Screening the mutagenic activities of coomonly used antiparasite drugs by the Simultest, a simplified Salmonella/microsome plate incorporation assay

Mélo, Maria Eliane Bezerra de; Ferreira, Luís Carlos S.

doi:10.1590/s0036-46651990000400006

Cited by 17 publications

(10 citation statements)

References 14 publications

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“…Several free radical species similar to those produced by NFX were thought to be involved [4, 14]. It is mutagenic for Salmonella typhimurium [19, 20, 22, 33–36] as well as the urine and blood of treated animals [25]. Its clastogenic ability is controversial since both positive [27, 28, 37–43] and negative [44] findings are reported.…”

Section: Introductionmentioning

confidence: 99%

Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

Buschini

Ferrarini

Franzoni

et al. 2009

Journal of Parasitology Research

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Nitroheterocyclic compounds are widely used as therapeutic agents against a variety of protozoan and bacterial infections. However, the literature on these compounds, suspected of being carcinogens, is widely controversial. In this study, cytotoxic and genotoxic potential of three drugs, Nifurtimox (NFX), Benznidazole (BNZ), and Metronidazole (MTZ) was re-evaluated by different assays. Only NFX reduces survival rate in actively proliferating cells. The compounds are more active for base-pair substitution than frameshift induction in Salmonella; NFX and BNZ are more mutagenic than MTZ; they are widely dependent from nitroreduction whereas microsomal fraction S9 weakly affects the mutagenic potential. Comet assay detects BNZ- and NFX-induced DNA damage at doses in the range of therapeutically treated patient plasma concentration; BNZ seems to mainly act through ROS generation whereas a dose-dependent mechanism of DNA damaging is suggested for NFX. The lack of effects on mammalian cells for MTZ is confirmed also in MN assay whereas MN induction is observed for NFX and BNZ. The effects of MTZ, that shows comparatively low reduction potential, seem to be strictly dependent on anaerobic/hypoxic conditions. Both NFX and BNZ may not only lead to cellular damage of the infective agent but also interact with the DNA of mammalian cells.

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Section: Introductionmentioning

confidence: 99%

Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

Buschini

Ferrarini

Franzoni

et al. 2009

Journal of Parasitology Research

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“…possible human carcinogen, as it has shown mutagenic activity in vitro including positive Ames test, although studies in vivo have failed to demonstrate a potential for genotoxicity 3,4 . This active substance has been used for the treatment of bacterial infections for above 45 years, but still metronidazole is successfully used for the treatment of vaginosis, trichomoniasis, amoebiasis, and giardiasis, and still it is the criterion standard for therapy of anaerobic bacterial infections 5 , although during last decades many new derivatives of metronidazole were investigated with antibacterial, antifungal and also H. pylori urease inhibitory activity.…”

Section: Fig 1 Metronidazolementioning

confidence: 99%

Metronidazole citrate ester as the new prodrug of metronidazole

Dąbrowska-Maś¹,

Raś²

2017

10.5267/j.ccl

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Many attempts have been made since 1960 th to obtain ester prodrugs of metronidazole active moiety to be used for parenteral forms, with the same action against microorganisms. Until now there is not any ester prodrug marketed for this route of administration. The synthesis from metronidazole and citric acid of new ester prodrug of metronidazole with citric acid in a form of disodium salt and the way of purification were described. The structure of sodium metronidazole citrate was elucidated with IR, MS, 1 H NMR and 13 C NMR spectra. Also impurities present in this ester were identified using 1 H NMR technique. Additionally, the solubility in water was measured as well as pH of 10% (w/w) aqueous solution, and both values indicated that there is a possibility to obtain concentrated solutions for injection of neutral pH, even without need of buffering. Finally, the Ames assay using six tester strains S. typhimurium TA98, TA100, TA1535, TA1537 and E. coli uvrA, [pKM101] shown weak genotoxic potential, comparable with metronidazole.

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“…Esto indica que el ensayo masivo en epimastigotes es una buena prueba de tamización con miras a encontrar compuestos activos en otros estadios del parásito.Todos los extractos y fracciones activos contra T. cruzi podrían ser candidatos para continuar los estudios, ya que la gran citotoxicidad podría deberse a sustancias diferentes a las que están actuando sobre los parásitos o a un efecto sinérgico entre las sustancias presentes en el extracto crudo, y podría disminuir con la separación en fracciones o con el aislamiento de moléculas (29). También, sería importante determinar la genotocixidad de los extractos activos como una aproximación a la identificación de las causas de los efectos colaterales, como ocurre con el benznidazol, cuyo potencial genotóxico se ha demostrado (30,31).…”

Section: Muy Activosunclassified

Actividad tripanocida y citotóxica de extractos de plantas colombianas

et al. 2011

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Introducción. El tratamiento de la enfermedad de Chagas está basado en sólo dos medicamentos de eficacia limitada y con importantes efectos colaterales. La gran biodiversidad de la flora colombiana hace de la bioprospección una alternativa potencial en la búsqueda de nuevos antiparasitarios. Objetivo. Evaluar in vitro el potencial tripanocida y la citotoxicidad de extractos obtenidos de 23 plantas colombianas. Materiales y métodos. Se obtuvieron extractos de hojas, de tallos o de la planta entera, en solventes de diferente polaridad. La actividad contra epimastigotes y la citotoxicidad se evaluaron por el micrométodo enzimático con MTT. Los extractos activos contra epimastigotes y con baja citotoxicidad se evaluaron también en tripomastigotes y amastigotes intracelulares. Resultados. Se reporta la actividad tripanocida de 13 plantas colombianas y se confirma el efecto biológico de cuatro especies previamente evaluadas. Cuatro extractos activos en epimastigotes también fueron activos en tripomastigotes y, uno de ellos, en amastigotes. Este extracto fue aislado de la planta Hieronyma antioquensis, y presentó CI 50 de 3,125, 11,48 y 2,85 μg/ml, e índices de selectividad de 25, 7 y 27, para epimastigotes, tripomastigotes y amastigotes, respectivamente. Los resultados sugieren que este extracto es un candidato promisorio para el tratamiento de la enfermedad de Chagas. Conclusión. La flora colombiana es una fuente potencial de nuevas sustancias para la quimioterapia contra la enfermedad de Chagas. El micrométodo enzimático con MTT es una herramienta útil para la tamización de la actividad biológica en epimastigotes y posterior selección para ensayos con otros estadios del parásito. Palabras clave: Trypanosoma cruzi, enfermedad de Chagas, extractos vegetales. Trypanocidal and cytotoxic activity of extracts of Colombian plantsIntroduction. The treatment of Chagas disease is based on only two drugs with limited efficacy and significant side effects. The rich biodiversity of the Colombian flora makes bio-prospecting a potential alternative in the search for new antiparasitic drugs. Objective. Potential trypanocidal activity and cytotoxicity was assessed in extracts from 23 Colombian plants. Materials and methods. Extracts of leaves, stems, or of the whole plants were obtained in solvents of a range of polarities. The activity against Trypanosoma cruzi epimastigotes and the cytotoxicity were evaluated by the MTT enzymatic micro-method. Extracts active against epimastigotes and with low cytotoxicity were also tested on trypomastigotes and intracellular amastigotes. Results. Among the extracts, biological activity was confirmed in 4 species. The extracts were active on epimastigotes and trypomastigotes; one was active also against amastigotes. The latter extract was isolated from the plant Hieronyma antioquensis and presented IC 50 of 3.1 mg/ml for epimastigotes, 11.5 mg/ml for trypomastigotes and 2.9 mg/ml for amastigotes. The selectivity indexes were 25, 7, and 27 respectively.

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Screening the mutagenic activities of coomonly used antiparasite drugs by the Simultest, a simplified Salmonella/microsome plate incorporation assay

Cited by 17 publications

References 14 publications

Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

Metronidazole citrate ester as the new prodrug of metronidazole

Actividad tripanocida y citotóxica de extractos de plantas colombianas

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