The pharmacodynamics of midazolam and its main metabolite alpha-hydroxymidazolam were characterized in individual subjects by use of saccadic eye movement and electroencephalographic (EEG) effect measurements. Eight healthy volunteers received 0.1 mg/kg midazolam intravenously in 15 minutes, 0.15 mg/kg alpha-hydroxymidazolam intravenously in 15 minutes, 7.5 mg midazolam orally and placebo in a randomized, double-blind, four-way crossover experiment. Plasma concentrations of midazolam, alpha-hydroxymidazolam and 4-hydroxymidazolam were measured by gas chromatography. The amplitudes in the 11.5 to 30 Hz (beta) frequency band were used as EEG effect measure. The concentration-effect relationships were quantified by the sigmoid maximum effect model. The median effective concentrations of midazolam and alpha-hydroxymidazolam were (mean +/- SE) 77 +/- 15 and 98 +/- 17 ng/ml, respectively, for the EEG effect measure. For peak saccadic velocity the values were 40 +/- 7 ng/ml for midazolam and 49 +/- 10 ng/ml for alpha-hydroxymidazolam. The maximum effect values were similar for both compounds. The effects observed after oral administration of midazolam could not be predicted accurately by an additive and competitive interaction model. It seems that alpha-hydroxymidazolam is highly potent with respect to the measured effects and contributes significantly to those effects of midazolam after oral administration.

The effects of single oral doses of 5, 10, and 20 mg temazepam were evaluated with the adaptive tracking test, analysis of smooth‐pursuit and saccadic eye movements, and visual analog lines in a placebo‐controlled, double‐blind, crossover experiment with 12 healthy volunteers. Pharmacodynamic testing was performed until 10 hours and pharmacokinetics were evaluated until 24 hours. Temazepam, 20 mg, caused effects in all tests, with peak effects occurring at 30 minutes. The 10 mg dose caused effects on saccadic eye movements and subjective scores of alertness, whereas 5 mg temazepam was detected only by analysis of saccadic eye movements. Linear relationships between plasma concentrations and effects were found in nine subjects for saccadic peak velocity and eight subjects for subjective scores of alertness. The results of this study demonstrate manifest differences in the sensitivities of performance tests and stress the importance of validation of methods when effects of drugs on human performance are studied. Clinical Pharmacology and Therapeutics (1991) 50, 172–180; doi:

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensitivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation. VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28-47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2-24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11-30%), saccadic eye movements decreased by 9-10 percent (95% CI, 5-13%/6-15%) and body sway increased by 37 percent (95% CI, 5-79%). In contrast, EEG beta2-amplitudes declined significantly at night by 18 percent (95% CI, 6-29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These results emphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may not reflect sedation in a stricter sense. The motivation and alertness necessary for DSST may overcome mild sedation.

1Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double‐blind, placebo controlled six‐way cross over experiment in 12 healthy volunteers, aged 19−26 years. 2Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target‐blood concentration of 0.5 g l−1 or a control infusion of 5% w/v glucose at 1 week intervals. 3CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales. 4Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo. 5There were no consistent indications for synergistic, supra‐additive pharmacodynamic interactions between alcohol and bretazenil or diazepam. 6Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests. 7No significant pharmacokinetic interactions were found. 8Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.