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

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

The impact of MK-467 on plasma drug concentrations, sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal.

The effect of MK-467, a peripheral α2 -adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2-week washout periods. Medetomidine (MED) 30 µg/kg alone or combined in the same syringe with MK-467 300 µg/kg (MMK) was injected intramuscular, followed by ATI 150 µg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK-467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine-related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK-467 was included. In this study, MK-467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.

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

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

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

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

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.

Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse.

OBJECTIVE: To describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight, mature healthy horses age 11.7 ± 4.6 (mean ± SD) years, weighing 557 ± 54 kg. METHODS: Medetomidine (10 µg kg(-1) ) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis. RESULTS: Pharmacokinetic analysis estimated that medetomidine peaked (8.86 ± 3.87 ng mL(-1) ) at 6.4 ± 2.7 minutes following administration and was last detected at 165 ± 77 minutes post administration. Medetomidine had a clearance of 39.6 ± 14.6 mL kg(-1) minute(-1) and a volume of distribution of 1854 ± 565 mL kg(-1). The elimination half-life was 29.1 ± 12.5 minutes. Glucose concentration reached a maximum of 176 ± 46 mg dL(-1) approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 ± 12 to 20 ± 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound. CONCLUSION AND CLINICAL RELEVANCE: Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration.

Liquid chromatography tandem mass spectrometry for the simultaneous quantitative analysis of ketamine and medetomidine in ovine plasma.

Ketamine and medetomidine are commonly combined to sedate or anaesthetize a wide range of animal species. Despite this, there are few methods for the simultaneous quantitative analysis of the two drugs. This study describes the use of solid-phase extraction sample preparation followed by liquid chromatography-tandem mass spectrometry for the quantitative analysis of both drugs in ovine plasma. Extraction recovery was 93% for ketamine and 95% for medetomidine. The lowest limit of detection for ketamine was 1 ng/mL and for medetomidine 2 ng/mL, with linearity greater than 0.99 for both. Intra-day and inter-day precisions for both drugs were less than 10 and 7%, respectively. Application of the method to samples obtained from pregnant ewes and their fetuses showed placental transfer of the drugs over time such that there was no significant difference in plasma concentration at delivery. In summary, a validated method has been developed for the simultaneous quantification of ketamine and medetomidine in ovine plasma samples which can be used to study the pharmacokinetics of these drugs.

A quick approach for medetomidine enantiomer determination in dog plasma by chiral liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study.

In the present study, a rapid, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of medetomidine enantiomers in dog plasma was developed and validated. The separation and individual quantification of chiral compounds can be a tricky task in LC. This is particularly true when target analytes have a relatively small mass, as is the case with medetomidine, a potent and highly specific α2-adrenoceptor agonist widely used in both human and veterinary medicine. The proposed approach is based on a quick liquid-liquid extraction with ethyl acetate and filtration prior to injection. The optimized mobile phase composition allowed to perfectly separate the two enantiomers of medetomidine in a short chromatographic run time, using a cellulose tris(4-methylbenzoate)-based chiral column. A lower limit of quantification of 0.1 ng/mL was reached for both analytes thanks to the high sensitivity and selectivity of MS/MS and the use of racemic medetomidine-d3 as internal standard prevented potential matrix effect. Linearity was satisfying (R2  > 0.99) over the range 0.1-25 ng/mL, as well as within- and between-session accuracy and precision, both always <15%. This method was also applied with success to a series of samples from a pharmacokinetic (PK) study aimed at comparing dex- and levomedetomidine behaviour after administration of the racemic mixture in dogs. The simple extraction procedure, which allows reduced solvent and time consumption without compromising analytical performances, makes this technique a useful tool for this kind of applications even when small animals are involved, due to the small amount of sample required.

Metabolic stability and determination of cytochrome P450 isoenzymes' contribution to the metabolism of medetomidine in dog liver microsomes.

Medetomidine is a potent and selective alpha2-adrenergic agonist. The activation of alpha2-adrenergic receptor mediates a variety of effects including sedation, analgesia, relief of anxiety, vasoconstriction and bradycardia. However, our main interest is the sedative effects of medetomidine when used as a premedicant prior surgery in companion animals, especially in dogs. Recently, data suggested that following intravenous infusion at six dosing regiments non-linear pharmacokinetics was observed. Major causes of non-linear pharmacokinetics are the elimination of the drug not following a simple first-order kinetics and/or the elimination half-life changing due to saturation of an enzyme system. The goal of this study was to establish the metabolic stability and determine the metabolic pathway of medetomidine in dog liver microsomes. Consequently, Michaelis-Menten parameters (V(max), K(m)), T(1/2) and CL(i) were determined. The incubations were performed in a microcentrifuge tube and containing various concentrations of medetomidine (10-5000 nM), 1 mg/mL of microsomal proteins suspended in 0.1 M phosphate buffer, pH 7.4. Microsomal suspensions were preincubated with NADPH (1 mM) for 5 min at 37 degrees C prior to fortification with medetomidine. Samples were taken at various time points for kinetic information and the initial velocity (v(i)) was determined after 10 min incubation. The reaction was stopped by the addition of an internal standard solution (100 ng/mL of dextrometorphan in acetone). Medetomidine concentrations were determined using a selective and sensitive HPLC-ESI/MS/MS method. Using non-linear regression, we determined a K(m) value of 577 nM, indicating relatively low threshold enzyme saturation consistent with previous in vivo observation. The metabolic stability was determined at a concentration of 100 nm (<

Tissue Residue Levels of the Tranquilizer Combination of Butorphanol, Azaperone, and Medetomidine, and the Antagonists, Naltrexone, Atipamezole, and Tolazoline, in Black Bears (Ursus americanus) Postimmobilization.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses.

BACKGROUND: Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2 -adrenoceptors. Vatinoxan, a peripheral α2 -antagonist, has been shown experimentally to alleviate the adverse effects of some α2 -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.

Regio- and stereospecific N-glucuronidation of medetomidine: the differences between UDP glucuronosyltransferase (UGT) 1A4 and UGT2B10 account for the complex kinetics of human liver microsomes.

Medetomidine is a chiral imidazole derivate whose dextroenantiomer is pharmacologically active. The major metabolic pathway of dexmedetomidine [(+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole] in humans is N-glucuronidation at the imidazolate nitrogens. We have purified the N3- and N1-glucuronides of dexmedetomidine, termed DG1 and DG2, respectively, according to their elution order in liquid chromatography and determined their structure by 1H nuclear magnetic resonance (NMR). Studying medetomidine glucuronidation by human liver microsomes (HLMs) and recombinant UDP glucuronosyltransferase (UGT) 1A4 indicated that another human UGT plays a major role in these activities. We now demonstrate that this enzyme is UGT2B10. HLMs catalyzed DG1 and DG2 formation, at a ratio of 3:1, with two-enzyme kinetics that contain both a high-affinity component, K(m1) values of 6.6 and 8.7 microM, and a low-affinity component, K(m2) values > 1 mM. The DG1/DG2 ratio in the case of UGT2B10 was lower, 1.4:1, whereas the substrate affinity for both reactions was high, K(m) values of 11 and 16 microM. UGT1A4 produced mainly DG1 (DG1/DG2 ratio of 6.6:1) at low substrate affinities, K(m) values above 0.6 mM, but superior expression-normalized V(max) values. Levomedetomidine [(-)-4-(R)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole] glucuronidation by HLMs yielded mostly the N3-glucuronide (LG1, structure determined by NMR), with monophasic kinetics and a K(m) value of 14 microM. The activity of UGT1A4 toward levomedetomide was low and generated both LG1 and LG2, whereas UGT2B10 exhibited relatively high activity and sharp regioselectivity, yielding only LG1, with a K(m) value of 7.4 microM. The results highlight the contribution of UGT2B10 to medetomidine glucuronidation and its potential importance for other N-glucuronidation reactions within the human liver.

Tissue Residue Levels after Immobilization of Rocky Mountain Elk ( Cervus elaphus nelsoni) using a Combination of Nalbuphine, Medetomidine, and Azaperone Antagonized with Naltrexone, Atipamezole, and Tolazoline.

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

Successful protocol of anaesthesia for measuring transepithelial nasal potential difference in spontaneously breathing mice.

Numerous difficulties arise during in vivo measurements of transepithelial nasal potential difference (PD) in mice, such as inadequate duration and depth of anaesthesia, bronchoaspiration of solutions perfused in the nose, and respiratory and/or cardiovascular depression. Anaesthesia was induced in adult C57 mice with intraperitoneal injection of a combination of fentanyl, droperidol and medetomidine, each of these at either a small dose (0.20, 10 and 0.33 mg/kg, respectively) or at a large dose (0.40, 20 and 0.40 mg/kg, respectively), combined with a fixed dose of 0.375 microg clonidine. In order to establish a pharmacokinetic-pharmacodynamic relationship, blood concentrations of the first three drugs were measured in 24 animals by liquid-chromatography tandem mass spectrometry. At the end of the experiment, naloxone, a competitive morphinic antagonist, and atipamezole, an alpha-2 adrenergic antagonist, were administered. Bronchoaspiration was prevented by tilting the animal head downwards and by absorbing the excess fluid from the opposite nostril and from the oral cavity. Optimal assessment of anaesthesia associated with regular respiration, loss of blink, pupillary and pedal withdrawal reflexes was obtained with doses of fentanyl, droperidol and medetomidine corresponding to 0.20, 20 and 0.40 mg/kg, respectively. Blood concentrations of fentanyl around 17 ng/mL induced loss of respiratory efforts and were followed by death during the experiment. Integrity of ion transport was demonstrated under continuous perfusion by successive depolarization after amiloride and repolarization after chloride-free solution. The combination investigated in this study lead to adequate surgical anaesthesia (stage III, plane 2) for prolonged nasal PD measurements in spontaneously breathing mice.

The bioavailability of medetomidine in eight sheep following oesophageal administration.

There is sound evidence that medetomidine is an effective analgesic for acute pain in sheep. In this study, 15 µg kg(-1) of medetomidine was administered intravenously, and into the oesophagus, in a cross-over study, using eight sheep. Following intravenous administration, medetomidine could be detected in the plasma of these sheep for 120-180 min but following oesophageal administration, medetomidine could not be detected in the plasma of any sheep at any of 17 time points over four days. It is suspected that this is due to high first pass metabolism in the liver. Consequently, we conclude that future studies investigating the use of analgesics in orally-administered osmotic pumps in sheep should consider higher doses of medetomidine (e.g. >100 µg kg(-1)), further investigations into the barriers of medetomidine bioavailability from the sheep gut, liver-bypass drug delivery systems, or other α2-adrenergic agonists (e.g. clonidine or xylazine).

Minimal alveolar concentration of desflurane in combination with an infusion of medetomidine for the anaesthesia of ponies.

The minimum alveolar concentration of desflurane when combined with a continuous infusion of medetomidine at 3.5 microg/kg/hour was measured in seven ponies. Anaesthesia was induced with medetomidine (7 microg/kg intravenously) followed by ketamine (2 mg/kg intravenously) and maintained with desflurane in oxygen. The infusion of medetomidine was started 20 minutes after the induction of anaesthesia. The electrical test stimulus was applied at the coronary band (50 V, 10 ms bursts at 5 Hz for one minute), and heart rates and rhythms, arterial blood pressures, and arterial blood gas tensions were measured at intervals, just before the application of the stimulus. The mean (sd) minimum alveolar concentration of desflurane was 5.3 (1.04) per cent (range 3.2 to 6.4 per cent), 28 per cent less than the previously published value for desflurane alone after the induction of anaesthesia with xylazine and ketamine. The cardiopulmonary parameters remained stable throughout the period of anaesthesia. The mean (sd) time taken by the ponies to stand after the administration of desflurane ceased was 16.5 (6.17) (range 5.8 to 26) minutes, and the quality of recovery was good or excellent. However, one pony died shortly after standing; a postmortem examination revealed that it had chronic left atrial dilatation.

Transplacental transfer of medetomidine and ketamine in pregnant ewes.

The extent of placental transfer of medetomidine and ketamine is unknown in pregnant ewes. Date-mated singleton (n = 8) and twin (n = 8) pregnant merino cross ewes were anaesthetized for Caesarean delivery of preterm lamb fetuses. A combination of medetomidine (20 µg/kg) and ketamine (10 mg/kg) was administered by intravenous injection and surgery performed immediately thereafter. Blood samples were collected from the ewe at one, five and 10 min after intravenous injection and from the umbilical vein of the fetus at delivery. Non-pregnant ewes were also anaesthetized (n = 8). There was no difference in the plasma concentration of medetomidine or ketamine when comparing singleton and twin ewes or pregnant and non-pregnant ewes for the short duration of the study. Fetal plasma concentrations of each drug were comparable to the maternal concentrations at the same time. We conclude that both drugs cross the placenta readily and provide anaesthesia and analgesia for the fetus when it is delivered.

Bioaccumulation of the new antifoulant medetomidine in marine organisms.

Biofouling is a huge problem globally and new alternative antifoulants are presently being investigated. One candidate is medetomidine, a commonly used sedative in veterinary medicine, which has been shown to effectively prevent settlement of barnacles. The purpose of this study was to measure uptake, elimination and bioconcentration of medetomidine in Mytilus edulis, Abra nitida, Crangon crangon and periphyton communities to evaluate the risk of bioaccumulation in the marine environment. Bioconcentration factors (BCF) and bioaccumulation factors (BAF) were used to assess the bioaccumulation. The calculations of these factors were based on the distribution of the radiolabelled medetomidine. BCF for C. crangon was 2.8 while M. edulis had a BCF of 134 and the periphyton communities' BCF was 1195 l/kg fresh weight (FW). The concentration of medetomidine in the animals reached steady state after 24-48 h for all test systems except for A. nitida, which never stabilised enough to calculate a bioaccumulation factor (BAF). Elimination from the organism's tissues was rapid for three of the test systems with half-lives between 1 and 24 h. A. nitida had a half-life of 96-120 h. This study demonstrates that the bioconcentration and bioaccumulation of medetomidine differs between aquatic organisms and that microalgal communities in the form of periphyton have the highest bioconcentration factor of the organisms tested.

Comparison of subcutaneous and intramuscular ketamine-medetomidine with and without reversal by atipamezole in Dutch belted rabbits (Oryctolagus cuniculus).

Forty male Dutch belted rabbits (Oryctolagus cuniculus) enrolled in a minimally invasive pharmacokinetics study were used to compare the efficacy of an anesthetic combination delivered through 2 injection routes. Rabbits were randomly assigned to 4 groups (n = 10/group) to determine the sedative and physiologic effects of ketamine (25 mg/kg)-medetomidine (0.5 mg/kg) given either intramuscularly (IM) or subcutaneously (SC). Palpebral, pedal, ear pinch, and righting reflexes, as well as cardiopulmonary parameters (heart rate, respiratory rate, and arterial blood oxyhemoglobin saturation), were recorded every 5 min. In addition, the reversal effects of an intravenous dose of atipamezole (1 mg/kg), an alpha 2 adrenoreceptor antagonist, were assessed by comparing the return of the righting reflex in rabbits given the reversal agent with those that recovered spontaneously. Compared with the IM route, SC ketamine-medetomidine effectively induced chemical restraint with less than a 2-min difference in onset of anesthesia and markedly less resistance (for example, fl inching, kicking, and so forth) during the injection. In all groups, the anesthetic regimen, regardless of the route of administration, provided an adequate level of anesthesia. Reversal with atipamezole improved arterial hemoglobin oxygen saturation for both the SC and IM groups; however, an enhanced rate of recovery from anesthesia was clinically apparent only for animals given the combination by the IM route.

The use and assessment of ketamine-medetomidine-butorphanol combinations for field anaesthesia in wild European badgers (Meles meles).

OBJECTIVE: To evaluate the effectiveness of four ketamine-based anaesthetics in badgers using a quantitative anaesthesia assessment technique. STUDY DESIGN: Prospective randomized 'blinded' experimental trial. METHODS: The quality of induction, of anaesthesia (at 5-minute intervals) and of recovery were assessed in 93 badgers, given either one of three ketamine (K)-medetomidine (M)-butorphanol (B) combinations: group A - M K B at 20/40/80 microg kg(-1); group B - M K B at 20/40/60 microg kg(-1); and group C - M K B at 20/60/40 microg kg(-1), or ketamine (K) alone at 2 mg kg(-1) (group D). The assessor was ignorant of the combination administered. Physiological variables (heart and respiratory rates and rectal temperature) were measured at 5-minute intervals during anaesthesia. Gingival mucus membrane colour was also recorded. RESULTS: Induction to anaesthesia was most rapid with ketamine (2 mg kg(-1)) although induction quality did not differ between techniques. Ketamine used alone gave the poorest score for anaesthesia quality. Heart rate (HR) and scores for gingival mucus membrane colour were higher in animals anaesthetized with ketamine alone. Rectal temperature did not differ significantly between the techniques at any time during anaesthesia. Ketamine used alone produced the poorest quality of recovery. CONCLUSION AND CLINICAL RELEVANCE: The M-K-B combinations investigated overcame several side effects associated with ketamine anaesthesia, but at the expense of more variable induction times, lower HRs, and poorer mucus membrane coloration.