Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model.

The commonly used sedative α2-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α2-adrenoceptor antagonist MK-467. An ancillary effect of dexmedetomidine is to decrease insulin release from the pancreas, whereas MK-467 stimulates insulin release. This study assessed the effects of co-administered dexmedetomidine and MK-467 in a canine glibenclamide-induced hypoglycaemia model. In a randomised, cross-over experiment, eight beagle dogs received five intravenous treatments, comprising two administrations of saline, with dexmedetomidine or dexmedetomidine and MK-467, and three administrations of glibenclamide, with saline, dexmedetomidine or dexmedetomidine and MK-467. Plasma concentrations of glucose, lactate, insulin, glucagon and the test drugs were monitored. Administration of glibenclamide significantly increased insulin secretion and decreased blood glucose concentrations. Dexmedetomidine counteracted glibenclamide-evoked hypoglycaemia. This was opposed by the α2-adrenoceptor antagonist MK-467, but the glibenclamide-evoked hypoglycaemia was not potentiated by co-administration of dexmedetomidine and MK-467. None of the dogs developed uncontrolled hypoglycaemia. Thus, the combination of dexmedetomidine and MK-467 appeared to be safe in this canine hypoglycaemia model. Nevertheless, when MK-467 is used to alleviate the undesired cardiovascular effects of α2-adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects.

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.

Cardiopulmonary effects of vatinoxan in sevoflurane-anaesthetised sheep receiving dexmedetomidine.

The effects of pre-treatment with vatinoxan (MK-467) on dexmedetomidine-induced cardiopulmonary alterations were investigated in sheep. In a crossover study design with a 20-day washout, seven sheep were anaesthetised with sevoflurane in oxygen and air. The sheep were ventilated with the pressure-limited volume-controlled mode and a positive end-expiratory pressure of 5cmH2O. Peak inspiratory pressure (PIP) was set at 25cmH2O. The sheep received either 150µg/kg vatinoxan HCl (VAT+DEX) or saline intravenously (IV) 10min before IV dexmedetomidine HCl (3µg/kg, DEX). Cardiopulmonary variables were measured before treatments (baseline), 3min after vatinoxan or saline, and 5, 15 and 25min after dexmedetomidine. Computed tomography (CT) of lung parenchyma was performed at baseline, 2min before dexmedetomidine, and 10, 20 and 30min after DEX. Bronchoalveolar lavage (BAL) was performed after the last CT scan and shortly before sheep recovered from anaesthesia. After VAT, cardiac output significantly increased from baseline. DEX alone significantly decreased partial arterial oxygen tension, total dynamic compliance and tidal volume, whereas PIP was significantly increased. With VAT+DEX, these changes were minimal. No significant changes were detected in haemodynamics from baseline after DEX. With VAT+DEX, mean arterial pressure and systemic vascular resistance were significantly decreased from baseline, although hypotension was not detected. On CT, lung density was significantly increased with DEX as compared to baseline. No visual abnormalities were detected in bronchoscopy and no differences were detected in the BAL fluid after either treatment. The pre-administration of vatinoxan alleviates dexmedetomidine-induced bronchoconstriction, oedema and hypoxaemia in sevoflurane-anaesthetised sheep.

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 impact of medetomidine on the protein-binding characteristics of MK-467 in canine plasma.

This study determined the unbound fraction of the peripheral α2 -adrenoceptor antagonist MK-467 alone and combined with medetomidine. MK-467 (0.1, 1 and 10 µm) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with α1-acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (fu ) of MK-467. Unbound fractions (fu ) of MK-467 in canine plasma (mean ± standard deviation) were 27.6 ± 3.5%, 26.6 ± 0.9% and 42.4 ± 1.2% at 0.1, 1.0 and 10 µm concentrations, respectively. In the presence of medetomidine, fu were 27.5 ± 0.4%, 26.6 ± 0.9% and 41.0 ± 2.4%. The fu of MK-467 in HSA were 50.1 ± 2.5% at 0.1 µm, 49.4 ± 1.2% at 1.0 µm and 56.7 ± 0.5% at 10 µm. fu of MK-467 in AGP was 56.3 ± 3.7% at 0.1 µm, 54.6 ± 5.6% at 1.0 µm and 65.3 ± 0.4% at 10 µm. Protein binding of MK-467 was approximately 70% between 0.1 and 1.0 µm. Medetomidine had no apparent effect on the protein binding of MK-467.

Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.

We investigated the influence of the peripherally acting α2 -adrenoceptor antagonist MK-467 on the sedative and antinociceptive actions and plasma drug concentrations of medetomidine, an α2 -adrenoceptor agonist that is used in veterinary medicine as a sedative and analgesic agent. Eight healthy beagle dogs received intravenous medetomidine (10 µg/kg) or medetomidine with MK-467 (250 µg/kg) in a randomized crossover design. A standardized nociceptive pressure stimulus was applied to a nail bed of a hindlimb. Times for withdrawal of the limb and for head lift were measured, and sedation was scored. EEG data were collected prior to and after stimulation. Plasma drug concentrations were measured. Co-administration of MK-467 significantly attenuated medetomidine analgesia, as assessed with limb withdrawal, and also shortened the duration of sedation. The apparent plasma clearance of both enantiomers of medetomidine, dexmedetomidine and levomedetomidine, was more than doubled in the presence of MK-467. Antagonism by MK-467 of medetomidine-evoked vasoconstriction is seen as the mechanism behind this pharmacokinetic drug interaction. Thus, MK-467 attenuated the antinociceptive and sedative effects of medetomidine. This can probably be explained by increased clearance and decreased concentrations of dexmedetomidine in plasma after co-administration of MK-467 with racemic medetomidine.

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.

The diet board: welfare impacts of a novel method of dietary restriction in laboratory rats.

Laboratory rats are commonly fed ad libitum (AL). Moderate dietary restriction (DR) decreases mortality and morbidity when compared with AL feeding, but there are several obstacles to the implementation of DR. Traditional methods of restricted feeding disrupt normal diurnal eating rhythms and are not compatible with group housing. We have designed a novel method, the diet board, to restrict the feeding of group-housed rats. Animals fed from the diet board had 15% lower body weight than the AL-fed animals at the age of 17 weeks. The welfare effects of diet board feeding were assessed by comparing the stress physiology of diet board fed animals with that of AL-fed animals. Diet board feeding was associated with higher serum corticosterone levels and lower faecal secretion of IgA, suggesting the diet board causes a stress reaction. However, the AL-fed group had larger adrenal glands with higher adrenaline and noradrenaline content than the diet board animals. No gastric ulcers were found in any of the animals at necropsy. The diet board thus appears to cause a stress reaction when compared with AL-fed rats, but no apparent pathology was associated with this reaction. The diet board could help to solve the health problems associated with AL feeding, while allowing the rats to be group-housed and to maintain their normal diurnal eating rhythms. The diet board can also be seen as a functional cage furniture item, dividing the cage into compartments and thus increasing the structural complexity of the environment. In conclusion, the diet board appears to possess refinement potential compared with traditional methods of DR.

Opinions of Finnish small animal owners about surgery and pain management in small animals.

OBJECTIVES: To examine the opinions among small animal owners regarding the management of pain and surgery in small animals. METHODS: A questionnaire was presented to 800 owners of dogs or cats who visited one of the four participating clinics in Finland in February 2006. RESULTS: A total of 482 owners completed the questionnaire (60.3 per cent response rate); 90 per cent of the respondents were female. Owners classified surgical procedures (for example, fracture repair, skin tumour removal and neutering) as more painful than medical conditions (otitis externa and lameness). In addition, owners disagreed most with statements that they had received sufficient information on the appropriate methods of management of animal pain and that the recognition of animal pain is easy. With respect to surgical procedures, owners expressed greatest concern in relation to the animal experiencing fear or anxiety during hospitalisation and the presence of postoperative pain. CLINICAL SIGNIFICANCE: The animal owners had concerns about the presence and management of animal pain, fear and anxiety. Knowledge of these animal owner opinions could aid veterinary practitioners when communicating with their clients on medical and surgical patient management. Furthermore, studies are merited to clearly define how best to successfully respond to these owner attitudes.

Relation between body temperature and dexmedetomidine-induced minimum alveolar concentration and respiratory changes in isoflurane-anesthetized miniature swine.

Dexmedetomidine (DEX), an alpha 2-receptor agonist, is the pharmacologically active d-isomer of medetomidine, a compound used as a sedative in veterinary medicine. Isoflurane anesthetic requirement (minimum alveolar concentration; MAC), rectal temperature, and cardiorespiratory variables were studied in chronically instrumented Yucatan miniature swine during DEX (20 micrograms/kg of body weight)-induced changes in body temperature. All studies were performed at room temperature of 22 C. The DEX was given as a 2-minute infusion into the left atrium. Each pig was studied twice. For protocol 1, the core temperature of the pigs was maintained at (mean +/- SD) 38.2 +/- 0.5 C by use of a thermostatically controlled water blanket and a heating lamp. For protocol 2, the core temperature was not externally manipulated and it decreased from 38.2 +/- 0.4 C to 32.2 +/- 1.2 C during the more than 3 hours of the protocol. Control isoflurane MAC was 1.66 +/- 0.2% and was 1.74 +/- 0.3% for protocols 1 and 2, respectively; DEX decreased MAC by 34 and 44%, respectively. For protocol 1, reduction in MAC after DEX administration returned by 50 and 80% at 84 and 138 minutes, respectively. If rectal temperature was not maintained (eg, allowed to decrease), MAC was reduced by 57% at the same time as the return to 80% in the swine with maintained body temperature. Respiratory rate and minute ventilation were significantly higher in swine with maintained temperature. The PaCO2 was lower and, accordingly, pH was higher in these swine. Blood pressure and heart rate were not affected by temperature changes.

Cardiovascular effects of a ketamine-medetomidine combination that produces deep sedation in Yucatan mini swine.

Seven chronically instrumented Yucatan minipigs were deeply sedated with the combination of ketamine (10 mg/kg), a dissociative anesthetic, and medetomidine (0.2 mg/kg), an alpha 2-adrenoceptor agonist used as an animal sedative in Europe. Both drugs were drawn in the same syringe and administered in the left atrium via a previously inserted permanent catheter. As a result, hypertension (mean arterial pressure from 116 +/- 12 mmHg to 142 +/- 18 mmHg) occurred and was followed by bradycardia (from 107 +/- 22 bpm to 71 +/- 9 bpm). Concomitantly, both the rate of increase in ventricular pressure (48%) and ventricular wall thickening fraction (37%) decreased, thus indicating some worsening of left ventricular function. Further, systemic vascular resistance increased (290%) resulting in a reduction in cardiac output from 0.4 +/- 0.3 l/minute. Also, left ventricular end diastolic pressure initially increased (maximum 10.2 +/- 10.8 mmHg) but returned to the control level in 5 minutes. In spite of an increase in respiratory frequency (3x), PaCO2 increased and PaO2 and pH declined. Rectal temperature decreased from 38.4 +/- 0.9 to 36.0 +/- 0.8 degrees C. All of these changes were transient and returned to control levels during the follow-up period (2 hours). However, epinephrine concentration was exceptionally decreased by the drugs and stayed under the detection limit (20 pg/kg) for the entire time, whereas norepinephrine was undetectable for 10 minutes postadministration. Ketamine-medetomidine, administered in a dose that produced deep sedation, induced marked but reversible changes in most of the cardiovascular variables; there were no pedal or palpebral reflexes for 30 minutes.