Electrophysiological aspects of benzodiazepine antagonists, Ro 15‐1788 and Ro 15‐3505.

Abstract

The comparative action of two specific benzodiazepine antagonists, Ro 15‐1788 and Ro 15‐3505 was examined in six healthy volunteers. Medication was given i.v. in a double‐blind cross over pattern, and EEG was recorded throughout each experimental session. Ten minutes after the injection of one of the antagonists or placebo, midazolam was injected in incremental doses until first signs of drowsiness appeared in the EEG. The EEG was computer analyzed, using adaptive segmentation and time‐dependent clustering. Continuous power profiles for various frequency bands, as well as power ratios for the physiological frequency bands (e.g. sigma/alpha power ratio) were generated. It has been found that sigma/alpha power ratio was the most sensitive parameter detecting early effects of midazolam on the EEG signal, thus enabling a semi‐quantitative titration of the antagonists by midazolam. Ro 15‐1788 in doses of 5 mg i.v. was counteracted on average by 7.3 mg midazolam. From the EEG analysis it has been found that Ro 15‐3505 was at least 4‐5 times more potent than Ro 15‐1788.

The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjects

“…On the whole the effect was greater for the higher dose indicating a dose-response relationship. These findings are not consistent with the earliest reports which found no EEG changes following intravenous administration (Ismail et al 1981;Gath et al 1984), but are in line with more recent findings. Two reports (Sch6pf etal.…”

“…Work on human subjects has shown that Ro 15-1788 is able to block the predicted effects of benzodiazepines whether given prior to (Gath et al 1984), simultaneously with (Ismail et al 1981;Gaillard and Blois 1983;Darragh et al 1981Darragh et al , 1982aO'Boyle et al 1983) or subsequent to benzodiazepine administration (Ismail etal. 198l;Ziegler and Schalch 1982;Laurian et al 1984).…”

Possible interaction of fluoroquinolones with the benzodiazepine‐GABAA‐ receptor complex.

“…Whereas in some studies (Doenicke et al, 1984, Gath et al, 1984Noderer et al, 1988) no significant changes compared with placebo were reported, Schopf et al (1984) found with 5 mg flumazenil a similar central stimulant action to that described above. Furthermore, Ziegler et al (1985) could demonstrate that flumazenil (10 mg i.v.)…”

Reversal of fetal benzodiazepine intoxication using flumazenil

“…Interestingly, several reports have shown a good correlation between the reversal of the clinical symptoms of benzodiazepine induced CNS depression in humans and normalisation of the electroencephalogram (EEG) employing flumazenil (Darragh et al 1981; Gath et al 1984; Hofer & Scollo‐Lavizzari 1985; Gijsenbergh et al 1989). Moreover, flumazenil does not seem to have any significant EEG effects of its own (Breimer et al 1991).…”