The effect of MK-467, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats

Honkavaara, Juhana; Pypendop, Bruno H.; Turunen, Heta; Ilkiw, Jan E.

doi:10.1111/vaa.12385

Cited by 33 publications

(12 citation statements)

References 35 publications

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“…Nevertheless, the ratios for AUC and C 0 suggest that, overall, the disposition of 25 lg/kg dexmedetomidine combined with 600 lg/kg MK-467 was more similar to the disposition of 12.5 lg/kg than that of 25 lg/kg dexmedetomidine alone. The dose of MK-467 (600 lg/kg) in the combination was selected based on the pharmacodynamic part of the study, as it was the dose achieving the largest reduction in dexmedetomidineinduced bradycardia (Honkavaara et al, 2016). The dose of MK-467 alone (300 lg/kg) was selected because it was an intermediate dose in the planned combination groups.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Pypendop

Honkavaara

Ilkiw

2016

Vet Pharm & Therapeutics

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Section: Discussionmentioning

confidence: 99%

“…The results reported here were obtained as part of a larger study, aiming at defining the optimal dose of MK-467 preventing dexmedetomidine-induced bradycardia without affecting dexmedetomidine-induced sedation (Honkavaara et al, 2016). The methods and results for heart rate measurement and sedation are presented in detail elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Pypendop

Honkavaara

Ilkiw

2016

Vet Pharm & Therapeutics

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“…Alterations in cardiovascular parameters after brimonidine administration are considered characteristic of α 2 -adrenoceptor agonists, similar to other agonists. 1,[23][24][25][26] However, no study has reported alterations in HR or blood pressure after maropitant administration alone in conscious cats. It has been suggested that changes in HR and MAP are induced by α 2 -adrenoceptors, not NK1 receptors.…”

Section: Discussionmentioning

confidence: 99%

Antiemetic effect of oral maropitant treatment before the administration of brimonidine ophthalmic solution in healthy cats

Kanda

Toda

Morimoto

et al. 2019

Journal of Feline Medicine and Surgery

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Objectives The aim of this study was to investigate the antiemetic, behavioural and physiological effects of oral maropitant treatment before the administration of brimonidine ophthalmic solution in healthy cats. Methods Five cats received oral maropitant 8 mg or no treatment (control) 18 h before the administration of one drop of brimonidine solution in both eyes. Each cat was administered each of the two treatments, with a washout period of 1 week. The incidence of emesis, retching, sialorrhoea and lip-licking after brimonidine administration was recorded, while behavioural and physiological parameters, including heart rate, mean blood pressure, respiratory frequency and rectal temperature, were recorded before and 0, 30, 60, 90, 120, 180 and 240 mins after brimonidine administration. Results Emesis and retching were not observed when maropitant was administered. However, 4/5 cats exhibited vomiting and retching in the absence of maropitant pretreatment. The incidence of emesis and retching after brimonidine administration was significantly lower in the treatment group than in the control group. Sialorrhoea occurred in one cat in the control group, while all cats showed lip-licking after brimonidine administration. There were no significant differences in the incidence of sialorrhoea and lip-licking between the two groups. Although behaviour scores were comparable between the two groups, those obtained during heart rate, mean blood pressure and respiratory frequency measurements were significantly lower than the baseline scores; this indicated a sedative effect after brimonidine administration. The heart rate and mean blood pressure significantly decreased after brimonidine administration in both groups, while there were no intergroup differences in the heart rate, mean blood pressure, respiratory frequency and rectal temperature. Conclusions and relevance Oral maropitant treatment before the administration of brimonidine ophthalmic solution in cats can alleviate emesis and retching without affecting the sedative effects of brimonidine and important physiological parameters.

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“…As vasoconstriction occurs, there is a possibility that the "shrinking" peripheral distribution increases central organ perfusion, reducing the volume of distribution of other drugs (Bennett, Salla, Raekallio, Scheinin, & Vainio, 2017). These effects may be reduced by co-administering the antagonist MK-467, as reported in cats (Honkavaara, Pypendop, Turunen, & Ilkiw, 2017; and horses (Pakkanen et al, 2015;de Vries et al, 2016).…”

Section: Ofv Methadone Submodelmentioning

confidence: 99%

A possible solution to model nonlinearity in elimination and distributional clearances with α₂‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

Gozalo-Marcilla

Silva

Luna

et al. 2019

Vet Pharm & Therapeutics

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The alpha(α)2‐agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo‐Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2‐hr constant rate infusions (STUDY 2) (Gozalo‐Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two‐compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: −160) and methadone (OFV: −132) submodels. Second, a detomidine concentration‐dependent reduction of distributional Cls of each drug further improved detomidine (OFV: −60) and methadone (OFV: −52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

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The effect of MK-467, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats

Cited by 33 publications

References 35 publications

Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Antiemetic effect of oral maropitant treatment before the administration of brimonidine ophthalmic solution in healthy cats

A possible solution to model nonlinearity in elimination and distributional clearances with α₂‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

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The effect of MK-467, a peripheral α2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats

Cited by 33 publications

References 35 publications

Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous administration in male cats

Antiemetic effect of oral maropitant treatment before the administration of brimonidine ophthalmic solution in healthy cats

A possible solution to model nonlinearity in elimination and distributional clearances with α2‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

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Product

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A possible solution to model nonlinearity in elimination and distributional clearances with α₂‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses