Antibacterial activities of the antiparasitic drugs nifurtimox and benznidazole.
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Both nifurtimox and benznidazole, which are used for the treatment of Chagas' disease, also display marked antibacterial activities. Characteristically for nitroheterocyclic compounds, they are much more active against anaerobic and microaerophilic bacteria than against aerobic bacteria. Nitroreductase-deficient aerobes are completely resistant, whereas SOS-repair-deficient strains are moderately susceptible. Those strains are rapidly killed. (+info)
The nitroimidazoles as radiosensitizers and cytotoxic agents.
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Using hamster cells in culture, the radiosensitizing and cytotoxic properties of 8 electron-affinic drugs have been compared. These include nitrofurans derivatives as well as 2 and 5-nitroimidazoles. Most work has been performed with misonidazole for which it appears that, at 37 degree C, the concentration of drug required to produce a given level of cell killing is inversely proportional to the square of the exposure time. Misonidazole was also compared with X-rays for its ability to produce neoplastic transformations in vitro, using the C3H 10T 1/2 cell line. (+info)
Some examples of anomalous radiosensitizing behaviour of electron-affinic compounds in vitro.
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Studies using V79 379A cells on about 50 nitroaromatic and nitroheterocyclic radisosensitizers have confirmed the relationship between sensitizing efficiency and electron affinity. Almost all the compounds studied behaved similarly by sensitizing hypoxic cells to X-irradiation in a dose-modifying manner whilst having no sensitizing effect on oxygenated cells. However, a small number of the radiosensitizers studied exhibited additional or atypical properties. A 4-nitroimidazole ring substituted with chlorine sensitized hypoxic cells much more efficiently than predicted from its redox potential. A 2-nitroimidazole substituted with a carboxylic acid side chain showed a low but constant level of sensitization over 5 decades of concentration. A 5-nitrofuran, in addition to sensitizing hypoxic cells by dose modification, sensitized oxygenated cells by a reduction in extrapolation number. (+info)
Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs.
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Catecholamine neurotransmitters such as norepinephrine, dopamine, and related catecholamine derivatives reduce nitroheterocyclic drugs such as nitrofurantoin, nifurtimox, nifuroxime, nitrofurazone, misonidazole, and metronidazole in slightly alkaline solutions. Drugs which contain 5-nitrofurans are reduced at lower pH than drugs which contain 2- and 5-nitroimidazoles. 5-Nitroimidazole derivatives such as metronidazole and ronidazole are known to be more difficult to reduce than 2-nitroimidazole derivatives, due to their lower redox potential. Catecholamines, when reducing nitro drugs, undergo concomitant oxidation to form semiquinone radicals. Both semiquinone radicals and nitro anion radicals formed in a reaction of nitro drug and catecholamine derivative were detected by electron spin resonance spectroscopy. Oxygen consumption studies in solutions containing nitro drug and catecholamine derivative showed that nitro anion radicals formed under aerobic conditions reduce oxygen to form the superoxide radical and hydrogen peroxide. Quinones formed in the reaction of catecholamine and nitro drug were detected by optical spectroscopy. Biosynthetic precursors and some metabolic products of catecholamines were also used in these studies, and they all exhibited reactions similar to catecholamines. Bovine chromaffin granules which synthesize and store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin. These radicals formed inside the granules were observed by ESR spectroscopy. The formation of nitrofurantoin radical, semiquinone radicals of catecholamines, and oxygen-derived radicals by chromaffin granules is proposed to cause damage to adrenal medulla, and this process may lead to neurotoxicity. (+info)
Differences in resistance to reinfection with low and high inocula of Trypanosoma cruzi in chagasic mice treated with nifurtimox and relation to immune response.
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Reinfection of chronic chagasic mice after treatment with nifurtimox resulted in different outcomes according to the number of parasites used for inoculation. Nifurtimox-treated chagasic animals injected with 2,500 trypomastigotes developed higher parasitemia and increased mortality compared with nontreated chagasic mice. When reinfection was done with 25 trypomastigotes, treated and nontreated animals showed similar parasitemias and mortalities, which were significantly higher in nonchagasic controls infected for the first time. Immunological studies showed that treatment with nifurtimox led to a decrease in anti-Trypanosoma cruzi antibodies engaged in parasite destruction, inducing either complement-dependent lysis or antibody-dependent cytotoxicity, but no difference in anti-T. cruzi cell-mediated immunity was found between treated and nontreated chagasic animals. It is concluded that treatment with nifurtimox leads to a loss of resistance to reinfection with a large number of trypanosomes, which is maintained with challenge with a few parasites, and that these two thresholds of premunition are probably associated with humoral and cell-mediated anti-T. cruzi immune responses, respectively. (+info)