The study of acute toxicity is a mandatory stage in the investigation of new drugs, which allows assessing the health of substances for health in the short-term and determining the class of toxicity and breadth of therapeutic action. Therefore, at the first stage of the study, the acute toxicity of Bendamin Cardiomatography was studied, in particular the determination of maximum tolerant, toxic and intermittent lethal doses for laboratory animals. The acute toxicity of Bendamin was determined in two stages: indicative and expanded experiments. In the indicative trial, the drug was administered intragastrically at doses of 50, 500 and 5000 mg/kg body weight. Three white mice and rats were used for each dose. In an expanded experiment, Bendamin was administered intragastrically at doses of 5000 and 10000 mg/kg body weight. In determining the acute toxicity of Bendamin, the DL50 value could not be determined, indicating a low toxicity of the test substance. Thus, the DL50 drug for intragastric administration to white mice is greater than 5000 mg/kg m. The general condition of animals in the studied groups did not differ from the state of intact animals: coordination of movements and skeletal muscle tone, pain response, tactile and acoustic stimuli were adequate, the frequency of breathing and the rhythm of heart rate were within the normal range. At administration of the preparation in a dose of 5000 mg/kg m. T, an insignificant inhibition was established, which is related to the introduction of a large amount of the drug. In determining the coefficients of the mass of the internal organs of laboratory animals, a slight decrease in the weight coefficient of the liver was found in both mice and in rats. The "Bendamin" drug when administered to white mice and rats in the stomach in the maximum amount does not cause symptoms of poisoning and behavioral abnormalities. According to GOST 12.1.007-76, Bendamin, for intragastric administration, according to the degree of hazard belongs to grade 4 toxicity -low toxicity substances (DL50 more than 10000 mg/kg body weight). In the future, it is planned to investigate the chronic toxicity and cumulative properties of the drug in laboratory animals.

The aim of this study was to investigate the effect of Bendamin on the antioxidant status of rats in experimental doxorubicin-induced cardiomyopathy. The studies were performed on white sexually mature young male of Vistar line rats weighing 180–200 g, which were kept on a standard diet of the Institute Vivarium of the State Research Institute of Veterinary Drugs and Feed Additives. Animals were divided into 3 groups of 6 animals in each: control group – intact animals; experimental group R1, in which animals were simulated with doxorubicin-induced cardiomyopathy by intraperitoneal administration of doxorubicin at a dose of 2.5 mg/kg 3 times a week for two weeks; experimental group R2, in which animals were injected with the drug “Bendamin” at a dose of 20 mg/kg after injection of doxorubicin. The data obtained indicate that the introduction into the experimental animals of the experimental group of doxorubicin is accompanied by intensification in the myocardium of the processes of free radical oxidation. The increase in diene conjugates was found to be 32.7% and TBK-active products increased by 37.6% compared to the control group of rats. Doxorubicin was also found to cause inhibition of the glutathione system of the animal's antioxidant protection after administration to rats. After administration of the drug “Bendamin”, rats of the second experimental group were suppressed with lipid peroxidation under the conditions of doxorubicin intoxication. In the rats of the second experimental group, the level of intermediates and end products is likely to decrease, so in the rat myocardial homogenate the level of diene conjugates decreased by 16.8% and the level of TBA-active products by 20.8% compared to the first experimental group. who had clinical signs of cardiomyopathy caused by doxorubicin administration. The use of the drug “Bendamin” in rats of the second experimental group contributed to the enhancement of the enzymatic and non-enzymatic element of the antioxidant system, protecting the structural and functional integrity of cell bioembranes. The results of the studies enrich the pharmacological characteristics of the drug “Bendamin”, indicate its sufficiently clear protective effect on the myocardium in experimental doxorubicin cardiomyopathy and is a convincing proof of the feasibility of the drug in veterinary practice.

Repeated introduction into the body of an animal of a medicinal substance can lead to its accumulation in the tissues of the body. Therefore, knowledge of the cumulative properties of substances or conditions that may lead to cumulations, are especially important for understanding the pathogenesis of intoxication, because this phenomenon often lies at the basis of acute and chronic poisoning. The purpose of the work was to study the degree of cumulation of the “Bendamin” preparation in the body of white rats. The properties of the cumulative drug were studied in 12 white rats weighing 150–160 g. Rats were divided into 2 groups: control and experimental. To determine the cumulative properties of Bendamin, it was administered to laboratory animals starting at a dose of 0.1 DL50, with a sequential increase in the dose of 1.5 times every 4 days. It was found that the cumulative coefficient of Bendamin was 8.31 units, indicating that the drug does not exhibit cumulative effects. In determining the mass coefficients of the internal organs in the animals of the experimental group, the tendency to increase the weight and liver mass coefficients was determined, respectively, by 5.2 and 5.1%. The weight ratio of the heart of the animals of the experimental group increased by 5.7% relative to the control group. After studying the morphological parameters of blood of rats at 24 days of the experiment for studying the cumulative properties of the “Bendamin” drug, an increase in the number of erythrocytes to 6.13 ± 0.27 T/L, white blood cells to 8.42 ± 0.54 G/L and hemoglobin up to 132.4 ± 2.44 g/l. In the analysis of leukocyte profile in rats, there was a decrease in the number of eosinophils and monocytes, respectively, at 1.1 and 1.3% relative to the control group. The number of lymphocytes in the blood of the experimental group of rats increased by 1.5%, while neutrophils by 0.9% compared to the control. When studying the level of total protein, its small increase was determined by 5.2%. The activity of aminotransferases in the blood serum of experimental rats on the 24th day of the experiment for the study of cumulative properties of the drug also increased by 13 and 8% relative to the control group. Also, creatinine and total bilirubin levels in their rat blood were decreased by 3.1 and 8.8%, respectively.

The study aimed to establish the parameters of chronic toxicity of the newly developed drug based on phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate in experiments on laboratory animals. The analysis was performed on white sexually mature young male Wistar rats weighing 170–185 g. Four groups of white rats were formed. The first experimental group was administered Bendamine based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate at a therapeutic dose. Rats of the second experimental group were injected with the experimental drug in a 5-fold dose. Rats of the third experimental group were administered the drug in a 10-fold dose. The fourth group served as control. The study of chronic toxicity of Bendamine in white rats indicates that long-term 30-day administration in therapeutic doses or 5-fold dose does not cause clinical signs of poisoning, as evidenced by the physiological limits of fluctuations in the studied morphological and biochemical parameters of blood rats. Prolonged administration of Bendamine to rats in a 10-fold dose is accompanied by a slight suppression of the body's physiological state, as indicated by a decrease in total erythrocytes and hemoglobin by 10.1 % against an increase in white blood cells by 59.8% (P < 0.001). In addition, there was a decrease in the functional state of the liver, as evidenced by a probable reduction in total protein by 8.0% and urea – by 13.5 %, as well as an increase in ALT, AST, and alkaline phosphatase by 31.6 %, 7.4 %, and 53.9% respectively. Probable changes in the coefficients of liver and spleen mass have been established. When administered intramuscularly to rats with the drug Bendamine for 30 days, the macroscopic and microscopic structure of the studied internal organs is preserved in all groups of animals. The second experimental group revealed reversible moderate histostructural changes in the liver and kidneys. In rats treated with ten times the therapeutic dose of the drug, histologically found hemodynamic disorders and alterations in dystrophic nature, mainly of protein origin, with focal localization in the parenchyma of the liver, kidneys, and myocardium, which in most cases are reversible and result from the compensatory response. Macroorganism on the introduction of a high dose of the study drug.

The study aimed to investigate the effect of the drug “Bendamine” on dogs' clinical and morphological parameters in heart failure. Two groups of dogs were formed for research: control (healthy) and experimental (sick). The 30-day experiment included ten dogs from the control group, ten dogs of the observed (unhealthy) spaniel breed, and 10–12 years old dogs. The treatment regimen for sick dogs: furosemide was administered orally on an empty stomach at 2 mg/kg every 12 hours; enalapril was administered orally at 0.5 mg/kg every 12 hours; Bendamine was administered orally on an empty stomach at 20 mg/kg every 24 hours. It is recommended to divide the dose into two doses. In the study of hematopoiesis, we found that erythrocytes in dogs with heart failure increased by 18.2 %, while hemoglobin levels decreased by 1.8 %. Before treatment, red blood cell counts were found to reduce the mean hemoglobin in the erythrocyte and the mean erythrocyte volume. In the experimental group of dogs treated with the “Bendamine”, normalization of morphological blood parameters was found. The number of erythrocytes was 5.8 ± 0.06 T/L, and the hemoglobin level was 143.5 ± 4.7 g/L. The use of the drug “Bendamine” contributed to the gradual restoration of the functional state of the hematopoietic system in dogs with heart failure. This is also indicated by the red blood cell index of the dogs after the course of treatment. The therapy application in the experimental group significantly reduced the frequency and severity of shortness of breath and increased endurance during exercise. There was also a decrease in the frequency and duration of cough attacks. After treatment, signs, and intensity of ascites decreased in dogs of the experimental group. It has been suggested that this is due to an increase in myocardial contractile function due to the positive ionotropic action of Bendamine. The owners also recorded an improvement in appetite in animals after 30 days of therapy. Even in the dogs of the experimental group, after treatment, physical activity and emotional reactions improved. They were less depressed and more inclined to communicate with the owners. Thus, the use of the cardiac drug “Bendamine” in dogs with heart failure positively affected the restoration of hematopoiesis and the normalization of morphological parameters of the blood.