RESUMEN
One amebicide (chloroquine diphosphate) and 2 anthelmintic compounds (niclosamide and pyrvinium pamoate) were found to be mutagenic for Salmonella typhimurium TA1537, TA1538, TA100 and TA98 Uvr- strains respectively. Drugs tested on homologous Uvr+ strains (TA1977, TA1978, UTH8414 and UTH8413) showed decreased mutagenic activity of the compounds. This indicates that premutational damage induced by the drugs was totally or partially repaired. Furthermore, results obtained in the present study suggest that niclosamide and pyrvinium pamoate induce premutational lesions by adduct formation, and that chloroquine diphosphate, known as an intercalating agent, behaves as an adduct-forming compound as regards its effects on Uvr- and Uvr+ S. typhimurium strains.
Asunto(s)
Amebicidas/toxicidad , Antihelmínticos/toxicidad , Reparación del ADN , Genes Bacterianos , Mutágenos , Cloroquina/análogos & derivados , Cloroquina/toxicidad , Reparación del ADN/efectos de los fármacos , Genes Bacterianos/efectos de los fármacos , Niclosamida/toxicidad , Compuestos de Pirvinio/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
The genetic activity of several medical grades of the anthelmintic drug pyrvinium pamoate, which is a dipyrvinium salt, was studied in a diploid mitotic recombination and gene conversion assay (strain D5 of Saccharomyces cerevisiae), and in several haploid yeast reversion assays (strains XV185-14C, XY718-1A, and 7854-1A). All of the samples were recombinogenic in strain D5 and mutagenic in the haploid strains, however, the degree of genetic activity varied considerably among the medical grades of pyrvinium pamoate that were tested. Similarly, these samples varied in degree of mutagenicity when they were tested in strains TA97, TA98, TA100, and TA102 of Salmonella typhimurium, but some of the medical grades of pyrvinium pamoate were mutagenic both in the presence and in the absence of the metabolic transformation system, whereas other medical grades of the drug required such activation to be mutagenic. In addition, the medical grades and dosage forms of several brands of pyrvinium pamoate were examined for purity by fluorescence high pressure liquid chromatography (HPLC) using a methanol:water (90:10) solvent system. The HPLC data indicate that monopyrvinium salts are the major contaminants in these pharmaceuticals. In general, there is a correlation between the degree of genetic activity and toxicity, and the number and relative quantity of impurities found in each sample.
Asunto(s)
Antihelmínticos/toxicidad , Mutágenos , Compuestos de Pirvinio/toxicidad , Saccharomyces cerevisiae/genética , Salmonella typhimurium/genética , Animales , Antihelmínticos/análisis , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos , Técnicas In Vitro , Pruebas de Mutagenicidad , Compuestos de Pirvinio/análisis , Ratas , Saccharomyces cerevisiae/efectos de los fármacos , Salmonella typhimurium/efectos de los fármacos , ComprimidosRESUMEN
Several anthelmintic drugs that are used routinely in oxyuriasis therapy were analyzed for genotoxicity in a diploid mitotic recombination and gene conversion assay (strain D5 of Saccharomyces cerevisiae), and in a haploid yeast reversion assay (strain XV185-14C). Piperazine citrate, piperazine adipate, mebendazole and thiabendazole did not appear to be genotoxic in either yeast strain. Pyrvinium pamoate induced the reversion of the missense, nonsense and frameshift alleles in strain XV185-14C, whereas pyrantel pamoate induced only the reversion of the frameshift allele. Pyrvinium pamoate was recombinogenic in strain D5, and there is an indication that pyrantel pamoate, at the lowest dose that was tested, might induce gene conversion or aneuploidy.
Asunto(s)
Antihelmínticos/toxicidad , Compuestos de Pirvinio/toxicidad , Ciclo Celular , Conversión Génica/efectos de los fármacos , Mebendazol/toxicidad , Mitosis/efectos de los fármacos , Pruebas de Mutagenicidad , Piperazina , Piperazinas/toxicidad , Pamoato de Pirantel/toxicidad , Recombinación Genética/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacos , Tiabendazol/toxicidad , Factores de TiempoRESUMEN
Pyrvinium pamoate, a widely used anthelmintic drug, has been previously tested for genotoxicity with equivocal results. Assays with bacterial or yeast test strains yielded positive results while in vitro tests with mammalian cells yielded negative results. In this study, the genotoxicity of pyrvinium was studied in vivo in the mouse colon, the therapeutic site of action of this agent. 1,2-Dimethylhydrazine (DMH), a colon carcinogen, was tested simultaneously as a positive control. The colonic nuclear aberration assay was used to determine genotoxicity. Pyrvinium delivered orally in three vehicles was not genotoxic in the murine colon, even at doses up to 12.5 times the recommended human dosage.
Asunto(s)
Antihelmínticos/toxicidad , Colon/efectos de los fármacos , Mutágenos , Compuestos de Pirvinio/toxicidad , 1,2-Dimetilhidrazina , Animales , Núcleo Celular/efectos de los fármacos , Dimetilhidrazinas/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Pruebas de MutagenicidadRESUMEN
A single preparation of U.S.P. pyrvinium pamoate that exhibited promutagen activity in Salmonella/mammalian microsome reverse mutation assays was subjected to in vitro mammalian cell bioassays. Cytotoxicity limiting doses of dimethyl sulfoxide-solubilized drug were without effect in the absence and/or presence of liver S9 fraction from Aroclor-1254-induced rats in an in vitro Chinese hamster ovary (CHO) cell assay for chromosome aberration and sister-chromatid exchange induction at concentrations of 0.025-0.78 microgram/ml. Forward gene mutation at the hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) locus in Chinese hamster (V-79) cells was studied with and without exogenous metabolic activation at concentrations ranging from 0.3 to 10 micrograms/ml. In concurrent promutagen controls, dimethylnitrosamine, benzo[a]pyrene, and cyclophosphamide caused significant (p less than 0.05) increases over controls in each respective assay endpoint under the metabolic activations used. These results suggest that intrinsic mutagenic activity manifested in lower microbial systems does not have a corresponding effect in mammalian cells. Coupled with the lack of solubility and poor absorption in vivo, we concluded that the drug, when used In the single oral dose mode of administration, possesses a negligible somatic and germinal genotoxicity risk.