A dose escalation study in sheep of the effects of the benzodiazepine CNS 7056 on sedation, the EEG and the respiratory and cardiovascular systems

Abstract

<h4>Background and purpose</h4>CNS 7056 is a new, rapidly metabolized benzodiazepine. The effects of escalating doses of CNS 7056 on sedation, and respiratory and cardiovascular function, were examined in conscious, chronically instrumented sheep for the first time.<h4>Experimental approach</h4>Three sheep were given doses of CNS 7056 (0, 0.037, 0.074, 0.18, 0.37, 0.74, 2.21, 4.41 and 8.82 mg kg(-1)) as 2 min intravenous infusions in order on consecutive days. A range of physiological variables, including the EEG, were measured.<h4>Key results</h4>Sheep became transiently drowsy for the lowest (0.037 and 0.074 mg kg(-1)) doses of CNS 7056, whereas the highest (8.82 mg kg(-1)) dose produced profound loss of consciousness (LOC) for over 30 min. The EEG alpha power correlated well (r=0.91) with duration of LOC and had a high signal-to-noise ratio. CNS 7056 reduced respiratory rate (maximum 33%) and dose-dependently increased arterial carbon dioxide tension (maximum 12%). There was a transient, dose-related reduction in arterial oxygen tension (maximum 34%), but haemoglobin desaturation was minimal (maximum 4%). CNS 7056 produced a dose-related transient drop in mean arterial blood pressure (maximum 12%) but cardiac output was unchanged.<h4>Conclusions and implications</h4>Doses of 0.37-2.21 mg kg(-1) of CNS 7056 produced sedation for 9-25 min without excessive respiratory or cardiovascular depression, and would be suitable for pharmacokinetic studies. The power in the alpha band of the EEG can be used as a continuous measure of the sedative effects of CNS 7056.