The impact of MK‐467 on plasma drug concentrations, sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal

Abstract

The effect of MK‐467, a peripheral α2‐adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2‐week washout periods. Medetomidine (MED) 30 μg/kg alone or combined in the same syringe with MK‐467 300 μg/kg (MMK) was injected intramuscular, followed by ATI 150 μg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK‐467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine‐related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK‐467 was included. In this study, MK‐467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs

“…Concentrations of dexmedetomidine in canine plasma were determined with chiral high-performance liquid chromatographyemass spectrometry (HPLCeMS/MS, Sciex API 4000; AB Sciex Pte. Ltd, ON, Canada) as described previously (Adam et al 2018). Reference samples were prepared in drug-free canine plasma.…”

Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs

“…In the last decade, renewed interest in its potential to prevent the peripheral, while preserving the central effects of α 2 -adrenoceptor agonists, has been the subject of numerous studies investigating cardiopulmonary, sedative and metabolic outcomes in several species. In brief, vatinoxan has been shown to either attenuate or prevent the cardiovascular effects of various α 2 -adrenoceptor agonists in dogs (Pagel et al 1998;Enouri et al 2008;Honkavaara et al 2008Honkavaara et al , 2011Rolfe et al 2012), horses (Bryant et al 1998;de Vries et al 2016;Tapio et al 2018), sheep (Bryant et al 1998;Raekallio et al 2010: Adam et al 2018) and cats (Pypendop et al 2017a;Siao et al 2017). Moreover, its impact on agonistinduced sedation appears to be minor and more related to alteration on the disposition of coadministered agonists drugs through attenuation of their cardiovascular effects (Vainionpaa et al 2013;Bennett et al 2016;Restitutti et al 2017;Adam et al 2018;Pypendop et al 2016Pypendop et al , 2017bHonkavaara et al 2017a, b).…”

Cardiovascular effects of intravenous vatinoxan in wild boars (Sus scrofa) anaesthetised with intramuscular medetomidine‐tiletamine‐zolazepam

“…39 Studies in sheep and dogs showed lower haemoglobin concentrations when the alpha-2-adrenergic agonist was combined with VTX. 12,13,41 All animals showed a sufficient level plane of anaesthesia, and no difference was detected between treatments. However, the additional anaesthetic effects of tiletamine and zolazepam used in the study does not allow interpretation of the impact of VTX on the level or duration of the medetomidine-induced sedation.…”