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  • Lilius, Tuomas O.; Blomqvist, Kim; Hauglund, Natalie; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka V.; Nedergaard, Maiken (2019)
    Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.
  • 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.
  • 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.
  • 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.