DETERMINATION OF INDICATORS OF ACUTE TOXICITY OF THE DRUG BY CARDISTIM
Keywords:
dog diseases, cardiovascular system, acute toxicity, pimobendan, mitral valve, endocardiosis
Abstract
Dogs, as companion animals, occupy a large part in the lives of many families. Owners pay great attention to the health of their animals, so they regularly visit veterinary clinics. One of the common groups of diseases is diseases accompanied by pathologies of the cardiovascular system, including myxomatous lesions of the mitral valve. For the treatment of dogs with such pathologies, it is necessary to develop effective treatment protocols that should include drugs that stimulate the work of the cardiovascular system. Such drugs include dosage forms based on pimobendan. Pimobendan belongs to benzimidazole-pyridazinone derivatives, and is a non-sympathomimetic, non-glycoside inotropic substance that has pronounced vasodilator properties. The aim of our research was to calculate the parameters of acute toxicity of the drug Cardistim based on pimobendan. The study was conducted at the Department of Veterinary Sanitary Inspection, Microbiology, Hygiene and Pathological Anatomy of the Faculty of Veterinary Medicine in the Laboratory "Veterinary Pharmacy" of Sumy National Agrarian University. To determine the parameters of acute toxicity, intragastric administration of the drug Cardistim to white rats aged 2 months was used. Toxicity indicators were determined using the LD50 program, by the methods of G. Kerber (1931) and G. Pershin (1950). The median lethal dose of the drug Cardistim when calculated by a computer program was 6059.72 mg/kg. The result of the calculation by the method of G. Pershin, the acute toxicity of the drug Cardistim when administered intragastrically to rats was 5952.37 mg per kg of weight. The acute toxicity index of the drug Cardistim when administered intragastrically to white rats by the method of G. Kerber (1931) was 568.34 mg of the drug per 1 kg of animal weight. As a result of calculations, it was found that the arithmetic mean toxicity index of Cardistim was 5906.81 mg/kg of weight. It was found that the drug Cardistim when administered into the stomach of white rats belongs to the fourth hazard class (low-toxic substances).
References
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9. Chetboul, V., & Tissier, R. (2012). Echocardiographic assessment of canine degenerative mitral valve disease. Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology, 14(1), 127–148. https://doi.org/10.1016/j.jvc.2011.11.005
10. Chetboul, V., Lefebvre, H. P., Sampedrano, C. C., Gouni, V., Saponaro, V., Serres, F., Concordet, D., Nicolle, A. P., & Pouchelon, J. L. (2007). Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. Journal of veterinary internal medicine, 21(4), 742–753. https://doi.org/10.1892/0891-6640(2007)21[742:caceop]2.0.co;2
11. Countries With The Most Pet Cats Globally https://www.worldatlas.com/articles/countries-with-the-most-pet-catsglobally.html (14.11.2024.)
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13. Doklinichni doslidzhennia veterynarnykh likarskykh zasobiv: [Preclinical studies of veterinary medicinal products] / Ed. I.Y. Kotsyumbas. Lviv: Triada plus, 2006, 360 p. (in Ukrainian)
14. Elliott, A. D., Middeldorp, M. E., Van Gelder, I. C., Albert, C. M., & Sanders, P. (2023). Epidemiology and modifiable risk factors for atrial fibrillation. Nature reviews. Cardiology, 20(6), 404–417. https://doi.org/10.1038/s41569-022-00820-8
15. Fleming, J. M., Creevy, K. E., & Promislow, D. E. (2011). Mortality in north american dogs from 1984 to 2004: an investigation into age-, size-, and breed-related causes of death. Journal of veterinary internal medicine, 25(2), 187–198. https://doi.org/10.1111/j.1939-1676.2011.0695.x
16. Gruber P, Roth W, Schepky G. (1994). Oral Pharmaceutical Forms of Pimobendan. US Patent 5,364,646. November 15, 1994.
17. Häggström, J., Boswood, A., O'Grady, M., Jöns, O., Smith, S., Swift, S., Borgarelli, M., Gavaghan, B., Kresken, J. G., Patteson, M., Ablad, B., Bussadori, C. M., Glaus, T., Kovacević, A., Rapp, M., Santilli, R. A., Tidholm, A., Eriksson, A., Belanger, M. C., Deinert, M., … DiFruscia, R. (2008). Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. Journal of veterinary internal medicine, 22(5), 1124–1135. https://doi.org/10.1111/j.1939-1676.2008.0150.x
18. Iwanuk, N., Nolte, I., Wall, L., Sehn, M., Raue, J., Pilgram, A., Rumstedt, K., & Bach, J. P. (2019). Effect of Pimobendan on NT-proBNP and c troponin I before and after a submaximal exercise test in dogs with preclinical mitral valve disease without cardiomegaly - a randomised, double-blinded trial. BMC veterinary research, 15(1), 237. https://doi.org/10.1186/s12917-019-1980-z
19. Jakovljev, I. O., Petrov, R. V. (2023). Monitoryng zahvorjuvannja sobak ta kotiv na bazi ZVC "10 druziv" m. Sumy. [Disease monitoring of dogs and cats on the basis of the "10 Druzh" medical center in the city of Amounts]. Visnyk Sums'kogo nacional'nogo agrarnogo universytetu Serija: Veterynarna medycyna, (4(63), 139-144. https://doi.org /10.32782/bsnau.vet.2023.4.22 (in Ukrainian).
20. Kanno, N., Kuse, H., Kawasaki, M., Hara, A., Kano, R., & Sasaki, Y. (2007). Effects of pimobendan for mitral valve regurgitation in dogs. The Journal of veterinary medical science, 69(4), 373–377. https://doi.org/10.1292/jvms.69.373
21. Keene, B. W., Atkins, C. E., Bonagura, J. D., Fox, P. R., Häggström, J., Fuentes, V. L., Oyama, M. A., Rush, J. E., Stepien, R., & Uechi, M. (2019). ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. Journal of veterinary internal medicine, 33(3), 1127–1140. https://doi.org/10.1111/jvim.15488
22. Lombard, C. W., Jöns, O., & Bussadori, C. M. (2006). Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. Journal of the American Animal Hospital Association, 42(4), 249–261. https://doi.org/10.5326/0420249
23. Mizuno, M., Yamano, S., Chimura, S., Hirakawa, A., Takusagawa, Y., Sawada, T., Maetani, S., Takahashi, A., Mizuno, T., Harada, K., Shinoda, A., Uchida, S., Takeuchi, J., Mizukoshi, T., Endo, M., & Uechi, M. (2017). Efficacy of pimobendan on survival and reoccurrence of pulmonary edema in canine congestive heart failure. The Journal of veterinary medical science, 79(1), 29–34. https://doi.org/10.1292/jvms.16-0069
24. Pro zatverdzhennia Poriadku provedennia naukovymy ustanovamy doslidiv, eksperymentiv na tvarynakh.[ On the approval of the Procedure for carrying out trials and experiments on animals by scientific institutions]. (2012). Access mode:https://zakon.rada.gov.ua/laws/show/z0416-12#Text. (in Ukrainian)
25. Schneider, P., Güttner, J., Eckenfels, A., Heinzel, G., von Nicolai, H., Trieb, G., & Lehmann, H. (1997). Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie, 49(3-4), 217–224. https://doi.org/10.1016/s0940-2993(97)80013-9
26. Serres, F., Chetboul, V., Tissier, R., Sampedrano, C. C., Gouni, V., Nicolle, A. P., & Pouchelon, J. L. (2007). Chordae tendineae rupture in dogs with degenerative mitral valve disease: prevalence, survival, and prognostic factors (114 cases, 2001-2006). Journal of veterinary internal medicine, 21(2), 258–264. https://doi.org/10.1892/0891-6640(2007)21[258:ctridw]2.0.co;2
27. Sisson D., Kvart C., Darke P. G.1999. Acquired valvular heart disease in dogs and cats. pp. 536–565. In: Textbook of Canine and Feline Cardiology, 2nd ed. (Fox, P. R., Sisson, D. and Moise, N. S. eds.) WB Saunders, Philadelphia.
28. Smith, P. J., French, A. T., Van Israël, N., Smith, S. G., Swift, S. T., Lee, A. J., Corcoran, B. M., & Dukes-McEwan, J. (2005). Efficacy and safet of pimobendan in canine heart failure caused by myxomatous mitral valve disease. The Journal of small animal practice, 46(3), 121–130. https://doi.org/10.1111/j.1748-5827.2005.tb00302.x
29. Tissier, R., Chetboul, V., Moraillon, R., Nicolle, A., Carlos, C., Enriquez, B., & Pouchelon, J. L. (2005). Increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long-term pimobendan therapy. Cardiovascular toxicology, 5(1), 43–51. https://doi.org/10.1385/ct:5:1:043
30. Varkholiak I.S., & Hutyi B.V. (2019). Vplyv preparatu “Bendamin” na pokaznyky antyoksydantnoho zakhystu miokardu shchuriv za eksperymentalnoho modeliuvannia sertsevoi nedostatnosti [Influence of the preparation “Bendamin” on the indicators of antioxidant protection of rat myocardium in experimental modeling of heart failure.]. Naukovyi visnyk Lvivskoho natsionalnoho universytetu veterynarnoi medytsyny ta biotekhnolohii imeni S.Z. Gzhytskoho , 21 (95), 98-101. https://doi: 10.32718/nvlvet9518 (in Ukrainian).
31. Whitney J. C. (1974). Observations on the effect of age on the severity of heart valve lesions in the dog. The Journal of small animal practice, 15(8), 511–522. https://doi.org/10.1111/j.1748-5827.1974.tb06529.x
2. Atkins, C., Bonagura, J., Ettinger, S., Fox, P., Gordon, S., Haggstrom, J., Hamlin, R., Keene, B., Luis-Fuentes, V., & Stepien, R. (2009). Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. Journal of veterinary internal medicine, 23(6), 1142–1150. https://doi.org/10.1111/j.1939-1676.2009.0392.x
3. Borgarelli, M., & Haggstrom, J. (2010). Canine degenerative myxomatous mitral valve disease: natural history, clinical presentation and therapy. The Veterinary clinics of North America. Small animal practice, 40(4), 651–663. https://doi.org/10.1016/j.cvsm.2010.03.008
4. Borgarelli, M., Savarino, P., Crosara, S., Santilli, R. A., Chiavegato, D., Poggi, M., Bellino, C., La Rosa, G., Zanatta, R., Haggstrom, J., & Tarducci, A. (2008). Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease. Journal of veterinary internal medicine, 22(1), 120–128. https://doi.org/10.1111/j.1939-1676.2007.0008.x
5. Boswood, A., Gordon, S. G., Häggström, J., Wess, G., Stepien, R. L., Oyama, M. A., Keene, B. W., Bonagura, J., MacDonald, K. A., Patteson, M., Smith, S., Fox, P. R., Sanderson, K., Woolley, R., Szatmári, V., Menaut, P., Church, W. M., O'Sullivan, M. L., Jaudon, J. P., Kresken, J. G., … Watson, P. (2018). Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study. Journal of veterinary internal medicine, 32(1), 72–85. https://doi.org/10.1111/jvim.14885
6. Boswood, A., Häggström, J., Gordon, S. G., Wess, G., Stepien, R. L., Oyama, M. A., Keene, B. W., Bonagura, J., MacDonald, K. A., Patteson, M., Smith, S., Fox, P. R., Sanderson, K., Woolley, R., Szatmári, V., Menaut, P., Church, W. M., O'Sullivan, M. L., Jaudon, J. P., Kresken, J. G., … Watson, P. (2016). Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial. Journal of veterinary internal medicine, 30(6), 1765–1779. https://doi.org/10.1111/jvim.14586
7. Bowles, D., & Fry, D. (2011). Pimobendan and its use in treating canine congestive heart failure. Compendium (Yardley, PA), 33(11), E1.
8. Boyle, K. L., & Leech, E. (2012). A review of the pharmacology and clinical uses of pimobendan. Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001), 22(4), 398–408. https://doi.org/10.1111/j.1476-4431.2012.00768.x
9. Chetboul, V., & Tissier, R. (2012). Echocardiographic assessment of canine degenerative mitral valve disease. Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology, 14(1), 127–148. https://doi.org/10.1016/j.jvc.2011.11.005
10. Chetboul, V., Lefebvre, H. P., Sampedrano, C. C., Gouni, V., Saponaro, V., Serres, F., Concordet, D., Nicolle, A. P., & Pouchelon, J. L. (2007). Comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative mitral valve disease: a prospective, controlled, blinded, and randomized study. Journal of veterinary internal medicine, 21(4), 742–753. https://doi.org/10.1892/0891-6640(2007)21[742:caceop]2.0.co;2
11. Countries With The Most Pet Cats Globally https://www.worldatlas.com/articles/countries-with-the-most-pet-catsglobally.html (14.11.2024.)
12. Detweiler, D. K., & Patterson, D. F. (1965). The prevalence and types of cardiovascular disease in dogs. Annals of the New York Academy of Sciences, 127(1), 481–516. https://doi.org/10.1111/j.1749-6632.1965.tb49421.x
13. Doklinichni doslidzhennia veterynarnykh likarskykh zasobiv: [Preclinical studies of veterinary medicinal products] / Ed. I.Y. Kotsyumbas. Lviv: Triada plus, 2006, 360 p. (in Ukrainian)
14. Elliott, A. D., Middeldorp, M. E., Van Gelder, I. C., Albert, C. M., & Sanders, P. (2023). Epidemiology and modifiable risk factors for atrial fibrillation. Nature reviews. Cardiology, 20(6), 404–417. https://doi.org/10.1038/s41569-022-00820-8
15. Fleming, J. M., Creevy, K. E., & Promislow, D. E. (2011). Mortality in north american dogs from 1984 to 2004: an investigation into age-, size-, and breed-related causes of death. Journal of veterinary internal medicine, 25(2), 187–198. https://doi.org/10.1111/j.1939-1676.2011.0695.x
16. Gruber P, Roth W, Schepky G. (1994). Oral Pharmaceutical Forms of Pimobendan. US Patent 5,364,646. November 15, 1994.
17. Häggström, J., Boswood, A., O'Grady, M., Jöns, O., Smith, S., Swift, S., Borgarelli, M., Gavaghan, B., Kresken, J. G., Patteson, M., Ablad, B., Bussadori, C. M., Glaus, T., Kovacević, A., Rapp, M., Santilli, R. A., Tidholm, A., Eriksson, A., Belanger, M. C., Deinert, M., … DiFruscia, R. (2008). Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. Journal of veterinary internal medicine, 22(5), 1124–1135. https://doi.org/10.1111/j.1939-1676.2008.0150.x
18. Iwanuk, N., Nolte, I., Wall, L., Sehn, M., Raue, J., Pilgram, A., Rumstedt, K., & Bach, J. P. (2019). Effect of Pimobendan on NT-proBNP and c troponin I before and after a submaximal exercise test in dogs with preclinical mitral valve disease without cardiomegaly - a randomised, double-blinded trial. BMC veterinary research, 15(1), 237. https://doi.org/10.1186/s12917-019-1980-z
19. Jakovljev, I. O., Petrov, R. V. (2023). Monitoryng zahvorjuvannja sobak ta kotiv na bazi ZVC "10 druziv" m. Sumy. [Disease monitoring of dogs and cats on the basis of the "10 Druzh" medical center in the city of Amounts]. Visnyk Sums'kogo nacional'nogo agrarnogo universytetu Serija: Veterynarna medycyna, (4(63), 139-144. https://doi.org /10.32782/bsnau.vet.2023.4.22 (in Ukrainian).
20. Kanno, N., Kuse, H., Kawasaki, M., Hara, A., Kano, R., & Sasaki, Y. (2007). Effects of pimobendan for mitral valve regurgitation in dogs. The Journal of veterinary medical science, 69(4), 373–377. https://doi.org/10.1292/jvms.69.373
21. Keene, B. W., Atkins, C. E., Bonagura, J. D., Fox, P. R., Häggström, J., Fuentes, V. L., Oyama, M. A., Rush, J. E., Stepien, R., & Uechi, M. (2019). ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. Journal of veterinary internal medicine, 33(3), 1127–1140. https://doi.org/10.1111/jvim.15488
22. Lombard, C. W., Jöns, O., & Bussadori, C. M. (2006). Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. Journal of the American Animal Hospital Association, 42(4), 249–261. https://doi.org/10.5326/0420249
23. Mizuno, M., Yamano, S., Chimura, S., Hirakawa, A., Takusagawa, Y., Sawada, T., Maetani, S., Takahashi, A., Mizuno, T., Harada, K., Shinoda, A., Uchida, S., Takeuchi, J., Mizukoshi, T., Endo, M., & Uechi, M. (2017). Efficacy of pimobendan on survival and reoccurrence of pulmonary edema in canine congestive heart failure. The Journal of veterinary medical science, 79(1), 29–34. https://doi.org/10.1292/jvms.16-0069
24. Pro zatverdzhennia Poriadku provedennia naukovymy ustanovamy doslidiv, eksperymentiv na tvarynakh.[ On the approval of the Procedure for carrying out trials and experiments on animals by scientific institutions]. (2012). Access mode:https://zakon.rada.gov.ua/laws/show/z0416-12#Text. (in Ukrainian)
25. Schneider, P., Güttner, J., Eckenfels, A., Heinzel, G., von Nicolai, H., Trieb, G., & Lehmann, H. (1997). Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie, 49(3-4), 217–224. https://doi.org/10.1016/s0940-2993(97)80013-9
26. Serres, F., Chetboul, V., Tissier, R., Sampedrano, C. C., Gouni, V., Nicolle, A. P., & Pouchelon, J. L. (2007). Chordae tendineae rupture in dogs with degenerative mitral valve disease: prevalence, survival, and prognostic factors (114 cases, 2001-2006). Journal of veterinary internal medicine, 21(2), 258–264. https://doi.org/10.1892/0891-6640(2007)21[258:ctridw]2.0.co;2
27. Sisson D., Kvart C., Darke P. G.1999. Acquired valvular heart disease in dogs and cats. pp. 536–565. In: Textbook of Canine and Feline Cardiology, 2nd ed. (Fox, P. R., Sisson, D. and Moise, N. S. eds.) WB Saunders, Philadelphia.
28. Smith, P. J., French, A. T., Van Israël, N., Smith, S. G., Swift, S. T., Lee, A. J., Corcoran, B. M., & Dukes-McEwan, J. (2005). Efficacy and safet of pimobendan in canine heart failure caused by myxomatous mitral valve disease. The Journal of small animal practice, 46(3), 121–130. https://doi.org/10.1111/j.1748-5827.2005.tb00302.x
29. Tissier, R., Chetboul, V., Moraillon, R., Nicolle, A., Carlos, C., Enriquez, B., & Pouchelon, J. L. (2005). Increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long-term pimobendan therapy. Cardiovascular toxicology, 5(1), 43–51. https://doi.org/10.1385/ct:5:1:043
30. Varkholiak I.S., & Hutyi B.V. (2019). Vplyv preparatu “Bendamin” na pokaznyky antyoksydantnoho zakhystu miokardu shchuriv za eksperymentalnoho modeliuvannia sertsevoi nedostatnosti [Influence of the preparation “Bendamin” on the indicators of antioxidant protection of rat myocardium in experimental modeling of heart failure.]. Naukovyi visnyk Lvivskoho natsionalnoho universytetu veterynarnoi medytsyny ta biotekhnolohii imeni S.Z. Gzhytskoho , 21 (95), 98-101. https://doi: 10.32718/nvlvet9518 (in Ukrainian).
31. Whitney J. C. (1974). Observations on the effect of age on the severity of heart valve lesions in the dog. The Journal of small animal practice, 15(8), 511–522. https://doi.org/10.1111/j.1748-5827.1974.tb06529.x
Published
2025-03-14
How to Cite
Petrov, R., & Iakovlev, I. (2025). DETERMINATION OF INDICATORS OF ACUTE TOXICITY OF THE DRUG BY CARDISTIM. Bulletin of Sumy National Agrarian University. The Series: Veterinary Medicine, (4(67), 83-89. https://doi.org/10.32782/bsnau.vet.2024.4.12
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