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

Juhana M. Honkavaara, Marja R. Raekallio, Pernilla M. Syrja, Bruno H. Pypendop, Heather K. Knych, Ira J. Kallio-Kujala, Outi M. Vainio

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Objectives 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 tissue (CNS) after intravenous (IV) co-administration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females, 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:plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dex- and levomedetomidine in the CNS were three to seven-fold those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when co-administered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.
Originalspråkengelska
TidskriftVeterinary Anaesthesia and Analgesia
ISSN1467-2987
DOI
StatusPublicerad - 29 aug 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 413 Veterinärvetenskap

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@article{4942d2b398a64cbbb73456c7f7b3ec33,
title = "Concentrations of medetomidine enantiomers and vatinoxan, an α2–adrenoceptor antagonist, in plasma and central nervous tissue after intravenous co-administration in dogs",
abstract = "Objectives 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 tissue (CNS) after intravenous (IV) co-administration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females, 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:plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dex- and levomedetomidine in the CNS were three to seven-fold those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when co-administered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.",
keywords = "central nervous system, distribution, dog, medetomidine, MK-467, vatinoxan, 413 Veterinary science",
author = "Honkavaara, {Juhana M.} and Raekallio, {Marja R.} and Syrja, {Pernilla M.} and Pypendop, {Bruno H.} and Knych, {Heather K.} and Kallio-Kujala, {Ira J.} and Vainio, {Outi M.}",
year = "2019",
month = "8",
day = "29",
doi = "10.1016/j.vaa.2019.07.004",
language = "English",
journal = "Veterinary Anaesthesia and Analgesia",
issn = "1467-2987",
publisher = "Elsevier Scientific Publ. Co",

}

TY - JOUR

T1 - Concentrations of medetomidine enantiomers and vatinoxan, an α2–adrenoceptor antagonist, in plasma and central nervous tissue after intravenous co-administration in dogs

AU - Honkavaara, Juhana M.

AU - Raekallio, Marja R.

AU - Syrja, Pernilla M.

AU - Pypendop, Bruno H.

AU - Knych, Heather K.

AU - Kallio-Kujala, Ira J.

AU - Vainio, Outi M.

PY - 2019/8/29

Y1 - 2019/8/29

N2 - Objectives 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 tissue (CNS) after intravenous (IV) co-administration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females, 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:plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dex- and levomedetomidine in the CNS were three to seven-fold those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when co-administered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.

AB - Objectives 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 tissue (CNS) after intravenous (IV) co-administration of vatinoxan and medetomidine. Study design Experimental, observational study. Animals A group of six healthy, purpose-bred Beagle dogs (four females, 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:plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dex- and levomedetomidine in the CNS were three to seven-fold those in plasma. Conclusions and clinical relevance With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when co-administered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.

KW - central nervous system

KW - distribution

KW - dog

KW - medetomidine

KW - MK-467

KW - vatinoxan

KW - 413 Veterinary science

U2 - 10.1016/j.vaa.2019.07.004

DO - 10.1016/j.vaa.2019.07.004

M3 - Article

JO - Veterinary Anaesthesia and Analgesia

JF - Veterinary Anaesthesia and Analgesia

SN - 1467-2987

ER -