PHARMACOTOXICOLOGICAL EVALUATION OF A NEW ORIGINAL MEDICINAL PRODUCT FOR DOGS TRAZAPENTINE® TABLETS (SUCCINATE TRAZODONE + GABAPENTIN)
Abstract and keywords
Abstract (English):
The study has established that the absolute (LD100) and median (LD50) lethal doses of the Trazapentin® tablets for dogs cannot be determined. According to the GOST 12.1.007-76 classification, the drug is classified as hazard class IV ‒ slightly hazardous substances. The study of chronic toxicity over a period of 90 days revealed no lethal outcomes or negative effects on the animals’ organisms, both during the administration period and after discontinuation of the Trazapentin®. The absence of allergenic and irritant properties of the drug has been proven.

Keywords:
succinate trazodone, gabapentin, Trazapentin® tablets, acute toxicity, chronic toxicity, allergenic properties
Text
Text (PDF): Read Download
References

1. Beloglazov, D.V. Ocenka effektivnosti novogo preparata Ekspress Uspokoin® tabletki pri situacionnoy korrekcii povedencheskih problem u koshek / D.V. Beloglazov, S.V. Mukaseev, O.A. Zeynalov // Rossiyskiy veterinarnyy zhurnal. – 2023. – № 2. – S. 14-22. – DOIhttps://doi.org/10.32416/2500-4379-2023-2-14-22.

2. Beloglazov, D.V. Ocenka effektivnosti novogo preparata «Ekspress Uspokoin® tabletki» pri situacionnoy korrekcii povedencheskih problem u sobak / D.V. Beloglazov, S.V. Mukaseev, O.A. Zeynalov // Sovremennaya veterinarnaya medicina. – 2023. ‒ № 1. ‒ C. 18-22.

3. Elizarova, E.A. Ocenka effektivnosti novogo lekarstvennogo preparata Kurs Uspokoin tabletki dlya korrekcii vozrastnyh kognitivnyh narusheniy u sobak / E.A. Elizarova, D.V. Beloglazov, O.A Zeynalov, S.V. Mukaseev // Rossiyskiy veterinarnyy zhurnal. ‒ 2024. ‒ № 3. ‒ S. 27-33. DOIhttps://doi.org/10.32416/2500-4379-2024-3-27-33.

4. Elizarova, E.A. Ocenka effektivnosti novogo lekarstvennogo preparata Kurs Uspokoin tabletki dlya korrekcii vozrastnyh kognitivnyh narusheniy u koshek / E.A. Elizarova, D.V. Beloglazov, S.V. Mukaseev, O.A. Zeynalov // Rossiyskiy veterinarnyy zhurnal. – 2024. – № 1. – S. 33-39. DOIhttps://doi.org/10.32416/2500-4379-2024-1-33-39.

5. Kurs Uspokoin tabletki. Instrukciya po veterinarnomu primeneniyu lekarstvennogo preparata [Elektronnyy resurs]. https://galen.vetrf.ru/files/5c1ac33d-9461-4add-bd1c-e04b2d82f1fb (data obrascheniya 21.01.25).

6. Prikaz Ministerstva sel'skogo hozyaystva RF №101 ot 06.03.2018 g. «Ob utverzhdenii Pravil provedeniya doklinicheskogo issledovaniya lekarstvennogo sredstva dlya veterinarnogo primeneniya, klinicheskogo issledovaniya lekarstvennogo preparata dlya veterinarnogo primeneniya, issledovaniya bioekvivalentnosti lekarstvennogo preparata dlya veterinarnogo primeneniya». Zaregistrirovan v Minyuste Rossii 05.06.2018 № 51296.

7. Rukovodstvo po provedeniyu doklinicheskih issledovaniy lekarstvennyh sredstv. Chast' pervaya / A.N. Mironov, N.D. Bunatyan i dr. – M.: Grif i K, 2012. – 944 s.

8. Rukovodstvo po eksperimental'nomu (doklinicheskomu) izucheniyu novyh farmakologicheskih veschestv / Pod red. R. U. Habrieva. – M.: Medicina, 2005. – 832 s.

9. Smirnov, A.V. Yantarnaya kislota i ee primenenie v medicine. Chast' I. Yantarnaya kislota: metabolit i regulyator metabolizma organizma cheloveka / A.V. Smirnov, O.B. Nesterova, R.V. Golubev // Nefrologiya. – 2014. – T. 18. – № 2. – S. 33-41.

10. Ekspress Uspokoin® tabletki. Instrukciya po veterinarnomu primeneniyu lekarstvennogo preparata [Elektronnyy resurs]. https://galen.vetrf.ru/files/41fc97ef-69b3-4502-bded-57bb87220cd6 (data obrascheniya 21.01.25).

11. Belshaw, Z. Assessment of quality of life and chronic pain in dogs / Z. Belshaw, J. Yeates // Vet J. ‒ 2018. ‒ No. 239. ‒ pp. 59-64. doihttps://doi.org/10.1016/j.tvjl.2018.07.010.

12. Belinskaia, D.A. Psychotropic Drugs for the Management of Chronic Pain and Itch. / D.A. Belinskaia, M.A. Belinskaia, O.I. Barygin, N.P. Vanchakova, N.N. Shestakova // Pharmaceuticals (Basel). ‒ 2019. ‒ No. 12(2). ‒ pp. 99. doihttps://doi.org/10.3390/ph12020099.

13. Boyle, Y. The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial / Y. Boyle, D. Fernando, H. Kurz, S.R. Miller, M. Zucchetto, J. Storey // Pain. ‒ 2014. ‒ No. 155(12). ‒ pp. 2510-2516. doi:https://doi.org/10.1016/j.pain.2014.09.003.

14. Cashmore, R.G. Clinical diagnosis and treatment of suspected neuropathic pain in three dogs / R.G. Cashmore, T.R. Harcourt-Brown, P.M. Freeman, N.D. Jeffery, N. Granger // Aust Vet J. ‒ 2009. ‒ No. 87(1). ‒ pp. 45-50. doihttps://doi.org/10.1111/j.1751-0813.2008.00379.x.

15. Chea, B. Trazodone: a review of its pharmacological properties and its off-label use in dogs and cats / B. Chea, M. Giorgi // Am J Anim Vet Sci. ‒ 2017. ‒ No. 12. ‒ pp. 188-194.

16. Chincholkar, M. Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review / Chincholkar M. // Br J Anaesth. ‒ 2018. ‒ No. 120(6). ‒ pp. 1315-1334. doihttps://doi.org/10.1016/j.bja.2018.02.066.

17. Cisani, F. Acute Low Dose of Trazodone Recovers Glutamate Release Efficiency and mGlu2/3 Autoreceptor Impairments in the Spinal Cord of Rats Suffering From Chronic Sciatic Ligation / F. Cisani, A. Roggeri, G. Olivero, et al. // Front Pharmacol. ‒ 2020. ‒ No. 11. ‒ pp. 1108. doihttps://doi.org/10.3389/fphar.2020.01108.

18. Colvonen, P.J. Recent Advancements in Treating Sleep Disorders in Co-Occurring PTSD / P.J. Colvonen, L.D. Straus, C. Stepnowsky, M.J. McCarthy, L.A. Goldstein, S.B. Norman // Curr Psychiatry Rep. ‒ 2018. ‒ No. 20(7). ‒ pp. 48. Published 2018 Jun 21. doihttps://doi.org/10.1007/s11920-018-0916-9.

19. Crociolli, G.C. Gabapentin as an adjuvant for postoperative pain management in dogs undergoing mastectomy / G.C. Crociolli, R.N. Cassu, R.C. Barbero, T.L. Rocha, D.R. Gomes, G.M. Nicácio // J Vet Med Sci. ‒ 2015. ‒ No. 77(8). ‒ pp. 1011-1015. doihttps://doi.org/10.1292/jvms.14-0602.

20. Della Rocca, G. Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide? / G. Della Rocca, D. Gamba // Animals (Basel). ‒ 2021. ‒ No. 11(4). ‒ pp. 952. doihttps://doi.org/10.3390/ani11040952.

21. Di Cesare, F. Gabapentin: Clinical Use and Pharmacokinetics in Dogs, Cats, and Horses / F. Di Cesare, V. Negro, G. Ravasio, R. Villa, S. Draghi, P. Cagnardi // Animals (Basel). ‒ 2023. ‒ No. 13(12). ‒ pp. 2045. doihttps://doi.org/10.3390/ani13122045.

22. Dooley, D.J. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission / D.J. Dooley, C.P. Taylor, S. Donevan, D. Feltner // Trends Pharmacol Sci. // 2007. ‒ No. 28(2). ‒ pp. 75-82. doihttps://doi.org/10.1016/j.tips.2006.12.006.

23. Edwards, R.R. Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis / R.R. Edwards, A.J. Dolman, M.O. Martel, et al. // BMC Musculoskelet Disord. ‒ 2016. ‒ No. 17. ‒ pp. 284. doihttps://doi.org/10.1186/s12891-016-1124-6.

24. Epstein, M.A. Managing Chronic Pain in Dogs and Cats, Part 2: The Best of the Rest in the Management of Osteoarthritis / M.A. Epstein. [Elektronnyy resurs]. – URL: https://todaysveterinarypractice.com/wp-content/uploads/sites/4/2016/06/T1409F03.pdf (data obrascheniya 15.01.2025)

25. Erickson, A. A review of pre-appointment medications to reduce fear and anxiety in dogs and cats at veterinary visits / A. Erickson, K. Harbin, J. MacPherson, K. Rundle, K.L. Overall // Can Vet J. ‒ 2021. ‒ No. 62(9). ‒ pp. 952-960.

26. Ghanbari, R. Sustained Administration of Trazodone Enhances Serotonergic Neurotransmission: In Vivo Electrophysiological Study in the Rat Brain / R. Ghanbari, et al. / Journal of Pharmacology and Experimental Therapeutics. ‒ 2010. ‒ No. 335. ‒ pp. 197-206.

27. Garrone, B. Synergistic interaction between trazodone and gabapentin in rodent models of neuropathic pain / B. Garrone // PLoS One. ‒ 2021. ‒ No. 16(1). ‒ e0244649.

28. Garry, E.M. Varicella zoster virus induces neuropathic changes in rat dorsal root ganglia and behavioral reflex sensitisation that is attenuated by gabapentin or sodium channel blocking drugs / E.M. Garry, A. Delaney, H.A. Anderson, et al. // Pain. ‒ 2005. ‒ No. 118 (1-2). ‒ pp. 97-111. doihttps://doi.org/10.1016/j.pain.2005.08.003.

29. Gilron, I. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial / I. Gilron, J.M. Bailey, D. Tu, R.R. Holden, A.C. Jackson, R.L. Houlden // Lancet. ‒ 2009. ‒ No. 374(9697). ‒ pp, 1252-1261. doihttps://doi.org/10.1016/S0140-6736(09)61081-3.

30. Gruen, M.E. AAHA Pain Management Guidelines for Dogs and Cats / M.E. Gruen, B.D.X. Lascelles, E. Colleran, et al. // J Am Anim Hosp Assoc. ‒ 2022. ‒ No. 58(2). ‒ pp. 55-76. doihttps://doi.org/10.5326/JAAHA-MS-7292.

31. Gildea, E. Use of Bedinvetmab (Librela®) for Canine Osteoarthritis in France, Germany, Italy, Spain, and the UK: Quantitative Analysis of Veterinarian Satisfaction and Real-World Treatment Patterns / E. Gildea, C. North, K. Walker, F. Adriaens, B.D.X. Lascelles // Animals (Basel). ‒ 2024. ‒ No. 14(15). ‒ pp. 2231. doihttps://doi.org/10.3390/ani14152231.

32. Govendir, M. Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent / M. Govendir, M. Perkins, R. Malik // Aust Vet J. ‒ 2005. ‒ No. 83(10). ‒ pp. 602-608. doihttps://doi.org/10.1111/j.1751-0813.2005.tb13269.x.

33. Grubb, T. Chronic neuropathic pain in veterinary patients / Grubb T. // Top Companion Anim Med. ‒ 2010. ‒ No. 25(1). ‒ pp. 45-52. doihttps://doi.org/10.1053/j.tcam.2009.10.007.

34. Guy, S. Anticonvulsant medication use for the management of pain following spinal cord injury: systematic review and effectiveness analysis / S. Guy, S. Mehta, L. Leff, R. Teasell, E. Loh // Spinal Cord. ‒ 2014. ‒ No. 52(2). ‒ pp. 89-96. doihttps://doi.org/10.1038/sc.2013.146.

35. Heughan, C.E. The interaction between gabapentin and amitriptyline in the rat formalin test after systemic administration / C.E. Heughan, J. Sawynok // Anesth Analg. ‒ 2002. ‒ No. 94(4). ‒ pp. 975-980. doihttps://doi.org/10.1097/00000539-200204000-00037.

36. Khurana, R.C. Treatment of painful diabetic neuropathy with trazodone / RC. Khurana / JAMA. ‒ 1983. ‒ No. 250(11). ‒ pp. 1392. doihttps://doi.org/10.1001/jama.1983.03340110016015.

37. Kukanich, B. Pharmacokinetics of oral gabapentin in greyhound dogs / B. Kukanich, R.L. Cohen // Vet J. ‒ 2011. ‒ No. 187(1). ‒ pp. 133-135. doihttps://doi.org/10.1016/j.tvjl.2009.09.022.

38. Kuner, R. Central mechanisms of pathological pain / R. Kuner // Nat Med. ‒ 2010. ‒ No. 16(11). ‒ pp. 1258-1266. doihttps://doi.org/10.1038/nm.2231.

39. Liu, V.W.C. Antidepressants for the Treatment of Neuropathic Pain / V.W.C. Liu, L.W. Lam, H.F.K. Chiu // Hong Kong J Psychiatry. ‒ 2002. ‒ No. 12(4). ‒ pp. 23-27.

40. Lipone, P. Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study / P. Lipone, E. Ehler, M. Nastaj, et al. // CNS Drugs. ‒ 2020. ‒ No. 34(11). ‒ pp. 1177-1189. doihttps://doi.org/10.1007/s40263-020-00760-2.

41. Malkani, R. How does chronic pain impact the lives of dogs: an investigation of factors that are associated with pain using the Animal Welfare Assessment Grid Front / R. Malkani, S. Paramasivam, S. Wolfensohn // Vet Sci. ‒ No. 2024. ‒ No. 11. ‒ pp. 1374858. doihttps://doi.org/10.3389/fvets.2024.1374858.

42. McPeake, K.J. The Canine Frustration Questionnaire-Development of a New Psychometric Tool for Measuring Frustration in Domestic Dogs (Canis familiaris) / K.J. McPeake, L.M. Collins, H. Zulch, D.S. Mills // Front Vet Sci. ‒ 2019. ‒ No. 6. ‒ pp. 152. doihttps://doi.org/10.3389/fvets.2019.00152.

43. Ménigaux, C. Preoperative gabapentin decreases anxiety and improves early functional recovery from knee surgery / C. Ménigaux, F. Adam, B. Guignard, D.I. Sessler, M. Chauvin // Anesth Analg. ‒ 2005. ‒ No. 100(5). ‒ pp. 1394-1399. doihttps://doi.org/10.1213/01.ANE.0000152010.74739.B8.

44. Michels, G.M. A prospective, randomized, double-blind, placebo-controlled multisite, parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab, a canine anti-nerve growth factor monoclonal antibody / G.M. Michels, N.A. Honsberger, R.R. Walters, S. Kira, J. Tena, D.M. Cleaver / Vet Anaesth Analg. ‒ 2023. ‒ No. 50(5). ‒ pp. 446-458. doihttps://doi.org/10.1016/j.vaa.2023.06.003.

45. Monteiro, B.P. WSAVA guidelines for the recognition, assessment and treatment of pain / B.P. Monteiro, et al. // J Small Anim Pract. ‒ 2022. ‒ No. 64 (4). ‒ pp. 177–254. doi:https://doi.org/10.1111/jsap.13566.

46. Moore, S.A. Managing Neuropathic Pain in Dogs / S.A. Moore // Front Vet Sci. ‒ 2016. ‒ No. 3. ‒ pp. 12. doihttps://doi.org/10.3389/fvets.2016.00012.

47. Okuda, K. Trazodone hydrochloride attenuates thermal hyperalgesia in a chronic constriction injury rat model / K. Okuda, T. Takanishi, K. Yoshimoto, S. Ueda // Eur J Anaesthesiol. ‒ 2003. ‒ No. 20(5). ‒ pp. 409-415. doihttps://doi.org/10.1017/s0265021503000632.

48. Olivero, G. 5-HT2A-mGlu2/3 receptor complex in rat spinal cord glutamatergic nerve endings: A 5-HT2A to mGlu2/3 signalling to amplify presynaptic mechanism of auto-control of glutamate exocytosis / G. Olivero, M. Grilli, M. Vergassola, et al. // Neuropharmacology. ‒ 2018. ‒ No. 133. ‒ pp. 429-439. doihttps://doi.org/10.1016/j.neuropharm.2018.02.030.

49. Platt, S.R. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy / S.R. Platt, V. Adams, L.S. Garosi, et al. // Vet Rec. ‒ 2006. ‒ No. 159(26). ‒ pp. 881-884.

50. Ruel, H.L.M. Pain burden, sensory profile and inflammatory cytokines of dogs with naturally-occurring neuropathic pain treated with gabapentin alone or with meloxicam / H.L.M. Ruel, R. Watanabe, M.C. Evangelista, et al. // PLoS One. ‒ 2020. ‒ No. 15(11). ‒ pp. e0237121. doihttps://doi.org/10.1371/journal.pone.0237121.

51. Stahl, S.M. Anticonvulsants as anxiolytics, part 2: Pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels / S.M. Stahl // J Clin Psychiatry. ‒ 2004. ‒ No. 65(4). ‒ pp. 460-461. doihttps://doi.org/10.4088/jcp.v65n0401.

52. Stahl, S.M. Mechanism of action of trazodone: a multifunctional drug / S.M. Stahl // CNS Spectr. ‒ 2009. ‒ No. 14(10). ‒ pp. 536-546. doihttps://doi.org/10.1017/s1092852900024020.

53. Stollar, O.O. Effects of a single dose of orally administered gabapentin in dogs during a veterinary visit: a double-blinded, placebo-controlled study / O.O. Stollar, G.E. Moore, A. Mukhopadhyay, W. Gwin, N. Ogata // J Am Vet Med Assoc. ‒ 2022. ‒ No. 260(9). ‒ pp. 1031-1040. doihttps://doi.org/10.2460/javma.21.03.0167.

54. Taylor, R. The utility of somatic items in the assessment of depression in patients with chronic pain: a comparison of the Zung Self-Rating Depression Scale and the Depression Anxiety Stress Scales in chronic pain and clinical and community samples / R. Taylor, P.F. Lovibond, M.K. Nicholas, C. Cayley, P.H. Wilson // Clin J Pain. ‒ 2005. ‒ No. 21(1). ‒ pp. 91-100. doihttps://doi.org/10.1097/00002508-200501000-00011.

55. Tesfaye, S. Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study / S. Tesfaye, P. Saravanan, E. Ehler, et al. // Pain Ther. ‒ 2024. ‒ No. 13(4). ‒ pp. 987-no. 1006. doihttps://doi.org/10.1007/s40122-024-00624-3.

56. Wagner, A.E. Clinical evaluation of perioperative administration of gabapentin as an adjunct for postoperative analgesia in dogs undergoing amputation of a forelimb / A.E. Wagner, P.M. Mich, S.R. Uhrig, P.W. Hellyer // J Am Vet Med Assoc. ‒ 2010. ‒ No. 236(7). ‒ pp. 751-756. doihttps://doi.org/10.2460/javma.236.7.751.

57. Walsh, K. Chronic pain management in dogs and cats / K. Walsh // In Pract. ‒ 2016. ‒ No. 38. ‒ pp. 155-65. doi:https://doi.org/10.1136/inp.i1489

58. Wallis, L.J. Utilising dog-computer interactions to provide mental stimulation in dogs especially during ageing / L.J. Wallis, F. Range, E. Kubinyi, D. Chapagain, J. Serra, L. Huber // ACI 2017 Improv Relat. ‒ 2017. ‒ No. 2017. ‒ pp. 1. doihttps://doi.org/10.1145/3152130.3152146

59. Wiffen, P.J. WITHDRAWN: Gabapentin for acute and chronic pain / P.J. Wiffen, H.J. McQuay, J. Edwards, R.A .Moore // Cochrane Database Syst Rev. ‒ 2011. ‒ No. 2011(3). ‒ CD005452. doihttps://doi.org/10.1002/14651858.CD005452.pub2.

60. Vasudevan, R. Alleviation of neuropathic pain by trazodone in rats / R. Vasudevan // Brazilian Journal of Pharmaceutical Sciences. ‒ 2022. ‒ No. 58. ‒ e19256.

Login or Create
* Forgot password?