Experimental assessment of the toxicity of a cardiac drug based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate


Keywords: rats, toxicology, pharmacology, ethylmethylhydroxypyridine succinate, a phosphodiesterase-3 inhibitor, Bendamine

Abstract

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.

Downloads

Download data is not yet available.

References

Borgarelli, M., & Buchanan, J. W. (2012). Historical re-view, epidemiology, and natural history of degenera-tive mitral valve disease. Journal of Veterinary Cardi-ology, 14(1), 93–101. DOI: 10.1016/j.jvc.2012.01.011.

Borgarelli, M., Tarducci, A., Zanatta, R., & Haggstrom, J. (2007). Decreased systolic function and inadequate hypertrophy in large and small breed dogs with chron-ic mitral valve insufficiency. Journal of Veterinary In-ternal Medicine, 21(1), 61–67. DOI: 10.1892/0891-6640(2007)21[61:dsfaih]2.0.co;2.

Brett, J, Wylie, C, & Brown, J. (2019). A case of signifi-cant hypotension following a human ingestion of vet-erinary pimobendan. Clin Toxicol (Phila), 20, 1–2. DOI: 10.1080/15563650.2019.1613550.

Fox, P. R. (2012). Pathology of myxomatous mitral valve disease in the dog. Journal of Veterinary Cardiology, 14(1), 103–126. DOI: 10.1016/j.jvc.2012.02.001.

Gutyj, B., Khariv, I., Binkevych, V., Binkevych, O., Levkivska, N., Levkivskyj, D., & Vavrysevich, Y. (2017). Research on acute and chronic toxity of the experimental drug Аmprolinsyl. Regulatory Mechanisms in Biosystems, 8(1), 41–45. DOI: 10.15421/021708.

Gutyj, B., Paska, M., Levkivska, N., Pelenyo, R., Nazaruk, N., & Guta, Z. (2016). Study of acute and chronic toxicity of ‘injectable mevesel’ investigational drug. Biological Bulletin of Bogdan Chmelnitskiy Melitopol State Pedagogical University, 6(2), 174–180. DOI: 10.15421/201649.

Hollmer, M., Willesen, J. L., Tolver, A., & Koch, J. (2017). Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease. Journal of Veterinary Cardiology, 19(1), 24–34. DOI: 10.1016/j.jvc.2016.08.006.

Kotsiumbas, I. Ia., Malyk, O. H., & Patereha, I.P. (2006). Doklinichni doslidzhennia veterynarnykh likarskykh zasobiv. L.: Triada plius (in Ukrainian).

Lavryshyn, Y. Y., Varkholyak, I. S., Martyschuk, T. V., Guta, Z. А., Ivankiv, L. B., Paladischuk, О. R., Murska, S. D., Gutyj, B. V., & Gufriy, D. F. (2016). The biological significance of the antioxidant defense system of animals body. Scientific Messen-ger LNUVMBT named after S.Z. Gzhytskyj, 18, 2(66), 100–111. DOI: 10.15421/nvlvet6622.

Malanin, L. P., Morozov, A. P., & Selivanova, A. S. (1988). Metodicheskie ukazanija po opredeleniju toksicheskih svojstv preparatov, primenjaemyh v veterinarii i zhivotnovodstve. Veterinarnye preparaty: Spravochnik. Moskva: Agropromizdat, 239–289 (in Russian).

Martyshuk, T. V. (2016). The influence of oxidative stress on the state of the antioxidant defense system in the organism of rats. Regulatory Mechanisms in Biosystems, 7(1), 8–12. DOI: 10.15421/021602.

Martyshuk, T. V., & Hutyi, B. V. (2021). Imunofiziolohichnyi stan ta antyoksydantnyi potentsial orhanizmu porosiat za umov oksydatsiinoho stresu ta dii koryhuiuchykh chynnykiv: monohrafiia. Lviv: SPOLOM (in Ukrainian).

Martyshuk, T. V., Gutyj, B. V., & Vishchur, O. I. (2016). Level of lipid peroxidation products in the blood of rats under the influ-ence of oxidative stress and under the action of liposomal prepa-ration of “Butaselmevit”. Biological Bulletin of Bogdan Khmelnitsky Melitopol State Pedagogical University, 6(2), 22–27. DOI: 10.15421/201631.

Martyshuk, T., & Gutyj, B. (2019). Influence of feed additive “Butaselmevit-Plus” on antioxidant status of rats in conditions of ox-idative stress. Scientific Messenger of LNU of Veterinary Medi-cine and Biotechnologies. Series: Agricultural Sciences, 21(90), 76–81. DOI: 10.32718/nvlvet-a9013.

Menciotti, G., Borgarelli, M., Aherne, M., Wesselowski, S., Haggstrom, J., Ljungvall, I., Lahmers, S. M., & Abbott, J. A. (2017). Mitral valve morphology assessed by three-dimensional transthoracic echocardiography in healthy dogs and dogs with myxomatous mitral valve disease. Journal of Veterinary Cardiology, 19(2), 113–123. DOI: 10.1016/j.jvc.2017.01.002.

Merveille, A.-C., Bolen, G., Krafft, E., Roels, E., Gomart, S., Etienne, A.-L., Clercx, C., & Entee, K. Mc. (2015). Pulmonary Vein-to-Pulmonary Artery Ratio is an Echocardiographic Index of Congestive Heart Failure in Dogs with Degenerative Mitral Valve Disease. Journal of Veterinary Internal Medicine, 29(6), 1502–1509. DOI: 10.1111/jvim.13634.

Morgan, K. R. S., Monteith, G., Raheb, S., Colpitts, M., & Fonfara, S. (2020). Echocardiographic parameters for the assessment of congestive heart failure in dogs with myxomatous mitral valve disease and moderate to severe mitral regurgitation. The Veterinary Journal, 263, 1–25. DOI: 10.1016/j.tvjl.2020.105518.

Oldach, M. S., Ueda, Y., Ontiveros, E. S., Fousse, S. L., Harris, S. P., & Stern, J. A. (2019). Cardiac Effects of a Single Dose of Pimobendan in Cats With Hypertrophic Cardiomyopathy; A Randomized, Placebo-Controlled, Crossover Study. Front Vet Sci, 6, 15. DOI: 10.3389/fvets.2019.00015.

Ramírez, V. L., Berrío, A., & Arias, M. P. (2016). Correlation between the clinical stage, echocardiographic findings and sys-temic blood pressure in dogs with Degenerative Disease of the Mitral Valve. CES Veterinary medicine and Zootechnics, 11(2), 61–72. DOI: 10.21615/cesmvz.11.2.5.

Rylova, M. L. (1964). Metody issledovanija hronicheskogo dejstvija vrednyh faktorov sredy v jeksperimente. L. (in Russian).

Tjostheim, S. S., Kellihan, H. B., Grint, K. A., & Stepien, R. L. (2019). Effect of sildenafil and pimobendan on intracardiac heartworm infections in four dogs. J Vet Cardiol, 23, 96–103. DOI: 10.1016/j.jvc.2019.02.001.

Todoriuk, V. B., Hunchak, V. M., Gutyj, B. V., Gufriy, D. F., Hariv, I. I., Khomyk, R. I., & Vasiv, R. O. (2018). Preclinical research of the experimental preparation “Ferosel T”. Ukrainian Journal of Veterinary and Ag-ricultural Sciences, 1(1), 3–9. DOI: 10.32718/ujvas1-1.01.

Trofimiak, R., & Slivinska, L. (2021). Diagnostic value of echocar-diographic indices of left atrial and ventricular morphology in dogs with myxomatous mitral valve disease (MMVD). Ukraini-an Journal of Veterinary and Agricultural Sciences, 4(1), 16–23. DOI: 10.32718/ujvas4-1.04.

Undhad, V. V., Fefar, D. T., Jivani, B. M., Gupta, H., Ghodasara, D. J., Joshi, B. P. & Prajapati, K. S. (2012). Cardiac troponin: an emerging cardiac biomarker in animal health. Vet. World, 5, 508–511. URL: https://agris.fao.org/agris-search/search.do?recordID= DJ2012076537.

Varkholiak, I. S., & Gutyj, B. V. (2018). Determination of acute toxicity of “Bendamin” drug in laboratory animals. Scientific Messenger of Lviv National Uni-versity of Veterinary Medicine and Biotechnologies, 20(92), 209–212. DOI: 10.32718/nvlvet9243.

Varkholiak, I. S., Gutyj, B. V., Leskiv, Kh. Ya., Kushnir, V. I., Hariv, I. I., Martyshuk, T. V., & Guta, Z. A. (2021). The effect of bendamine on antioxidant protection of rats' myocardium in doxorubicin intoxication. Colloquium-journal, 7(94), 18–21. DOI: 10.24412/2520-6990-2021-794-18-21.

Varkholiak, I., Gutyj, B., Gufriy, D., Sachuk, R., Mylostyvyi, R., Radzykhovskyi, M., Sedilo, H., & Izhboldina, O. (2021). The effect of the drug “Ben-damine” on the clinical and morphological parame-ters of dogs in heart failure. Ukrainian Journal of Vet-erinary and Agricultural Sciences, 4(3), 76–83. DOI: 10.32718/ujvas4-3.13.

Vlizlo, V. V., Fedoruk, R. S., & Raty`ch, I. B. (2012). La-boratorni metody` doslidzhen` u biologiyi, tvary`nny`cztvi ta vetery`narnij medy`cy`ni: dovid-ny`k. L`viv: Spolom (in Ukrainian).

Yata, M., Kooistra, H. S., & Beijerink, N. J. (2019). Cardiorenal and endocrine effects of synthetic canine BNP1-32 in dogs with compensated congestive heart failure caused by myxomatous mitral valve disease. J Vet Intern Med, 33(2), 462–470. DOI: 10.1111/jvim.15416.

Zhulikova, O. A. (2016). Monitoring rasprostranenija serdechno-sosudistyh zabolevanij sredi koshek i sobak v g. Blagoveshhensk amurskoj oblasti. Dal'-nevostochnyj agrarnyj vestnik, 2(38), 49–56. https://cyberleninka.ru/article/n/monitoring-rasprostraneniya-serdechno-sosudistyh-zabolevaniy-sredi-koshek-i-sobak-v-g-blagoveschensk-amurskoy-oblasti (in Russian).

Abstract views: 68
PDF Downloads: 34
Published
2022-05-04
How to Cite
Varkholiak, I., Gutyj, B., Zolototska, O., Goralskyi, L., Sokulskyi, I., Khalak, V., Parchenko, V., Shcherbatyy, A., Martyshuk, T., & Guta, Z. (2022). Experimental assessment of the toxicity of a cardiac drug based on a phosphodiesterase-3 inhibitor and ethylmethylhydroxypyridine succinate. Scientific Messenger of LNU of Veterinary Medicine and Biotechnologies. Series: Veterinary Sciences, 24(105), 109-119. https://doi.org/10.32718/nvlvet10516

Most read articles by the same author(s)

<< < 1 2 3 4 5 6 7 8 > >>