Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems
Introduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxi...
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| Format: | Article |
| Language: | Russian |
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Central Research Institute for Epidemiology
2021-11-01
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| Series: | Журнал микробиологии, эпидемиологии и иммунобиологии |
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| Online Access: | https://microbiol.elpub.ru/jour/article/view/1112 |
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| author | E. A. Jain D. Pleimes A. A. Globenko |
| author_facet | E. A. Jain D. Pleimes A. A. Globenko |
| author_sort | E. A. Jain |
| collection | DOAJ |
| description | Introduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxic properties in in vitro and in vivo models, as well as to study the toxicity of IPA following chronic oral administration to rats and dogs.Materials and methods. Mutagenic and genotoxic properties of IPA were assessed using the Ames test, the test of chromosomal aberrations in human lymphocytes, and the micronucleus test in rats. The chronic toxicity of IPA was studied in Sprague Dawley rats and beagle dogs of both sexes, to which IPA was administered orally at doses of 30-300 mg/kg/day for 26 and 39 weeks, respectively.Results and discussion. In the Ames test, the addition of IPA up to the maximum dose (5000 mcg/plate) did not result in the increase in the number of revertant colonies. At a concentration of up to 5000 mcg/ml, IPA did not cause chromosomal aberrations in human leukocytes. At doses doses ≤ 2000 mg/kg, IPA did not increase the amount of micronuclei in the bone marrow of rats. In chronic experiments, animals tolerated the administration of IPA well: the dose without an observed effect (NOEL) for rats and dogs was 300 mg/kg/day.Conclusion. IPA did not show mutagenic and genotoxic properties in standard in vitro and in vivo tests. With chronic oral administration to rats and dogs, NOEL IPA equal to 300 mg/kg/day provided a systemic exposure that was 8-10 and 41-65 times higher than that in humans, respectively. The results obtained allow us to consider the safety profile of the prolonged use in humans as favorable. |
| first_indexed | 2024-04-13T02:42:33Z |
| format | Article |
| id | doaj.art-d386a2531a044f70afc8c008b33bacdd |
| institution | Directory Open Access Journal |
| issn | 0372-9311 2686-7613 |
| language | Russian |
| last_indexed | 2024-04-13T02:42:33Z |
| publishDate | 2021-11-01 |
| publisher | Central Research Institute for Epidemiology |
| record_format | Article |
| series | Журнал микробиологии, эпидемиологии и иммунобиологии |
| spelling | doaj.art-d386a2531a044f70afc8c008b33bacdd2022-12-22T03:06:10ZrusCentral Research Institute for EpidemiologyЖурнал микробиологии, эпидемиологии и иммунобиологии0372-93112686-76132021-11-0198554855710.36233/0372-9311-180769Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systemsE. A. Jain0D. Pleimes1A. A. Globenko2JSC Valenta Pharm Pharmaceutical CompanyMyelo Therapeutics GmbHJSC Valenta Pharm Pharmaceutical CompanyIntroduction. The antiviral properties of imidazolyl ethanamide pentandioic acid (IPA), the active compound of the drug product, has been proven in various experimental models. However, the literature data on the toxicological properties of IPA are limited.Purpose. To evaluate mutagenic and genotoxic properties in in vitro and in vivo models, as well as to study the toxicity of IPA following chronic oral administration to rats and dogs.Materials and methods. Mutagenic and genotoxic properties of IPA were assessed using the Ames test, the test of chromosomal aberrations in human lymphocytes, and the micronucleus test in rats. The chronic toxicity of IPA was studied in Sprague Dawley rats and beagle dogs of both sexes, to which IPA was administered orally at doses of 30-300 mg/kg/day for 26 and 39 weeks, respectively.Results and discussion. In the Ames test, the addition of IPA up to the maximum dose (5000 mcg/plate) did not result in the increase in the number of revertant colonies. At a concentration of up to 5000 mcg/ml, IPA did not cause chromosomal aberrations in human leukocytes. At doses doses ≤ 2000 mg/kg, IPA did not increase the amount of micronuclei in the bone marrow of rats. In chronic experiments, animals tolerated the administration of IPA well: the dose without an observed effect (NOEL) for rats and dogs was 300 mg/kg/day.Conclusion. IPA did not show mutagenic and genotoxic properties in standard in vitro and in vivo tests. With chronic oral administration to rats and dogs, NOEL IPA equal to 300 mg/kg/day provided a systemic exposure that was 8-10 and 41-65 times higher than that in humans, respectively. The results obtained allow us to consider the safety profile of the prolonged use in humans as favorable.https://microbiol.elpub.ru/jour/article/view/1112ames testchromosomal aberrationsmicronucleus testimidazolyl ethanamide pentandioic acidingavirin |
| spellingShingle | E. A. Jain D. Pleimes A. A. Globenko Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems Журнал микробиологии, эпидемиологии и иммунобиологии ames test chromosomal aberrations micronucleus test imidazolyl ethanamide pentandioic acid ingavirin |
| title | Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems |
| title_full | Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems |
| title_fullStr | Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems |
| title_full_unstemmed | Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems |
| title_short | Evaluation of mutagenicity, genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in <i>in vitro</i> and <i>in vivo</i> test systems |
| title_sort | evaluation of mutagenicity genotoxicity and chronic toxicity of antiviral drug imidazolyl ethanamide pentandioic acid in i in vitro i and i in vivo i test systems |
| topic | ames test chromosomal aberrations micronucleus test imidazolyl ethanamide pentandioic acid ingavirin |
| url | https://microbiol.elpub.ru/jour/article/view/1112 |
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