Introduction . The appearance of high-quality and effective generics can significantly reduce the cost of health care for the drug supply of the population of Russia. According to expert estimates, the cost of treatment of cancer patients with generics of domestic can be 30– 40 % cheaper as compared to the original drugs. In Russia the pharmaceutical production company “Ozon” created by the domestic analogue of the original anticancer drug hydrea – hydroxycarbamide.Objective: comparative study of chronic toxicity of the drug hydroxycarbamide (“Ozon”, Russia) and registered reference drug hydrea (Corden Pharma Latina S. p. A., Italy) on rats.Materials and methods . A comparative study of the toxicity of drugs was carried out on 70 non-inbred white male rats weighing 220– 250 g obtained from the accredited laboratory animal nursery of LLC “Krolinfo”. Both drugs were administered in parallel daily orally 5-fold in 3 doses. As a solvent, 1 % starch paste was used. Doses were calculated according to the literature data on the basis of maximum tolerated dose. Standard methods of evaluation of chronic toxicity of drugs in rats were used.Results . The obtained data on chronic toxicity of the compared forms of the domestic drug hydroxycarbamide and the reference drug hydrea do not differ significantly in terms of quantitative and qualitative toxicity (lethality, biomarkers of toxicity, morphometry of organs). Conclusion . The compared generic and commercial preparations are practically equitoxic by 5 times oral administration to rats.

In accordance with Russian Federal program of import substitution of foreign medicines quality of Russian drugs in the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, played vincristine-RONC (VC-RONC), which as a drug – the generic’s passed preclinical pharmacological and toxicological testing in comparison with foreign firms vincristine Teva of Israel (VC-Teva). The aim. The aim of present study was the comparative pathomorphological evaluation of the effect of VC-RONC and VC-Teva on the internal organs of rats. Materials and methods. Used 50 weinbrenner male rats, at 10 rats per group. VC-RONC and VC-Teva rats were administered intravenously 3 times daily at aquatoxicity total dose corresponding to the MTD and 1/2 MTD. Control rats in the same regime intravenously administered of 0,9 % sodium chloride solution. Rats were deduced from the experience of 3 and 30 days after the end of administration of the drugs. Conducted macroscopic and histological examination of internal organs by conventional methods, including fixation of the material in 10 % formalin and coloring sections with hematoxylin and eosin. The micropreparations of the internal organs was analyzed under light microscope at magnifications of 100, 400, 1000. Results. VC-RONC, as VC-Teva in cumulative doses of 0,5 and 0,25 mg/kg in 3 days after the end of introductions in the internal organs of rats cause similar slightly pronounced morphological changes: hypoplasia in the bone marrow and spleen, destructive changes in the testes, focal degenerative changes in the kidney and liver of individual rats. On the 30th day after the application of both drugs, some rats regardless of the dose occurred similar symptoms residual morphological changes in the bone marrow, testes, kidneys and liver. Conclusion. Based on the results of macroscopic and histological examination the conclusion about the similarity of the influence of VC-RONC and VC-Teva on the internal organs of rats was made.

Результаты. В результате изучения острой токсичности на мышах и крысах-самках и самцах-при введении ЦФ в максимально возможной концентрации и максимально возможных объемах препарат не вызывал гибели животных, не оказывал влияния на общее состояние животных, не вызывал внешних проявлений токсичности, не изменял поведенческие реакции животных. При изучении хронической токсичности ЦФ на крысах и собаках при ежедневном пероральном применении в течение 15 дней во всех исследованных дозах также не наблюдалось гибели животных, препарат не вызывал каких-либо внешних проявлений токсичности. Лимитирующий вид токсичности не установлен, так как препарат вызывает незначительные морфофункциональные изменения различной степени обратимости практически во всех органах и системах организма крыс и собак. На основании полученных на экспериментальных животных данных о функциональных и морфологических изменениях в органах и тканях показано, что самки более чувствительны к препарату, чем самцы. Заключение. С учетом функциональных и морфологических изменений во внутренних органах как крыс, так и собак изученные дозы ЦФ охарактеризованы как дозы, вызывающие слабые незначительные изменения-низкие токсические дозы. На основании анализа данных определена начальная (стартовая) безопасная доза для человека на I фазу клинических испытаний, которая проводится в настоящее время.

The paper presents the results of the study of «acute» toxicity and some results of the study of «subchronic» toxicity of Ormustin, a new anticancer drug belonging to nitrosourea class, in small laboratory animals. In the experiments the laboratory animals - hybrid mice (C57Bl/6J×DBA/2)F1 male and female and outbred male and female rats have been used. On the results of study has been obtained the calculated toxic doses of Ormustin at intravenous administration of the drug in mice and rats; has been given the preliminary assessment of the impact of Ormustin on organs and systems of rats at multiple intravenous administration.

Thus, the PBF as a prolong drug needs to correct its parameters for further drug formulation development.