Cardiovascular effects of dobutamine, norepinephrine and phenylephrine in isoflurane-anaesthetized dogs administered dexmedetomidine-vatinoxan.

OBJECTIVE: To determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine with vatinoxan. STUDY DESIGN: Balanced, randomized crossover trial. ANIMALS: A total of eight healthy Beagle dogs. METHODS: Each dog was anaesthetized with isoflurane (end-tidal isoflurane 1.3%) and five treatments: dexmedetomidine hydrochloride (2.5 µg kg-1) bolus followed by 0.9% saline infusion (DEX-S); dexmedetomidine and vatinoxan hydrochloride (100 µg kg-1) bolus followed by an infusion of 0.9% saline (DEX-VAT-S), dobutamine (DEX-VAT-D), norepinephrine (DEX-VAT-N) or phenylephrine (DEX-VAT-P). The dexmedetomidine and vatinoxan boluses were administered at baseline (T0) and the treatment infusion was started after 15 minutes (T15) if mean arterial pressure (MAP) was < 90 mmHg. The treatment infusion rate was adjusted every 5 minutes as required. Systemic haemodynamics were recorded at T0 and 10 (T10) and 45 (T45) minutes. A repeated measures analysis of covariance model was used. RESULTS: Most dogs had a MAP < 70 mmHg at T0 before treatment. Treatments DEX-S and DEX-VAT all significantly increased MAP at T10, but systemic vascular resistance index (SVRI) was significantly higher and cardiac index (CI) lower after DEX-S than after DEX-VAT. CI did not significantly differ between DEX-S and DEX-VAT-S at T45, while SVRI remained higher with DEX-S. Normotension was achieved by all vasoactive infusions in every dog, whereas MAP was below baseline with DEX-VAT-S, and higher than baseline with DEX-S at T45. Median infusion rates were 3.75, 0.25 and 0.5 µg kg-1 minute-1 for dobutamine, norepinephrine and phenylephrine, respectively. Dobutamine and norepinephrine increased CI (mean ± standard deviation, 3.35 ± 0.70 and 3.97 ± 1.24 L minute-1 m-2, respectively) and decreased SVRI, whereas phenylephrine had the opposite effect (CI 2.13 ± 0.45 L minute-1 m-2). CONCLUSIONS AND CLINICAL RELEVANCE: Hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine and vatinoxan can be treated with either dobutamine or norepinephrine.

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.

Dog-Owner Relationship, Owner Interpretations and Dog Personality Are Connected with the Emotional Reactivity of Dogs.

We evaluated the effect of the dog-owner relationship on dogs' emotional reactivity, quantified with heart rate variability (HRV), behavioral changes, physical activity and dog owner interpretations. Twenty nine adult dogs encountered five different emotional situations (i.e., stroking, a feeding toy, separation from the owner, reunion with the owner, a sudden appearance of a novel object). The results showed that both negative and positive situations provoked signs of heightened arousal in dogs. During negative situations, owners' ratings about the heightened emotional arousal correlated with lower HRV, higher physical activity and more behaviors that typically index arousal and fear. The three factors of The Monash Dog-Owner Relationship Scale (MDORS) were reflected in the dogs' heart rate variability and behaviors: the Emotional Closeness factor was related to increased HRV (p = 0.009), suggesting this aspect is associated with the secure base effect, and the Shared Activities factor showed a trend toward lower HRV (p = 0.067) along with more owner-directed behaviors reflecting attachment related arousal. In contrast, the Perceived Costs factor was related to higher HRV (p = 0.009) along with less fear and less owner-directed behaviors, which may reflect the dog's more independent personality. In conclusion, dogs' emotional reactivity and the dog-owner relationship modulate each other, depending on the aspect of the relationship and dogs' individual responsivity.

Description of movement sensor dataset for dog behavior classification.

Movement sensor data from seven static and dynamic dog behaviors (sitting, standing, lying down, trotting, walking, playing, and (treat) searching i.e. sniffing) was collected from 45 middle to large sized dogs with six degree-of-freedom movement sensors attached to the collar and the harness. With 17 dogs the collection procedure was repeated. The duration of each of the seven behaviors was approximately three minutes. The order of the tasks was varied between the dogs and the two repetitions (for the 17 dogs). The behaviors were annotated post-hoc based on the video recordings made with two camcorders during the tests with one second resolution. The annotations were accurately synchronized with the raw movement sensors data. The annotated data was originally used for training behavior classification machine learning algorithms for classifying the seven behaviors. The developed signal processing and classification algorithms are provided together with the raw measurement data and reference annotations. The description and results of the original investigation that the dataset relates to are found in: P. Kumpulainen, A. Valldeoriola Cardó, S. Somppi, H. Törnqvist, H. Väätäjä, P. Majaranta, Y. Gizatdinova, C. Hoog Antink, V. Surakka, M. V. Kujala, O. Vainio, A. Vehkaoja, Dog behavior classification with movement sensors placed on the harness and the collar, Applied Animal behavior Science, 241 (2021), 105,393.

The Interplay Between Affect, Dog's Physical Activity and Dog-Owner Relationship.

Leaving a dog home alone is part of everyday life for most dog owners. Previous research shows that dog-owner relationship has multifarious effects on dog behavior. However, little is known about the interplay between dog-owner relationship, physical activity of the dog, and affective experiences at the time of the owner leaving home and reunion when the owner comes home. In this paper, we explored how the general (daily, home alone, and over the 2-week study period) physical activity of the dog, and owner's perceptions of the dog's affective state were correlated at those particular moments. Nineteen volunteer dog owners had their dogs (N = 19) wear two activity trackers (ActiGraph wGT2X-GT and FitBark2) for 2 weeks 24 h/day. Prior to the 2-week continuous physical activity measurement period, the owners filled in questionnaires about the dog-owner relationship and the dog behavior. In daily questionnaires, owners described and assessed their own and their perception of the emotion-related experiences of their dog and behavior of the dog at the moment of separation and reunion. The results indicated that the dog-owner relationship has an interplay with the mean daily and weekly physical activity levels of the dog. An indication of strong emotional dog-owner relationship (especially related to the attentiveness of the dog, continuous companionship, and time spent together when relaxing) correlated positively with the mean daily activity levels of the dog during the first measurement week of the study. Results also suggest that the mean daily and over the 2-week measurement period physical activity of the dog correlated the affective experiences of the dog and owner as reported by the owner when the dog was left home alone. More research is needed to understand the interplay between affect, physical activity of the dog, dog-owner relationship, and the effects of these factors on, and their interplay with, the welfare of dogs.

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.

Observing animals and humans: dogs target their gaze to the biological information in natural scenes.

BACKGROUND: This study examines how dogs observe images of natural scenes containing living creatures (wild animals, dogs and humans) recorded with eye gaze tracking. Because dogs have had limited exposure to wild animals in their lives, we also consider the natural novelty of the wild animal images for the dogs. METHODS: The eye gaze of dogs was recorded while they viewed natural images containing dogs, humans, and wild animals. Three categories of images were used: naturalistic landscape images containing single humans or animals, full body images containing a single human or an animal, and full body images containing a pair of humans or animals. The gazing behavior of two dog populations, family and kennel dogs, were compared. RESULTS: As a main effect, dogs gazed at living creatures (object areas) longer than the background areas of the images; heads longer than bodies; heads longer than background areas; and bodies longer than background areas. Dogs gazed less at the object areas vs. the background in landscape images than in the other image categories. Both dog groups also gazed wild animal heads longer than human or dog heads in the images. When viewing single animal and human images, family dogs focused their gaze very prominently on the head areas, but in images containing a pair of animals or humans, they gazed more at the body than the head areas. In kennel dogs, the difference in gazing times of the head and body areas within single or paired images failed to reach significance. DISCUSSION: Dogs focused their gaze on living creatures in all image categories, also detecting them in the natural landscape images. Generally, they also gazed at the biologically informative areas of the images, such as the head, which supports the importance of the head/face area for dogs in obtaining social information. The natural novelty of the species represented in the images as well as the image category affected the gazing behavior of dogs. Furthermore, differences in the gazing strategy between family and kennel dogs was obtained, suggesting an influence of different social living environments and life experiences.

Time-resolved classification of dog brain signals reveals early processing of faces, species and emotion.

Dogs process faces and emotional expressions much like humans, but the time windows important for face processing in dogs are largely unknown. By combining our non-invasive electroencephalography (EEG) protocol on dogs with machine-learning algorithms, we show category-specific dog brain responses to pictures of human and dog facial expressions, objects, and phase-scrambled faces. We trained a support vector machine classifier with spatiotemporal EEG data to discriminate between responses to pairs of images. The classification accuracy was highest for humans or dogs vs. scrambled images, with most informative time intervals of 100-140 ms and 240-280 ms. We also detected a response sensitive to threatening dog faces at 30-40 ms; generally, responses differentiating emotional expressions were found at 130-170 ms, and differentiation of faces from objects occurred at 120-130 ms. The cortical sources underlying the highest-amplitude EEG signals were localized to the dog visual cortex.

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

OBJECTIVE: To investigate the impact of intramuscular (IM) co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. STUDY DESIGN: Randomized, masked crossover study. ANIMALS: A total of eight purpose-bred Beagle dogs aged 3 years. METHODS: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 µg kg-1) and butorphanol (100 µg kg-1) premedication with vatinoxan (500 µg kg-1; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg-1). Atipamezole (100 µg kg-1) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed. RESULTS: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. CONCLUSIONS AND CLINICAL RELEVANCE: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.

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.

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.

Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2-adrenoceptor antagonist vatinoxan hydrochloride.

OBJECTIVE: To investigate the cardiovascular and sedation reversal effects of IM administration of atipamezole (AA) in dogs treated with medetomidine hydrochloride (MED) or MED and vatinoxan (MK-467). ANIMALS: 8 purpose-bred, 2-year-old Beagles. PROCEDURES: A randomized, blinded, crossover study was performed in which each dog received 2 IM treatments at a ≥ 2-week interval as follows: injection of MED (20 µg/kg) or MED mixed with 400 µg of vatinoxan/kg (MEDVAT) 30 minutes before AA (100 µg/kg). Sedation score, heart rate, mean arterial and central venous blood pressures, and cardiac output were recorded before and at various time points (up to 90 minutes) after AA. Cardiac and systemic vascular resistance indices were calculated. Venous blood samples were collected at intervals until 210 minutes after AA for drug concentration analysis. RESULTS: Heart rate following MED administration was lower, compared with findings after MEDVAT administration, prior to and at ≥ 10 minutes after AA. Mean arterial blood pressure was lower with MEDVAT than with MED at 5 minutes after AA, when its nadir was detected. Overall, cardiac index was higher and systemic vascular resistance index lower, indicating better cardiovascular function, in MEDVAT-atipamezole-treated dogs. Plasma dexmedetomidine concentrations were lower and recoveries from sedation were faster and more complete after MEDVAT treatment with AA than after MED treatment with AA. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole failed to restore heart rate and cardiac index in medetomidine-sedated dogs, and relapses into sedation were observed. Coadministration of vatinoxan with MED helped to maintain hemodynamic function and hastened the recovery from sedation after AA in dogs.

INTRAVENOUS VATINOXAN IN MARKHORS (CAPRA FALCONERI HEPTNERi) IMMOBILIZED WITH INTRAMUSCULAR MEDETOMIDINE AND KETAMINE-A PRELIMINARY DOSESCREENING STUDY.

Medetomidine is an α-2 adrenoceptor agonist commonly combined with ketamine for immobilization of nondomestic mammals. However, it may cause some remarkable adverse effects such as bradycardia, hypertension, and hypoxemia. Vatinoxan (previously called MK-467 and L-659,066) is an α-2 adrenoceptor antagonist that affects mostly the peripheral receptors due to its minimal ability to cross the blood-brain barrier. Therefore it alleviates the peripheral cardiovascular and pulmonary effects of medetomidine while sedation is maintained. In this study, the hypothesis was that vatinoxan would dose-dependently alleviate medetomidineinduced bradycardia, hypertension, and hypoxemia when administered intravenously (IV) after medetomidine and ketamine were administered intramuscularly (IM) to markhors (Capra falconeri heptneri), without impairing the immobilization. Various doses of vatinoxan were studied. In this prospective, randomized, assessor-blinded, clinical crossover study, eight markhors were immobilized two times (16 paired immobilizations altogether) with medetomidine (80 µg/kg) and ketamine (1.5 mg/kg), according to the estimated weight, IM in the same dart. Approximately 19 min later, vatinoxan (117-297 µg/kg) or saline placebo was injected IV. Atipamezole was used as a reversal agent. Pulse and respiratory rates, indirect blood pressures, arterial oxygen saturation, and body temperature were measured and blood samples collected. In general, vatinoxan alleviated the hypertension induced by medetomidine without affecting the quality of immobilization. The dose of vatinoxan correlated significantly with the reduction in arterial blood pressure. Vatinoxan showed potential to enhance cardiovascular function in captive nondomestic small ruminants immobilized with medetomidine-ketamine.

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.

Effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole.

OBJECTIVE To evaluate effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 µg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 µg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 µg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao2 decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

Evaluation of Dry Electrodes in Canine Heart Rate Monitoring.

The functionality of three dry electrocardiogram electrode constructions was evaluated by measuring canine heart rate during four different behaviors: Standing, sitting, lying and walking. The testing was repeated (n = 9) in each of the 36 scenarios with three dogs. Two of the electrodes were constructed with spring-loaded test pins while the third electrode was a molded polymer electrode with Ag/AgCl coating. During the measurement, a specifically designed harness was used to attach the electrodes to the dogs. The performance of the electrodes was evaluated and compared in terms of heartbeat detection coverage. The effect on the respective heart rate coverage was studied by computing the heart rate coverage from the measured electrocardiogram signal using a pattern-matching algorithm to extract the R-peaks and further the beat-to-beat heart rate. The results show that the overall coverage ratios regarding the electrodes varied between 45⁻95% in four different activity modes. The lowest coverage was for lying and walking and the highest was for standing and sitting.

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.

Changes in energy metabolism, and levels of stress-related hormones and electrolytes in horses after intravenous administration of romifidine and the peripheral α-2 adrenoceptor antagonist vatinoxan.

BACKGROUND: Romifidine, an α-2 adrenoceptor agonist, is a widely-used sedative in equine medicine. Besides the desired sedative and analgesic actions, α-2 adrenoceptor agonists have side effects like alterations of plasma concentrations of glucose and certain stress-related hormones and metabolites in various species. Vatinoxan (previously known as MK-467), in turn, is an antagonist of α-2 adrenoceptors. Because vatinoxan does not cross the blood brain barrier in significant amounts, it has only minor effect on sedation induced by α-2 adrenoceptor agonists. Previously, vatinoxan is shown to prevent the hyperglycaemia, increase of plasma lactate concentration and the decrease of insulin and non-esterified free fatty acids (FFAs) caused by α-2 adrenoceptor agonists in different species. The aim of our study was to investigate the effects of intravenous romifidine and vatinoxan, alone and combined, on plasma concentrations of glucose and some stress-related hormones and metabolites in horses. RESULTS: Plasma glucose concentration differed between all intravenous treatments: romifidine (80 µg/kg; ROM), vatinoxan (200 µg/kg; V) and the combination of these (ROM + V). Glucose concentration was the highest after ROM and the lowest after V. Serum FFA concentration was higher after V than after ROM or ROM + V. The baseline serum concentration of insulin varied widely between the individual horses. No differences were detected in serum insulin, cortisol or plasma adrenocorticotropic hormone (ACTH) concentrations between the treatments. Plasma lactate, serum triglyceride or blood sodium and chloride concentrations did not differ from baseline or between the treatments. Compared with baseline, plasma glucose concentration increased after ROM and ROM + V, serum cortisol, FFA and base excess increased after all treatments and plasma ACTH concentration increased after V. Serum insulin concentration decreased after V and blood potassium decreased after all treatments. CONCLUSIONS: Romifidine induced hyperglycaemia, which vatinoxan partially prevented despite of the variations in baseline levels of serum insulin. The effects of romifidine and vatinoxan on the insulin concentration in horses need further investigation.

Effects of MK-467 hydrochloride and hyoscine butylbromide on cardiorespiratory and gastrointestinal changes induced by detomidine hydrochloride in horses.

OBJECTIVE To compare the effects of MK-467 and hyoscine butylbromide on detomidine hydrochloride-induced cardiorespiratory and gastrointestinal changes in horses. ANIMALS 6 healthy adult horses. PROCEDURES Horses received detomidine hydrochloride (20 µg/kg, IV), followed 10 minutes later by MK-467 hydrochloride (150 µg/kg; DET-MK), hyoscine butylbromide (0.2 mg/kg; DET-HYO), or saline (0.9% NaCl) solution (DET-S), IV, in a Latin square design. Heart rate, respiratory rate, rectal temperature, arterial and venous blood pressures, and cardiac output were measured; blood gases and arterial plasma drug concentrations were analyzed; selected cardiopulmonary variables were calculated; and sedation and gastrointestinal borborygmi were scored at predetermined time points. Differences among treatments or within treatments over time were analyzed statistically. RESULTS With DET-MK, detomidine-induced hypertension and bradycardia were reversed shortly after MK-467 injection. Marked tachycardia and hypertension were observed with DET-HYO. Mean heart rate and mean arterial blood pressure differed significantly among all treatments from 15 to 35 and 15 to 40 minutes after detomidine injection, respectively. Cardiac output was greater with DET-MK and DET-HYO than with DET-S 15 minutes after detomidine injection, but left ventricular workload was significantly higher with DET-HYO. Borborygmus score, reduced with all treatments, was most rapidly restored with DET-MK. Sedation scores and pharmacokinetic parameters of detomidine did not differ between DET-S and DET-MK. CONCLUSIONS AND CLINICAL RELEVANCE MK-467 reversed or attenuated cardiovascular and gastrointestinal effects of detomidine without notable adverse effects or alterations in detomidine-induced sedation in horses. Further research is needed to determine whether these advantages are found in clinical patients and to assess whether the drug influences analgesic effects of detomidine.