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

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.

The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.

Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 µg/kg [D]), MK-467 (250 µg/kg [M250] or dexmedetomidine (10 µg/kg) with increasing doses of MK-467 (250 µg/kg [DM250], 500 µg/kg [DM500] and 750 µg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidine's systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function.

The effects of L-659,066, a peripheral α2-adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep.

We investigated whether administration of L-659,066, a peripheral α(2) -adrenoceptor antagonist, or verapamil, a calcium-channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross-over design: dexmedetomidine (5 µg/kg, DEX); DEX with L-659,066 (250 µg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 ± 10.7 to 120.8 ± 11.7 mmHg), central venous pressure (CVP) (3.3 ± 3.2 to 14.7 ± 5.0 mmHg) and systemic vascular resistance (SVR) (1579 ± 338 to 2301 ± 523 dyne s/cm(5) ), and decreases in cardiac output (CO) (5.36 ± 0.87 to 3.93 ± 1.30 L/min) and heart rate (HR) (88.6 ± 15.3 to 49.7 ± 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 ± 226 dyne s/cm(5) ) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 ± 6.8 to 89.3 ± 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2-20 min with no differences between treatments. L-659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral α(2) -adrenoceptors, whereas the effects of verapamil were marginal.

Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomised, clinical trial.

The aim of this study was to investigate the clinical usefulness of MK-467 (vatinoxan; L-659'066) in dogs sedated for diagnostic imaging with medetomidine-butorphanol. It was hypothesised that MK-467 would alleviate bradycardia, hasten drug absorption and thus intensify the early-stage sedation. In a prospective, randomised, blinded clinical trial, 56 client-owned dogs received one of two IM treatments: (1) 0.5mg/m2 medetomidine+0.1mg/kg butorphanol (MB, n=29); or (2) 0.5mg/m2 medetomidine+0.1mg/kg butorphanol+10mg/m2 MK-467 (MB-MK, n=27). Heart rates and visual sedation scores were recorded at intervals. Plasma drug concentrations were determined in venous samples obtained approximately 14min after injection. Additional sedation (50% of original dose of medetomidine IM) and/or IM atipamezole for reversal were given when needed. The area under the sedation score-time curve for visual analogue scale (AUCVAS30) was calculated for the first 30min after treatment using the trapezoidal method. Repeated ANOVA, Mann-Whitney U test and Fisher's exact test were used for parametric, non-parametric and dichotomous data. Heart rate was significantly higher from 10 to 40min with MB-MK than with MB. AUCVAS30 was significantly higher after MB-MK. More dogs treated with MB-MK required additional sedation after 30min, but fewer needed atipamezole for reversal compared with MB. Plasma concentrations of both medetomidine and butorphanol were higher after MB-MK. All procedures were successfully completed. MK-467 alleviated the bradycardia, intensified the early stage sedation and shortened its duration in healthy dogs that received IM medetomidine-butorphanol.