Pharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep

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dc.contributor.authorUpton, R.
dc.contributor.authorSomogyi, A.
dc.contributor.authorMartinez, A.
dc.contributor.authorColvill, J.
dc.contributor.authorGrant, C.
dc.date.issued2010
dc.description.abstractBackground: CNS 7056 is a new short-acting esterase-metabolized benzodiazepine. We report the first pharmacokinetic (PK) and pharmacodynamic (PD) study of CNS 7056 and its inactive metabolite CNS 7054 in sheep. Methods: The stability of CNS 7056 in blood samples was examined ex vivo. Six sheep were prepared with physiological instrumentation, and were given doses of 0.37, 0.74, and 1.47 mg kg−1 (2 min infusion) of CNS 7056 in alternating order on separate days. Results: CNS 7056 was degraded in warm whole sheep blood (23% over 2 h), but not in plasma or blood stored on ice. Using non-compartmental analysis (NCA), CNS 7056 had a mean (sd) clearance of 4.52 (0.96) litre min−1 and a terminal half-life of 21.3 (10.9) min. There was a rapid conversion of CNS 7056 to its metabolite CNS 7054, which had a terminal half-life of 22.5 (3.4) min. The arterial kinetics of CNS 7056 could be described by a three-compartment model, with volumes of 1.9, 3.9, and 79 litre, a clearance of 4.2 litre min−1, and inter-compartmental clearances of 2.85 and 1.44 litre min−1, while the metabolite could be described by a two-compartment model. Cardiac output was an important covariate. Sedation as measured by the alpha power band of the EEG showed rapid onset and offset. The t1/2,ke0 for sedation was 1.78 min, and the EC50 was 0.10 µg ml−1. Conclusions: CNS 7056 has PK–PD properties compatible with its potential human use as a short-acting i.v. sedative.
dc.description.statementofresponsibilityR. N. Upton, A. A. Somogyi, A. M. Martinez, J. Colvill and C. Grant
dc.identifier.citationBritish Journal of Anaesthesia, 2010; 105(6):798-809
dc.identifier.doi10.1093/bja/aeq260
dc.identifier.issn0007-0912
dc.identifier.issn1471-6771
dc.identifier.orcidUpton, R. [0000-0001-9996-4886]
dc.identifier.orcidSomogyi, A. [0000-0003-4779-0380]
dc.identifier.urihttp://hdl.handle.net/2440/62066
dc.language.isoen
dc.publisherOxford Univ Press
dc.rights© The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
dc.source.urihttps://doi.org/10.1093/bja/aeq260
dc.subjectbenzodiazepine
dc.subjectcardiac output
dc.subjectCNS 7056
dc.subjectpharmacodynamics
dc.subjectpharmacokinetics
dc.subjectsedation
dc.subjectsheep
dc.titlePharmacokinetics and pharmacodynamics of the short-acting sedative CNS 7056 in sheep
dc.typeJournal article
pubs.publication-statusPublished

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