Chromatography, Liquid↗
PubMed1976

Mutagenic activity of carcinogenic and noncarcinogenic nitrofurans and of urine of rats fed these compounds.

The nitrofurans, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2), N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), nitrofurantoin, 5-nitro-2-furoic acid, 5-nitro-2-furamidoxime, 5-nitrofurfurylidene diacetate and the urine of rats fed these compounds, were assayed for mutagenic activity in Salmonella typhimurium strains TA100 and TA100FR1. All the nitrofurans were mutagenic in the order: AF-2 and FANFT greater than nitrofurantoin greater than 5-nitro-2-furamidoxime greater than 5-nitrofurfurylidene diacetate greater than 5-nitro-2-furoic acid. Strain TA100 was more sensitive than TA100FR1 to the mutagenic influence of these nitrofurans. Only the urine of rats fed AF-2, FANFT and nitrofurantoin had mutagenic activity. Again, TA100 was more sensitive than TA100FR1. The mutagenicity of the urine was not increased by treatment with beta-glucuronidase. AF-2, 2-amino-4-(5-nitro-2-furyl)thiazole (deformylated product of FANFT) and nitrofurantoin were excreted in the urine of rats fed these compounds; whereas the other nitrofurans were not excreted.

Animals↗
PubMed1979

Influence of subcellular fractions of mammalian testes on the mutagenic activity of nitrofurans toward Escherichia coli; presence of a co-mutagen-like factor.

The activation of nitrofurans to mutagenic intermediates by testicular tissue was investigated. AF-2 and nitrofurazone were tested in a microsomal suspension assay with strain E. coli K-12 343/113 as indicator and subcellular fractions from rabbit testes. Different mutation patterns were observed in the presence or absence of testicular homogenate, indicating the presence of different mutagenic intermediates. The frequency of arg+ reversion increased proportionally to the homogenate concentration suggesting that the nitrofurans were activated by testicular components to intermediates that induced base-pair substitutions. Other experiments showed that a component of low molecular weight, present in the soluble fraction of homogenates of testes from rabbits, rats and monkeys, was responsible for the increased mutation frequency. It is concluded that this "co-mutagen-like" factor either alters the metabolism of nitrofurans in E. coli and/or promotes the formation of base-pair substitution-type mutations. This direct interaction between a nonenzymic component of mammalian testes and the mutation induction/expression process in E. coli suggests the role of co-mutagen-like factors in the sensitivity of testes to nitrofurans.

Animals↗
PubMed1981

Mutagenic activities of simple nitrofuran derivatives. I. Comparison of related compounds in the phage inductest, chloroplast-bleaching and bacterial-repair and mutagenicity tests.

Several simple furan and nitrofuran compounds were tested for mutagenicity and related biological activities, in the Ames test, the bacterial repair test, the prophage-induction test and the chloroplast-bleaching test. Only those compounds having the nitro-group were found to be active in the test. If the nitro-group was in the beta instead of the alpha position, the mutagenic activity was much reduced (0.3 revertants per nanomole, the other simple nitrofurans producing 5-15 reversions per nanomole, as did 5-nitrofuran and 5,2-dinitrofuran). The vinyl-group-containing compound, 5-nitro-2-furylacrylic acid, was by one decadic order more effective both in the Ames test and in the prophage-induction test. In the repair tests all nitrofurans displayed a much higher dependence on the recA-repair system than on the uvrA system. For 2 compounds, the dinitrofuran and, especially, the 5-nitrofuraldehyde, the urA cells were even less sensitive than the wild-type cells.

Animals↗
PubMed1991

Interaction of nitrofurans with glutathione reductase.

Nitrofurans inhibit the oxidation of NADPH by glutathione, catalyzed by yeast glutathione reductase (EC 1.6.4.2). acting as uncompetitive incomplete inhibitors for NADPH and glutathione. The quinoline-substituted nitrofurans were the most effective inhibitors. These compounds increased the turnover numbers of enzyme at fixed concentrations of reduced glutathione, in the reverse reaction of glutathione reductase, but in most cases diminished the affinity of the enzyme for NAD+. Nitrofurans are weak one-electron oxidants of glutathione reductase. Their reactivity is close to that of p-quinones possessing the analoguous one-electron reduction potential (Cénas, N.K., Rakauskiené, G.A. and Kulys, J.J. (1989) Biochim. Biophys. Acta 973, 399-404), and reaction is stimulated by NADP+. It is assumed, that nitrofurans bind to the 'regulative' site of glutathione reductase (Karplus, P.A., Pai, E.F. and Schulz, G.E. (1989) Eur. J. Biochem. 178, 693-703).

Glutathione↗
PubMed2006

Aquatic photochemistry of nitrofuran antibiotics.

The aquatic photochemical degradation of a class of pharmaceuticals known as the nitrofuran antibiotics (furaltadone, furazolidone, and nitrofurantoin) was investigated. Direct photolysis is the dominant photodegradation pathway for these compounds with the formation of a photostationary state between the syn and the anti isomers occurring during the first minutes of photolysis. The direct photolysis rate constant and quantum yield were calculated for each of the three nitrofurans. Reaction rate constants with reactive oxygen species (ROS), 102 and *OH, were also measured, and half-lives were calculated using environmentally relevant ROS concentrations. Half-lives calculated for reaction with 1O2 and *OH are in the ranges of 120-1900 and 74-82 h, respectively. When compared to the direct photolysis half-lives, 0.080-0.44 h in mid-summer at 45 degrees N latitude, it is clear that indirect photochemical processes cannot compete with direct photolysis. The major photodegradation product of the nitrofurans was found to be nitrofuraldehyde, which is also photolabile. Upon photolysis, nitrofuraldehyde produces NO, which is easily oxidized to nitrous acid. The acid produced further catalyzes the photodegradation of the parent nitrofuran antibiotics, leading to autocatalytic behavior. Natural waters were found to buffer the acid formation.

Anti-Bacterial Agents↗
PubMed2006

Proficiency study for the determination of nitrofuran metabolites in shrimps.

A proficiency test for the determination of nitrofuran metabolites in shrimp tissue was organized in the first half of 2003. This test was intended to allow the participants to use their routine method and to assess their competence on this specific analysis. The participation in this proficiency test was offered to all the National Reference Laboratories (NRLs) of the European Union (EU) in charge of the analysis of nitrofurans, to Official Laboratories of the then 10 Candidate Countries for entry in EU and to some countries exporting food to the EU. The participants (20) analysed nitrofuran metabolites in eight randomly coded frozen samples including three blank samples. All participants performed a confirmatory method using liquid chromatography/mass spectrometry to detect total nitrofuran metabolite residues. Both qualitative and quantitative analyses of the results were investigated. Qualitatively, 16 laboratories out of 20 gave the correct interpretation of the results in term of compliant/non-compliant sample. Quantitatively, laboratory performance was evaluated by calculating the z-scores.

Animals↗
PubMed2002

Enzymes associated with reductive activation and action of nitazoxanide, nitrofurans, and metronidazole in Helicobacter pylori.

Nitazoxanide (NTZ) is a redox-active nitrothiazolyl-salicylamide prodrug that kills Helicobacter pylori and also many anaerobic bacterial, protozoan, and helminthic species. Here we describe development and use of a spectrophotometric assay, based on nitroreduction of NTZ at 412 nm, to identify H. pylori enzymes responsible for its activation and mode of action. Three enzymes that reduce NTZ were identified: two related NADPH nitroreductases, which also mediate susceptibility to metronidazole (MTZ) (RdxA and FrxA), and pyruvate oxidoreductase (POR). Recombinant His-tagged RdxA, FrxA, and POR, overexpressed in nitroreductase-deficient Escherichia coli, each rapidly reduced NTZ, whereas only FrxA and to a lesser extent POR reduced nitrofuran substrates (furazolidone, nitrofurantoin, and nitrofurazone). POR exhibited no MTZ reductase activity either in extracts of H. pylori or following overexpression in E. coli; RdxA exhibited no nitrofuran reductase activity, and FrxA exhibited no MTZ reductase activity. Analysis of mutation to rifampin resistance (Rif(r)) indicated that NTZ was not mutagenic and that nitrofurans were only weakly mutagenic. Alkaline gel DNA electrophoresis indicated that none of these prodrugs caused DNA breakage. In contrast, MTZ caused DNA damage and was strongly mutagenic. We conclude that POR, an essential enzyme, is responsible for most or all of the bactericidal effects of NTZ against H. pylori. While loss-of-function mutations in rdxA and frxA produce a Mtz(r) phenotype, they do not contribute much to the innate susceptibility of H. pylori to NTZ or nitrofurans.

Biotransformation↗
PubMed1980

Combined treatment with a nitrofuranic and a corticoid in experimental Chagas' disease in the dog.

In order to study the effect of combined treatment of Trypanosoma cruzi infection with a nitrofuranic drug and a corticoid, 27 dogs from three different litters infected with T. cruzi (12 SF strain) were randomly litter-paired in three experimental groups: animals infected and not treated; infected and treated with Bay 2502 (2-methyl-4-[5'nitrofurfurylideneamino]-tetrahydro-4H-1,4-thiazine-1,1-dioxine) (nifurtimox); infected and treated with nifurtimox plus betamethasone. While an enhanced myocarditis appeared in the animals treated with a nitrofuranic drug alone, inflammation was almost abolished when corticoid treatment was added. Both groups showed considerable intracellular parasite destruction. These changes were monitored by serial electrocardiograms and a final histopathologic study which included an investigation of the changes in the conducting tissue by serial sectioning. The survival period was prolonged in animals treated with the combination of the nitrofuranic drug and corticoid, and only in this group did some of the animals reach the chronic phase of the infection. Thus, the association of a nitrofuranic drug with a corticoid in the treatment of acute Chagas' disease produced parasite destruction and inhibited the inflammatory responses that are enhanced by such destruction

Animals↗
PubMed1975

A screening method for determining nitrofuran drug residues in animal tissues.

A method was developed for measuring low levels of total nitrofurans in animal tissues and milk. The antimicrobial nitrofurans (5 or more products) used in agriculture are extracted from tissue with aqueous acid in the presence of ethyl acetate. After centrifugation and evaporation, the organic residue is washed with hexane and the nitrofurans are hydrolyzed to 5-nitrofuraldehyde in aqueous acid at 70 degrees C. The hydrolysis product is extracted with benzene and measured by gas-liquid chromatography with electron capture detection. Recoveries of nitrofurazone and furazolidone from fortified poultry and swine tissues at the levels of 0.5 and 0.1 ppm are 75 and 65%, respectively. This procedure can be used to detect the total nitrofuran content of as little as 10 ppb muscle tissues and milk, 100 ppb liver, and 50 ppb fat with no interference from related veterinary nitrodrugs.

Adipose Tissue↗