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PubMed1994

Effects of zopiclone on sleep and symptoms in schizophrenia: comparison with benzodiazepine hypnotics.

Sleep variables and psychiatric symptoms were investigated in 6 male chronic schizophrenic outpatients. The patients were being treated with benzodiazepine (BZD) hypnotics for more than 8 weeks, and BZDs were replaced with zopiclone (ZPC) 15 mg/day. Polysomnographic examinations, subjective sleep assessments and BPRS scoring were performed during BZD therapy and at the end of 8 weeks of ZPC therapy. The doses of neuroleptics and anticholinergic agents remained fixed throughout the study. The amount of slow-wave sleep (SWS) was markedly small and that of stage 1 sleep was moderately large during BZD therapy. The amount of stage 1 was smaller and that of stage 2 was larger during treatment with ZPC than BZDs. There were no significant change in the amount of SWS between the treatment. Half of the patients exhibited a sleep-onset REM period (SOREMP) during ZPC therapy. Both total BPRS score and negative symptom score were lower during treatment with ZPC than BZDs. These results suggest that ZPC may be more beneficial in treating schizophrenic insomnia than BZD hypnotics and that reduced SWS and SOREMP may be partly involved in the pathophysiology of schizophrenia.

Adult↗
PubMed1990

Cyclopyrrolones, unlike some benzodiazepines, do not induce physical dependence in mice.

In a model of physical dependence in mice, treatment with cyclopyrrolones such as zopiclone and suriclone (from 4 to 400 mg/kg/day), did not modify the sensitivity of the gamma-aminobutyric acid (GABA) receptor complex to the partial inverse agonist FG 7142 following their withdrawal, whereas sensitivity changes were observed after treatment and withdrawal from some benzodiazepines (e.g. lorazepam, diazepam, flunitrazepam and triazolam). These data suggest that, in contrast to some benzodiazepines, zopiclone and suriclone may not produce physical dependence.

Animals↗
PubMed1990

Effects of GABA and anxiolytics on the single unit discharge of suprachiasmatic neurons in rat hypothalamic slices.

The effects of gamma-aminobutyric acid (GABA), muscimol, baclofen and the anxiolytics; diazepam (DZP), flurazepam (FZP) and zopiclone on single-unit neural activities in the suprachiasmatic nucleus (SCN) were investigated using the rat hypothalamic slice preparation. Exposure of the slice to GABA 10(-4) M produced inhibitory responses in 65% of the 49 SCN neurons examined. The threshold concentration of GABA ranged from 10(-6) to 10(-4) M. Neurons responsive to GABA were not found to be restricted to a subdivision of the SCN, but were diffusely distributed throughout the nucleus. DZP, FZP and zopiclone produced responses similar to those of GABA. The inhibitory effects of GABA (10(-5) M) were potentiated by coadministration of DZP (10(-5) M). Muscimol and baclofen (10(-7) M to 10(-4) M) also inhibited SCN neuronal activity in a dose-dependent manner. Bicuculline (10(-5) M-10(-4) M) scarcely affected the baclofen-induced inhibition (1/6) but strongly antagonized the effects of muscimol (6/6), GABA (6/8) and DZP (4/5). These results suggest that the receptors mediating the inhibitory effects of GABA and anxiolytics within the SCN may be GABAA and/or GABAB or GABA-BDZ receptor complex, respectively.

Animals↗
PubMed1991

Determination of zopiclone enantiomers in plasma by liquid chromatography using a chiral cellulose carbamate column.

The enantiomers of zopiclone were determined in human plasma using a sequential achiral-chiral liquid chromatographic method. Zopiclone was separated from the biological matrix and quantified on an achiral silica column. The limit of detection was 5 ng/ml. The eluent fraction containing zopiclone was collected, evaporated, reconstituted with the mobile phase and injected onto a chiral cellulose carbamate column where the enantiomeric ratio was calculated. This validated method, applied to a pilot study, suggests that pharmacokinetics of zopiclone is stereoselective.

Azabicyclo Compounds↗
PubMed1992

Determination of zopiclone in plasma using column liquid chromatography with ultraviolet detection.

A reversed-phase liquid chromatographic method with ultraviolet detection for the determination of zopiclone in plasma is described. It is rapid, sensitive, reproducible and linear over a wide range. The method was used to study plasma zopiclone concentrations in a case of acute intoxication after oral ingestion of 300 mg of the drug. The plasma level was 1600 ng/ml 4.5 h after the dose and the elimination half-life was 3.5 h.

Adult↗
PubMed1992

Development of a method for the determination of zopiclone in whole blood.

Mass spectrometry in both electron-impact and positive chemical ionisation modes has been used to elucidate the structures of the decomposition products of zopiclone after gas chromatography. A high-performance liquid chromatographic method has been developed for the determination of zopiclone in whole blood. After selective extraction (butyl chloride) the extracts are chromatographed on Spherisorb ODS-5 (5 microns) using dibasic ammonium phosphate-acetonitrile (40:60). The zopiclone is measured by ultraviolet detection with a limit of quantitation of 4 ng/ml. This method has been successfully applied to the determination of zopiclone in post-mortem blood. Zopiclone levels found in five post-mortem cases are presented.

Azabicyclo Compounds↗
PubMed1993

Gas chromatographic determination of zopiclone in plasma after solid-phase extraction.

A gas chromatographic technique for determining zopiclone based on a solid-phase extraction procedure with C18 cartridge for sample clean-up is presented. Quantification can be achieved with 1 ml of plasma. The method uses prazepam as internal standard. Zopiclone is separated on a 5% phenyl methyl silicone analytical column and detected with an electron-capture detector, which consequently allows a limit of quantitation of 2 micrograms/l. It is thus simple, rapid, sensitive and linear over the range 5-2000 micrograms/l.

Azabicyclo Compounds↗
PubMed1993

High-performance liquid chromatographic assay with diode-array detection for toxicological screening of zopiclone, zolpidem, suriclone and alpidem in human plasma.

A high-performance liquid chromatographic assay with diode-array detection has been developed for the toxicological screening of the newly developed non-benzodiazepine hypnotics and anxiolytics zopiclone, zolpidem, suriclone and alpidem. After single-step liquid-liquid extraction of plasma at pH 9.5 using chloroform-2-propanol-n-heptane (60:14:26, v/v), the substances are separated on a Nova-Pak C18 4-microns column (300 mm x 3.9 mm, I.D.), with methanol-tetrahydrofuran-pH 2.6 phosphate buffer (65:5:30, v/v) as the mobile phase (flow-rate 0.8 ml/min). Full ultraviolet spectra from 200 to 400 nm are recorded on-line during the entire analysis and may be automatically compared to spectra stored in a library. The retention times of the four drugs are 4.05 min (zopiclone), 4.66 min (zolpidem), 6.74 min (suriclone) and 10.97 min (alpidem). The analysis is performed in 15 min. The method is simple, rapid and highly specific. It is the first assay to be described for convenient screening of cyclopyrrolones and imidazopyridines.

Adult↗
PubMed1993

Determination of the enantiomers of zopiclone and its two chiral metabolites in urine using an automated coupled achiral-chiral chromatographic system.

The enantiomers of zopiclone and its two chiral N-desmethyl and N-oxide metabolites were determined in urine using a coupled achiral-chiral liquid chromatographic method. After liquid-liquid extraction, zopiclone and its two metabolites were quantified on a cyanopropyl column. After fluorimetric detection on the achiral system, the eluent was switched through a silica precolumn in order to trap and concentrate the analytes. Each fraction was then backflushed separately onto a carbamate cellulose chiral stationary phase in order to determine the enantiomeric ratios. The coupled system was automated with an autosampler and a switching valve programmed by an integrator. The method was validated, and a first trial was performed on urine samples of a volunteer treated with 15 mg of racemic zopiclone.

Azabicyclo Compounds↗
PubMed1994

Stereospecific high-performance liquid chromatographic assay of zopiclone in human plasma.

A high-performance liquid chromatographic (HPLC) assay for the analysis of the enantiomers of zopiclone (ZPC), a cyclopyrrolone hypnotic, in plasma was developed. Following the addition of chlordiazepoxide as internal standard (I.S.), plasma containing the ZPC enantiomers and I.S. was extracted by liquid-liquid extraction at an alkaline pH. After evaporation of the organic layer, the drug and I.S. were reconstituted in ethanol-hexane (80:20, v/v) and injected onto the HPLC column. The enantiomers were separated at ambient temperature on a 25-cm Chiralcel OD-H column with ethanol-hexane (60:40, v/v) as the mobile phase pumped at a flow-rate of 0.6 ml/min. The enantiomers of ZPC were quantified by fluorescence detection with excitation and emission wavelengths of 300 and 470 nm, respectively. The assay described allows for the direct quantitation of ZPC without pre-column derivatization, and is suitable for clinical studies of ZPC in humans after administration of therapeutic doses.

Azabicyclo Compounds↗
PubMed1995

Rapid and sensitive detection of benzodiazepines and zopiclone in serum using high-performance thin-layer chromatography.

We developed a rapid and sensitive method of identifying benzodiazepines and zopiclone in human serum using high-performance thin-layer chromatography (HPTLC). These drugs were developed and separated on plates within 8-11 min and detected by means of UV radiation and colour. Each drug was accurately identified by means of the values of RF x 100 and the spot colour in three systems. The detection limit of the benzodiazepines in serum was 0.1-0.4 micrograms/ml, except for cloxazolam and haloxazolam. The sensitivity was increased about ten-fold over the conventional method. These results suggested that the HPTLC system is useful for the initial detection and identification of these drugs in emergencies.

Azabicyclo Compounds↗
PubMed1996

Enantioselective determination of zopiclone and its metabolites in urine by capillary electrophoresis.

A method has been developed for the stereoselective determination of zopiclone and its main metabolites in urine. After the addition of the internal standard zolpidem the urine samples were extracted at pH 8 with chloroform-isopropanol (9:1). Analyses were carried out using capillary electrophoresis (CE) with beta-cyclodextrin as the chiral selector. The analytes were detected using UV laser-induced fluorescence detection with a He-Cd laser operated at 325 nm. Urine samples of two volunteers after oral administration of 7.5 mg zopiclone were investigated. The S-(+)-enantiomers of zopiclone and its metabolites were always excreted in higher amounts than the R-(-)-enantiomers. With the same method the zopiclone enantiomers were quantified in saliva. Compared to high-performance liquid chromatography, the CE method is very fast and simple.

Azabicyclo Compounds↗
PubMed1994

Zopiclone poisoning: tissue distribution and potential for postmortem diffusion.

Zopiclone is the first cyclopyrrolone hypnotic and is chemically unrelated to any existing drug. The authors studied the tissue distribution and postmortem redistribution of zopiclone in a fatal suicidal overdose. A 29-year-old female weighing 64 kg had cardiac blood ethanol 153 mg% and zopiclone blood concentrations in the range 0.9-2.0 microgram/ml in 10 distinct sampling sites. After 40 h at room temperature the range was 0.9-1.8 micrograms/ml in 15 samples. Portal venous blood and urine concentrations were 3.0 and 10.5 micrograms/ml, respectively. Tissue concentrations (microgram/g) were spleen 5.8, peri-renal fat 5.0, psoas muscle 3.3, brainstem 2.8, gastrocnemius muscle 1.9, myocardium 1.6, and kidney 1.7. Eight liver samples had concentrations in the range 0.5-4.9 micrograms/g, with highest concentrations in the left lobe and adjacent to the gallbladder, probably reflecting postmortem diffusion from gastric residue (700 ml, 55.1 micrograms/ml) and bile (14.1 micrograms/ml). Of six lung samples, paired upper and middle samples had concentrations in the range 2.1-2.3 micrograms/g, the right postero-basal 1.3 micrograms/g and the left postero-basal 3.4 micrograms/g. Drug concentration in putrefactive pleural fluid was also higher on the left (2.1 micrograms/ml) than the right (1.4 micrograms/ml), probably reflecting postmortem diffusion from gastric residue. The authors conclude that zopiclone showed little preferential concentration in solid organs and consequently has relatively stable postmortem blood concentrations, with little drug redistribution artefacts. Postmortem diffusion from gastric drug residue elevates drug levels in the left lobe of the liver and left lung lower lobe.

Adipose Tissue↗
PubMed1996

Detection and quantification of the hypnotic zopiclone, connected with an uncommon case of drowning.

A fatality, attributed to a suicidal ingestion of zopiclone and subsequent death by drowning, is described. A radioimmunoassay was performed to prescreen for the presence of the analyte. HPLC analysis with fluorescence detection demonstrated a testicular tissue concentration of 2.2 micrograms/g zopiclone. Further toxicological analysis revealed also the presence of diazepam in a concentration of 150 ng/g.

Adult↗
PubMed1995

A quantitative sleep-EEG study on the effects of benzodiazepine and zopiclone in schizophrenic patients.

Polysomnographic examinations (PSG) were performed on 6 male schizophrenic outpatients who were being treated with benzodiazepine (BZD) hypnotics in combination with neuroleptics and 6 healthy male volunteers. In schizophrenic subjects, zopiclone (ZPC), 15 mg/day, was substituted for the BZD hypnotics, and PSGs were recorded again during ZPC therapy. All-night sleep stage scoring was carried out by visual analysis, and computerized period-amplitude analysis of sleep EEG was also performed. The schizophrenics showed marked reduction in the amount of slow-wave sleep (SWS) and in the number of delta half-waves during all-night sleep, especially those with higher amplitude, as compared to the normals. The number of delta half-waves in the patients was markedly reduced during the first sleep cycle. The average amplitude of delta half-waves during all-night sleep in the schizophrenics was significantly lower than that in the normals. The half-wave count of total delta waves in the schizophrenics was higher during treatment with ZPC than with BZDs, although no significant differences were observed in the amount of SWS between the two treatments. Soundness of sleep in the subjective sleep assessment was better evaluated during treatment with ZPC than BZDs. These results suggest that reduction of SWS in schizophrenia may be attributable mainly to the decrease in the number of delta waves with higher amplitude and that ZPC may induce deeper sleep in schizophrenics than BZDs.

Adult↗
PubMed1994

Functional properties of the brain during sleep under subchronic zopiclone administration in man.

Zopiclone, a non-benzodiazepine, has been shown to be efficient in the treatment of transient, short-term or chronic sleep disorders. Apart from its hypnotic effects zopiclone has anxiolytic, anticonvulsant and myorelaxant properties and is therefore hardly distinguishable from benzodiazepines. Dependence liability and discontinuation effects have been reported to be less pronounced. Therefore zopiclone seems to be a hypnotic drug which may cause fewer side effects than conventional benzodiazepines. From the electrophysiological point of view one requires from a hypnotic drug the induction of a physiological sleep pattern as well as no alterations of information processing by the brain. The aim of the present study was to investigate the subchronic effect of zopiclone medication on some functional properties of the sleep EEG in healthy subjects. In order to get better insight into the principles of information processing by the brain during sleep and its alterations under the influence of zopiclone we applied some tools from linear system theory to sleep EEG data. For this purpose we investigated late components of auditory and visual evoked potentials during different sleep stages and calculated from these the so-called amplitude-frequency characteristic of the brain. This function describes the relationship between an input and the output of the investigated system. The main advantage of this kind of analysis is that it enables one to detect functional differences during sleep stages. This information can hardly be obtained from conventional spectral analysis. As a result we could demonstrate that under subchronic zopiclone medication no quantitative or qualitative alterations of the functional sleep EEG properties concerning the transfer properties of the brain under auditory and visual stimulation were detectable.

Adult↗
PubMed1996

Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion.

Zopiclone is a new short half-life cyclopyrrolone hypnotic agent acting at the GABA-benzodiazepine receptor complex. In order to characterize its pharmacological profile, the effects of 7.5 mg zopiclone on nocturnal melatonin secretion were investigated under polysomnographic control in 11 healthy subjects following acute and subchronic administration as well as after abrupt discontinuation of the drug. No effect of zopiclone on the melatonin plasma levels could be observed. Regarding both total melatonin production and the temporal pattern of melatonin secretion during the night, there was no difference between placebo baseline condition, acute and subchronic administration, and discontinuation. In contrast, the sleep EEG data demonstrated the hypnotic efficacy of zopiclone under acute administration and indicated a rebound insomnia after abrupt discontinuation. Moreover, alterations of sleep architecture were found under treatment as well as after discontinuation. Whereas, with regard to sleep EEG parameters, zopiclone appears to be comparable with some short-acting benzodiazepines, a discrepancy between the missing effect of zopiclone on pineal function and the suppressing influence of benzodiazepines known from the literature becomes obvious. The fact that zopiclone does not interfere with nocturnal melatonin secretion at pharmacologically active doses as indicated by alterations in sleep EEG parameters might possibly point to a pharmacodynamic difference between the two drug classes.

Adult↗