Use of the DNA-repair host-mediated assay for determining the organ distribution of genotoxic factors in mice treated orally with nitro-aromatic compounds.

The distribution of genotoxic factors in various organs of mice treated orally with nitro-aromatic compounds of actual or potential use as chemotherapeutic (antiprotozoal and anthelminthical) agents was investigated in the DNA-repair host-mediated assay, with mice as host animals and a pair of E. coli K12 strains differing in DNA-repair capacity as indicators of genotoxicity. The test substances were derivatives of nitroimidazole (metronidazole), nitrofuran (SQ 18 506) and nitrodiphenylamine (amoscanate). Animal-mediated assays were performed by injecting mixtures of the two E. coli strains both intravenously and orally into mice, which were subsequently treated with the test chemicals, and from which the differential survival of indicator bacteria present in liver, lungs, spleen, kidneys, stomach, small intestine, colon and the blood stream was determined on selective agar medium. The same strains and selection procedures were used for assessing the genotoxic activity of the compounds in vitro. All three compounds displayed genotoxic activity in vitro, the order of potency on the basis of exposure concentration being SQ 18 506 greater than metronidazole greater than amoscanate. In the animal-mediated assays the same ranking order of genotoxic activity was observed, but the exposure levels required to produce significant genotoxic effects in vivo were (substantially) higher than in the in vitro tests: SQ 18 506 was active at 0.1 mg/kg body weight, metronidazole at 4 mg/kg, and amoscanate at dosages higher than 10 mg/kg. In host-mediated assays the highest genotoxic activity for all three chemicals was observed in organs of the gastro-intestinal tract (usually in the stomach). All three chemicals also induced genotoxic effects in organs remote from the gastro-intestinal tract although with substantially lower activity, the order of potency being again SQ 18 506 greater than metronidazole greater than amoscanate. In the case of SQ 18 506 and metronidazole, dose-dependent genotoxic activities were observed in liver, spleen, lungs, kidneys and the blood stream, with no clear indication of a preferential target or non-target organ, while the minor genotoxic effects of amoscanate were restricted to bacteria present in the blood stream. This can be taken as an indication that the substances (or active metabolites thereof) have been transported from the intestinal tract into the blood stream and distributed evenly in organ tissues, without an indication of organ specific deactivation during the time periods (less than 180 min) presently investigated.(ABSTRACT TRUNCATED AT 400 WORDS)

Genetic analysis of ad-3 mutants induced by AF-2 and two other nitrofurans in Neurospora crassa.

Our previous studies have shown that the nitrofurans AF-2, SQ18506, and FANFT are potent mutagens in Neurospora crassa. The genetic damage produced by these chemicals at the ad-3 region in N crassa has been characterized by a series of genetic tests. The results of these tests indicate that all three agents induce a high frequency of point mutations and probably a low frequency of multilocus deletions. A comparison of the complementation patterns among the AF-2--induced ad-3B mutants and those induced by other chemical agents indicates that the spectra of intragenic alterations induced by AF-2 in N crassa are similar to those induced by monofunctional alkylating agents.

In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.

Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.

Genetic activity of niridazole in yeast.

Niridazole, one of several drugs presently known to be of value in the treatment of human schistosomiasis, was tested for its activity in inducing mitotic recombination in yeast. It was found that niridazole is genetically active when the treatment of yeast cells is performed in a rich medium (YPG-medium) under growing conditions, but not when treatment is carried out in a non-nutrient suspension (phosphate buffer). The data suggest that niridazole might be converted to an active compound by yeast metabolism. The results of the experiments with niridazole in the non-nutrient medium were compared with those of AF-2 and SQ18, 506, two agents which have been shown to be genetically active in the present assay system.

New antimicrobial nitrofuran, trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-delta2-1,2,4-oxadiazole: antibacterial, antifungal, and antiprotozoal activities in vitro.

trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-Delta(2) -1,2,4-oxadiazole, a new antimicrobial nitrofuran, has shown microbial activity in vitro against a wide range of bacteria and fungi, and against several protozoa. The antimicrobial activity of the nitrofuran is not significantly diminished in vitro in the presence of 50% human serum. The compound is not cross-resistant with a number of common antibiotics or synthetic antimicrobial agents; some cross-resistance with furazolidone is encountered. The development of resistance to the compound in vitro, when it occurs, is mixed, but is unrelated to increase in pathogenicity of the test organism.