Equitoxicity of domestic hydroxycarbamide and reference drug hydrea in rats

Коняева, О. И.; Кульбачевская, Н. Ю.; Чалей, В. А.; Ермакова, Н. П.; Меркулова, И. Б.; Abramova, Tatiana; Касаткина, И. С.

doi:10.17650/1726-9784-2019-18-1-80-86

Cited by 2 publications

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“…Порівняно недавно удосконаленням відомих методів синтезу для впровадження вітчизняного аналогу оригінального протипухлинного препарату гідреа (ГД) -гідроксикарбамід (HC) проведені у країнах Східної Європи: Білорусії (Andreeva et al, 2001) та Росії (Konyaeva et al, 2019). Метою дослідження було вивчення хронічної токсичності препарату ГК (ТОВ "Озон", Росія) і зареєстрованого препарату порівняння Гідреа (Corden Pharma Latina S. p. A., Італія) на щурах.…”

Section: вступunclassified

The mechanism of action and modified synthesis of hydroxyurea

et al. 2020

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Searching of new drugs with antimitotic characteristics which can be used for decreasing of cancer cells dividing is the important issue of nowadays. One of such substances there is a hydroxyurea (HU) that is known as mitotical poison, because of characteristic to block a cellular cycle and as the specific inhibitor of DNA synthesis. It blocks the transition of cells from G1 – in S-phase. HU is a cytostatic agent with antineoplastic activity and presents great clinical efficiency in the treatment of sickle cell disease. HU and its derivatives exhibit versatile biological activities. HU is currently used in the treatment of various neoplastic and non-neoplastic diseases such as cancer, sickle cell anemia and HIV.Currently anticancer drugs are available that significantly reduce the mortality rates for some cancers (e.g. leukemia and testicular and ovarian cancer), and give longer overall patient survival times. In order to drug belongs to the pharmacotherapeutic group – antineoplastic agents and widely used for myelogenous leukemia, essential thrombocythemia treatment, our research was concerning the literature review on the ways and mechanisms of action of HU in living organisms. The ways and mechanisms of HU action in living organisms, research of antiviral and antimicrobial action of HU, the mechanism of HU influence at the cellular level and in antitumor and anticancer therapy have been studied. Under studying of radioprotector properties of hydroxyurea was established, that its efficiency is estimated by the values FCD (Factor of change of dose) within the limits of 1.2–1.4 – (to the peas 1.4 and corn – 1.3). A factor of change of dose is a relation of effective dose at the irradiation of organism with a radioprotector to the effective dose that predetermines the same radio-biology effect in control without a radioprotector. It was established that compounds with sulfurhydryl bonding possess the most radioprotective properties. It is considered that they have strong reduction properties and can be used as spin trapping of free radicals, shutting them out before binding with macromoleculas occurs, in particular to DNA. In order to obtain a sufficient amount of the drug hydroxyurea for analytical and pharmacological research, a modified method of it synthesis has been developed and proposed. The optimized synthesis conditions include conducting the experiment at lower temperatures -15 °C (wise -10 °C lit.), neutralization of the reaction mixture with concentrated 50 % sulfuric acid (wise dilute sulfuric acid, lit.); providing concentrated solution by reducing the total amount of water in the reaction 300 ml (wise 500 ml); evaporation and the filtration at room temperature by air flow (wise evaporation in vacuum at 40 °C, lit.); replacement of the solvent for extraction with butanol ( wise alcohol, lit.). Such conditions provided complete dissolution of urethane after 1 h and allow to receive the hydroxyurea pure enough, without further recrystallization. The target product was obtained with a higher yield (up to 91 %) and achieved simplicity and one-step method. The less toxic and cost-effective starting reagents were also used to reduce the cost of the synthesis process.

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Section: вступunclassified

The mechanism of action and modified synthesis of hydroxyurea

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“…На 3-и сутки после окончания применения ГК и ГД в суммарной дозе 3000 мг / кг у большинства животных, в отличие от контрольной группы, наблюдали уменьшение величины тимуса и селезенки, что согласуется с некоторым уменьшением массы этих органов [16]. А после применения ГК и ГД в суммарной дозе 1500 отмечали лишь уменьшение величины тимуса у отдельных крыс.…”

Section: результаты и обсуждениеunclassified

“…Н. Н. Блохина в сравнении с препаратом гидреа (ГД) фирмы «Кор-ден Фарма Латина С. п. A.» (Италия). На основании результатов токсикологического исследования установлено, что ГК и ГД по показателям субхронической токсичности вполне идентичны [16]. Патоморфологическое исследование при изучении субхронической токсичности ГК является конечным этапом доклинического токсикологического исследования и проводится в соответствии с требованиями по доклиническому изучению новых противоопухолевых, а также воспроизведенных препаратов [17][18][19].…”

Section: Introduction In Accordance With Russian Federal Program Ofunclassified

Comparative pathomorphological research of hydroxycarbamide and hydrea

Меркулова

Abramova

Коняева

et al. 2019

Rossijskij bioterapevtičeskij žurnal

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Introduction . In accordance with Russian Federal Program of import substitution of foreign medicines replacement for high-quality Russian drugs in Russia reproduced нydroxycarbamide (HC), which passed preclinical toxicological and pathomorphological testing in comparison with hydrea (HD), producted by Italy.The aim . The aim of present study was the comparative evaluation of HC and HD effect on the internal organs of rats for the clearing up of their identity according to the morphological criterions. Materials and methods. 70 non-inbred male rats, by 10 rats per group, were used. HC and HD were administered to rats oral daily for 5 days in the same total doses correspond with to the 2, 1 and 1 / 2 maximum tolerated dose. In the same regime control rats were oral administered with 1 % starch paste solution. Of animals were removed from the experience on days 3 and 30 after the end of the administration of the drugs. The macroscopic and histological examination of internal organs were perform by routine methods, including fixation of the material in 10 % formalin and staining of sections with hematoxylin and eosin. The histological preparations of the internal organs was analyzed in the light microscope at magnifications of 100, 400, 1000. Results . HС, as well as HD, in total doses of 3000 and 1500 mg / kg at the 3 day after the end of the introduction caused different degrees of similar morphological changes in rat internal organs: moderate hypoplasia in the thymus, bone marrow and spleen, destructive and inflammatory changes in the stomach, duodenum and kidney. At the 30 day after the application of both drugs morphological changes in the thymus, the bone marrow and the spleen disappeared completely, residual morphological changes persisted in the duodenum and kidneys; in the testes of rats – moderate atrophic changes. HС, as well as HD in total dose 750 mg / kg did not cause changes in the internal organs of the rats. Conclusion . Based on the results of macroscopic and histological examination the conclusion about of the identity of the influence of HC and HD on the internal organs of rats was made.

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Equitoxicity of domestic hydroxycarbamide and reference drug hydrea in rats

Cited by 2 publications

References 1 publication

The mechanism of action and modified synthesis of hydroxyurea

The mechanism of action and modified synthesis of hydroxyurea

Comparative pathomorphological research of hydroxycarbamide and hydrea

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