Effect of the Specific Benzodiazepine Antagonist Ro 15-1788 on Sleep

Abstract

In troductionThe selective antagonistic efficacy of the benzodiazepine antagonist Ro 15-1788 is weil established. In the first clinical trials it was found that this drug could reverse the sedative-hypnotic effects of clonazepam, diazepam, flunitrazepam, midazolam, and other benzodiazepines rapidly ( see Hunkeler et al., 1981;Bonetti et al., 1982;Klotz et al., 1985). The very short duration of action corresponds weil to the elimination half-life time of about 0.97 ± 0.2 hours (Klotz et al., 1984).Most studies for evaluating the possible intrinsic effects of Ro 15-1788 were done in waking probands and showed no behavioral or physiological effects (Polc et al., 1981; Darragh et al., 1983 b) even up to very high doses of 600 mg. In contrast, Schöpf et al. (1984) could demonstrate a slight central stimulation after a single iv-dose of 5 mg in normal waking subjects. Some preliminary clinical data indicate an anticonvulsant effect (Scollo-Lavizzari, 1984) and possibly clinical improvement in hepatic encephalopathy (Bansky et al., 1985), both accociated with a modulation of GABAergic activity.In an own study (Klotz et al., 1985), we demonstrated an imperative awakening of the subjects after an iv-bolus of 2.5 mg of Ro 15··1788 from slow-wave-sleep induced by infusion with Midazolam. It is well known that benzodiazepines (BZD) act on GABAergic system by amplifying the GABAtransmission in the CNS. Since the GABAergic system is also involved in sleep regulation, we studied the intrinsic effect of a single dose of 10 mg Ro 15-1788 on sleep in normal subjects without premedication of any drug. MethodsThe study was carried out in a sleep-laboratory in a double-blind cross-over design with 7 healthy volunteers (5 male, : female, aged 22-29 years, mean 24.5 ± 2.2). The subjects were free of any drugs and had no difficulties in sleep habits. They were all screened by a physical and psychological test and fully informed about the study, their written consent was given.After one adaptation night with EEG-recording, either 10 mg Ro 15-1788 or identical Placebo was given in a randomized order as a bolus intravenously via an infusion tube with smaU volume from outside the room without awakening the probands.Injection was done while the first slow wave sleep epochs (stable over > 3 min) triggered by EEG, which was monitored continously and recorded according to the standardized rules by Rechtschaffen & KaIes (1968). Injection times were not different between the conditions. Sieep records were analyzed by a well trained rater without knowledge of injection times and drug condition by visual rating in 30-sec epochs over the whole night and for the 60 min after injection, in accord with the short duration of action of Ro 15-1788.Sieep parameters were computed by a software package (SLAP) and statistically analyzed by the t-test and parameter-free (Wilcoxon-test) if data were not normally distributed. Additionally. all subjects were asked each morning about sleep-q uahty using visual analogue scales. ResultsAs can be seen from Table 1...

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