A. Patat

Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics

The effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale - Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective residual effect.

Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic

Zolpidem is a new imidazopyridine‐hypnotic that selectively binds to the central ω1‐receptor subtype. A double‐blind, randomized, three‐way, crossover placebo‐controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system–depressant effects of Zolpidem by flumazenil. Subjects received Zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. Vigilance and performance were assessed by a trained anesthetist with use of ciliary reflex, response to a verbal instruction, subjective sedation, a tracking task, and a free recall task. Zolpidem produced a clinically relevant hypnotic effect in five subjects and significantly impaired performance in all nine subjects up to 90 minutes after dosing. Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change Zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with Zolpidem overdosage.

Pharmacodynamics and Pharmacokinetics of Two Dose Regimens of Befloxatone, a New Reversible and Selective Monoamine Oxidase Inhibitor, at Steady State in Healthy Volunteers

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO‐A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double‐blind, three‐way crossover, placebo‐controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3–4 dihydroxyphenylglycol (DHPG), as measured by high‐performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose‐related reduction in plasma DHPG levels, as shown by the decrease in the 24‐hour area under the concentration‐time curve (AUC0–24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO‐A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration‐time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady‐state levels of DHPG.

Use of zolpidem 10 mg as a benzodiazepine substitute in 84 patients with insomnia

The antagonistic effects of zolpidem 10 mg on withdrawal symptoms caused by abrupt or gradual discontinuation (half‐dose over 4 nights) of triazolam 0·25 mg in patients with chronic insomnia, who had been receiving regular treatment for over one month, were assessed in a randomized, double‐blind, placebo‐controlled clinical trial in general practice. Eighty‐four patients were enrolled, mostly women (67·9%), with a mean age of 54·3±11·0 years. Twenty‐one different general practitioners were solicitated for the recruitment. The subjects were randomized into four groups, and all received triazolam 0·25 mg during the run‐in phase from day 1 (D1) to day 3 (D3). The following treatments were given from D4 to D7: triazolam 0·125 mg+zolpidem 10 mg (Group 1); zolpidem 10 mg (Group 2); placebo (Group 3); or triazolam 0·125 mg+placebo (Group 4). Groups 1 and 2 received zolpidem 10 mg from D7 to D24, while Groups 3 and 4 received placebo. Finally, all four groups received placebo (blind withdrawal phase) from D25 to D28. The following assessment criteria were used: clinical global impression (CGI) scale completed by the practitioner; patient questionnaire based on routine sleep criteria, wakefulness and daytime alertness. Secondary criteria were sleep diaries and visual analogue scales. Study drop‐outs were reported and explained. The effectiveness/tolerance ratio was found to be statistically significant using the CGI (p<0·007) in favour of zolpidem 10 mg. There was no significant difference in patients subjective assessment between the groups except for nightmares (p<0·04) less frequent in patients receiving zolpidem. Zolpidem was found to be more effective than placebo at D21 (CGI) according to sleep diaries; the zolpidem group showed a statistically significant difference as compared to the three other concerning four sleep parameters: number of awakenings, anxiety, sleep duration, energy. Drop‐out rates were significantly lower in the zolpidem group than in other ones (p<0·01). Abrupt and gradual triazolam withdrawal over 4 nights induced withdrawal symptoms. Equally no specific phenomena were observed at the end of the trial during the blind withdrawal phase. This study shows that zolpidem 10 mg improves sleep quality and reduces withdrawal symptoms after abrupt or gradual discontinuation of triazolam 0·25 mg in chronic patients with chronic insomnia. Copyright

Effect of bromazepam versus placebo on inhibition and waiting capacity in young women with traits of anxiety

Summary— The effect of 3 dosages of bromazepam administered as single oral doses (1.5, 3 and 6 mg) on anxious inhibition phenomena was studied in a population of 16 young women (18–30 years) with anxiety‐traits, selected on the criteria of Cattells anxiety scale supported by two personality inventory (Eysencks, MMPI). A double‐blind, placebo study design was chosen. The main assessment criteria were based on the go/no‐go test (Logans procedure), slow response rate (SRR) and a task of forced or unforced decision (use of the CFF). Attentional processes and declarative memory were analyzed as secondary criteria. None of the three dosages modified inhibition or acting‐out. Sustained attention was reduced with 1.5 mg and 6 mg, as was memory performance with 3 and 6 mg, 3.5 h after drug administration. In contradistinction with studies carried out in healthy volunteers or with other benzodiazepine compounds, bromazepam at single low dosages does not modify inhibition capacity in these subjects with traits of anxiety, in this particular procedure.

EEG, MAO-A inhibition, pharmacokinetics and safety of befloxatone in the elderly

Befloxatone is a new reversible and selective MAO‐A inhibitor. The present study aimed to assess the pharmacodynamics (EEG profile and MAO‐A inhibition using plasma levels of DHPG), pharmacokinetics and safety after a single dose of 10 mg of befloxatone compared to amitriptyline 50 mg in a randomized, double‐blind, three‐way crossover, placebo‐controlled trial involving 12 elderly subjects. Befloxatone did not show any sedative profile on EEG as no significant changes occurred in slow delta and theta waves or in alpha waves. In contrast, befloxatone produced a non‐significant decrease in delta relative power and a significant increase in the (12–40 Hz) beta waves compared to placebo and/or amitriptyline depending on the EEG lead. MAO‐A inhibition by befloxatone was evidenced by a significant reduction in DHPG plasma levels (peak activity of −85 per cent and AUC0–24 h of −46 per cent compared to placebo). The pharmacokinetics parameters obtained after a single 10‐mg oral dose of befloxatone were: tmax, 2 h; Cmax, 33·7 ng/ml; t1/2β, 14·5 h; AUC0–∞, 255 ng/ml for befloxatone and tmax, 2 h; Cmax, 29·4 ng/ml; t1/2β, 16 h; AUC0–∞, 596 ng/ml for its main metabolite, O‐demethyl befloxatone. These parameters are in the same range as those obtained in healthy young subjects. In conclusion, the present study demonstrated that a single oral dose of 10 mg of befloxatone is safe in the elderly, possesses potent MAO‐A inhibition activity and the EEG profile of a non‐sedative antidepressant and did not justify dose adjustment compared to young subjects.

Effects of zopiclone, zolpidem and flunitrazepam on nocturnal psychomotor and cognitive functions in normal young subjects

1987) was completed daily each morning. Sleep lab studies were carried out on 7 nights (pre-drug placebo nights 6, 7; drug nights I, 27, 28; post-drug placebo nights 1,7) and included polysomnography, evaluation of subjective sleep quality, subjective and objective awakening quality measured by psychometry. An activity monitor was worn by the patients throughout the 6 weeks to investigate the sleep-wake cycle. Preliminary evaluations demonstrated significant improvement of the anxiety syndrome and the sleep quality during both active compounds, as compared with placebo, with a worsening of symptoms on the I st night of placebo substitution, levelling off until the 7th night. Differential drug effects will be discussed.

Determination of the maximal tolerated dose of a new acute oral caffeine formulation in healthy volunteers

Clinical Pharmacology & Therapeutics (1996) 59, 179–179; doi: 10.1038/sj.clpt.1996.215