Effects of vatinoxan in dogs premedicated with medetomidine and butorphanol followed by sevoflurane anaesthesia: a randomized clinical study.

OBJECTIVE: To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration. STUDY DESIGN: A randomized, controlled, blinded, clinical trial. ANIMALS: A total of 28 client-owned dogs. METHODS: Dogs were premedicated with medetomidine (0.125 mg m-2) and butorphanol (0.2 mg kg-1) (group MB; n = 14), or medetomidine (0.25 mg m-2), butorphanol (0.2 mg kg-1) and vatinoxan (5 mg m-2) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg-1) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg-1) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (fR), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (Fe'Sevo) and carbon dioxide (Pe'CO2) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations. RESULTS: At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute-1 (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in fR, Pe'CO2, Fe'Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.

The impact of vatinoxan on medetomidine-ketamine-midazolam immobilization in Patagonian maras (Dolichotis patagonum).

OBJECTIVE: To compare cardiovascular and ventilatory effects, immobilization quality and effects on tissue perfusion of a medetomidine-ketamine-midazolam combination with or without vatinoxan (MK-467), a peripherally acting α2-adrenoceptor antagonist. STUDY DESIGN: Randomized, blinded, crossover study. ANIMALS: A group of nine healthy Patagonian maras (Dolichotis patagonum). METHODS: Maras were immobilized twice with: 1) medetomidine hydrochloride (0.1 mg kg-1) + ketamine (5 mg kg-1) + midazolam (0.1 mg kg-1) (MKM) + saline or 2) MKM + vatinoxan hydrochloride (0.8 mg kg-1), administered intramuscularly. Drugs were mixed in the same syringe. At 20, 30 and 40 minutes after injection, invasive blood pressure, heart rate, respiration rate, end-tidal CO2, haemoglobin oxygen saturation, and muscle oxygenation were measured, arteriovenous oxygen content difference was calculated. Muscle tone, jaw tone, spontaneous blinking and palpebral reflex were evaluated. Times to initial effect, recumbency, initial arousal and control of the head were recorded. Paired t test, Wilcoxon matched-pairs signed rank test and analysis of variance were used to compare protocols; (p < 0.05). RESULTS: Vatinoxan significantly reduced systolic (p = 0.0002), mean (MAP; p < 0.0001) and diastolic (p < 0.0001) arterial blood pressures between 20 and 40 minutes. MAPs at 30 minutes (mean ± standard deviation) with MKM and MKM + vatinoxan were 105 ± 12 and 71 ± 14 mmHg, respectively. Without vatinoxan, four animals were hypertensive (MAP > 120 mmHg), whereas with vatinoxan, four animals were hypotensive (MAP < 60 mmHg). Muscle and jaw tone were significantly more frequently present with MKM (both p = 0.039). Other measurements did not significantly differ between protocols. CONCLUSIONS AND CLINICAL RELEVANCE: In Patagonian maras, vatinoxan attenuated the increase in blood pressure induced by medetomidine. Muscle and jaw tone were more frequently present with MKM, indicating that quality of immobilization with vatinoxan was more profound.

Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs.

OBJECTIVE: To evaluate the effects of combined infusions of vatinoxan and dexmedetomidine on inhalant anesthetic requirement and cardiopulmonary function in dogs. STUDY DESIGN: Prospective experimental study. METHODS: A total of six Beagle dogs were anesthetized to determine sevoflurane minimum alveolar concentration (MAC) prior to and after an intravenous (IV) dose (loading, then continuous infusion) of dexmedetomidine (4.5 µg kg-1 hour-1) and after two IV doses of vatinoxan in sequence (90 and 180 µg kg-1 hour-1). Blood was collected for plasma dexmedetomidine and vatinoxan concentrations. During a separate anesthesia, cardiac output (CO) was measured under equivalent MAC conditions of sevoflurane and dexmedetomidine, and then with each added dose of vatinoxan. For each treatment, cardiovascular variables were measured with spontaneous and controlled ventilation. Repeated measures analyses were performed for each response variable; for all analyses, p < 0.05 was considered significant. RESULTS: Dexmedetomidine reduced sevoflurane MAC by 67% (0.64 ± 0.1%), mean ± standard deviation in dogs. The addition of vatinoxan attenuated this to 57% (0.81 ± 0.1%) and 43% (1.1 ± 0.1%) with low and high doses, respectively, and caused a reduction in plasma dexmedetomidine concentrations. Heart rate and CO decreased while systemic vascular resistance increased with dexmedetomidine regardless of ventilation mode. The co-administration of vatinoxan dose-dependently modified these effects such that cardiovascular variables approached baseline. CONCLUSIONS AND CLINICAL RELEVANCE: IV infusions of 90 and 180 µg kg-1 hour-1 of vatinoxan combined with 4.5 µg kg-1 hour-1 dexmedetomidine provide a meaningful reduction in sevoflurane requirement in dogs. Although sevoflurane MAC-sparing properties of dexmedetomidine in dogs are attenuated by vatinoxan, the cardiovascular function is improved. Doses of vatinoxan >180 µg kg-1 hour-1 might improve cardiovascular function further in combination with this dose of dexmedetomidine, but beneficial effects on anesthesia plane and recovery quality may be lost.

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

OBJECTIVE: To quantify the peripheral selectivity of vatinoxan (L-659,066, MK-467) in dogs by comparing the concentrations of vatinoxan, dexmedetomidine and levomedetomidine in plasma and central nervous system (CNS) tissue after intravenous (IV) coadministration of vatinoxan and medetomidine. STUDY DESIGN: Experimental, observational study. ANIMALS: A group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 ± 0.1 years (mean ± standard deviation). METHODS: All dogs were administered a combination of medetomidine (40 µg kg-1) and vatinoxan (800 µg kg-1) as IV bolus. After 20 minutes, the dogs were euthanized with an IV overdose of pentobarbital (140 mg kg-1) and both venous plasma and CNS tissues (brain, cervical and lumbar spinal cord) were harvested. Concentrations of dexmedetomidine, levomedetomidine and vatinoxan in all samples were quantified by liquid chromatography-tandem mass spectrometry and data were analyzed with nonparametric tests with post hoc corrections where appropriate. RESULTS: All dogs became deeply sedated after the treatment. The CNS-to-plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dexmedetomidine and levomedetomidine in the CNS were three- to seven-fold of those in plasma. CONCLUSIONS AND CLINICAL RELEVANCE: With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when coadministered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.

Sedative effect of intramuscular medetomidine with and without vatinoxan (MK-467), and its reversal with atipamezole in sheep.

OBJECTIVE: To evaluate the effect of the peripherally acting α2-adrenoceptor antagonist vatinoxan (MK-467) on the sedative properties of medetomidine (MED) when injected intramuscularly (IM) in the same syringe and on reversal of this sedation with atipamezole in sheep. STUDY DESIGN: Randomized, blinded, crossover experimental trial. ANIMALS: Eight healthy adult female sheep. METHODS: Sheep received MED (30 µg kg-1 IM) alone or combined in the same syringe with vatinoxan (300 µg kg-1 IM, MED+VAT) with a 2 week washout period. Atipamezole (150 µg kg-1 IM) was administered 30 minutes later for reversal. Sedation was assessed using two sedation scores, a visual analog score and a descriptive scale before treatments (T0) and at intervals up to 5 hours thereafter. Pulse rate (PR) was counted at T0 and at 30 (T30) and 90 (T90) minutes. Rectal temperature was measured at T0 and T90 postinjection. Plasma samples were analyzed for drug concentrations at T30 and T90. RESULTS: The first signs of sedation were seen significantly earlier after MED+VAT (4.6 ± 1.7 minutes versus 9.4 ± 2.6 minutes after MED) and the sedation scores were significantly higher after MED+VAT than MED. All animals laid with head down 10.0 ± 3.4 minutes after MED+VAT, whereas three MED animals did not become recumbent before atipamezole was administered. The plasma concentrations of dexmedetomidine were significantly higher at T30 (2.47 ± 0.2 ng mL-1) and significantly lower at T90 (1.23 ± 0.3 ng mL-1) with MED+VAT than with MED (1.19 ± 0.8 and 1.83 ± 0.4 ng mL-1, respectively). While no significant differences were observed between treatments in PR at T30, PR at T90 was significantly higher with MED+VAT than with MED. CONCLUSIONS AND CLINICAL RELEVANCE: When administered IM in the same syringe, vatinoxan hastened and intensified the initial sedative effects of MED and enhanced the sedation reversal by atipamezole.

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

OBJECTIVE: We determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. STUDY DESIGN: Randomized, experimental, blinded crossover study. ANIMALS: Six healthy Beagle dogs. METHODS: Two IM treatments were administered: 1) medetomidine hydrochloride (20 µg kg-1) + butorphanol (100 µg kg-1) + midazolam (200 µg kg-1; MBM) and 2) MBM + MK-467 hydrochloride (500 µg kg-1; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. RESULTS: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Adverse reactions of α2-adrenoceptor agonists in cats reported in 2003-2013 in Finland.

OBJECTIVE: To describe suspected adverse drug reactions in cats associated with use of α2-adrenoceptor agonists. STUDY DESIGN: Retrospective study. ANIMALS: A total of 90 cats. METHODS: Data were collected from reports on adverse reactions to veterinary medicines sent to the Finnish Medicines Agency during 2003-2013. All reports of suspected adverse reactions associated with use of α2-adrenoceptor agonists in cats were included. Probable pulmonary oedema was diagnosed based on post mortem or radiological examination, or presence of frothy or excess fluid from the nostrils or trachea. If only dyspnoea and crackles on auscultation were reported, possible pulmonary oedema was presumed. RESULTS: Pulmonary oedema was suspected in 61 cases. Of these cats, 37 were categorised as probable and 24 as possible pulmonary oedema. The first clinical signs had been noted between 1 minute and 2 days (median, 15 minutes) after α2-adrenoceptor agonist administration. Many cats probably had no intravenous overhydration when the first clinical signs were detected, as either they presumably had no intravenous cannula or the signs appeared before, during or immediately after cannulation. Of the 61 cats, 43 survived, 14 died and for four the outcome was not clearly stated. CONCLUSIONS AND CLINICAL RELEVANCE: Pulmonary oedema is a perilous condition that may appear within minutes of an intramuscular administration of sedative or anaesthetic agent in cats. The symptoms were not caused by intravenous overhydration, at least in cats having no venous cannula when the first clinical signs were detected.

Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs.

OBJECTIVE: We investigated the plasma concentrations and cardiovascular effects of intramuscularly (IM) administered medetomidine, administered alone or with three different doses of MK-467. STUDY DESIGN: Prospective, randomized, open, crossover trial. ANIMALS: Eight purpose-bred healthy Beagle dogs. METHODS: Each dog was administered four treatments: medetomidine 20 µg kg-1 IM alone or mixed in the same syringe with MK-467 (200 µg kg-1, 400 µg kg-1 or 600 µg kg-1). Instrumentation was performed under standardized anaesthesia. The dogs were allowed to recover before measurement of baseline values. Composite sedation scores, cardiovascular variables, i.e., heart rate (HR), cardiac output (CO), mean arterial and central venous blood pressures (MAP and CVP) and arterial blood gases were recorded at baseline and for 60 minutes after treatment. Drug concentrations in venous plasma were analysed. Generalized linear mixed models for repeated measures with post hoc Bonferroni correction were used with statistical significance level set at α=0.05. RESULTS: All treatments initially demonstrated the effects of medetomidine: HR and CO decreased and CVP increased. MAP transiently increased and then significantly decreased from baseline with the two highest MK-467 doses. The cardiovascular effects of medetomidine disappeared more rapidly with MK-467 than with medetomidine alone. With medetomidine alone, sedation scores remained high until the end of the 60 minute follow-up. Maximum concentrations of medetomidine were more rapidly achieved and were higher with MK-467. CONCLUSIONS AND CLINICAL RELEVANCE: Initial haemodynamic effects of medetomidine were not prevented by MK-467, but these effects were attenuated and their duration shortened by MK-467, independently of dose. Absorption of medetomidine was accelerated by MK-467, when administered concomitantly IM, resulting in faster sedation; addition of MK-467 shortened the sedative effect of medetomidine.

Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral α2-adrenoceptor antagonist, MK-467, on sevoflurane minimum alveolar concentration (MAC) in dogs. STUDY DESIGN: Crossover experimental study. ANIMALS: Six healthy, adult Beagle dogs weighing 12.6±0.9 kg (mean±standard deviation). METHODS: Dogs were anesthetized with sevoflurane in oxygen. After a 60-minute instrumentation and equilibration period, the MAC of sevoflurane was determined in triplicate using the tail clamp technique. PaCO2 and temperature were maintained at 40±5 mmHg (5.3±0.7 kPa) and 38±0.5 ºC, respectively. After baseline MAC determination, dogs were administered two incremental loading and infusion doses of either dexmedetomidine (1.5 µg kg-1 then 1.5 µg kg-1 hour-1 and 4.5 µg kg-1 then 4.5 µg kg-1 hour-1) or MK-467 (90 µg kg-1 then 90 µg kg-1 hour-1 and 180 µg kg-1 then 180 µg kg-1 hour-1); loading doses were administered over 10 minutes. MAC was redetermined in duplicate starting 30 minutes after the start of drug administration at each dose. End-tidal sevoflurane concentrations were corrected for calibration and adjusted to sea level. A repeated-measures analysis was performed and comparisons between doses were conducted using Tukey's method. Statistical significance was considered at p<0.05. RESULTS: Sevoflurane MAC decreased significantly from 1.86±0.3% to 1.04±0.1% and 0.57±0.1% with incremental doses of dexmedetomidine. Sevoflurane MAC significantly increased with high dose MK-467, from 1.93±0.3% to 2.29±0.5%. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine caused a dose-dependent decrease in sevoflurane MAC, whereas MK-467 caused an increase in MAC at the higher infusion dose. Further studies evaluating the combined effects of dexmedetomidine and MK-467 on MAC and cardiovascular function may elucidate potential benefits of the addition of a peripheral α2-adrenergic antagonist to inhalation anesthesia in dogs.

Clinical effects and pharmacokinetic variables of romifidine and the peripheral α2 -adrenoceptor antagonist MK-467 in horses.

OBJECTIVES: To investigate the effects of MK-467 on sedation quality, and cardiopulmonary and pharmacokinetic variables in horses sedated intravenously (IV) with romifidine. STUDY DESIGN: Experimental, randomized, crossover design. ANIMALS: Seven healthy mares. METHODS: Romifidine (80 µg kg-1 ; R) and MK-467 (200 µg kg-1 ; MK) were administered IV alone and in combination (R + MK). Levels of sedation and borborygmi were scored. Heart rate (HR), direct arterial blood pressure (ABP) and respiratory rate (fR ) were recorded. Arterial and venous blood gas analyses were performed and venous plasma drug concentrations were measured. Pharmacokinetic parameters were calculated. Linear mixed modelling for repeated measures, contrasts of least square means by Bonferroni correction tests, one-way anova for repeated measures with Bonferroni multiple comparison tests and paired Student's t-tests were used to compare results within and between treatments as appropriate. Significance was set at p < 0.05. RESULTS: After R, ABP increased and HR and fR decreased significantly. After R + MK, HR, fR , systolic and mean ABP decreased. MK alone increased both HR and fR . After R, ABP was significantly higher than after R + MK. HR and fR were significantly higher after MK than after R and R + MK. Areas under the curve for sedation time were similar after R and R + MK. Intestinal activity decreased markedly after R and less after R + MK. Volume of distribution and clearance of romifidine were significantly higher and area under the concentration time curve extrapolated to infinity significantly lower after R + MK than after R. CONCLUSIONS: Combined romifidine and MK-467 prevented the cardiovascular changes commonly seen with romifidine but did not affect sedation quality. CLINICAL RELEVANCE: Combined IV romifidine and MK-467 can be used to attenuate the cardiovascular effects of romifidine, such as in horses with colic or undergoing general anaesthesia.

Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane.

OBJECTIVE: To investigate MK-467 as part of premedication in horses anaesthetized with isoflurane. STUDY DESIGN: Experimental, crossover study with a 14 day wash-out period. ANIMALS: Seven healthy horses. METHODS: The horses received either detomidine (20 µg kg(-1) IV) and butorphanol (20 µg kg(-1) IV) alone (DET) or with MK-467 (200 µg kg(-1) IV; DET + MK) as premedication. Anaesthesia was induced with ketamine (2.2 mg kg(-1) ) and midazolam (0.06 mg kg(-1) ) IV and maintained with isoflurane. Heart rate (HR), mean arterial pressure (MAP), end-tidal isoflurane concentration, end-tidal carbon dioxide tension, central venous pressure, fraction of inspired oxygen (FiO2 ) and cardiac output were recorded. Blood samples were taken for blood gas analysis and to determine plasma drug concentrations. The cardiac index (CI), systemic vascular resistance (SVR), ratio of arterial oxygen tension to inspired oxygen (Pa O2 /FiO2 ) and tissue oxygen delivery (DO2 ) were calculated. Repeated measures anova was applied for HR, CI, MAP, SVR, lactate and blood gas variables. The Student's t-test was used for pairwise comparisons of drug concentrations, induction times and the amount of dobutamine administered. Significance was set at p < 0.05. RESULTS: The induction time was shorter, reduction in MAP was detected, more dobutamine was given and HR and CI were higher after DET+MK, while SVR was higher with DET. Arterial oxygen tension and Pa O2 /FiO2 (40 minutes after induction), DO2 and venous partial pressure of oxygen (40 and 60 minutes after induction) were higher with DET+MK. Plasma detomidine concentrations were reduced in the group receiving MK-467. After DET+MK, the area under the plasma concentration time curve of butorphanol was smaller. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 enhances cardiac function and tissue oxygen delivery in horses sedated with detomidine before isoflurane anaesthesia. This finding could improve patient safety in the perioperative period. The dosage of MK-467 needs to be investigated to minimise the effect of MK-467 on MAP.

Sublingual administration of detomidine to calves prior to disbudding: a comparison with the intravenous route.

OBJECTIVE: To study the effects of oromucosal detomidine gel administered sublingually to calves prior to disbudding, and to compare its efficacy with intravenously (IV) administered detomidine. STUDY DESIGN: Randomised, prospective clinical study. ANIMALS: Twenty dairy calves aged 12.4 ± 4.4days (mean ± SD), weight 50.5 ± 9.0 kg. METHODS: Detomidine at 80 µg kg(-1) was administered to ten calves sublingually (GEL) and at 30 µg kg(-1) to ten control calves IV (V. jugularis). Meloxicam (0.5 mg kg(-1) ) and local anaesthetic (lidocaine 3 mg kg(-1) ) were administered before heat cauterization of horn buds. Heart rate (HR), body temperature and clinical sedation were monitored over 240 minutes. Blood was collected from the V. cephalica during the same period for drug concentration analysis. Pharmacokinetic variables were calculated from the plasma detomidine concentration-time data using non-compartmental methods. Statistical analyses compared routes of administration by Student's t-test and linear mixed models as relevant. RESULTS: The maximum plasma detomidine concentration after GEL was 2.1 ± 1.2 ng mL(-1) (mean ±SD) and the time of maximum concentration was 66.0 ± 36.9 minutes. The bioavailability of detomidine was approximately 34% with GEL. Similar sedation scores were reached in both groups after administration of detomidine, but maximal sedation was reached earlier in the IV group (10 minutes) than in the GEL group (40 minutes). HR was lower after IV than GEL from 5 to 10 minutes after administration. All animals were adequately sedated, and we were able to administer local anaesthetic without resistance to all of the calves before disbudding. CONCLUSIONS AND CLINICAL RELEVANCE: Oromucosally administered detomidine is an effective sedative agent for calves prior to disbudding.

Effect of MK-467 on organ blood flow parameters detected by contrast-enhanced ultrasound in dogs treated with dexmedetomidine.

OBJECTIVE: To evaluate the dexmedetomidine-induced reduction in organ blood flow with quantitative contrast-enhanced ultrasound (CEUS) method and to observe the influence of MK-467 on such reduction. STUDY DESIGN: Randomized cross-over study. ANIMALS: Six adult purpose-bred laboratory beagle dogs (mean body weight 15.3 ± 1.9 kg). METHODS: Contrast-enhanced ultrasound was performed on six conscious healthy laboratory beagles. The animals on separate occasions underwent three treatments: awake without any medication (CTRL), dexmedetomidine 10 µg kg(-1) (DEX) and DEX + MK-467 500 µg kg(-1) (DMK) intravenously (IV). The kidney (10-15 minutes post-treatment), spleen (25-30 minutes post-treatment), small intestine (40-45 minutes post-treatment) and liver (50-55 minutes post-treatment) were examined with CEUS. A time curve was generated and the following perfusion parameters were analysed: arrival time (AT), time to peak from injection (TTPinj), peak intensity (PI) and wash-in rate (Wi). In addition to CEUS, renal glomerular filtration rate was indirectly estimated by the rate of iohexol elimination. RESULTS: AT and TTPinj were significantly higher for DEX than for CTRL in all studied organs. The same parameters were significantly higher for DEX than for DMK in the kidney, spleen and small intestine. PI was significantly lower for DEX than for CTRL or DMK in the kidney. Wi was significantly lower for DEX than for CTRL or DMK in the kidney and significantly lower than for CTRL only in the small intestine. Plasma concentration of iohexol was significantly higher after DEX than CTRL administration. CONCLUSIONS: Contrast-enhanced ultrasound was effective in detecting DEX-induced changes in blood flow. MK-467 attenuated these changes. CLINICAL RELEVANCE: Clinicians should consider the effects of the sedation protocol when performing CEUS. Addition of MK-467 might beneficially impact the haemodynamic function of sedation with alpha-2 adrenoceptor agonists.

Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

OBJECTIVE: To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. STUDY DESIGN: Experimental randomized blinded crossover study. ANIMALS: Six healthy horses. METHODS: Detomidine (10 µg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 µg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p < 0.05. RESULTS: A significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses.

Variation in insulin response to oral sugar test in a cohort of horses throughout the year and evaluation of risk factors for insulin dysregulation.

BACKGROUND: The oral sugar test (OST) is commonly used to diagnose insulin dysregulation (ID) and equine metabolic syndrome; however, possible seasonal changes in OST results have not been evaluated. OBJECTIVE: To determine the possible variation in insulin response to OST throughout the year and risk factors associated with maximum insulin concentration (InsMax) and ID. STUDY DESIGN: Prospective, longitudinal cohort study. METHODS: The OST was performed on 29 Finnhorses every other month six times. Serum total adiponectin concentration and phenotypic variables related to obesity were also measured. Changes in InsMax, adiponectin, scale weight, body condition score, cresty neck score (CNS), and fasting glucose concentration were assessed. Risk factor analyses were performed on InsMax and ID status, and ID groups were compared with each other. RESULTS: Fourteen horses were categorised with non-ID each time and 15 as having ID at least once during the follow-up period. The ID status of 12 horses varied throughout the year, but neither the insulin variables measured during the OST nor adiponectin expressed significant seasonal variation. Increasing age and CNS, and decreasing adiponectin were observed as risk factors for a high InsMax after OST. The risk of ID was higher in horses with no exercise compared to horses with exercise (OR 7.6, 95% CI 1.2-49.3, P = .03). Horses with ID had lower serum adiponectin concentrations, longer neck circumference and larger height than horses in the non-ID group. MAIN LIMITATIONS: The environmental conditions (feeding, exercise) were not constant for all horses throughout the study and only one breed was used. CONCLUSIONS: Neither OST results nor adiponectin varies with season; however, there were a substantial number of horses with variable ID status throughout the year, in which repeated OSTs may be beneficial. Lack of exercise was a risk factor for ID.

Effects of different doses of L-659'066 on the bispectral index and clinical sedation in dogs treated with dexmedetomidine.

OBJECTIVE: To evaluate the effects of three doses of L-659'066 (MK-467) on the bispectral index (BIS) and clinical sedation in dexmedetomidine-sedated Beagles. STUDY DESIGN: Randomized, experimental cross over study. ANIMALS: Eight purpose-bred healthy laboratory Beagles. METHODS: Dexmedetomidine (10 µg kg(-1) IV [DEX]) was administered alone or in combination with three doses of L-659'066 (250 µg kg(-1) [DL250]; 500 µg kg(-1) [DL500] and 750 µg kg(-1) [DL750] IV) in the same syringe in a randomized crossover manner. The bispectral index (BIS), electromyography (EMG) and sedation score were recorded at baseline and 5, 10, 20, 30, 45 and 60 minutes after treatment. RESULTS: When compared to DEX, BIS and EMG were significantly higher and the sedation score significantly lower with DL500 and DL750. With DEX, BIS was significantly decreased at times 20, 30 and 60 minutes whereas the sedation scores were significantly increased at all time points after drug administration in all groups. Bioequivalence for clinical sedation was detected between DEX and all doses of L-659'066, reaching European Medicines Agency (EMA) standards. CONCLUSIONS AND CLINICAL RELEVANCE: Although L-659'066 interfered with dexmedetomidine induced sedation, the degree of the reduction was not clinically relevant. Despite performing better when dexmedetomidine was used alone, BIS did not reflect the clinical sedative status when the antagonist was added.

Quantitative contrast-enhanced ultrasonographic analysis of perfusion in the kidneys, liver, pancreas, small intestine, and mesenteric lymph nodes in healthy cats.

OBJECTIVE: To evaluate perfusion of abdominal organs in healthy cats by use of contrast-enhanced ultrasonography. ANIMALS: 10 young healthy anesthetized cats. PROCEDURES: Contrast-enhanced ultrasonography of the liver, left kidney, pancreas, small intestine, and mesenteric lymph nodes was performed on anesthetized cats. RESULTS: Typical perfusion patterns were found for each of the studied organs. Differences in perfusion among organs were associated with specific physiologic features. The liver was enhanced gradually and had a more heterogeneous perfusion pattern because of its dual blood supply and close proximity to the diaphragm, compared with other organs. An obvious and significant difference in perfusion was detected between the renal cortex and medulla. No significant differences in perfusion were detected among the pancreas, small intestine, and mesenteric lymph nodes. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that contrast-enhanced ultrasonography can be used in cats to estimate organ perfusion as in other species. Observed differences in perfusion variables can be mostly explained by physiologic differences in vascularity.

Early detection of ketoprofen-induced acute kidney injury in sheep as determined by evaluation of urinary enzyme activities.

OBJECTIVE: To evaluate early indicators of renal tissue destruction and changes in urinary enzyme activities in sheep during the first hours after acute kidney injury induced by administration of an overdose of an NSAID. ANIMALS: 12 adult female sheep. PROCEDURES: Acute kidney injury was induced in 6 sheep by administration of ketoprofen (30 mg/kg, IV) and detected by evaluation of urinary protein concentration, iohexol clearance, and results of histologic examination. Six sheep served as control animals. Blood and urine samples were collected for up to 24 hours after administration of ketoprofen. Plasma concentrations of urea, creatinine, albumin, and total protein; plasma activities of alkaline phosphatase, acid phosphatase, γ-glutamyl transpeptidase (GGT), matrix metalloproteinase (MMP)-2, and MMP-9; and urinary creatinine and protein concentrations, specific gravity, and activities of alkaline phosphatase, acid phosphatase, GGT lactate dehydrogenase, N-acetyl-ß-D-glucosaminidase (NAG), MMP-2, and MMP-9 were measured. Urinary protein concentration and enzyme activities were normalized on the basis of urinary creatinine concentrations and reported as ratios. RESULTS: Many urinary enzyme-to-creatinine ratios increased before the plasma creatinine concentration exceeded the reference value. Urine NAG, lactate dehydrogenase, and acid phosphatase activities were increased beginning at 2 hours after ketoprofen administration, and alkaline phosphatase, GGT, and MMP-2 activities were increased beginning at 4 hours after ketoprofen administration. Most peak urinary enzyme-to-creatinine ratios were detected earlier than were the highest plasma creatinine and urea concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Urinary enzyme activities were sensitive early indicators of acute kidney injury induced by an overdose of an NSAID in sheep.

Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.

OBJECTIVE: To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. ANIMALS: 8 healthy Beagles. PROCEDURES: Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 µg/kg], medetomidine [20 µg/kg] and vatinoxan [400 µg/kg], and medetomidine [40 µg/kg] and vatinoxan [800 µg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments. RESULTS: Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.

Insulin dysregulation in a population of Finnhorses and associated phenotypic markers of obesity.

BACKGROUND: Obesity and insulin dysregulation (ID) predispose horses to laminitis. Determination of management practices or phenotypic markers associated with ID may benefit animal welfare. OBJECTIVES: Determine ID status of a population of Finnhorses using an oral sugar test (OST) and compare phenotypes and management factors between ID and non-ID Finnhorses. ANIMALS: One hundred twenty-eight purebred Finnhorses ≥3 years of age. METHODS: Owners were recruited using an online questionnaire regarding signalment, history, feeding, and exercise of their horses. Selected contributing stables within a predefined area were visited. Phenotypic markers of obesity and the weight of each horse were recorded. After fasting overnight, horses received 0.45 mL/kg corn syrup PO. Serum samples before and at 60 and 90 minutes after syrup administration were analyzed for insulin by chemiluminescent assay. Horses met ID criteria if insulin concentrations were ≥33 µIU/mL at T0, ≥66 µIU/mL at T60 or T90 or some combination thereof. Associations between phenotypic markers, feeding and exercise variables, and ID were examined using mixed effects logistic regression modeling. RESULTS: Several phenotypic markers of obesity were significant on univariable analysis but in the final multivariable model, only obesity (body condition score ≥8) was associated with ID (P = .04). Over half of the horses (60% [95% confidence interval (CI), 51%-68%]) were considered overweight or obese whereas 16% (95% CI, 10%-23%) were classified as having ID. CONCLUSIONS AND CLINICAL IMPORTANCE: Because obesity is associated with ID in cold-blooded type horses, objective monitoring of phenotypic markers by owners may be beneficial for health outcomes.