Dexmedetomidine and MK-467, a peripherally acting α2-adrenoceptor antagonist, in dogs

The effects of MK-467, a peripherally acting α2-adrenoceptor antagonist, on the cardiopulmonary changes induced by dexmedetomidine, a specific and selective α2- adrenoceptor agonist, were investigated in dogs. Plasma concentrations of both drugs were also quantified, along with influence of MK-467 on the quality of clinical sedation achieved with dexmedetomidine. The main focus of this study was on preventing or attenuating the cardiovascular effects of dexmedetomidine. The effects of three different doses of MK-467, administered simultaneously with the agonist, on the main hemodynamic parameters were evaluated and compared with a single dose of both dexmedetomidine and MK- 467 administered alone. Respiratory effects were evaluated with arterial blood gases, and indices such as oxygen delivery were calculated. The pharmacokinetic interaction between the two drugs was evaluated in vivo and general information on the disposition of intravenously administered MK-467 in dogs was produced. The degree of clinical sedation was subjectively assessed during the studies. The effect of MK-467 on the quality of reversal of dexmedetomidine-induced sedation with atipamezole was also determined. M K-467 dose-dependently reduced or prevented all relevant cardiovascular changes induced by dexmedetomidine. The heart rate, arterial and central venous blood pressure, cardiac index, systemic vascular resistance and oxygen delivery remained within acceptable physiological limits throughout the observational period with all doses of MK-467 administered with the agonist. Moderate hypotension was seen with the highest dose of MK-467. No significant differences in respiratory function were observed between treatments. MK-467, when administered alone, induced sinus tachycardia along with increases in the cardiac index and reductions in systemic vascular resistance. Arterial blood pressures remained unchanged. The degree of clinical sedation was reduced by MK-467, most likely by increasing the disposition of dexmedetomidine, which led to lower plasma concentrations of the agonist. However, the differences in clinical sedation were minor. MK-467 did not interfere with the ability of atipamezole to reverse dexmedetomidine-induced sedation.Alfa-2- adrenergiset agonistit (α2A), kuten deksmedetomidiini (DEX), ovat yleisimpiä koiralla käytettäviä rauhoitteita ja yleisanestesian esilääkkeitä. Ne aikaansaavat rauhoittumisen, lihasrentouden ja kivunlievityksen aktivoimalla tiettyjä keskushermoston reseptoreita, mistä aiheutuu noradrenaliini-hermovälittäjäaineen erityksen väheneminen ja vireystilan lasku. Näiden toivottujen keskushermostovaikutusten lisäksi α2A:lla on myös keskushermoston ulkopuolisia vaikutuksia. Kliinisesti merkittävimpiä ovat vaikutukset sydän- ja verenkiertoelimistöön. Ne ilmenevät sydämen syketiheyden vähenemisenä ja rytmihäiriöinä, vähentyneenä sydämen minuuttitilavuutena sekä lisääntyneenä verenkierron vastuksena. α2A:t aktivoivat verisuonten seinämissä olevia reseptoreja aiheuttaen verisuonten supistumisen, minkä seurauksena verenpaine nousee voimakkaasti. Kohonnut verenpaine aiheuttaa refleksikaaren, minkä seurauksena sydämen syke ja sen teho laskevat merkittävästi. Voimakkaiden ääreisvaikutustensa vuoksi α2A:n käyttö onkin perusteltua vain terveille eläimille. Tässä väitöstutkimuksessa keskityttiin estämään DEX:n keskushermoston ulkopuolisia vaikutuksia antamalla koirille samanaikaisesti spesifiä vasta-ainetta (MK-467), joka ei läpäise veri-aivoestettä. Tutkimuksen hypoteesina oli, että MK-467 sallii DEX:n suotuisat keskushermostovaikutukset estäen samalla haitalliset sydän- ja verenkiertovaikutukset ääreiskudoksissa. MK-467:n annostelu lievensi tai esti kokonaan samanaikaisesti annostellun DEX:n sydän- ja verenkiertovaikutukset koiralla. Estovaikutus oli annosvasteinen. MK-467 myös vähensi hieman DEX:n aikaansaamaa kliinistä rauhoittumista, todennäköisimmin alentamalla DEX:n veripitoisuuksia tehostuneen verenkiertoelimistön toiminnan seurauksena. Ääreiskudoksissa aktiivinen MK-467 voisi parantaa α2A:n turvallisuutta koiralla

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

Publisher Copyright: © 2022 The Author(s)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.Peer reviewe

Aberrant migration and surgical removal of a heartworm (Dirofilaria immitis) from the femoral artery of a cat.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs

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

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

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

Objective: We determined the possible effects of a peripherally acting alpha2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) co-administered medetomidine, butorphanol and midazolam. Study design: Randomized, experimental, blinded cross-over 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 until 90 minutes after MBM-MK. The Tmax for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with co-administration 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 co-administered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.Peer reviewe

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 levo-medetomidine 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 mu g kg(-1)) and vatinoxan (800 mu g 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 alpha(2)-adrenoceptors outside the CNS.Peer reviewe

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

Peer reviewe

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

OBJECTIVE To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. ANIMALS 8 healthy Beagles. PROCEDURES Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 mu g/kg], medetomidine [20 mu g/kg] and vatinoxan [400 mu g/kg], and medetomidine [40 mu g/kg] and vatinoxan [800 mu g/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 non inferior 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.Peer reviewe