Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol

Abstract

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.

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

“…These results correspond to literature findings. Effects on postural stability, subjective assessments (visuo-) motor control and oculomotor coordination or attention are frequently observed after alcohol administration [8,9]. Some of these effects fluctuated significantly during the plateau phase, despite relatively constant alcohol levels.…”

“…Visual analogue scales (VAS), as originally described by Norris [13], have been used previously to quantify subjective effects of a variety of sedative agents [8,9,14,15]. In the current study alertness, mood and calmness were derived from a VAS previously described by Bond and Lader [16].…”

“…The 'Neurocart' is a battery of sensitive tests for a wide range of CNS domains that has been developed at CHDR to examine different kinds of CNS-active drugs [7][8][9]. The following tests were performed twice at baseline, and repeated hourly during the plateau and wash-out phases in a quiet room with ambient illumination, in the following order.…”

“…Numerous test methods have been developed to study these parameters, such as alertness, oculomotor function (visio-)motor control, attention and subjective effects [4][5][6]. All of these CNS domains are covered in the 'Neurocart' test battery that has been developed at the Centre for Human Drug Research (CHDR) to examine different kinds of CNS-active drugs [7][8][9]. In the current exploratory study, these methods were used to determine the pharmacodynamic CNS effects of alcohol at a pseudo-steady-state level of 0.6 g l -1 for 5 h, and to investigate whether this intensive battery of CNS measurements could be performed during clamping without affecting its concomitant execution or vice versa.…”

Drugability of Extracellular Targets: Discovery of Small Molecule Drugs Targeting Allosteric, Functional, and Subunit-Selective Sites on GPCRs and Ion Channels

“…Several compounds have progressed to the clinic, but whereas they have demonstrated anxiolytic efficacy in animal models with reduced effects on sedation, muscle relaxation, and withdrawal, these effects were not completely borne out in man, and these attempts were discontinued (Figure 10). Bretazenil (Roche; compound 29, Figure 10; Busto et al, 1994;van Steveninck et al, 1996) demonstrated clinical efficacy but was unable to show a separation between the anxiolytic benefit and the sedative liability. Abecarnil (Schering; compound 30, Figure 10; Dubinsky et al, 2002;Stephens et al, 1990), having demonstrated partial agonism in some animal models, was unable to demonstrate significant efficacy once in the clinic.…”