Cardiopulmonary, Sedative, and Drug Disposition Effects of Vatinoxan in Sheep Receiving Dexmedetomidine, Medetomidine, Ketamine and Atipamezole

The impact of the peripherally selective α2-adrenoceptor antagonist, vatinoxan, on selected pharmacodynamic and pharmacokinetic properties of two selective α2-adrenoceptor agonists, medetomidine and dexmedetomidine, were investigated in sheep. Moreover, certain interactions between vatinoxan and atipamezole, a specific α2-adrenoceptor antagonist, were evaluated. The initial objective of this study was to identify a dose of vatinoxan that would best mitigate the undesirable cardiopulmonary changes produced by intramuscular (IM) medetomidine-ketamine in sheep. Specifically, three doses of vatinoxan (150, 300 and 600 μg/kg) or saline were combined in the same syringe with medetomidine (30 μg/kg) and ketamine (1 mg/kg) and given IM. Systemic hemodynamics, arterial blood gas tensions, clinical sedation and plasma drug concentrations were compared, both before and after reversal with IM atipamezole (150 μg/kg). The middle dose of vatinoxan (300 μg/kg), which appeared to be optimal among the other doses, was then added to medetomidine (30 μg/kg) and co-administered IM, followed by atipamezole for reversal. Last, the influence of intravenous pre-treatment with vatinoxan on dexmedetomidine-induced cardiopulmonary alterations was investigated in sevoflurane-anesthetized sheep. Following concomitant IM administration, vatinoxan dose-dependently attenuated some of medetomidine’s cardiopulmonary side effects. Vatinoxan did not significantly affect the level of sedation or the plasma concentrations of drugs when ketamine was included in the same syringe. Conversely, vatinoxan significantly increased the plasma concentrations of medetomidine, and accelerated the onset and intensified the degree of sedation when compared with the agonist alone. Moreover, recoveries after atipamezole-reversal were more complete in the presence of vatinoxan. No deleterious effects were noted between vatinoxan and atipamezole. Pre-treatment with vatinoxan prevented all dexmedetomidine-induced pulmonary alterations in sheep anesthetized with sevoflurane. In conclusion, vatinoxan alleviated or prevented the unwanted cardiopulmonary effects of (dex-) medetomidine by blocking the peripheral α2-adrenoceptors. Presumably, when co-administered IM in the same syringe, vatinoxan accelerated the absorption of medetomidine and increased its concentration in blood, which resulted in a faster and more intense sedation than when the agonist was used alone. Vatinoxan also decreased later exposure to dexmedetomidine, which appeared to improve atipamezole’s efficacy to reverse both the central and peripheral effect of the agonist. LIST OF PUBLICATIONS This thesis is based on the following original articles referred to in the text by their Roman numerals: Study I Adam, M. , Raekallio, M.R. , Salla, K.M. , Honkavaara, J.M. , Männikkö, S. , Scheinin, M. , Kajula, M. , Mölsä, S. & Vainio, O.M. (2018) Effects of the peripherally acting α2-adrenoceptor antagonist MK467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole. American Journal of Veterinary Research, 79, 921–932. Study II Adam, M. , Raekallio, M.R. , Keskitalo, T. , Honkavaara, J.M. , Scheinin, M. , Kajula, M. , Mölsä, S. & Vainio, O.M. (2018) The impact of MK-467 on plasma drug concentrations, sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal. Journal of Veterinary Pharmacology and Therapeutics, 41, 447–456. Study III Adam, M. , Raekallio, M.R. & Vainio, O.M. (2018) Sedative effect of intramuscular medetomidine with and without vatinoxan (MK-467), and its reversal with atipamezole in sheep. Veterinary Anaesthesia and Analgesia, 45, 788–793. Study IV Adam, M. , Huuskonen, V. , Raekallio, M.R. , Casoni, D. , Mykkänen, A.K. , Lappalainen, A.K. , Kajula, M. , Kallio-Kujala, I.J. & Vainio, O.M. (2018) Cardiopulmonary effects of vatinoxan in sevofluraneanaesthetised sheep receiving dexmedetomidine. Veterinary Journal, 238, 63–69. Reprints of the original articles are published with the permission of their copyright holders. In addition, some unpublished material is presented.