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PubMed1982

Evaluation of zopiclone physical dependence liability in normal volunteers.

The potential of zopiclone, a non-benzodiazepine sedative hypnotic, to induce physical dependence in normal human volunteers was investigated. 9 male subjects (age range 21-39 years) participated in a 56-day double-blind study with random assignment to initial treatment A or B: (A) zopiclone 7.5 mg p.o. nightly for 21 days followed by placebo for 7 days, and (B) placebo nightly for 21 days followed by placebo for 7 days. Heart rate, blood pressure, hand tremor and auditory-evoked EEG were repeatedly measured during the withdrawal periods. No differences in any of these variables between phases were found (beta = 0.90 for mean differences of 16% between phases). Subjects slept longer (mean 28 min, p less than 0.013) on zopiclone than on placebo. Symptoms of state anxiety were greater on days 2 and 4 after discontinuing zopiclone compared to all other withdrawal days (p less than 0.0021). The mean relative increase on days 2 and 4 was 30%. Sleep depth (self-rating scale) was no deeper on drug than on placebo, but during the withdrawal phases, sleep was less deep on days 2 and 4 of withdrawal from zopiclone compared to all other withdrawal days (p less than 0.0001). Subjects were unable to identify the pattern of drug administration on withdrawal, and none reported important symptoms. Discontinuation of zopiclone (7.5 mg for 21 days) is associated with detectable increase in state anxiety and lighter sleep on days 2 and 4 of withdrawal. Quantitatively, similar changes occur with other hypnotic drugs of relatively low dependence liability.

Adult↗
PubMed1982

Zopiclone: sleep and performance studies in healthy man.

Effects of 2.5, 5.0, 7.5, and 10.0 mg zopiclone on sleep and on performance the next day were studied in 6 healthy adult males aged between 21 and 33 years. The experiment was double-blind and placebo controlled. 5.0 and 10.0 mg zopiclone decreased the amount of awake activity and drowsy (stage 1) sleep over the first 6 h of sleep, but this effect was only present for the whole sleep period with the 10.0-mg dose. The duration and percentage of stage 3 sleep were increased with 7.5 mg. The 7.5- and 10.0-mg doses increased the combined duration of stages 2, 3, and 4 sleep over the first 6 h and over the whole night. The first period of rapid eye movement sleep was delayed with 7.5 mg, and with 10.0 mg the time spent in rapid eye movement sleep was reduced during the first 6 h of sleep, but not over the whole night. The number of substitutions in the digit symbol substitution test was decreased 9 h after ingestion of 7.5 and 10.0 mg, and the number of symbols copied reduced after 10.0 mg. The clinical dose range of zopiclone is likely to be up to 7.5 mg. The latter dose provides a useful hypnotic effect with minimal residual effects the next day, whilst 5.0 mg is appropriate for those involved in skilled tasks where even the most minor changes in performance during the early part of the next day must be avoided.

Adult↗
PubMed1982

A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers.

A double-blind study was designed to establish the residual effects of zopiclone on performance in healthy volunteers. 10 healthy male volunteers aged 22-45 years (mean age 27.4 years) were included in this study. 6 of the volunteers were cigar/cigarette smokers and were asked to smoke as little as possible on the study days. The subjects were randomly allocated to a balanced design in which each subject received single oral doses of placebo, 2.5-, 5-, 7.5- and 10-mg tablets of zopiclone under double-blind conditions. A battery of tests were performed 10 and 13 h after overnight ingestion of the drug. The tests comprised: EEG, auditory reaction time, tapping rate, digit symbol substitution test, symbol copying test, mood rating scales, side effects rating scales, and subjective assessments of sleep and performance. Zopiclone is shown to have useful hypnotic properties but residual effects are detectable using EEG and psychological tests both 10 and 13 h after ingestion. The 10-mg dose significantly impairs performance the next day; the 5-mg dose is almost devoid of residual psychomotor effects but is only marginally effective in hastening onset of sleep and does not improve sleep quality. The 7.5-mg dose has definite effects on sleep and limited residual effects the next day. No significant side effects were reported. In this study, using single doses in healthy subjects, the best balance between wanted hypnotic effects and unwanted residual effects the next day was provided by the 7.5-mg dose of zopiclone. It is recommended that further studies with repeated doses in healthy volunteer subjects and in insomniac patients use the 7.5-mg dose as the reference point.

Adult↗
PubMed1980

[Study of vigilance after ingestion of zopiclone in comparison with nitrazepam and placebo (author's transl)].

Increasing importance is being given to the residual effects of hypnotics on the day following absorption; with zopiclone, a new hypnotic, we have studied vigilance 9, 12 and 15 hours after a single evening dose of 10 mg, on a double-blind basis in comparison with 10 mg of nitrazepam and a placebo. The assessment of vigilance is based on responses to self-rating questionnaires and psychometric tests. Twenty-one healthy subjects forming a homogeneous group as regards age, I.Q., and vigilance were included in this study. Each subject received the three products in random distributed order, with an interval of three months between each trial. The results of these tests reveal modifications which, particularly 9 hours after administration, reflect a modification in vigilance, appearing to be more marked with nitrazepam than with zopiclone. Thus, from the point of view of the residual effects of hypnotics on vigilance, it is possible to position the products tested in the following order: placebo -- zopiclone -- nitrazepam.

Arousal↗
PubMed1995

[Study of zopiclone with quantitative EEG analysis and topography].

Zopiclone is a cyclopyrrolone derivative which possesses hypnotic activity. This drug is known to increase the slow sleep stage compared to benzodiazepines in polysomnography. The subjects were 10 right-handed healthy male volunteers aged 21-23 years. Double-blind crossover trials with placebo control were conducted in a random sequence at intervals of 1 week. Zopiclone 7.5 mg and placebo were administered as single oral doses. Three-minute vigilance controlled EEGs at before and at 1, 3, and 5 h after drug administration, and the response times were recorded. One minute out of the 3-minute EEGs was analyzed with FFT and the power spectrum was obtained. Then the absolute amplitude power (microV) was calculated. These results were subjected to Student's t-test (double difference) and displayed with topographic maps (t statistic significance probability mapping). Zopiclone prolonged the latency of the response time, and increased the amount of delta absolute amplitude power over the right central region, beta 1 absolute amplitude power over the left central region and beta 2 absolute amplitude power over the right central area along with decreased alpha absolute amplitude power over the occipital region and theta power over the left frontal pole area after 1 h, when the peak pharmacological effect was expected. The EEG profiles of zopiclone were different from that of diazepam reported previously concerning the increase in delta activity.

Adult↗
PubMed1995

A comparative study of imovane and estazolam treatment on sleep disturbances.

Twenty-six patients with sleep disturbances who had completed therapy with hypnotics were observed under single-blind and self-comparable method for 7 days each. We found that patients treated with imovane or estazolam had no statistical differences with respect to sleep time onset, total sleep time, nocturnal awakening, feeling after awakening, dream, drug side effects and sleep quality. Imovane performed better than estazolam in sleep time onset and total sleep time. From this study, imovane can be recommended as a new hypuotic to treat patients with sleep disturbances.

Adolescent↗
PubMed1993

Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptors.

Previous studies with cloned gamma-aminobutyric acid type A receptors expressed in human embryonic kidney cells have indicated that the alpha 1 beta 2 gamma 2 and alpha 1 gamma 2 (but not alpha 1 beta 2) subtypes have benzodiazepine sites. We found in this study that even the beta 2 gamma 2 subtype displays gamma-aminobutyric acid-induced Cl- currents that are potentiated by triazolam (a triazolobenzodiazepine). The maximal efficacy of the drug among the subtypes was highest with the alpha 1 beta 2 gamma 2 subtype, followed by the alpha 1 gamma 2 and beta 2 gamma 2 subtypes. These observations led us to compare the ability of several benzodiazepine site agonists of diverse chemical structures to potentiate Cl- currents with these subtypes. With the alpha 1 gamma 2 subtype, diazepam, alpidem, zolpidem, Cl-218872, zopiclone, U-79098 (an imidazoquinoxaline derivative), and U-90167 (a diimidazoquinazoline derivative) at 5 microM potentiated Cl- currents to essentially similar levels (slightly lower for a few ligands), compared with those with the alpha 1 beta 2 gamma 2 subtype. With the beta 2 gamma 2 subtype, the type 1 ligands zolpidem, alpidem, and Cl-218872 showed no or very low levels of potentiation, whereas less selective ligands such as diazepam, zopiclone, U-78098, and U-90167 displayed levels of Cl- current potentiation comparable to those observed with the subtypes containing the alpha 1 and gamma 2 subunits. These data indicate that, in the presence of gamma 2, beta 2 may substitute for alpha 1 in forming the benzodiazepine site of limited sensitivity to the type 1 ligands. It appears that individual ligands for benzodiazepine sites have their own sets of interacting domains, which are distributed in alpha 1 and gamma 2, and the agonistic activity of type 1 ligands may be more dependent on the alpha 1-specific domains than is that of less selective ligands.

Anti-Anxiety Agents↗
PubMedDate not supplied

Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers.

The disposition of the enantiomers of zopiclone and its two chiral metabolites was investigated after oral administration of a single dose of 15 mg of a racemic mixture (twice the usual therapeutic regimen) in 12 adult Caucasian volunteers. Determination of concentrations of zopiclone enantiomers in plasma showed that zopiclone pharmacokinetics is stereoselective with AUC0-->infinity values of 691.3 and 209.5 ng.ml-1.hr (p < 0.001), Cmax values of 87.3 and 44.0 ng.ml-1 (p < 0.001), oral CLtot/F values of 195.5 and 659.8 ml.min-1 (p < 0.001), Vd/F values of 98.6 and 192.8 liters (p < 0.01) and elimination half-life of 399.2 and 225.6 min (p < 0.01) for (+)-zopiclone and (-)-zopiclone, respectively. On the contrary, absorption half-life and Tmax values were not significantly different. In 48-hr urine, 3.6% of unchanged zopiclone was excreted, whereas 14.2% and 13.8% of both metabolites, N-desmethylzopiclone and N-oxidezopiclone, respectively, were found. Quantities of (+)-zopiclone excreted in urine were always higher compared with its antipode (-)-zopiclone for the 12 volunteers (p < 0.001). For the metabolites, quantities of both enantiomers were either equal or different and when different, it was always in favor of the (+)-enantiomer.

Administration, Oral↗
PubMed1994

Screening, identification and determination of the two new hypnotics zolpidem and zopiclone.

This article reports basic analytical data for screening and detection of the hypnotics zolpidem (CAS 82626-48-0) and zopiclone (CAS 43200-80-2) by using corrected hR-values, GC (gas chromatography) retention indices, UV solvent spectra and remission spectra. Beside this a HPTLC (high-performance thin-layer chromatography)-procedure for quantification is described.

Azabicyclo Compounds↗
PubMedDate not supplied

[Zopiclone. Data of experimental pharmacology and clinical use].

Zopiclone is the first of the cyclopyrrolones, a new class of psychotropic agents which is chemically different from the benzodiazepines (BZD). From an experimental point of view it has qualitatively the pharmacological profile of the tranquilizer-hyponotics, and activity quantitatively differs from hypnotic BZD by its lower myorelaxant. The electroencephalographic studies also demonstrated that its power spectrum is characteristic of a product having a tranquilizing hypnotic potential. The cyclopyrrolones interact with GABA ergic neurotransmission, and have a high affinity for GABA receptor complex. They act on sites close to BZD sites, but physically different. The sleep polygraphic studies have shown that zopiclone has a specific profile. It respects the sleep architecture, specially the delta sleep which is even increased, in some studies. Its residual effects are absent or minimal, and its acceptability is good in the usual conditions of hypnotic prescription.

Animals↗
PubMed1996

Zopiclone pharmacodynamics: by monitoring event-related potentials and psychometric scores.

To investigate the pharmacological effects of zopiclone in the central nervous system, we monitored event-related potentials (ERPs, N100 and P300), the reaction time and the scores for subjective mental and emotional state (by using the Polarity Profile Questionnaire, PPQ) on 10 healthy right-handed male volunteers between 21 and 32 years old. Subjects were randomly allocated to receive a single oral administration of zopiclone 7.5 mg or placebo at the first-session, and the drug was crossed over at the second session 1 week later. ERPs, the reaction time and the psychometric scores were monitored at pre-drug, and 1, 3 and 5 hours after drug administration. In the zopiclone group, the reaction time was prolonged significantly at 1 hour after drug administration, the amplitudes of the ERPs significantly decreased at 1 and 3 hours after, and the PPQ scores showed significant changes. Maximum effects on the psychometric scores appeared later than those on ERPs and reaction time. Zopiclone decreased the arousal level and sensory sensitivity, and induced sedation through changes in subjective mental and emotional states.

Administration, Oral↗
PubMed1996

Pharmacotherapy of transient insomnia related to night work.

Shiftworkers working on the night shift transpose their sleeping hours to the time of day which is inconvenient for sleep because of the endogenous circadian rhythm sleep wakefulness, the circadian rhythms of other body functions and the environmental schedule. As a result of this, a certain number of workers suffer from insomnia. This study aimed at examining the effects of two hypnotic agents with different elimination times on sleep disturbances which follow night shift work. Three groups of shiftworkers took zopiclone, nitrazepam and placebo capsules during a week of work on the night shift repeating it three times so that each week of capsule taking was separated from the next by a three-week break. In the two groups on hypnotics total length and efficacy of main sleep improved as did the efficacy of all day sleeps at the very beginning of the week, and these sleep characteristics persisted throughout the week. In contrast, in the group which took a placebo sleep was shorter and loss efficacious at the beginning but improved towards the end of the week. There was no negative effect of hypnotics on the shiftworker's mood after waking up. To an extent, the hypnotics proved to be useful for periodical pharmacological improvement of the length and efficacy of day sleep after night work in the slowly rotating shift system.

Adult↗
PubMed1997

Zopiclone fatality in a hospitalized patient.

The death of a 72-year-old man is described who overdosed himself while in hospital. The man was being treated for lung cancer and ingested 90 mg of zopiclone in a suicide attempt. He died between 4 and 10 h after the ingestion. Zopiclone, quantitated by GC-MS in the femoral blood, cardiac blood, vitreous humor, urine and bile was found to be 254, 408, 94, 7,330, and 114,700 ng/mL, respectively. Considering the man's weakened physical condition, 90 mg could represent a minimum lethal zopiclone dose.

Aged↗