Renal reduced nicotinamide adenine dinucleotide phosphate:cytochrome c reductase-mediated metabolism of the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide.
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N-[4-(5-Nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) metabolism was examined in vitro using microsomes prepared from rat liver and renal cortex and from rabbit liver and renal cortex and outer and inner medulla. NFTA nitroreduction was observed with each tissue. Three mol of NADPH were used per mol of NFTA reduced. Substrate and inhibitor specificity suggested that the microsomal nitroreduction was due to NADPH:cytochrome c reductase. Metabolite(s) formed bound to protein, RNA, DNA, and synthetic polyribonucleotides. Maximum covalent binding was seen with polyguanylic acid. A guanosine-NFTA adduct was isolated. Binding was inhibited by sulfhydryl compounds and vitamin E. The [14C]NFTA:glutathione or [3H]glutathione:NFTA conjugates obtained from microsomal incubations showed identical chromatographic properties as the product obtained by the reaction of synthetic N-hydroxy-NFTA with [3H]glutathione. Structures of synthetic N-hydroxy-NFTA and the microsomal reduction product 1-[4-(2-acetylaminothiazolyl)]-3-cyano-1-propanone were established by mass spectrometry. The latter reduction product did not bind macromolecules. These results suggest that renal NADPH:cytochrome c reductase reduces NFTA to an N-hydroxy-NFTA intermediate that binds nucleophilic sites on macromolecules. (+info)
Evaluation of chemotherapy with benznidazole and nifurtimox in mice infected with Trypanosoma cruzi strains of different types.
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A test was made of the susceptibility of 30 strains of Trypanosoma cruzi to chemotherapy with nifurtimox (Bay 2502) and benznidazole (Ro 7-1051). The strains had previously been classified as type I, II, or III according to their morphobiological and isoenzymic characteristics. Three type I strains, 14 type II strains, and 13 type III strains were studied. Mice were infected with 2 x 10(5) blood forms of these parasites and treated for 90 days with benznidazole or nifurtimox. All the surviving mice were submitted to parasitological tests (direct parasitaemia, xenodiagnosis, inoculation in new-born mice, and haemoculture) and serological tests (indirect immunofluorescence). As the latter remained positive in about 80% of the parasitologically negative animals, the cure rates were based on the more reliable parasitological tests. Type I strains displayed high susceptibility, type II strains showed medium to high susceptibility, and type III strains were highly resistant to both drugs. The fact that a particular strain type, with its own level of susceptibility, usually predominates in a given geographical area may explain the contradictory results after chemotherapy from different endemic areas. (+info)
Cell-mediated immunity in Chagas' disease: Alterations induced by treatment with a trypanocidal drug (nifurtimox).
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Peripheral leucocyte migration inhibition (LMI) with Trypanosoma cruzi-specific antigens, measured as a migration index (MI), was studied in chronic Chagas' disease patients. The MI of untreated patients with polymerized antigens from culture forms (epimastigotes) of T. cruzi was significantly lower than that of controls. In contrast, when chronic Chagas' patients were treated with nifurtimox, 10 mg/kg/day for 2 months, the MI was not different from control values. Treated and untreated patients had normal T- and B-lymphocyte markers, measured by the ability to form rosettes either with sheep erythrocytes (E-RFC) or with sheep erythrocytes--antibody--complement (EAC-RFC). In addition, the number of lymphocytes bearing surface membrane Ig (SMIg) was the same as that of controls. Non-specific functional assays, such as PHA-induced blastogenesis and antibody-dependent cell-mediated cytotoxicity (ADCC) to sensitized chicken erythrocytes were also normal, both in treated and untreated patients. Thus, nifurtimox produced a particularly effect on cell-mediated immunity, specially detectable using LMI. (+info)
Nifurtimox-induced alterations in the cell-mediated immune response to PPD tin guinea-pigs.
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Positive skin reactions to PPD in guinea-pigs immunized with Freund's complete adjuvant (FCA) were reversed after treatment with 10 mg/kg/day nifurtimox for 12 days. The in vitro migration of peripheral blood leucocytes from FCA-immunized guinea-pigs was inhibited with PPD, but it returned to normal values after nifurtimox treatment. Furthermore, the cell-free supernatant from PPD-stimulated lymphocytes from FCA-immunized nifurtimox-treated guinea-pigs did not inhibit the migration of normal cells. Thus the administration of nifurtimox impaired the specific cell-mediated immune response to PPD both in vivo and in vitro. (+info)
Small-cell formation of Staphylococcus aureus by subinhibitory concentrations of nitrofuran derivatives.
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Small-cell formation of Staphylococcus aureus by subinhibitory concentration of nitrofuran derivatives was examined by scanning and transparent electron microscopy. (+info)
Cell division and prophage induction in Escherichia coli: effects of pantoyl lactone and various furan derivatives.
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Strain T-44 is a thermosensitive mutant of Escherichia coli in which both cell division and prophage repression are altered at elevated temperatures. The effects of various ribosides, pantoyl lactone, and the furfural derivatives nitrofurazone and 5-methyl furfural suggest that some low-molecular-weight compound is important in the control of cell division and prophage repression in this strain. This low-molecular-weight compound may have a five-membered oxygen-containing ring as part of its structure. (+info)
Inhibition of DNA synthesis by nitroheterocycles. I. Correlation with half-wave reduction potential.
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Twenty-one nitroheterocycles, including metronidazole, misonidazole and AF-2, were tested for their ability to inhibit DNA synthesis in mouse L-929 cells growing in culture. All those tested inhibited the rate of incorporation of 3H-thymidine into L cells following drug treatment for 4 h under aerobic conditions. Only 4 drugs reached their limits of solubility before the uptake of 3H-thymidine was inhibited by 50% or more. For the remaining 17, the log of the concentration producing 50% inhibition of incorporation was directly correlated with the half-wave reduction potential of the compound. (+info)
Escherichia coli with resistance factors in vegetarians, babies, and nonvegetarians.
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The prevalence of Escherichia coli carrying resistance factors (R factors) was examined in meat-consuming individuals and in those not consuming meat (vegetarians and babies below the age of 6 months). Assuming that the transport of resistant E. coli from animals through meat and meat products to the human consumer is most important, with regard to the incidence of resistant E. coli in man, we expected a significant difference in the proportions of people with resistant E. coli between the two groups. However, the percentage with resistant E. coli was larger in the group of vegetarians and babies than in the group of meat-eating individuals. (+info)