Lack of effect of the benzodiazepine antagonist flumazenil (Ro 15-1788) on the performance of healthy subjects during experimentally induced ethanol intoxication.

Flumazenil is a specific benzodiazepine antagonist. This study was designed to determine whether it also reverses CNS depression due to acute alcohol intoxication. Intoxication was experimentally induced in 6 healthy volunteers by intravenous infusion of ethanol. Individual constant ethanol plasma concentrations in the range 1.47 +/- 0.04 g.l-1 to 1.71 +/- 0.03 g.l-1 were maintained over 6 h. Two doses of flumazenil (0.1 or 0.2 mg.kg-1) and placebo were administered intravenously in a randomized, double-blind, two-way cross-over fashion. A battery of psychometric tests and subjective ratings of mood and performance were performed at baseline and at regular intervals during the study. Before the administration of flumazenil the characteristic symptoms and signs of ethanol intoxication were present in all subjects. Performance (measured by visual analogue scales), reaction time, digit symbol substitution test, and a tracing test, were markedly impaired by ethanol. After the injection of flumazenil three volunteers reported some subjective improvement in performance. However, in none of the subjects was there a difference between either dose of flumazenil and placebo in terms of an improvement in the objective psychometric variables.

Flumazenil in benzodiazepine antagonism. Actions and clinical use in intoxications and anaesthesiology.

In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to 1.0mg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour). Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Antihypertensive properties of tiapamil (RO 11-1781)--a new calcium antagonist--in patients with mild and moderate essential hypertension.

An open, non-comparative study, with a new calcium antagonist-tiapamil, was undertaken in 22 patients with mild and moderate essential hypertension (stage I-II WHO). After a two-week placebo period, patients were treated with tiapamil, 300-600 mg twice daily during a period of six weeks (Dose-finding period). Thereafter patients were continued on tiapamil during a 54 week period (Long-term follow-up). In some patients it was necessary to add the diuretic hydrochlorothiazide to obtain adequate control of the arterial hypertension. Monotherapy with tiapamil normalized supine diastolic blood pressure after the first six weeks in 17 of the 21 evaluable patients, and reduced it by greater than or equal to 10 mmHg (1.3 kPa) from baseline without normalization in two patients. In the two remaining cases the decrease was less than 10 mmHg. The optimal dose administered at six weeks in those patients who responded to treatment (normalization or decrease by greater than or equal to 10 mmHg.) was 600 mg/day in 32% of the cases, 750-900 mg/day in 47% and more than 900 mg/day in 21%. After completion of the dose-finding part, 19 patients continued treatment for a further 54 weeks. In 16 out of 19 patients hydrochlorothiazide was added to enhance the antihypertensive effect. All three patients who received tiapamil monotherapy throughout the trial, had normalized supine diastolic blood pressure on completing the study. In the 16 patients with the combination therapy, the addition of hydrochlorothiazide led in two patients to no further decrease in supine diastolic blood pressure, to an additional decrease by less than 10 mmHg in ten patients and by greater than or equal to 10 mmHg in four in comparison with the values obtained before starting combination therapy. At the end of the study 11 of these 16 patients had normalized supine diastolic blood pressure. The mean daily dose was 900 +/- 45 mg of tiapamil and 39 +/- 4 mg of hydrochlorothiazide. Both monotherapy and the combination regimen were well tolerated, and no effects attributable to drug interactions were observed. It may be concluded that tiapamil in oral doses of 300-600 mg twice daily is an effective antihypertensive agent with an excellent tolerance when administered for a period of 54 weeks.

Pharmacokinetic and clinical considerations in the choice of a hypnotic.

Not only has insomnia become much more frequent in the last hundred years but its causes have also changed considerably. In the treatment of insomnia, benzodiazepines--because of their additional anxiolytic effect--offer substantial advantages over other sleep-inducing agents. The residual fraction--the quotient of plasma concentration at 12 h after drug intake to maximum plasma concentration--makes it possible to differentiate between the benzodiazepines according to their suitability as anxiolytics or hypnotics. Midazolam has the lowest residual fraction of all known benzodiazepines and thus, administered in the appropriate dosage, also has the shortest duration of activity.

Comparison of the effects of intravenously administered midazolam, triazolam and their hydroxy metabolites.

The aim of the study was to compare the pharmacological activity and clinical effect after i.v. administration of midazolam, triazolam and their hydroxy metabolites, and, secondly, to compare the clinical effects of midazolam and triazolam in doses yielding the same duration of action (15 mg and 0.25 mg, respectively). In a randomized, cross-over procedure, six healthy volunteers received one of the following in the morning at approximately weekly intervals: 15 mg midazolam; 9 mg alpha-hydroxy midazolam; 1 mg triazolam; 1 mg alpha-hydroxy triazolam; 1 mg 4-hydroxy triazolam. Tests of drug effect (investigator's assessment, psychometric testing, and self-rating by subjects) were carried out at different times in the 24-h period following administration. Triazolam 0.25 mg was also studied in four of these six subjects to supplement the findings in the cross-over study. Triazolam 1 mg was shown to have the strongest, most long-lasting effect. Midazolam 15 mg had almost the same intensity of effect but this was shorter lasting, i.e. 5 h as against 10 h for 1 mg triazolam. The alpha-hydroxy metabolites had a duration of action about half that of the parent compounds and a less potent effect, and 4-hydroxy triazolam was virtually devoid of effect. The lower 0.25-mg dose of triazolam had about the same duration of action as 15 mg midazolam but did not achieve the same degree of maximum effect as measured by psychometric tests and self-assessment by subjects. The findings of this study indicate that midazolam would be suitable for use in situations in which a brief but intense hypnotic sedative effect is desired.