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PubMed2003

Zopiclone, but not brotizolam, impairs memory storage during sleep.

We compared the effect of a single bedtime dose of two short half-time hypnotics, brotizolam (0.25 mg) and zopiclone (7.5 mg), on memory storage during sleep in a double blind, placebo-controlled, three-way crossover design trial in eight healthy volunteers. Memory was evaluated using a standard word list free-recall test learned before the bedtime dose by the subjects, who were asked to remember the list the following morning. Digit Symbol Substitution Test revealed no residual sedation by brotizolam or zopiclone. Brotizolam did not affect the morning recall compared to placebo, but subjects remembered less words under zopiclone treatment, suggesting that this drug could affect memory storage during sleep.

Adolescent↗
PubMed2001

The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers.

The effects of single oral doses of zopiclone and temazepam were investigated in eight healthy male volunteers using a single blind, placebo controlled cross over study. Doses of zopiclone were 7.5 and 15 mg while the dose of temazepam was 20 mg. Each dose was separated by at least a one-week washout period. For each subject the dim light melatonin onset (DLMO) was determined on a screening night and the drugs were administered at the time of the DLMO. Melatonin concentrations were determined by radioimmunoassay from plasma samples collected throughout the night. Both temazepam and zopiclone tended to reduce the amount of melatonin secreted, as determined by the area under the plasma concentration time curve. The differences from placebo were not statistically significant (F 3.31 = 1.07, P > 0.1). Similarly a repeated measures analysis of variance on the plasma concentration-time curves did not show any statistically significant differences between drugs and placebo (F 3.28 = 1.15, P > 0.1). There was no evidence from this study of a phase shifting effect of the drugs used. The reasons for the lack of effect on melatonin may be due to the differences in potency of the interaction of these drugs with the GABA-benzodiazepine-chloride ion channel.

Anti-Anxiety Agents↗
PubMed1997

Is hypnotic withdrawal facilitated by the transitory use of a substitute drug?

PURPOSE: Long-term consumption of hypnotics may lead to various side-effects, including impaired daytime and cognitive functioning and increased risk of accidents. Unfortunately, few guidelines exist for physicians to apply when attempting to withdraw hypnotics from patients. This study investigated whether withdrawal is facilitated by using zopiclone as a substitute drug and evaluated abrupt and gradual substitution techniques. METHODS: This open, multicentre and randomized study involved 1,002 male and female outpatients aged 18 years or over recruited by psychiatrists in Lyon, France. Patients had a mean age of 44 years, and 65.9% were women. Outpatients were chronic insomniacs being treated with a hypnotic for at least three weeks. The study included a substitution (D0-D35) and a withdrawal (D36-D56) stage. Patients were randomly drawn into three parallel groups: Group A underwent gradual substitution of zopiclone for the initial BZD; Group B was subjected to complete and immediate withdrawal of the initial BZD in favor of zopiclone; and Group C remained on the initial BZD, though told otherwise. The withdrawal stage began on D36 with a 50% reduction in medication and ended on D50 with complete withdrawal. RESULTS: Groups A (gradual substitution) and B (abrupt substitution) presented a net improvement in sleep during the substitution stage. However, Group B displayed a better improvement in sleep-onset period, a decrease in nocturnal awakenings and an increased quantity of sleep. In the withdrawal stage, Groups A and B were similar but Group C displayed a deterioration in sleep. Following the withdrawal stage, 29% of patients in Group C, 18% in Group A and 19% in Group B resumed hypnotic use. CONCLUSIONS: Discontinuation of this type of medication is possible in over three quarters of cases, provided that the prescribing physician adheres to a precise withdrawal protocol. Patients on zopiclone were less likely to resume consumption of hypnotics during the week of full withdrawal and were more satisfied with sleep than when treated with a BZD hypnotic. Finally, the results of the study showed that abrupt substitution yielded better results for chronic users of hypnotics.

Adolescent↗
PubMed2000

Determination of zopiclone in tablets by HPLC and UV-spectrophotometry.

Rapid, simple and accurate chromatographic (HPLC) and spectrophotometric methods for the determination of zopiclone in tablets were elaborated. Acetonitrile was found to be a suitable extraction solvent. The samples were chromatographed on Nova-Pak C18 column and UV detection at 304 nm. The elution was achieved isocratically with a mobile phase of 0.067 M phosphate buffer pH 7.95 - acetonitrile (55:45, v/v). Diazepam was applied as an internal standard. The method was validated for precision, linearity, accuracy and limit of detection. The recovery (mean +/- SD) in HPLC was 99.85 + 0.04% and in the UV-spectrophotometry 100.08 +/- 0.09%.

Azabicyclo Compounds↗
PubMed2003

Effects of zolpidem 10 mg, zopiclone 7.5 mg and flunitrazepam 1 mg on night-time motor activity.

The effects of a single dose of zolpidem (10 mg), zopiclone (7.5 mg) and flunitrazepam (1 mg) on motor activity the following 3 nights were compared to those of a placebo in a double-blind, crossover study. Thirty-three healthy subjects received medication between 10.30 and 11.30 p.m. and were asked to rise between 7.30 and 8.30 a.m. During the night under treatment, flunitrazepam, zopiclone and zolpidem significantly reduced motor activity. Changes in motor activity are quantitatively compatible with the hypothesis of reduced light sleep and wakefulness after sleep onset. During the first or second post-drug night, for zolpidem and zopiclone the opposite effect was observed, i.e. increased activity compared with placebo. These modifications cannot be explained by modified sleep structure. This last result underlines our inadequate understanding of the underlying mechanisms of motor activity during sleep. However, being sensitive and easy to use, actigraphy is an ideal technique to assess the effect of hypnotics on large populations and for long duration studies.

Adult↗
PubMed1999

The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

Animals↗
PubMed1999

Labeling of zopiclone with iodine-131.

Zopiclone (ZPC) was labeled with 131I by using the halogen exchange method. Temperature and reaction time effects to labeling yields were studied. Infrared, nuclear magnetic resonance, and gas chromatography-mass spectroscopy spectra were undertaken to identify chemical structure. High performance liquid chromatography (HPLC) was performed to determine purity of cold zopiclone. Biodistribution studies were performed on rabbits and rats. 131IZPC was administered intravenously to rabbits. Static images were taken by a Sophy DX Gamma Camera. 131IZPC was also administered intraperitoneally to rats. Activities were counted in a NaI(Tl) scintillation detector for several organs (liver, brain, spleen, lung, blood, fat) after rats were decapitated on different times. Biodistribution profiles were obtained depending on the time.

Animals↗
PubMed1989

[Effects of zopiclone on sleep, daytime somnolence and nocturnal and daytime performance in healthy volunteers].

Ten healthy volunteers, aged 20 to 39, underwent 2 adaptation nights and 3 sessions of 2 consecutive experimental nights and days at 1 week intervals. In the 3 sessions, subjects received under double blind conditions either Zopiclone 3.75 mg or 7.5 mg or placebo, according to a latin-square design. On nights 1 and 2 of each session, subjects were continuously polygraphically monitored, except for a 45 min provoked wake episode 135 min after sleep onset on night 2. Sleep continuity and architecture were evaluated during night 1, degree of daytime somnolence during day 1 and residual effects during night 2 (0 h 00) and day 2 (8 h 00 and 12 h 00). Sleep continuity was not modified, except for a reduction of the number of night awakenings. NREM sleep stage 1 was reduced and stage 2 was increased (in duration but not in percentage) with Zopiclone 3.75 and 7.5 mg. NREM sleep stages 3 and 4 were increased with Zopiclone 3.75 mg only. REM sleep was reduced (in percentage only) with Zopiclone 3.75 and 7.5 mg. Daytime somnolence varied according to the time but not with the 3 different conditions. One performance test only (choice reaction time test) showed a significant impairment at 0 h 00 with Zopiclone 7.5 mg. From a subjective point of view, sleep quality was improved and night time awakening was reduced with Zopiclone 7.5 mg.

Adult↗
PubMed1999

Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects.

OBJECTIVES: Habituation and adverse withdrawal reactions after prolonged medication with benzodiazepine (BZ) hypnotics are believed to play a role in dose escalation and the development of dependence. METHODS: In the current sleep EEG study in 43 healthy male subjects, the known property of BZ- and similar hypnotics to change the NREM sleep EEG spectrum is utilized for a detailed quantitative analysis across 4 weeks of continuous medication and a subsequent two-week withdrawal period. The BZ hypnotic triazolam and the non-BZ hypnotics zopiclone and zolpidem, differing in pharmacological properties and reported adverse effects, were examined in parallel to a placebo group. RESULTS: Reliably occurring spectral effects in the sleep stage 2 EEG were found in the 3 frequency bands 0.8-5 Hz, 5-10 Hz and 10-15 Hz. All 3 hypnotics showed the typical 'benzodiazepine signature', a 10-15 Hz increase and lower-frequency (<10 Hz) suppression relative to the preceding drug-free night. However, these effects developed differently across the first medication night, across the 4 medication weeks and after withdrawal: While the 5-10 Hz effect covaried with the blood presence of the drugs as estimated from the known plasma half-lifes, showed habituation and a rebound after withdrawal, the 10-15 Hz power increased across medication days and showed no rebound. Effects in the 0.8-5 Hz band in the first medication night correlated with the decrease of sleep efficiency at later withdrawal for triazolam and zolpidem.

Adult↗
PubMed2004

Construction of azacycles based on endo-mode cyclization of allenes.

A new procedure for constructing monocyclic five- and six-membered azacycles by the endo-mode ring-closing reaction of allenylazido derivatives under neutral conditions has been developed. The azabicyclo[m.n.0] compounds were prepared by applying this newly developed procedure. The seven-membered azacycle was prepared when the allene possessing an unsubstituted carboxyl amido functionality was submitted to the basic conditions. In addition, indole and quinoline skeletons were synthesized using this procedure.

Alkadienes↗
PubMed1999

Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.

1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of alpha and beta half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.

Anti-Anxiety Agents↗