Preclinical study of the safety aspects of the substance of a new benzimidazole derivative with an antithrombotic effect during the course administration of the substance to rats

Introduction. Currently existing antiplatelet agents exhibit a wide range of side effects that limit their use.
It is urgent to search for and create an effective agent for the correction of increased thrombogenic potential and having a wide profile of drug safety. This article presents the results of a toxicological study of a new benzimidazole derivative of the compound RU-891, which exhibits pronounced antiplatelet properties.
Material and methods. Groups of control and experimental animals – nonlinear rats of both sexes – were formed to conduct research. The introduction of the tested PS (pharmaceutical substance) on a solution of distilled water in a volume of 4 ml/kg was carried out intragastrically, daily for 6 months. The studied PS RU-891 was administered to rats in doses: 23 mg/kg – 1st experimental group; 460 mg/kg – 2nd experimental group. The control group of animals was intragastrically injected with distilled water at a dose of 4 ml/kg. During the experiment, weekly measurements of body weight were carried out, body weight was expressed in g, an increase in %. Behavioral activity was studied in the classic “open field” test at the end of the 1st, 6th and 7th months of the chronic experiment. The study of the state of the cardiovascular system was carried out by electrocardiography recorded in anesthetized animals. The assessment of the excretory function of the liver and the excretory function of the kidneys was carried out using stress tests with the dyes “bromosulfalein” and “phenolic red”. The effect of PS RU-891 on the hematological parameters of the peripheral blood of rats was assessed according to the following indicators: the total number of erythrocytes, platelets, hemoglobin levels, hematocrit, and the number of leukocytes. The classic Mas-Magro test was used to assess the effect on blood clotting. During morphological examination, a macro- and microscopic assessment of the state of organs was performed and the coefficients of organ masses were determined. Histological microscopic studies were performed on a LUMAN I2 microscope using an eyepiece 7 and a lens 40.
To carry out statistical processing of the results, the Microsoft Excel and Statistica 6.0 application software package was used.
Results. Preclinical studies were conducted in experiments on sexually mature autobred rats, males and females, to assess the toxicological properties of a new benzimidazole derivative, the compound RU-891, with 6-month intragastric administration at doses of 23 mg/kg (experimentally proven therapeutic dose) and 460 mg/kg (exceeding TD by 20 times). It was found that under the action of the substance RU-891 at a dose of 23 mg/kg, the general condition of the animals, body weight gain, hematological, biochemical, electrocardiographic parameters, as well as the functional state of the detoxification and excretion organs corresponded to the values of the control group. In studies on animals treated with the substance RU-891 at a dose of 460 mg/kg (20 TD), a gradual deterioration in the general condition was noted (an increase in body weight, most pronounced in male rats), activation of behavioral activity in females, but its suppression in males, changes dependent on the sex of animals in peripheral blood (increased erythrocyte levels and blood clotting time in male rats and no effect on these parameters in females), decreased excretory liver function, but activation of excretory kidney function, pathomorphological negative changes in the liver. In studies conducted one month after discontinuation of the administration of the compound RU-891 at a dose of 460 mg/kg, integral indicators (body weight gain, general condition, behavioral activity) in animals, as well as changes recorded from hematological, functional and structural pathomorphological disorders in the liver were practically leveled to control values, which probably may indicate the absence of pathological toxic effects of the studied substance RU-891 when administered orally to rats at a dose of 460 for 6 months. At the same time, taking into account the results of morphological and functional studies, it can be assumed that the RU-891 compound at a dose of 460 mg/kg has an effect on the liver as a “target organ”. However, this damaging effect of the studied compound on the detoxification function of the liver was reversible, since it was practically leveled to a state of control within a month after the cancellation of its administration to animals.
Limitation. Sexually mature nonlinear rats of both sexes were used in the study, the number of individuals
in the control and experimental groups was sufficient to obtain statistically significant results.
Conclusion. PS RU-891 at a dose of 23 mg/kg with 6-month administration to rats is non-toxic and safe, since it does not cause irreversible changes in general condition, behavior, hematological parameters, biochemical parameters of blood and urine, and functional activity of the heart. With daily administration of PS RU-891 at a dose of 460 mg/kg, pathological effects on the liver and kidneys were revealed, which persisted during the withdrawal period.

toxic properties, 6-month repeated administration to rats, preclinical study, benzimidazole derivative, antithrombotic activity, RU-891, course introduction