The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15–1788 has been investigated in six healthy male volunteers. Hypnotic steady‐state concentrations of midazolam (55 ± 11 ng/mL; mean ± SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two‐hour control period, the antagonist (2.5 mg) or the solvent were injected double‐blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight‐hour trial (Clearance = 670 ± 96 mL/min) concentrations of Ro 15–1788 declined rapidly with an elimination half‐life between 0.7 and 1.8 hours and a total plasma clearance of 702 ± 235 mL/min. Concentrations of Ro 15–1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15–1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15–1788. In conclusion, a small intravenous bolus of 2.5 mg Ro 15–1788 reverses rapidly the hypnotic action of midazolam. The relative short duration of the antagonistic effect is due to the fast hepatic elimination of Ro 15–1788, which might be a suitable antidote of benzodiazepine‐induced oversedation in special clinical situations.
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...
In the past, pharmacokinetics of benzodiazepines have been extensively described. However, knowledge about relationships between their plasma levels and pharmacodynamic effects are scanty. Therefore, we investigated under several experimental conditions the disposition and the psychological response of the short acting midazolam (single dose 0,075 mg/kg i.v. and 15 mg po) and of the moderate long acting oxazepam (30 mg/die for 5 days). Psychological and psychomotoric effects were evaluated by analogue scales (sedation index), d-2 letter cancellation test, reaction time, critical flicker fusion frequency and adjective mood list. In general, good correlations were found between those tests and plasma levels, especially for midazolam. Analogue scales and reaction-time proved to be most useful in our "effect-kinetic" approach.
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