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Alpha-2-adrenoceptor agonist detomidine is a commonly used sedative agent in horses. In addition to the sedative effect, detomidine has been reported to elicit changes in energy metabolism such as hypoinsulinaemia and hyperglycaemia. This study aimed to investigate the effects of detomidine with and without peripherally acting alpha-2-adrenoceptor antagonist vatinoxan on insulin and blood glucose (BG) concentrations in horses after a standard dose of oral carbohydrates. Sixteen horses were assigned to four intravenous treatments in a randomised cross-over design: saline (SAL), detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), and a combination of detomidine and vatinoxan (DET+VAT). Horses were administered corn syrup (0.45 mL/kg) immediately before each treatment. Blood samples were collected until 360 min. The differences between treatments were evaluated with repeated measures analysis of covariance and change from baseline was used as a response. P<0.05 was considered significant. After oral carbohydrate load, DET reduced insulin (median 30 min nadir 3.7, min-max 0.6-7.4 µIU/mL) significantly compared with SAL (P<0.0001; 17.4, 9.3-65.4 µIU/mL) and DET+VAT (P=0.0005; 6.4, 2.9-12.9 µIU/mL). BG increased significantly after DET (peak; 130.5, 8.8-15.8 mmol/L) compared with SAL (P<0.0001; 8.7, 6.9-12.4 mmol/L) and DET+VAT (P<0.0001; 8.5, 6.8-10.6 mmol/L). Vatinoxan alone reduced BG (peak median 7.6, 7.0-9.9 mmol/L) compared with SAL (P=0.02) and delayed insulin responses to carbohydrates. In conclusion, vatinoxan alleviated the detomidine-induced changes (DET+VAT compared to DET) in insulin and BG after oral carbohydrate load. Additionally, vatinoxan is potentially able to modulate BG concentration and insulin response after oral carbohydrate administration in horses, but more research is warranted., Competing Interests: Declaration of Competing Interest The authors declare the following interests of financial nature, which may be considered as potential competing interests: the drugs (detomidine, vatinoxan) used in this study were manufactured and donated by Vetcare Finland Oy (Helsinki, Finland). Vetcare Finland Oy did not partake in study planning, study designing, sampling, analysis, interpretation of results, preparation of the manuscript or the decision to submit the manuscript for publication. Marja Raekallio is named as one of the inventors, with no financial gain, in a patent concerning vatinoxan; the patent holder is Vetcare Ltd. The other authors have no financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Equine metabolic syndrome (EMS) is a common welfare problem in horses worldwide. It is characterized by insulin dysregulation (ID), predisposition to laminitis and often obesity. EMS is multifactorial by nature, with both the environment and genetics contributing to the phenotype. Environmental factors, such as feeding and exercise, can be controlled, thus forming the basis for treatment and prevention. Genetic factors, by contrast, are less well-known and not easily controllable. The aim of this study was to identify potential genetic loci influencing ID/EMS in Finnhorses. A single-breed (Finnhorse) case-control genome-wide association study (GWAS) of ID was conducted with controls that included age-appropriate non-ID horses. ID status was determined with an oral sugar test (OST) for fasted horses. Seventy-one Finnhorses participated (n = 34 ID, n = 37 control). DNA samples (hair roots) were genotyped for 65 157 single-nucleotide polymorphisms (SNPs) with the Illumina Equine SNP70 BeadChip, and these data were analysed for association and F ST outliers with genomic tools. P-values that exceeded the suggestive threshold (P = 1.00 ×10 -5 ) were found in SNP BIEC2&#95;383954 (P = 3.45 ×10 -6 ) in chromosome 17 and SNP BIEC2&#95;312374 (P = 1.89 ×10 -5 ) in chromosome 15. Hierarchical and Bayesian F ST outlier tests also detected these SNPs. Potential candidate genes associated with the ID close to SNP BIEC2&#95;383954, with functions in carbohydrate metabolism, were Arginine and Glutamate Rich 1 (ARGLU1) and Ephrin-B2 (EFNB2)., Competing Interests: Declaration of Competing Interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The science of veterinary medicine is currently lacking studies on medication safety, although its importance in protecting animals from medication errors is central. Pharmacy professionals have an important role in ensuring medication safety of both prescription and over-the-counter medications of animals. However, this requires adequate competencies of pharmacy professionals in veterinary pharmacotherapy. The present study aimed to explore the competencies of pharmaceutical staff in community pharmacies in veterinary pharmacotherapy, which factors influence these competencies and what kind of information sources they typically use on veterinary pharmacotherapy. The study was conducted as a cross-sectional online survey targeted to pharmacy professionals in the Finnish community pharmacies, providing 596 responses. Less than half of the respondents (41%, n  = 246) are considered to possess good competencies in veterinary pharmacotherapy. A third of the respondents (35%, n  = 211) would dispense an anti-inflammatory drug for an animal off-label, whereas 24% ( n  = 145) would not interview the pet owner to discover the need for internal parasite medication before dispensing the drug. A small proportion (<1%, n  = 5) would have dispensed a broad-spectrum internal parasite medication. Approximately a quarter of the respondents (27%, n  = 159) stated that they acquired information on pharmacotherapy only from the material produced by the manufacturers of veterinary drugs. The competencies of pharmacy professionals in veterinary pharmacotherapy need to be strengthened in many areas to better promote veterinary medication safety. It should also be ensured that pharmacy professionals can access and use independent, high-quality information on veterinary pharmacotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

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 (f R ), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (Fe'Sevo) and carbon dioxide (Pe'CO 2 ) 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 f R , Pe'CO 2 , 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., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2021 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

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 α 2 -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 CO 2 , 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., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0, 1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values ≤0.05 were considered significant. Comparing DET vs. SAL and DET vs. DET + VAT, insulin was higher at 2 h in the non-ID group and 2 and 4 h in the ID group. There was no difference in insulin between SAL and DET + VAT or VAT. Comparing DET vs. SAL, BG was higher at 1 and 2 h then was lower at 4 h in both ID and non-ID groups. At 1 h in both groups, BG after DET + VAT was lower than after DET but higher than after SAL. Comparing DET vs. SAL, glucagon was lower at 1 h in the ID group and 1 and 2 h in the non-ID group. Vatinoxan was effective in preventing detomidine-induced hyperglycaemia as well as the subsequent insulin increase in horses with ID., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

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.

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 α 2 -adrenoceptors outside the CNS., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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.

Background: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α 2 -adrenoceptors. Vatinoxan, a peripheral α 2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α 2 -agonists in horses. However, vatinoxan has not been investigated during constant-rate infusion (CRI) of medetomidine in standing horses., Objectives: To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine., Study Design: Experimental, randomised, blinded, cross-over study., Methods: Six healthy horses were given medetomidine hydrochloride, 7 μg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 μg/kg i.v., followed by CRI of medetomidine at 3.5 μg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t-tests as appropriate., Results: Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01)., Main Limitations: Experimental study with healthy, unstimulated animals., Conclusions: Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese - see Supporting Information., (© 2019 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7μg/kg IV alone (MED) or with vatinoxan hydrochloride 140μg/kg IV (MED+V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied. Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED+V (P=0.018). Cardiac index (CI) and oxygen delivery index (DO 2 I) decreased significantly more with MED, with the largest difference observed at 20min: CI was 39±2 and 73±18 (P=0.009) and DO 2 I 7.4±1.2 and 15.3±4.8 (P=0.014)mL/min/kg with MED and MED+V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED+V., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clinical problems related to intestinal sand accumulation in horses are common in certain geographic areas, but the clinical signs appear nonspecific and the course of the accumulation remains somewhat obscure. This study examined the association between the presence and size of intestinal sand accumulations and owner-reported clinical signs, management, and feeding practices, as well as behavioral patterns in horses with radiographic diagnosis of sand accumulation. Owners of the horses filled in an online questionnaire. A total of 447 responses met the inclusion criteria. The size of the sand accumulation detected in the radiographs was not significantly associated with the age, body condition score, sex, or use of the horses. Horses reported to have expressed colic had significantly larger sand accumulations than those without this sign, and a similar association was detected in horses with poor performance. The highest odds ratio for sand accumulation was for the combination of colic and poor performance, followed by colic combined with diarrhea/loose feces or hyperesthesia to touch of the abdominal wall. Larger sand accumulations were detected in greedy horses that eat all their roughage, whereas dominant position in group hierarchy was associated with less sand. The possibility of abdominal sand accumulation should be considered as one of the differentials in horses with multiple owner-reported clinical signs such as colic, poor performance, diarrhea, and hyperesthesia to touch of the abdomen., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The commonly used sedative α 2 -adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting α 2 -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 α 2 -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 α 2 -adrenoceptor agonists in dogs, it should be used with caution in animals at risk for hypoglycaemia because of its insulin-releasing and hypoglycaemic effects., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate the effect of the peripherally acting α 2 -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., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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/m 2 medetomidine+0.1mg/kg butorphanol (MB, n=29); or (2) 0.5mg/m 2 medetomidine+0.1mg/kg butorphanol+10mg/m 2 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 (AUC VAS30 ) 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. AUC VAS30 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., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

OBJECTIVE To evaluate effects of the peripherally acting α 2 -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 Pao 2 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.

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 5cmH 2 O. Peak inspiratory pressure (PIP) was set at 25cmH 2 O. 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., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Enteropathy associated with sand accumulation in the large colon of horses has been reported worldwide. Intestinal sand accumulations are commonly treated medically, but randomised controlled clinical trials on horses are scarce. This prospective study evaluated the efficacy of an enterally administered combination of psyllium and magnesium sulphate (MgSO 4 ) for the removal of large colonic sand accumulations in horses without clinical signs of acute colic. The two groups comprised 20 untreated control horses and 20 horses treated with 1g/kg bodyweight (bwt) of psyllium and 1g/kg bwt of MgSO 4 administered by nasogastric intubation once daily for 4 days. Both groups had no access to soil during the study period. The amounts of accumulated sand were evaluated radiographically before and after treatment. Significantly more treated horses cleared their sand accumulations than horses in the control group. This clearance was determined by observing the estimated quantity by area of sand remaining in the large colon (P<0.001) and by comparing the numbers of successfully treated horses (P=0.004) between the two groups after 4days of treatment. However, there were unexplained individual variations in the clearance of sand accumulation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: We determined the possible effects of a peripherally acting α 2 -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 (C max ) and time to C max (T max ) 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 T max 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., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The effect of MK-467, a peripheral α 2 -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., (© 2018 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.)

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.

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.

OBJECTIVE To compare cardiovascular effects of premedication with medetomidine alone and with each of 3 doses of MK-467 or after glycopyrrolate in dogs subsequently anesthetized with isoflurane. ANIMALS 8 healthy purpose-bred 5-year-old Beagles. PROCEDURES In a randomized crossover study, each dog received 5 premedication protocols (medetomidine [10 μg/kg, IV] alone [MED] and in combination with MK-467 at doses of 50 [MMK50], 100 [MMK100], and 150 [MMK150] μg/kg and 15 minutes after glycopyrrolate [10 μg/kg, SC; MGP]), with at least 14 days between treatments. Twenty minutes after medetomidine administration, anesthesia was induced with ketamine (0.5 mg/kg, IV) and midazolam (0.1 mg/kg, IV) increments given to effect and maintained with isoflurane (1.2%) for 50 minutes. Cardiovascular variables were recorded, and blood samples for determination of plasma dexmedetomidine, levomedetomidine, and MK-467 concentrations were collected at predetermined times. Variables were compared among the 5 treatments. RESULTS The mean arterial pressure and systemic vascular resistance index increased following the MED treatment, and those increases were augmented and obtunded following the MGP and MMK150 treatments, respectively. Mean cardiac index for the MMK100 and MMK150 treatments was significantly greater than that for the MGP treatment. The area under the time-concentration curve to the last sampling point for dexmedetomidine for the MMK150 treatment was significantly lower than that for the MED treatment. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated concurrent administration of MK-467 with medetomidine alleviated medetomidine-induced hemodynamic changes in a dose-dependent manner prior to isoflurane anesthesia. Following MK-467 administration to healthy dogs, mean arterial pressure was sustained at acceptable levels during isoflurane anesthesia.

OBJECTIVE To assess the possible impact of medetomidine on concentrations of alfaxalone in plasma, when coadministered as a constant rate infusion (CRI) to dogs, and to determine the possible impact of medetomidine on the cardiopulmonary effects of alfaxalone during CRI. ANIMALS 8 healthy adult Beagles. PROCEDURES 3 treatments were administered in a randomized crossover design as follows: 1 = saline (0.9% NaCl) solution injection, followed in 10 minutes by induction of anesthesia with alfaxalone (loading dose, 2.4 mg/kg; CRI, 3.6 mg/kg/h, for 60 minutes); 2 = medetomidine premedication (loading dose, 4.0 μg/kg; CRI, 4.0 μg/kg/h), followed by alfaxalone (as in treatment 1); and, 3 = medetomidine (as in treatment 2) and MK-467 (loading dose, 150 μg/kg; CRI, 120 μg/kg/h), followed by alfaxalone (as in treatment 1). The peripherally acting α 2 -adrenoceptor antagonist MK-467 was used to distinguish between the peripheral and central effects of medetomidine. Drugs were administered IV via cephalic catheters, and there was a minimum of 14 days between treatments. Cardiopulmonary parameters were measured for 70 minutes, and jugular venous blood samples were collected until 130 minutes after premedication. Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry. RESULTS The characteristic cardiovascular effects of medetomidine, such as bradycardia, hypertension, and reduction in cardiac index, were obtunded by MK-467. The concentrations of alfaxalone in plasma were significantly increased in the presence of medetomidine, indicative of impaired drug distribution and clearance. This was counteracted by MK-467. CONCLUSIONS AND CLINICAL RELEVANCE The alteration in alfaxalone clearance when coadministered with medetomidine may be attributed to the systemic vasoconstrictive and bradycardic effects of the α 2 -adrenoceptor agonist. This could be clinically important because the use of α 2 -adrenoceptor agonists may increase the risk of adverse effects if standard doses of alfaxalone are used.

Objective: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral α 2 -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. PaCO 2 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 α 2 -adrenergic antagonist to inhalation anesthesia in dogs., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To describe suspected adverse drug reactions in cats associated with use of α 2 -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 α 2 -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 α 2 -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., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

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 (f R ) 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 f R decreased significantly. After R + MK, HR, f R , systolic and mean ABP decreased. MK alone increased both HR and f R . After R, ABP was significantly higher than after R + MK. HR and f R 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., (© 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

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., (© 2016 John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons Ltd.)

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., (© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

The haemodynamic interactions of a step infusion with medetomidine (MED) and the peripherally acting alpha-2 antagonist MK-467 (MK) were compared with MED infused alone in isoflurane-anaesthetised dogs. Eight purposely-bred Beagles were used in a randomised crossover study. Anaesthesia was induced with propofol intravenously (IV) and maintained with isoflurane in oxygen. Dogs received 1.25 µg/kg MED as a 1 min loading dose IV, along with a step-down MED infusion at rates of 8.0 µg/kg/h (step 1: 0-20 min), 5.5 µg/kg/h (step 2: 20-40 min) and 4.0 µg/kg/h (step 3: 40-95 min). Five minutes after starting the MED infusion, the dogs received MK-467 in a step-up infusion at rates of 100 µg/kg/h (step 1: 5-35 min), 200 µg/kg/h (step 2: 35-65 min) and 500 µg/kg/h (step 3: 65-95 min). Heart rate (HR), systolic (SAP) and mean arterial (MAP) blood pressures and arteriovenous oxygen content differences (a-vO2 diff) were calculated. Plasma drug concentrations were analysed. Repeated-measures general linear mixed models with Bonferroni correction were used for statistical analyses. MED infusion alone increased SAP maximally by 24.9%, MAP by 34.7% and a-vO2 diff by 222.5%, and reduced HR by 32.3%, but these changes were significantly attenuated by MK-467. Most MED effects returned to baseline during step 2 of MK-467 infusion and step 3 of MED infusion (MED/MK-467 ratio 1:18 to 1:50). Plasma concentrations of MED tended to be lower with the addition of MK-467. The use of step infusions helped to narrow down the therapeutic range for the MED/MK-467 infusion dose ratio during isoflurane anaesthesia in dogs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (© 2014 The Authors Veterinary Anaesthesia and Analgesia published by John Wiley & Sons Ltd on behalf of Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

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., (© 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

The reason why some horses begin an oral stereotypy such as crib-biting is not known. The aim of this study was to measure ghrelin and leptin concentrations in plasma concentrations to determine whether there is a link to crib-biting in horses. Plasma samples (n=3) were collected for plasma leptin and ghrelin assay before and during the morning first feeding in the usual environments of 15 horses with stereotypic crib-biting and 15 matched controls. The crib-biting intensity was scored in three 5-min phases, and a subgroup of verified crib-biters (n=8) was defined as horses that were seen to crib-bite during this study. Plasma leptin concentration (mean and 95% confidence interval [CI]) was lower in horses observed to crib-bite before and after feeding of concentrates (1.2, CI 0.8-1.7 ng/mL and 1.0, CI 0.6-1.7) than in non-crib-biters (2.3, CI 1.6-3.4 and 2.3, CI 1.6-3.4 ng/mL, respectively) and correlated negatively with crib-biting intensity. Crib-biting intensity was significantly higher shortly after feeding than before or 30 min later. Plasma ghrelin concentration was significantly higher before feeding concentrate than before hay feeding or after the concentrate, but did not differ between groups. There was a significant negative correlation between body composition score and plasma ghrelin concentration. These findings suggest that leptin concentrations may be associated with crib-biting behaviour in horses., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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., (© 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Pain recognition in cats is difficult and requires a multidisciplinary approach for diagnosis. A total of 103 client-owned cats were enrolled in this prospective, blinded clinical trial. Cats were invited to the clinic, or presented for annual rechecks/vaccinations, or gastrointestinal, dental or locomotor problems. The cats were of different breeds; both shorthaired and longhaired cats were included. Those cats that tolerated it were palpated and all cats were examined with the non-invasive method of thermographic imaging. Owners filled out a questionnaire about their cat's behaviour and estimated whether the cat was in any pain. The agreement between a questionnaire and thermographic imaging or palpation was low. Also, the agreement between the owner's estimation of pain and thermographic imaging or palpation was low. The agreement between palpation and thermographic imaging was moderate, suggesting that thermographic imaging is a potential tool in clinical practice for detecting and screening cats that are, potentially, in pain.

Objective: To evaluate protein expression in bronchoalveolar lavage fluid (BALF) obtained from West Highland White Terriers with idiopathic pulmonary fibrosis (IPF), dogs with chronic bronchitis, and healthy control dogs to identify potential biomarkers for IPF., Samples: BALF samples obtained from 6 West Highland White Terriers with histologically confirmed IPF, 5 dogs with chronic bronchitis, and 4 healthy Beagles., Procedures: Equal amounts of proteins in concentrated BALF samples were separated via 2-D differential gel electrophoresis. Proteins that were differentially expressed relative to results for healthy control dogs were identified with mass spectrometry and further verified via western blotting., Results: Expression of 6 proteins was upregulated and that of 1 protein was downregulated in dogs with IPF or chronic bronchitis, compared with results for healthy dogs. Expression of proteins β-actin, complement C3, α-1-antitrypsin, apolipoprotein A-1, haptoglobin, and transketolase was upregulated, whereas expression of lysozyme C was downregulated., Conclusions and Clinical Relevance: Proteomics can be used to search for biomarkers and to reveal disease-specific mechanisms. The quantitative comparison of proteomes for BALF obtained from dogs with IPF and chronic bronchitis and healthy dogs revealed similar changes for the dogs with IPF and chronic bronchitis, which suggested a common response to disease processes in otherwise different lung diseases. Specific biomarkers for IPF were not identified.

MCT1-CD147 complex is the prime lactate transporter in mammalian plasma membranes. In equine red blood cells (RBCs), activity of the complex and expression of MCT1 and CD147 is bimodal; high in 70% and low in 30%. We studied whether sequence variations contribute to the bimodal expression of MCT1 and CD147. Samples of blood and cremaster muscle were collected in connection of castration from 24 horses. Additional gluteus muscle samples were collected from 15 Standardbreds of which seven were known to express low amounts of CD147 in RBCs. The cDNA of MCT1 and CD147 together with a promoter region of CD147 was sequenced. The amounts of MCT1 and CD147 expressed in RBC and muscle membranes were measured by Western blot and mRNA levels in muscles by qPCR. MCT1 and CD147 were expressed in 20 castrates, and in four only were traces found. Sequence variations found in MCT1 were not linked to MCT1 expression. In CD147 linked heterozygous single nucleotide polymorphisms (SNPs) 389A>G (Met(125)Val) and 990C>T (3'-UTR) were associated to low expression of CD147. Also a mutation 168A>G (Ile(51)Val) in CD147 was associated to low MCT1 and CD147 expression. Low MCT1 and CD147 mRNA levels in gluteus were found in Standardbreds with low CD147 expression in RBCs. The results suggest that sequence variations affect the expression level of CD147, but do not explain its bimodality. The levels of MCT1 and CD147 mRNA correlated with the expression of CD147 and suggest that bimodality of their expression is regulated at transcriptional level., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The spleens of 18 healthy cats were imaged using contrast-enhanced ultrasound (CEUS) to evaluate splenic perfusion and to compare perfusion patterns in awake and anaesthetised cats. Two groups of cats were imaged; the first (Group 1) consisted of 10 young, anaesthetised cats and the second (Group 2) comprised eight young to middle aged cats that were initially imaged when awake and later following anaesthesia. A two-phase enhancement of the spleen was observed both in awake and in anaesthetised cats. The time to first appearance of the contrast was significantly faster in awake (3.9±0.6s) than anaesthetised (4.8±1.0s) cats in Group 2 (P=0.031). A marked heterogeneous perfusion pattern was more prevalent in the anaesthetised (50%) compared to the awake (12.5%) animals in Group 2. The spleen was heterogeneous for approximately 30s in all groups. The results indicated that CEUS suspected focal perfusion defects of the spleen, especially during general anaesthesia, should be evaluated with caution and only after the initial heterogeneity has disappeared., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Contrast-enhanced ultrasound (CEUS) of the left kidney was performed on eight non-anesthetized, young, purpose bred, domestic shorthaired cats. Each cat underwent a physical examination before and 4h and 48h after CEUS. Complete blood count (CBC), serum biochemical analysis, urinalysis, including evaluation of the enzymatic activities of urinary N-acetyl-β-d-glucosaminidase (NAG) and gamma-glutamyl transferase (GGT), were also performed. No changes were observed in CBC or serum biochemical analyses, with the exception of a decrease in blood urea concentration at 48h post-contrast ultrasound. A small elevation in NAG (U/g creatinine) was observed with a mean (SD) increase from 0.53 (0.35) to 1.43 (0.59) U/g creatinine. The magnitude of the rise was less than the circadian variation reported earlier for healthy cats. These results suggest that CEUS can be safely used to assess kidney perfusion in cats. The changes observed in laboratory values after CEUS did not appear to be related to detrimental effects on the kidneys., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

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., (© 2010 Blackwell Publishing Ltd.)

Contrast-enhanced ultrasound can be used to quantify tissue perfusion based on region of interest (ROI) analysis. The effect of the location and size of the ROI on the obtained perfusion parameters has been described in phantom, ex vivo and in vivo studies. We assessed the effects of location and size of the ROI on perfusion parameters in the renal cortex of 10 healthy, anesthetized cats using Definity contrast-enhanced ultrasound to estimate the importance of the ROI on quantification of tissue perfusion with contrast-enhanced ultrasound. Three separate sets of ROIs were placed in the renal cortex, varying in location, size or depth. There was a significant inverse association between increased depth or increased size of the ROI and peak intensity (P < 0.05). There was no statistically significant difference in the peak intensity between the ROIs placed in a row in the near field cortex. There was no significant difference in the ROIs with regard to arrival time, time to peak intensity and wash-in rate. When comparing two different ROIs in a patient with focal lesions, such as suspected neoplasia or infarction, the ROIs should always be placed at same depth and be as similar in size as possible.

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.

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., (© 2010 Blackwell Publishing Ltd.)