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Br J Anaesth. 2010 Dec;105(6):798-809. doi: 10.1093/bja/aeq260. Epub 2010 Oct 6.

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

Author information

1
Discipline of Anaesthesia and Intensive Care, Royal Adelaide Hospital, Adelaide, Australia. richard.upton@unisa.edu.au

Abstract

BACKGROUND:

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 t(1/2,)(k)(e0) for sedation was 1.78 min, and the EC(50) 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.

PMID:
20926479
DOI:
10.1093/bja/aeq260
[Indexed for MEDLINE]
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