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Genetic toxicity in vitro

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in in-vivo and in-vitro studies with chlordiazepoxide, there are indications for a mutagenic effect. Nevertheless, in similar test systems results are negative. The relevance of the positive findings is currently unclear.

[EMC LIBRIUM CAPSULES 5MG, Last Updated on eMC 10-Jul-2015.]

The mutagenic effect of chlordiazepoxide hydrochloride was evaluated in the bone-marrow cells of Swiss mice by the micronucleus test. The results showed that the drug chlordiazepoxide induced a significant increase of micronuclei in the polychromatic erythrocytes.

[Susheela M, Rao MS.Genotoxicity of chlordiazepoxide hydrochloride on the bone-marrow cells of Swiss mice.Toxicol Lett. 1983 Aug;18(1-2):45-8.]

Chlordiazepoxide reacts in acidic conditions with sodium nitrite yielding N-nitrosochlordiazepoxide, previously shown to exert genotoxic effects in some in vitro systems. The possible intragastric nitrosation of chlordiazepoxide to N-nitrosochlordiazepoxide has been investigated in rats given by gavage high single doses of this benzodiazepine along with sodium nitrite. Liver DNA fragmentation, as revealed by both DNA alkaline elution and a more sensitive viscometric method, was found to occur consistently and to be essentially independent of the molar ration drug/nitrite or of gastric pH. The significant increase in the frequency of DNA lesions observed in rats treated for 15 successive days indicates that DNA repair did not keep pace with the accumulation of the damage. Oral administration of single doses of N-nitrosochlordiazepoxide induced similar dose-dependent amounts of DNA fragmentation in liver, gastric mucosa, and brain. Due to the demonstrated absence of carcinogenic activity in rodents, the present results should be interpreted solely as indicating that N-nitrosochlordiazepoxide is intrinsically capable of producing DNA lesions in vivo, an effect by itself not sufficient to induce tumor growth.

[(7) Robbiano L et al; Toxicol Appl Pharmacol 102 (1): 186-90 (1990)]

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