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Vatinoxan

Vatinoxan
Clinical data
Other namesMK 467; mk-467 free base; vatinoxanum
Drug classAlpha blocker
ATC code
  • None
Identifiers
  • N-[2-[(2R,12bS)-2'-oxospiro[1,3,4,6,7,12b-hexahydro-[1]benzofuro[2,3-a]quinolizine-2,5'-imidazolidine]-1'-yl]ethyl]methanesulfonamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC20H26N4O4S
Molar mass418.51 g·mol−1
3D model (JSmol)
  • [H][C@@]12C[C@@]3(CNC(=O)N3CCNS(C)(=O)=O)CCN1CCC1=C2OC2=CC=CC=C12
  • InChI=1S/C20H26N4O4S/c1-29(26,27)22-8-11-24-19(25)21-13-20(24)7-10-23-9-6-15-14-4-2-3-5-17(14)28-18(15)16(23)12-20/h2-5,16,22H,6-13H2,1H3,(H,21,25)/t16-,20+/m0/s1
  • Key:GTBKISRCRQUFNL-OXJNMPFZSA-N

Vatinoxan, originally known as MK-467, is an α2-adrenergic receptor antagonist used in veterinary medicine alongside α2-adrenergic receptor agonists to counteract vasoconstriction and hypertension while maintaining sedation.[1][2][3] Vatinoxan does not cross the blood–brain barrier giving it a unique pharmacological profile compared to the other α2-adrenergic receptor antagonists and distinct clinical application.[4]

Medical uses

[edit]

Vatinoxan mitigates the cardiovascular depression caused by medetomidine and dexmedetomidine, although hypotension may still occur.[4][5][6][7][8][9] Administration of dobutamine, norepinephrine, or phenylephrine has been shown to restore normotension.[4][10][11]

Vatinoxan does not reduce central nervous system depression, as it is unable to cross the blood–brain barrier. However, it may influence the sedative effects of α2-adrenergic receptor agonists.[4]

Combination with medetomidine

[edit]
Main article: medetomidine/vatinoxan

A fixed-dose combination of medetomidine with vatinoxan (medetomidine/vatinoxan) is used to provide sedation whilst negating some of the negative cardiovascular effects of medetomidine.[4] This combination medication was approved in the US in 2022, and is sold under the brand name Zenalpha.[12]

Co-administration of vatinoxan and medetomidine improves recovery following atipamezole administration in sheep and dogs.[4][13][14]

Pharmacology

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Vatinoxan binds to the α2-adrenergic receptor at a ratio of 105:1 over the α1-adrenergic receptor.[4] Vatinoxan appears to have no clinically relevant effect on the α1-adrenergic receptor based on a study in the horse and sheep.[15][4] Vatinoxan's low lipid solubility, molecular weight, ionisation, and protein binding cause it to poorly antagonise the α2-adrenergic receptors in the central nervous system whilst selectively antagonising peripheral and cardiovascular receptors. These properties make vatinoxan unique to the other α2-adrenergic receptor antagonists.[4]

Research

[edit]

In a study on horses, vatinoxan administration was found to reduce medetomidine-induced sedation, which the authors hypothesised was due to altered clearance of medetomidine.[4][16] Conversely, a study in sheep reported that co-administration of vatinoxan and medetomidine enhanced sedation.[4][13]

Vatinoxan may also counteract the severe respiratory effects caused by α2-adrenergic receptor agonists in sheep.[4][17][18]

Additionally, vatinoxan has been shown to reduce the minimum alveolar concentration (MAC) of isoflurane and sevoflurane in two studies, although the underlying mechanism remains unclear and warrants further investigation.[4][19][20]

References

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  1. ^ Love L (2024). "α2 Receptor Agonists and Antagonists". In Aarnes T, Lerche P (eds.). Pharmacology in Veterinary Anesthesia and Analgesia. John Wiley & Sons, Ltd. pp. 36–54. doi:10.1002/9781118975169.ch4. ISBN 978-1-118-97516-9. Retrieved 1 August 2025.
  2. ^ Bennett R (September 2021). "Vatinoxan: a new development in the clinical use of α2-adrenoceptor agonists in dogs, part 1". Companion Animal. 26 (8): 176–181. doi:10.12968/coan.2021.0040.
  3. ^ Bennett R (November 2021). "Vatinoxan: a new development in the clinical use of α2-adrenoceptor agonists in dogs, part 2". Companion Animal. 26 (10): 1–4. doi:10.12968/coan.2021.0073.
  4. ^ a b c d e f g h i j k l m Lamont LA, Creighton CM (2024). "Sedatives and Tranquilizers". In Lamont L, Grimm K, Robertson S, Love L, Schroeder C (eds.). Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. pp. 338–344. ISBN 978-1-119-83027-6.
  5. ^ Tapio H, Raekallio M, Mykkänen A, Al-Ramahi D, Scheinin M, Hautajärvi H, et al. (2019). "Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine". The Veterinary Journal. 251 105345. doi:10.1016/j.tvjl.2019.105345. PMID 31492389.
  6. ^ Neudeck S, Twele L, Kopp V, Kästner S (2021). "Pharmacodynamics and plasma concentrations of dexmedetomidine with or without vatinoxan as a constant-rate infusion in horses anaesthetized with isoflurane—A pilot study". Journal of Veterinary Pharmacology and Therapeutics. 44 (5): 754–765. doi:10.1111/jvp.12992. ISSN 0140-7783. PMID 34159620.
  7. ^ Pypendop BH, Honkavaara J, Ilkiw JE (2017). "Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats". Veterinary Anaesthesia and Analgesia. 44 (1): 52–62. doi:10.1111/vaa.12397. PMID 27377604.
  8. ^ Honkavaara JM, Restitutti F, Raekallio MR, Kuusela EK, Vainio OM (2011). "The effects of increasing doses of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs". Journal of Veterinary Pharmacology and Therapeutics. 34 (4): 332–337. doi:10.1111/j.1365-2885.2010.01242.x. ISSN 0140-7783. PMID 20969603.
  9. ^ Restitutti F, Kaartinen MJ, Raekallio MR, Wejberg O, Mikkola E, del Castillo JR, et al. (2017). "Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs" (PDF). Veterinary Anaesthesia and Analgesia. 44 (3): 417–426. doi:10.1016/j.vaa.2016.04.006. PMID 28552594.
  10. ^ Huuskonen V, Restitutti F, Raekallio M, Honkavaara J, Pesonen T, Vainio O (2022). "Cardiovascular effects of dobutamine, norepinephrine and phenylephrine in isoflurane-anaesthetized dogs administered dexmedetomidine–vatinoxan" (PDF). Veterinary Anaesthesia and Analgesia. 49 (6): 546–555. doi:10.1016/j.vaa.2022.07.007. PMID 36058821.
  11. ^ Pypendop BH, Honkavaara J, Ilkiw JE (2017). "Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats". Veterinary Anaesthesia and Analgesia. 44 (1): 52–62. doi:10.1111/vaa.12397. PMID 27377604.
  12. ^ "Zenalpha- vatinoxan hydrochloride and medetomidine hydrochloride solution". DailyMed. 11 May 2022. Retrieved 3 March 2024.
  13. ^ a b Adam M, Raekallio MR, Vainio OM (2018). "Sedative effect of intramuscular medetomidine with and without vatinoxan (MK-467), and its reversal with atipamezole in sheep". Veterinary Anaesthesia and Analgesia. 45 (6): 788–793. doi:10.1016/j.vaa.2018.06.009. PMID 30301665.
  14. ^ Turunen H, Raekallio MR, Honkavaara JM, Restitutti F, Kallio-Kujala IJ, Adam M, et al. (2019). "Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2-adrenoceptor antagonist vatinoxan hydrochloride". American Journal of Veterinary Research. 80 (10): 912–922. doi:10.2460/ajvr.80.10.912. ISSN 0002-9645. PMID 31556714.
  15. ^ Bryant C, Thompson J, Clarke K (1998). "Characterisation of the cardiovascular pharmacology of medetomidine in the horse and sheep". Research in Veterinary Science. 65 (2): 149–154. doi:10.1016/S0034-5288(98)90167-9. PMID 9839894. Retrieved 30 July 2025.
  16. ^ Tapio H, Raekallio MR, Mykkänen A, Männikkö S, Scheinin M, Bennett RC, et al. (2019). "Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses". Equine Veterinary Journal. 51 (5): 646–652. doi:10.1111/evj.13085. ISSN 0425-1644. PMC 6767159. PMID 30793362.
  17. ^ Adam M, Huuskonen V, Raekallio M, Casoni D, Mykkänen A, Lappalainen A, et al. (2018). "Cardiopulmonary effects of vatinoxan in sevoflurane-anaesthetised sheep receiving dexmedetomidine". The Veterinary Journal. 238: 63–69. doi:10.1016/j.tvjl.2018.07.007. PMID 30103917.
  18. ^ Adam M, Lindén J, Raekallio M, Meller A, Mannerström B, Abu-Shahba A, et al. (2022). "Effects of vatinoxan on xylazine-induced pulmonary alterations in sheep". Journal of Veterinary Pharmacology and Therapeutics. 45 (1): 117–125. doi:10.1111/jvp.13013. ISSN 0140-7783. PMID 34478172.
  19. ^ Pypendop BH, Ahokoivu H, Honkavaara J (2019). "Effects of dexmedetomidine, with or without vatinoxan (MK-467), on minimum alveolar concentration of isoflurane in cats". Veterinary Anaesthesia and Analgesia. 46 (4): 443–451. doi:10.1016/j.vaa.2019.02.004. PMID 30982711.
  20. ^ Hector RC, Rezende ML, Mama KR, Steffey EP, Knych HK, Hess AM, et al. (2017). "Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs". Veterinary Anaesthesia and Analgesia. 44 (4): 755–765. doi:10.1016/j.vaa.2016.12.058. PMID 28734855.