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


METHODS
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.


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
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.
Upton
Rn
R
Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia. richard.upton@adelaide.edu.au
Martinez
Am
A
Grant
C
C
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003243:Consciousness / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D015656:Respiratory Mechanics / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects*; D012756:Sheep; D013997:Time Factors
D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; C522201:remimazolam