Effects of vatinoxan in rats sedated with a combination of medetomidine, midazolam and fentanyl.

BACKGROUND: Alpha2-adrenoceptor agonists (α2-agonists) are widely used in animals as sedatives and for pre-anaesthetic medication. Medetomidine has often been given subcutaneously (SC) to rats, although its absorption rate is slow and the individual variation in serum drug concentrations is high via this route. In addition, α2-agonists have various effects on metabolic and endocrine functions such as hypoinsulinaemia, hyperglycaemia and diuresis. Vatinoxan is a peripherally acting α2-adrenoceptor antagonist that, as a hydrophilic molecule, does not cross the blood-brain barrier in significant quantities and thus alleviates peripheral cardiovascular effects and adverse metabolic effects of α2-agonists. Aim of this study was to evaluate the effects of vatinoxan on sedation, blood glucose concentration, voiding and heart and respiratory rates and arterial oxygen saturation in rats sedated with subcutaneous medetomidine, midazolam and fentanyl. RESULTS: Onset of sedation and loss of righting reflex occurred significantly faster with vatinoxan [5.35 ± 1.08 (mean ± SD) versus 12.97 ± 6.18 min and 6.53 ± 2.18 versus 14.47 ± 7.28 min, respectively]. No significant differences were detected in heart and respiratory rates and arterial oxygen saturation between treatments. Blood glucose concentration (18.3 ± 3.6 versus 11.8 ± 1.2 mmol/L) and spontaneous urinary voiding [35.9 (15.1-41.6), range (median) versus 0.9 (0-8.0) mL /kg/min] were significantly higher without vatinoxan. CONCLUSIONS: Acceleration of induction of sedation, alleviation of hyperglycaemia and prevention of profuse diuresis by vatinoxan may be beneficial when sedating rats for clinical and experimental purposes with subcutaneous medetomidine, midazolam and fentanyl.

Pharmacokinetics of meloxicam in pre-ruminant calves after intravenous, oral, and subcutaneous administration.

Meloxicam is routinely used for pain alleviation in pre-ruminant calves during husbandry procedures. The pharmacokinetics of a single dose (0.5 mg/kg) of meloxicam was investigated after intravenous (IV), subcutaneous (SC), and oral (PO) administration in 30 pre-ruminant calves. Each group included 10 calves. Oral meloxicam was administered at least 1 h after feeding. Plasma samples were collected for up to 168 h, and the meloxicam concentration was analysed with liquid chromatography and mass spectrometry, followed by a noncompartmental pharmacokinetic analysis. The maximum meloxicam concentrations in plasma were 1.91 ± 0.27 µg/mL and 1.77 ± 0.16 µg/mL after SC and PO routes, respectively. The time of maximum concentration was 7.6 ± 2.8 h after SC and 10.0 ± 5.7 h after PO administration. The approximate bioavailability of meloxicam was 97% for SC and PO routes. The elimination half-lives were 79.2 ± 12.4, 84.6 ± 24.8, and 84.8 ± 22.3 h after IV, SC, and PO routes, respectively. The results suggest that the therapeutic meloxicam concentrations in plasma that are required for pain relief in other species, such as horses, may be maintained for several days following a single dose (0.5 mg/kg) administered IV, SC, or PO in calves.

Effect of constant rate infusion of detomidine with and without vatinoxan on blood glucose and insulin concentrations in horses.

OBJECTIVE: To assess the effects of an α2-adrenoceptor agonist (detomidine) constant rate infusion (CRI) with and without an α2-adrenoceptor antagonist (vatinoxan) CRI on blood insulin and glucose concentrations, heart rate, intestinal borborygmi, and sedation during and after infusion in horses. STUDY DESIGN: Randomized, blinded, crossover, experimental study. ANIMALS: A total of nine healthy, adult Finnhorse mares. METHODS: Horses were treated with an intravenous (IV) detomidine loading dose (0.01 mg kg-1), followed by CRI (0.015 mg kg-1 hour-1), and the same doses of detomidine combined with an IV vatinoxan loading dose (0.15 mg kg-1), followed by CRI (detomidine and vatinoxan; 0.05 mg kg-1 hour-1) with an 18 day washout period. Infusion time was 60 minutes and horses were monitored for 240 minutes after the infusion. Heart rate, borborygmi score and sedation were assessed, and blood glucose, insulin and triglyceride concentrations were measured. Data were analyzed using repeated measures ancova and Wilcoxon signed-rank tests. Values of p < 0.05 were considered statistically significant. RESULTS: Insulin concentration decreased during (median nadir 1.7, range 0.0-2.9 µIU mL-1 at 60 minutes, p < 0.0001) and increased after detomidine CRI (median 36.6, range 11.7-78.4 µIU mL-1 at 180 minutes, p = 0.0001) significantly compared with detomidine and vatinoxan CRI. A significant elevation of blood glucose (peak 11.5 ± 1.6 mmol L-1 at 60 minutes, p < 0.0001) was detected during detomidine CRI. Vatinoxan alleviated the insulin changes and abolished the significant increase in blood glucose. Vatinoxan alleviated the decrease in heart rate (p = 0.0001) during detomidine infusion. No significant differences were detected in sedation scores between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan attenuated the negative adverse effects of detomidine CRI and thus is potentially beneficial when used in combination with an α2-adrenoceptor agonist CRI in horses.

Validity and Repeatability Characteristics of a Non-Invasive, Infrared-Based Method Estimating Plasma Indocyanine Green Decay in Healthy Dogs.

Plasma clearance of indocyanine green (ICG-CL) is an invasive method to evaluate liver dysfunction. We aimed to investigate the practicality of a noninvasive, transcutaneous, infrared-based method estimating the disappearance rate of indocyanine green (ICG-PDR). In a randomized, cross-over study, both ICG-CL and ICG-PDR were determined in eight healthy dogs while conscious and when sedated with medetomidine and medetomidine-vatinoxan. ICG-PDR was further repeated in six of the dogs to assess its repeatability. Differences were tested with repeated-measures analysis of variance and post hoc t-tests with Bonferroni corrections, while associations were evaluated by both Spearman and Pearson correlation analyses. Furthermore, repeatability was assessed by examining calculated coefficients of variation (CV). A significant decrease in ICG-CL was observed in dogs sedated with medetomidine, while no difference between conscious and sedated states was detected with ICG-PDR. Overall, correlations between ICG-CL and ICG-PDR were poor, as was the intrasubject repeatability of ICG-PDR in conscious dogs with CV consistently above 20%. While some of the results may be explained by poor signal quality for the non-invasive method, we conclude that in healthy dogs ICG-PDR performed poorly.

Equine osteoarthritis modifies fatty acid signatures in synovial fluid and its extracellular vesicles.

BACKGROUND: Individual fatty acids (FAs) and their derivatives (lipid mediators) with pro-inflammatory or dual anti-inflammatory and pro-resolving properties have potential to influence the health of joint tissues. Osteoarthritis (OA) is an age-associated chronic joint disease that can be featured with altered FA composition in the synovial fluid (SF) of human patients. The counts and cargo of extracellular vesicles (EVs), membrane-bound particles released by synovial joint cells and transporting bioactive lipids, can also be modified by OA. The detailed FA signatures of SF and its EVs have remained unexplored in the horse - a well-recognized veterinary model for OA research. METHODS: The aim of the present study was to compare the FA profiles in equine SF and its ultracentrifuged EV fraction between control, contralateral, and OA metacarpophalangeal joints (n = 8/group). The FA profiles of total lipids were determined by gas chromatography and the data compared with univariate and multivariate analyses. RESULTS: The data revealed distinct FA profiles in SF and its EV-enriched pellet that were modified by naturally occurring equine OA. Regarding SFs, linoleic acid (generalized linear model, p = 0.0006), myristic acid (p = 0.003), palmitoleic acid (p < 0.0005), and n-3/n-6 polyunsaturated FA ratio (p < 0.0005) were among the important variables that separated OA from control samples. In EV-enriched pellets, saturated FAs palmitic acid (p = 0.020), stearic acid (p = 0.002), and behenic acid (p = 0.003) indicated OA. The observed FA modifications are potentially detrimental and could contribute to inflammatory processes and cartilage degradation in OA. CONCLUSIONS: Equine OA joints can be distinguished from normal joints based on their FA signatures in SF and its EV-enriched pellet. Clarifying the roles of SF and EV FA compositions in the pathogenesis of OA and their potential as joint disease biomarkers and therapeutic targets warrants future studies.

Comparison of Asymmetry During Trot In-Hand With Evaluations of Discomfort and Pain in Horses While Exercised.

Traditional visual lameness assessment is subjective. Ethograms have been developed for evaluating pain and objective sensors to detect lameness. Heart rate (HR) and heart rate variability (HRV) have been used to evaluate stress and pain. The aim of our study was to compare subjective and behavioral lameness scores, a sensor system measuring movement asymmetry, HR, and HRV. We hypothesized that these measures would show related trends. In 30 horses, an inertial sensor system was used to measure movement asymmetries during trot in-hand. A horse was categorized as sound if each asymmetry was less than 10 mm. We recorded riding to observe lameness and evaluate behavior. Heart rate and RR intervals were measured. Root mean squares of successive RR intervals (RMSSD) were calculated. Five horses were categorized as sound and 25 horses as lame by the inertial sensor system. No significant differences were detected between sound and lame horses in the ethogram, subjective lameness score, HR, and RMSSD. Overall asymmetry, ethogram, and lameness score had no significant correlation with each other, whereas overall asymmetry and ethogram correlated significantly with HR and RMSSD during certain phases of the ridden exercise. The main limitation of our study was the small number of sound horses detected by the inertial sensor system. The association between gait asymmetry and HRV suggests that the more gait asymmetry a horse shows during trot in-hand, the more pain or discomfort it probably experiences when ridden with a higher intensity. The threshold for lameness used by the inertial sensor system may require further evaluation.

Behavioral Signs Associated With Equine Cheek Tooth Findings.

Equine dental diseases are often underdiagnosed and their signs inadequately reported. Many horse owners have difficulties in recognizing pain-related behavioral signs and in associating them with dental pain. Our objective was to determine what type and degree of dental findings may cause behavioral signs associated with dental pain. In this cross-sectional study, dental examination was performed on 183 adult horses and cheek tooth findings were scored. Owners filled in an internet-based questionnaire including 35 questions concerning eating behavior, bit behavior, and general behavior of the horse. Descriptive statistics and logistic regression analyses were performed. Broadened or darkened fissures [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.04-5.7), complicated fractures (OR 2.3, CI 1.01-5.2) and secondary dentine defects of at least the second degree (OR 3.1, CI 1.2-7.7) were associated with the expression of at least five behavioral signs in the univariable binomial logistic regression analyses. Horses with at least one of these potentially painful cheek tooth findings expressed more signs related to eating behavior, bit behavior, and general behavior than did the other horses. The results suggest that cheek tooth findings indicated by this study as being potentially painful, i.e. broadened or darkened fissures, complicated fractures and secondary dentine defects of at least the second degree, may require intervention, particularly if the horse expresses any behavioral signs that might be related to dental pain.

Counts of hyaluronic acid-containing extracellular vesicles decrease in naturally occurring equine osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease with inadequately understood pathogenesis leading to pain and functional limitations. Extracellular vesicles (EVs) released by synovial joint cells can induce both pro- and anti-OA effects. Hyaluronic acid (HA) lubricates the surfaces of articular cartilage and is one of the bioactive molecules transported by EVs. In humans, altered EV counts and composition can be observed in OA synovial fluid (SF), while EV research is in early stages in the horse-a well-recognized OA model. The aim was to characterize SF EVs and their HA cargo in 19 horses. SF was collected after euthanasia from control, OA, and contralateral metacarpophalangeal joints. The SF HA concentrations and size distribution were determined with a sandwich-type enzyme-linked sorbent assay and size-exclusion chromatography. Ultracentrifugation followed by nanoparticle tracking analysis (NTA) were utilized to quantify small EVs, while confocal laser scanning microscopy (CLSM) and image analysis characterized larger EVs. The number and size distribution of small EVs measured by NTA were unaffected by OA, but these results may be limited by the lack of hyaluronidase pre-treatment of the samples. When visualized by CLSM, the number and proportion of larger HA-containing EVs (HA-EVs) decreased in OA SF (generalized linear model, count: p = 0.024, %: p = 0.028). There was an inverse association between the OA grade and total EV count, HA-EV count, and HA-EV % (rs = - 0.264 to - 0.327, p = 0.012-0.045). The total HA concentrations were also lower in OA (generalized linear model, p = 0.002). To conclude, the present study discovered a potential SF biomarker (HA-EVs) for naturally occurring equine OA. The roles of HA-EVs in the pathogenesis of OA and their potential as a joint disease biomarker and therapeutic target warrant future studies.

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.

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.

Oral Dimensions Related to Bit Size in Adult Horses and Ponies.

A bit that fits is essential for horse welfare and good communication with the ridden, driven or led horses. The bit causes pressure on the sensitive structures of the horse mouth. The aim of this study was to investigate variation in oral dimensions related to bit fit in adult horses and ponies and to evaluate bit fit by comparing oral dimensions with the currently used bit size selected by the horse owner. The study population consisted of 554 horses and ponies, 308 geldings and 246 mares, age 5-29 years, presented for routine dental care. Oral dimensions: mouth width, distance between upper and lower jaw, tongue thickness and lower jaw width, were measured under sedation. Oral dimensions were compared with the most used bit mouthpiece size presented to the researcher by the owner. Bit type and material were recorded. All oral dimensions in adult horses and ponies varied by breed and sex. Mouth width and distance between upper and lower jaw correlated positively with age. Oral dimensions were significantly smaller in mares than in geldings. In coldblood Finnhorses, oral dimensions were greater than in other breeds; in ponies they were smaller. The majority of the oral dimensions correlated positively with each other. Lower jaw width did not correlate with tongue thickness. It was common to use a bit that did not fit the horse: the bit was either too short or too long (over 10 mm longer) compared to mouth width, compressed the tongue in between the upper and lower jaw, or the center link was of similar length compared to lower jaw width, thus possibly causing pressure points or a nutcracker effect on the bars of the lower jaw. Horses had, on average, space for a 14 mm thick bit without compressing the tongue. The results of this study can aid in choosing a horse bit size that fits correctly and does not cause discomfort. It is recommended that the fit of the bit is evaluated regularly as the horse ages.

Wintertime pharmacokinetics of intravenously and orally administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).

OBJECTIVE: To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus). STUDY DESIGN: A crossover design with an 11 day washout period. ANIMALS: A total of eight young male reindeer, aged 1.5-2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation. METHODS: The reindeer were administered meloxicam (0.5 mg kg-1 IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed. RESULTS: The pharmacokinetic values, median (range), were determined. Elimination half-life (t½) with the IV route (n = 4) was 15.2 (13.2-16.8) hours, the volume of distribution at steady state was 133 (113-151) mL kg-1 and clearance was 3.98 (2.63-5.29) mL hour-1 kg-1. After oral administration (n = 7), the peak plasma concentration (Cmax) was detected at 6 hours, t½ was 19.3 (16.7-20.5) hours, Cmax 1.82 (1.17-2.78) µg mL-1 and bioavailability (n = 3) 49 (46-73)%. No evident adverse effects were detected after either administration route. CONCLUSIONS AND CLINICAL RELEVANCE: A single dose of meloxicam (0.5 mg kg-1 IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.

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

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

Cardiovascular effects of intravenous vatinoxan in wild boars (Sus scrofa) anaesthetised with intramuscular medetomidine-tiletamine-zolazepam.

BACKGROUND: The potent sedative medetomidine is a commonly used adjunct for the immobilisation of non-domestic mammals. However, its use is associated with pronounced cardiovascular side effects, such as bradycardia, vasoconstriction and decreased cardiac output. We investigated the effects of the peripherally-acting alpha-2-adrenoceptor antagonist vatinoxan on cardiovascular properties in medetomidine-tiletamine-zolazepam anaesthetised wild boar (Sus scrofa). METHODS: Twelve wild boars, anaesthetised twice with medetomidine (0.1 mg/kg) and tiletamine/zolazepam (2.5 mg/kg) IM in a randomised, crossover study, were administered (0.1 mg/kg) vatinoxan or an equivalent volume of saline IV (control). Cardiovascular variables, including heart rate (HR), mean arterial blood pressure (MAP), pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP) and cardiac output (CO), were assessed 5 min prior to vatinoxan/saline administration until the end of anaesthesia 30 min later. RESULTS: MAP (p < 0.0001), MPAP (p < 0.001) and MPAOP (p < 0.0001) significantly decreased from baseline after vatinoxan until the end of anaesthesia. HR increased significantly (p < 0.0001) from baseline after vatinoxan administration. However, the effect on HR subsided 3 min after vatinoxan. All variables remained constant after saline injection. There was no significant effect of vatinoxan or saline on CO. CONCLUSION: Vatinoxan significantly reduced systemic and pulmonary artery hypertension, induced by medetomidine in wild boar.

Effects of vatinoxan on xylazine-induced pulmonary alterations in sheep.

It was hypothesized that premedication with vatinoxan, a peripheral α2 -adrenoceptor antagonist, would mitigate xylazine-induced pulmonary alterations in sheep. Fourteen adult sheep were allotted into two equal groups and premedicated with either vatinoxan (750 µg/kg IV) or saline and sedated 10 min later with xylazine (500 µg/kg IV). Arterial oxygen saturation (SpO2 ) was measured and respiratory rate (RR) counted at intervals. The sheep were euthanized with IV pentobarbital 10 min after xylazine administration. The severity of pulmonary parenchymal alterations was assessed and graded grossly and histologically and correlations of the morphological changes with SpO2 evaluated. Following xylazine injection, SpO2 was significantly higher and RR significantly lower with vatinoxan than with saline and the sheep administered vatinoxan exhibited significantly smaller quantities of tracheal foam than those receiving saline. No significant differences in macroscopic oedema scores were detected between treatments. In contrast, the vatinoxan-treated animals exhibited significantly graver microscopic interstitial alveolar oedema and haemorrhage than saline-treated animals. The histological severity scores did not correlate with changes in SpO2 . In conclusion, xylazine induced a marked reduction in SpO2 which was abolished by the prior administration of vatinoxan. The histologically detected alterations after pentobarbital euthanasia with vatinoxan premedication need to be studied further.

A comparison of sedative effects of xylazine alone or combined with levomethadone or ketamine in calves prior to disbudding.

OBJECTIVE: To compare the sedative effects of intramuscular xylazine alone or combined with levomethadone or ketamine in calves before cautery disbudding. STUDY DESIGN: Randomized, blinded, clinical trial. ANIMALS: A total of 28 dairy calves, aged 21 ± 5 days and weighing 61.0 ± 9.3 kg (mean ± standard deviation). METHODS: Calves were randomly allocated to three groups: xylazine (0.1 mg kg-1) and levomethadone (0.05 mg kg-1; group XL), xylazine (0.1 mg kg-1) and ketamine (1 mg kg-1; group XK) and xylazine alone (0.2 mg kg-1; group X). Local anaesthesia (procaine hydrochloride) and meloxicam were administered subcutaneously 15 minutes after sedation and 15 minutes before disbudding. The calves' responses to the administration of local anaesthesia and disbudding were recorded. Sedation was assessed at baseline and at intervals up to 240 minutes postsedation. Times of recumbency, first head lift and first standing were recorded. Drug plasma concentrations were measured. RESULTS: Data were obtained from 27 animals. All protocols resulted in sedation sufficient to administer local anaesthesia and to perform disbudding. Sedation scores significantly correlated with drug plasma concentrations (p ≤ 0.002). Times to recumbency did not differ among protocols (2.8 ± 0.3, 3.1 ± 1.1 and 2.1 ± 0.8 minutes for groups XL, XK and X, respectively), whereas interval from drug(s) administration until first head lift was significantly shorter in group XK than X (47.3 ± 14.1, 34.4 ± 5.3 and 62.6 ± 31.9 minutes for groups XL, XK and X, respectively). The area under the time-sedation curve was significantly greater in group X than XK or XL (754 ± 215, 665 ± 118 and 1005 ± 258 minutes for groups XL, XK and X, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Levomethadone or ketamine with a low dose of xylazine produced short but sufficient sedation for local anaesthesia and disbudding with minimum resistance.

Concentrations of vatinoxan and xylazine in plasma, cerebrospinal fluid and brain tissue following intravenous administration in sheep.

OBJECTIVES: To investigate the extent of vatinoxan distribution into sheep brain, and whether vatinoxan influences brain concentrations of xylazine; and to examine the utility of cerebrospinal fluid (CSF) as a surrogate of brain tissue concentrations for vatinoxan and xylazine. STUDY DESIGN: Randomised, blinded, experimental study. ANIMALS: A total of 14 adult female sheep. METHODS: Sheep were randomly allocated into two equal groups and premedicated with either intravenous (IV) vatinoxan (750 µg kg-1, VX) or saline (SX) administered 10 minutes before IV xylazine (500 µg kg-1). Sedation was subjectively assessed at selected intervals before and after treatments. At 10 minutes after xylazine administration, a venous blood sample was collected and the sheep were immediately euthanised with IV pentobarbital (100 mg kg-1). Plasma, CSF and brain tissues were harvested, and concentrations of vatinoxan and xylazine were quantified using liquid chromatography-tandem mass spectrometry. Drug ratios were then calculated and the data were analysed as appropriate. RESULTS: The brain-to-plasma and CSF-to-plasma ratios of vatinoxan were 0.06 ± 0.013 and 0.05 ± 0.01 (mean ± standard deviation), respectively. Xylazine brain concentrations were not significantly different (835 ± 262 versus 1029 ± 297 ng g-1 in groups VX and SX, respectively) and were approximately 15-fold higher than those in plasma. The CSF-to-brain ratio of vatinoxan was 0.8 ± 0.2, whereas xylazine concentrations in the brain were approximately 17-fold greater than those in CSF, with and without vatinoxan. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan did not significantly affect sedation with xylazine or the concentrations of xylazine in the brain. CSF is not a good predictor of xylazine concentrations in the brain, whereas vatinoxan concentrations were concordant between the brain and CSF, using the dosages in this study.

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

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

Effects of Bedding Material on Equine Lower Airway Inflammation: A Crossover Study Comparing Peat and Wood Shavings.

Bedding materials affect stable air hygiene, and thus the development and exacerbation of equine asthma. There is limited knowledge concerning the effects of different types of bedding material on equine lower airway inflammation. The objective of our study was to investigate the effects of bedding materials on respiratory signs, tracheal mucus score, and lower airway cytology in healthy adult horses. The study design was a prospective controlled study, and the subjects were healthy adult riding school horses (n = 32) from a single stable. Wood shavings were compared to peat, which was used as a reference bedding material. Lower airway endoscopy and sampling (tracheal wash and bronchoalveolar lavage fluid) for cytological examination were performed after each 35-day bedding period. No difference between bedding periods was observed in the respiratory rate or tracheal mucus score. Tracheal wash neutrophil percentage with the wood shavings was higher compared to the previous (P = 0.040) or following (P = 0.0045) peat period. Bronchoalveolar lavage fluid neutrophil percentage with the wood shavings was higher compared to the following peat period (P < 0.001). We conclude that, between the two bedding materials used in this study, peat caused less neutrophilic lower airway inflammation in horses. The information gained from this study may assist veterinarians and horse owners in selecting bedding materials, especially for horses suffering from equine asthma.

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.