Comparison of the sedative properties of CNS 7056, midazolam, and propofol in sheep

Abstract

Background: CNS 7056 is an esterase-metabolized benzodiazepine sedative currently under development. Its short duration of action would suggest a clinical role similar to midazolam or propofol.

Methods: The effect of a range of doses of CNS 7056, midazolam, and propofol on depth of sedation, the respiratory system, and the cardiovascular system was studied in chronically instrumented sheep (n=5 or 6). The low, medium, and high doses of CNS 7056, midazolam, and propofol were 0.37, 0.74, and 1.47 mg kg(-1); 0.05, 0.1, and 0.2 mg kg(-1); and 1, 2, and 4 mg kg(-1), respectively.

Results: CNS 7056 produced substantial sedation with rapid onset and offset for all doses, with duration rather than depth of sedation increasing with the dose. The lower doses of midazolam had minimal sedative effect; increasing the dose produced variable but longer term sedation. Sedation from propofol was comparable with that of CNS 7056 for the medium and high doses only. The high doses produced approximately 20 min of sedation. All three drugs produced dose-dependent respiratory (e.g. reductions in arterial oxygen tension) and cardiovascular depression (e.g. reductions in mean arterial pressure). For CNS 7056, midazolam, and propofol, the magnitude of the cardiovascular and respiratory depression was proportional to the depth of sedation achieved for any given drug or dose. For all three drugs, the respiratory and cardiovascular depression was not of sufficient magnitude to endanger the animals.

Conclusions: CNS 7056 is a powerful and short-acting anaesthetic in sheep with respiratory and cardiovascular effects consistent with its sedative/anaesthetic qualities.