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. 2008 Sep;155(1):52-61.
doi: 10.1038/bjp.2008.228. Epub 2008 Jun 16.

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

Rn Upton  1 , Am Martinez, C Grant
Affiliations

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

Rn Upton et al. Br J Pharmacol. 2008 Sep.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: 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.

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Figures

Figure 1
Figure 1
Structure of CNS 7056 and its metabolite CNS 7054.
Figure 2
Figure 2
Effect of CNS 7056 on the EEG power spectrum. Data are shown for one sheep. CNS 7056 (0.74 mg kg−1) was infused over 2 min, starting at zero seconds. There was 5 min (300 s) of pre-drug baseline readings. Note the large increases in spectral power in the lower frequencies during the period of sedation. Consciousness had returned in this animal at approximately 10 min (600 s), where after the EEG had also returned to baseline.
Figure 3
Figure 3
The effect of increasing doses of CNS 7056 on EEG alpha power. The data for each dose group were pooled and fitted with a loess smoothing function. The vertical lines are the start of the 2-min drug infusions. The increase in alpha power before the start of the infusion is an artefact of the loess smoothing function applied to the data.
Figure 4
Figure 4
The effect of CNS 7056 dose on the time of recovery of consciousness (ROC) through EEG alpha power. Each point is one dose in one sheep.
Figure 5
Figure 5
The effect of increasing doses of CNS 7056 on mean arterial blood pressure. Data are the mean in each dose group. The vertical lines are the start of the drug infusions.
Figure 6
Figure 6
The effect of the dose of CNS 7056 on the lowest recorded mean arterial blood pressure. Each point is one dose in one sheep.
See this image and copyright information in PMC

References

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