Browsing by Subject "MK-467"

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  • Pakkanen, Soile Anja Eliisa; de Vries, Annemarie; Raekallio, Marja Riitta; Mykkänen, Anna Kristina; Palviainen, Mari Johanna; Sankari, Satu Marja; Vainio, Outi Maritta (2018)
    Background: Romifidine, an alpha-2 adrenoceptor agonist, is a widely-used sedative in equine medicine. Besides the desired sedative and analgesic actions, alpha-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 alpha-2 adrenoceptors. Because vatinoxan does not cross the blood brain barrier in significant amounts, it has only minor effect on sedation induced by alpha-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 alpha-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 mu g/kg; ROM), vatinoxan (200 mu g/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.
  • Pakkanen, Soile A E; de Vries, Annemarie; Raekallio, Marja R; Mykkänen, Anna K; Palviainen, Mari J; Sankari, Satu M; Vainio, Outi M (BioMed Central, 2018)
    Abstract 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.
  • Honkavaara, Juhana M.; Raekallio, Marja R.; Syrja, Pernilla M.; Pypendop, Bruno H.; Knych, Heather K.; Kallio-Kujala, Ira J.; Vainio, Outi M. (2020)
    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.
  • Kallio-Kujala, I. J.; Bennett, R. C.; Raekallio, M. R.; Yatkin, E.; Meierjohann, A.; Savontaus, E.; Scheinin, M.; Spillmann, T.; Vainio, O. M. (2018)
    The commonly used sedative alpha(2)-adrenoceptor agonist dexmedetomidine has adverse cardiovascular effects in dogs that can be prevented by concomitant administration of the peripherally acting alpha(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 alpha(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 alpha(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. (C) 2018 The Author(s). Published by Elsevier Ltd.
  • Rossi, Heini; Raekallio, Marja; Määttä, Merita; Tapio, Heidi Anneli; Hanifeh, Mohsen; Junnila, Jouni; Rajamäki, Minna; Mykkänen, Anna (2019)
    Pneumonia is one of the potential complications of general anaesthesia in horses. Anaesthesia is known to increase neutrophils in bronchoalveolar lavage fluid (BALF) of horses after lateral recumbency, but studies after dorsal recumbency are lacking. Our primary aim was to determine when lung inflammation reaches its maximum and how rapidly BALF cytology returns to baseline after anaesthesia in dorsal recumbency. A secondary aim was to investigate the possible effect of vatinoxan, a novel drug, on the BALF cytology results. Six healthy experimental horses were enrolled in this observational crossover study. The horses were subject to repeated BALF and blood sampling for 7 days after general anaesthesia with two treatment protocols, and without anaesthesia (control). During the two treatments, the horses received either medetomidine-vatinoxan or medetomidine-placebo as premedication, and anaesthesia was induced with ketamine-midazolam and maintained with isoflurane for 1 h in dorsal recumbency. The differences in BALF and blood variables between the two anaesthesia protocols and control were analysed with repeated measures analysis of variance models. In this study, anaesthesia in dorsal recumbency resulted in no clinically relevant changes in airway cytology that could be differentiated from the effect of repeated BALF sampling. No differences in BALF matrix metalloproteinase gelatinolytic activity could be detected between the two treatments or the control series. Marked increase in serum amyloid A was detected in some animals. Vatinoxan as premedication did not consistently affect lung cytology or blood inflammatory markers after anaesthesia. (C) 2019 The Author(s). Published by Elsevier Ltd.
  • Tapio, H.; Raekallio, M. R.; Mykkänen, A.; Männikkö, S.; Scheinin, M.; Bennett, R. C.; Vainio, O. (2019)
    Background Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral alpha(2)-adrenoceptors. Vatinoxan, a peripheral alpha(2)-antagonist, has been shown experimentally to alleviate the adverse effects of some alpha(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 mu g/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 mu g/kg i.v., followed by CRI of medetomidine at 3.5 mu g/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
  • Tapio, H. A.; Raekallio, M. R.; Mykkänen, A. K.; Al-Ramahi, D.; Scheinin, M.; Hautajarvi, H. J.; Männikkö, S.; Vainio, O. (2019)
    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 a2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7 mu g/kg IV alone (MED) or with vatinoxan hydrochloride 140 mu g/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 (DO2I) decreased significantly more with MED, with the largest difference observed at 20min: CI was 39 +/- 2 and 73 +/- 18 (P = 0.009) and DO2I 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. (C) 2019 The Authors. Published by Elsevier Ltd.
  • Huuskonen, Vilhelmiina; Restitutti, Flavia; Honkavaara, Juhana M.; Raekallio, Marja R.; Männikkö, Sofia; Scheinin, Mika; Vainio, Outi M. (2020)
    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.
  • Wejberg, Otto (Helsingfors universitet, 2015)
    Medetomidiini on eläinlääketieteessä yleisesti käytetty α2-adrenoreseptorien agonisti. Sen toivottuja vaikutuksia ovat rauhoittuminen eli sedaatio, jännittyneisyyden väheneminen ja kivunlievitys. Sillä on supra-additiivinen, vaikutuksia voimistava, yhteisvaikutus opioidien kanssa ja se vähentää inhalaatioanesteettien tarvetta. Medetomidiinilla on myös haittavaikutuksia, joihin kuuluvat sydämen harvalyöntisyys (bradykardia), rytmihäiriöt (arytmiat), keskuslaskimopaineen nousu sekä hengitystiheyden aleneminen. α2-adrenoreseptorien agonistien aiheuttamia perifeerisiä haittavaikutuksia pystytään kumoamaan kokeellisessa käytössä olevalla MK-467:llä, joka on α2-adrenoreseptorien antagonisti. Tämän tutkimuksen tarkoituksena oli selvittää medetomidiinin ja MK-467:n vaikutuksia samassa ruiskussa lihaksensisäisesti (i.m.) annosteltuna. Tutkielmassa käsitellään hoitojen vaikutusta hengitystiheyteen, verikaasuihin ja subjektiivisesti arvioidun sedaation voimakkuuteen. MK-467:n samanaikaisen annostelun medetomidiinin kanssa voidaan olettaa parantavan hengityselinparametreja, tai vähintään pitävän ne fysiologisella normaalitasolla, vaikuttamatta sedaatioon. Tutkimuksessa käytetyt koirat olivat tavoitekasvatettuja beagleja (n=8). Koirista kuusi oli kastroituja uroksia ja kaksi steriloituja naaraita. Koirien paino oli 13,9±1,2 kg. Kaikki koirat kävivät läpi kaksi hoitokertaa: MED (medetomidiinia 20 μg/kg i.m.) sekä MK400 (medetomidiinia 20 μg/kg ja MK-467:ää 400 μg/kg i.m.) Tutkimus suoritettiin satunnaistettuna ristikkäiskokeena. Hoitokertojen välissä koirilla oli vähintään kahden viikon pituinen palautumisjakso. Sedaatiota arvioitiin asteikolla 0-16 missä 0 on täysin virkeä ja 16 syvin mahdollinen sedaatio. Sedaation arvioijaa ei oltu sokkoutettu hoitojen osalta. Hengitystiheys laskettiin rintakehän liikkeistä. Verinäytteet otettiin takajalan jalkaterän valtimosta. Näytteet analysoitiin 15 minuutin sisällä näytteenotosta verikaasuanalysaattorilla. Medetomidiinin sedatiivinen vaikutus hävisi nopeammin, kun se oli yhdistetty MK-467:ään. Lääkeaineyhdistelmä alensi hengitystiheyttä, verrattaessa pelkkään medetomidiiniin. Sekä hengitystiheys että valtimoveren happi- ja hiilidioksidiosapaineet pysyivät viiterajoissa tunnin seurantajakson ajan. Jatkotutkimuksia MK-467 ja medetomidiini yhdistelmän vaikutuksista lääkeaineiden farmakokinetiikkaan ja keuhkotuuletukseen tarvittaisiin, ennen yhdistelmän mahdollista kliinistä käyttöä.
  • Mikkola, Emmi (Helsingfors universitet, 2015)
    Deksmedetomidiini ja medetomidiini ovat alfa-2-agonistien luokkaan kuuluvia pieneläinlääketieteessä yleisesti rauhoitusaineena käytettyjä lääkeaineita. Alfa-2- agonistien hyödylliset vaikutukset aiheutuvat keskushermostossa sijaitsevien alfa-2- adrenoreseptorien aktivaatiosta. Alfa-2-reseptoreita on myös perifeerisesti verisuonten sileissä lihassoluissa. Näiden reseptorien aktivaatiosta seuraa verisuonten supistuminen, joka johtaa äkilliseen verenpaineen nousuun ja edelleen refleksivälitteiseen sydämen syketiheyden laskuun. MK-467 (L-659,0669) on kokeellinen, perifeerisesti vaikuttava alfa-2-reseptorien antagonisti, josta on useissa tutkimuksissa saatu lupaavia tuloksia edellä kuvattujen haitallisten sydän- ja verenkiertoelimistöön kohdistuvien vaikutusten lieventämiseen. MK-467:n ei ole koirilla tehdyissä tutkimuksissa havaittu heikentävän rauhoitusvastetta. Lähes kaikissa aiemmissa tutkimuksissa, joissa on havainnoitu (deks)medetomidiinin ja MK-467:n yhteisvaikutuksia, lääkeaineille on käytetty suonensisäistä antoreittiä. Rauhoitusaineille tarkoituksenmukaisin antoreitti olisi kuitenkin lihaksensisäinen pistos. Tutkielmani kirjallisuuskatsauksen pääpainopiste on (deks)medetomidiinin sydän- ja verenkiertoelimistöön kohdistuvissa haittavaikutuksissa. Lisäksi aiempien tutkimusten pohjalta kuvaillaan (deks)medetomidiinin ja MK-467:n yhteisvaikutuksia sydän- ja verenkiertoelimistön toimintaa kuvaaviin muuttujiin. Tutkimuksessamme medetomidiini ja MK-467 annettiin samassa ruiskussa yhtenä lihaksensisäisenä pistoksena ja kokeiltavana oli pelkän medetomidiinin lisäksi kolme erilaista medetomidiini/MK-467-lääkeaineyhdistelmän sekoitussuhdetta. Tutkimukseen osallistui kahdeksan tavoitekasvatettua koiraa, joista jokainen sai kaikki hoidot satunnaisessa järjestyksessä. Tutkielmassani raportoin medetomidiinin (20 μg/kg) vaikutusta yksin ja yhdessä MK-467:n (400 μg/kg) kanssa tiettyihin sydän- ja verenkiertoelimistön toimintaa kuvaaviin muuttujiin (keskiverenpaine, keskuslaskimopaine, syketiheys ja sydämen minuuttitilavuus). Hypoteesina oli aiempien tutkimusten perusteella, että MK-467 lieventäisi medetomidiinin haitallisina pidettyjä vaikutuksia. Tulokset olivat hypoteesin mukaiset. Hoitojen välillä havaittiin tilastollisesti merkitsevä ero kaikissa mitatuissa muuttujissa 30 minuutista alkaen. Medetomidiini/MK-467- lääkeaineyhdistelmää saaneilla koirilla muuttujien arvot olivat lähempänä lähtötasoa kuin pelkkää medetomidiinia saaneilla koirilla. Tuloksissamme oli yhtäläisyyksiä aiempien tutkimusten tulosten kanssa, mutta myös eroavaisuuksia. Niiden selittämisen tueksi kaivataan uusia tutkimustuloksia etenkin MK-467:n farmakokineettisistä ominaisuuksista.
  • Kallio-Kujala, Ira J.; Raekallio, Marja R.; Honkavaara, Juhana; Bennett, Rachel C.; Turunen, Heta; Scheinin, Mika; Hautajärvi, Heidi; Vainio, Outi (2018)
    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.
  • Kallio-Kujala, I. J.; Turunen, H. A.; Raekallio, M. R.; Honkavaara, J. M.; Salla, K. M.; Casoni, D.; Hautajarvi, H. J.; Vainio, O. M. (2018)
  • Adam, M.; Raekallio, M. R.; Keskitalo, T.; Honkavaara, J. M.; Scheinin, M.; Kajula, M.; Mölsä, S.; Vainio, O. M. (2018)
    The effect of MK-467, a peripheral alpha(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 mu g/kg alone or combined in the same syringe with MK-467 300 mu g/kg (MMK) was injected intramuscular, followed by ATI 150 mu g/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.