Treatment of chronic insomnia with cognitive behavioral therapy vs zopiclone.
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Azabicyclo Compounds↗
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Treatment of chronic insomnia with cognitive behavioral therapy vs zopiclone.
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Azabicyclo Compounds↗
Stereoselective binding of zopiclone to human plasma proteins.
The binding of racemic zopiclone (ZOP) and of its two enantiomers to plasma proteins, albumin and alpha 1-acid glycoprotein were compared. Our work shows that the binding of ZOP to human plasma proteins is stereoselective. The total plasma protein binding percentages were 79.3 +/- 5.5%, 83.8 +/- 5.2%, and 75.1 +/- 2.1%, for racemic zopiclone, (-)zopiclone and (+)zopiclone, respectively. These results were confirmed by the analysis of samples obtained from healthy volunteers after the oral administration of ZOP. The anticoagulant used for sampling was also shown to have an influence on the percentage binding and on its stereoselectivity. Considering albumin and alpha 1-acid glycoprotein separately, stereoselectivity was also observed.
Azabicyclo Compounds↗
Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers.
Zopiclone is a new sedative showing a rapid onset of hypnotic effect and a relatively short duration of action. The goal of this study was to assess the kinetic parameters of zopiclone and its interaction with trimipramine when administered concomitantly. Ten normal subjects each received doses of zopiclone (7.5 mg), trimipramine (50 mg), and zopiclone (7.5 mg) + trimipramine (50 mg) orally at 7-day intervals. The absorption of zopiclone was rapid, the observed plasma peak concentration and 95 per cent of all absorption occurring within one hour. The average elimination half-life was 3.8 +/- 0.2 h. The volunteers reported a bitter taste at an average of 24 min after zopiclone administration at which time concentrations in saliva were approximately 50 ng ml-1. Trimipramine decreased the relative bioavailability determined for zopiclone by 13.7 per cent, while zopiclone decreased the relative bioavailability of trimipramine by an average of 26.6 per cent, although neither of these changes was statistically significant (p greater than 0.05); there were no substantial changes in other kinetic parameters. It is concluded that zopiclone presents advantages over some other sedative drugs as it is rapidly absorbed and eliminated. When zopiclone is administered with trimipramine, the decrease in the relative bioavailability of trimipramine may be clinically significant.
Adolescent↗
The effects of low and moderate doses of alcohol on the pharmacokinetic parameters of zopiclone.
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Adult↗
Validation of a high-performance liquid chromatographic method for the enantiospecific quantitation of zopiclone in plasma.
Zopiclone is a hypnosedative with clinical effects similar to benzodiazepines but thought to have less potential for rebound insomnia and withdrawal effects. Zopiclone is administered as a racemic mixture, and an enantiospecific method of analysis of zopiclone in plasma is desirable in the study of pharmacokinetic drug interactions. We report a modification of an HPLC method reported by Foster et al. using a closely related structural analogue of zopiclone as internal standard. Zopiclone was detected at 306 nm and linear calibration curves were constructed in the range of 1.0-250 ng/mL for each enantiomer. The % CV at 2.5 ng/mL was 12.0% for (-)-zopiclone and 14.3% for (+)-zopiclone, and the limit of quantification of each enantiomer was 2.5 ng/mL. At higher concentrations, the coefficient of variation was less than 10%. The nominal concentration of quality control samples was predicted with an accuracy within a range of +/-11.6%. The method was used in the analysis of plasma obtained from psychiatric patients. One sample obtained following a non-fatal overdose with zopiclone contained the metabolites (-)-N-oxide zopiclone and both enantiomers of desmethyl zopiclone. The metabolite enantiomers were resolved on the column with retention times similar to zopiclone. The N-oxide metabolite co-eluted with internal standard.
Azabicyclo Compounds↗
Quantitation of zopiclone and desmethylzopiclone in human plasma by high-performance liquid chromatography using fluorescence detection.
A simple, reliable HPLC method using fluorescence detection (excitation 307 and emission 483 nm) was developed and validated for simultaneous quantitation of zopiclone and its metabolite desmethylzopiclone in human plasma. Following a single-step liquid-liquid extraction, the analytes and internal standard (zaleplon) were separated using an isocratic mobile phase on a reversed-phase C18 column. The lower limit of quantitation was 3 ng/mL for zopiclone and 6 ng/mL for desmethylzopiclone with a relative standard deviation of less than 5%. A linear dynamic range of 3-300 ng/mL for zopiclone and of 6-500 ng/mL for desmethylzopiclone was established. This HPLC method was validated with between-batch precision of 1.7-4.2% and 3.2-7.5% for zopiclone and desmethylzopiclone respectively. The between-batch accuracy was 99.4-111.5% and 101.6-104.8% for zopiclone and desmethylzopiclone, respectively. Frequently coadministered drugs did not interfere with the described methodology. Stability of zopiclone and desmethylzopiclone in plasma was excellent, with no evidence of degradation during sample processing (autosampler) and 30 days' storage in a freezer. This validated method is simple and repeatable enough to be used in pharmacokinetic studies.
Azabicyclo Compounds↗
Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site.
We report the preparative separation of rac-zopiclone using malic acid as the resolving agent. Furthermore, two different methods for the analytical determination of zopiclone enantiomers by HPLC on chiral stationary phases are described. The benzodiazepine receptor binding of the isolated enantiomers was investigated. Half-maximal inhibitory concentrations of (+)- and (-)-zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times higher affinity of the (+)-enantiomer toward the receptor.
Animals↗
Zopiclone and zaleplon vs benzodiazepines in the treatment of insomnia: Canadian consensus statement.
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Acetamides↗
Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis.
OBJECTIVES: To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z-drugs) with either benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other. METHODS: MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z-drugs or any two of the Z-drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. RESULTS AND CONCLUSIONS: Twenty four eligible studies were identified with a total study population of 3,909 (17 studies comparing a Z-drug with a benzodiazepine and 7 comparing a Z-drug). Insufficient or inappropriately reported data meant that meta-analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs.
Acetamides↗
Acid catalyzed hydrolysis of a series of zopiclone analogues.
The pKa values of acid-base equilibria involved in the protonation of zopiclone and analogues are determined by UV-visible absorption spectrometry and pH-metry. Hydrogen ion catalysis is evidenced in the carbamate hydrolysis.
Azabicyclo Compounds↗
Determination of zolpidem and zopiclone in serum by capillary column gas chromatography.
A gas chromatographic method using a short, high-resolution capillary column connected to a specific thermoionic detector and requiring a simple and short extraction step without evaporation was developed for the rapid and precise determination of two new hypnotics, zolpidem and zopiclone, in serum at concentrations greater than 5 ng/mL. The assay was linear between 5 and 200 ng/mL, with coefficients of intra- and interassay variation less than 5% for both. The method was validated and then used to analyze zolpidem serum concentrations in nine rabbits after oral administration of 0.5 mg/kg and zopiclone serum concentrations in six patients treated orally with a 7.5-g dose.
Animals↗
Zopiclone potentiates the antinociceptive effect of morphine in rats.
The antinociceptive effect of morphine, as determined by the tail-flick test, was dose-dependently increased by the intraperitoneal injection of zopiclone. The benzodiazepine antagonists Ro 15-1788 (flumazepil) and Ro 15-3505, when intraperitoneally injected, significantly antagonized the effect of intraperitoneal injection of zopiclone on morphine antinociception. Intrathecal injection of zopiclone potentiated morphine antinociception, while the intracerebroventricular injection of zopiclone failed to enhance morphine antinociception and the intracerebroventricular injection of flumazepil to antagonize the intraperitoneal-zopiclone-induced increase in morphine antinociception. These results suggest that benzodiazepine sites are specifically involved in the potentiating effect of zopiclone on morphine antinociception. The anatomical locations of the receptors involved seem to be at the spinal level.
Animals↗
Suriclone enhances the actions of chlorpromazine on human psychomotor performance but not on memory or plasma prolactin in healthy subjects.
Twelve healthy subjects received single oral doses of 0.4 mg suriclone (SU), 7.5 mg zopiclone (ZO) and placebo, alone and together with 50 mg chlorpromazine (CP), double blind and crossover, in Latin square order, at one-week intervals. Performance tests administered before and 1.5, 3.5 and 6 h after drug intake included digit symbol substitution and simulated driving combined in a "Global test", flicker fusion frequency, body balance and memory and subjective assessments. Changes from baseline were examined statistically. Performance and memory data were analysed from only 11 subjects. Compared to placebo, SU minimally affected "global" performance, although it slowed reactions and tended to impair digit substitution. ZO impaired "global" performance at 1.5 h, affected performance in several separate tests, and produced subjective muzziness. CP did not impair "global" performance, although it did impair digit substitution and render the subjects drowsy, weak and dreamy. The combinations SU + CP and ZO + CP definitely impaired "global" performance more than CP alone. This difference was also found in most objective tests but less so in the subjective tests. CP and its combinations produced similar increases in plasma prolactin. Active drugs and their combinations variably lowered blood pressure and increased heart rate, and one subject collapsed after CP. The treatments irregularly impaired spatial memory and learning acquisition. No pharmacokinetic interactions were seen in the plasma levels of suriclone, zopiclone and chlorpromazine. The impairment of performance after these combinations resembles that previously encountered after 2.5 mg lorazepam, or 15 mg diazepam + 100 mg remoxipride.
Adult↗
Difference in action between oral triazolam and zopiclone.
The effects of oral triazolam 0.25 mg and zopiclone 7.5 mg in 7 supine volunteers were compared by means of quantitative measurements of the EEG, saccadic eye movements, visual analogue scale (VAS) for alertness, critical flicker fusion frequency (CFF) and the Maddox wing. Zopiclone reached its maximum effect earlier (62 min) than triazolam (91 min; CFF). On linear regression analysis the average rate constant (regression coefficient) of onset of action of zopiclone was significantly greater than that of triazolam (0.29 vs. 0.17). Triazolam and zopiclone had similar effects, but zopiclone seemed to have a faster onset of action, probably indicating swifter absorption in supine subjects. Quantitative EEG evaluation gave parallel results to the other parameters used, but triazolam and zopiclone showed a dissimilar mechanism of action, as characterized by changes in the alpha frequency.
Administration, Oral↗
Zopiclone in insomniac shiftworkers. Evaluation of its hypnotic properties and its effects on mood and work performance.
Fifty adult insomniac shiftworkers (47 males and 3 females) between the ages of 22 and 55 participated in this two-week, double-blind comparative study of the hypnotic properties and effects on mood and work performance of zopiclone 7.5 mg and placebo. All subjects took inactive medication on the first night of the study and then received either zopiclone or placebo for the following 13 nights according to randomization. Pre-study variables included a demographic profile, medical history, physical examination, laboratory data, profile of insomnia and work shift pattern description. A sleep questionnaire along with mood and work performance questionnaires were filled out on Days 1, 2, 4, 9 and 12 of the study; on Days 7 and 14, adverse events were recorded. After the first placebo night, subjects assigned to receive zopiclone showed significantly improved sleep induction; from the second night on, a distinct pharmacological effect over placebo was observed and maintained since statistically significant increases in quantitative sleep induction and sleep soundness (qualitative and quantitative) were noted during the course of zopiclone treatment. Active hypnotic treatment did not interfere with morning awakening and functioning, nor did it affect mood or work performance. Zopiclone treatment produced significantly more taste disturbance and drowsiness. In summary, zopiclone was shown to be an effective, fast-acting hypnotic which maintained its efficacy over a two-week period in our sample of insomniac shiftworkers and did not produce mood changes or influence work performance.
Adult↗
Anxiolytic drugs and the acquisition of conditioned fear in mice.
Previous studies have shown that, in rodents, chlordiazepoxide and other benzodiazepines can interfere with learning in passive avoidance or conditioned suppression procedures. The most consistent effects are observed when the drugs are administered before the acquisition trial and subjects are re-tested in the non-drugged state. It is not clear, however, whether this effect on learning is associated with the behavioural depressant actions of these drugs. In the present study mice were injected with chloridiazepoxide, diazepam, zopiclone, or CGS 9896 and locomotor activity measured in a two-compartment box. The animals were then enclosed in one of the compartments and received a series of footshocks. On a second trial, 24 h after the first, the mice were returned to the box without injection and locomotion and time spent in each compartment were measured. During trial 1 chlordiazepoxide, diazepam, and zopiclone produced dose-related decreases in locomotor activity. The same doses disrupted fear conditioning. CGS 9896 also interfered with the conditioning of fear but did not reduce exploratory activity during the first trial at any of a wide range of doses, showing that learning can be affected without direct behavioural depressant activity. In a further experiment, chlordiazepoxide and CGS 9896 disrupted fear conditioning when injected before trial 1 but not when injected immediately after this trial. Mice drugged with chlordiazepoxide or CGS 9896 before both trials 1 and 2 also showed disrupted conditioning, demonstrating that the drug effects cannot be interpreted in terms of state dependent learning.
Animals↗
A new physiological tool for assessing anxiolytic effects in humans: frontal midline theta activity.
The theta activity which appears in the frontal midline area during performance of mental tasks has been designated as "Fm theta". In the present study, the possible use of zopiclone as an anxiolytic agent was investigated using Fm theta, in a comparison with diazepam. Sixteen male university students were given placebo, diazepam 5 mg, zopiclone 5 mg and 10 mg, in a double-blind, cross-over design. EEGs were recorded before and during performance of an arithmetic addition test. This test was repeated twice, prior to and 1 h following drug administration. Diazepam markedly increased Fm theta; however, both zopiclone 10 mg and placebo only slightly affected Fm theta, while zopiclone 5 mg failed to affect Fm theta. Scores of state anxiety were reduced markedly by diazepam and only slightly by zopiclone 10 mg, but were not affected by either zopiclone 5 mg or by placebo. Task performance was reduced markedly and in a dose-dependent manner by zopiclone, and very slightly by diazepam. These results suggest that zopiclone possesses a rather potent hypnotic effect, rather than an anxiolytic effect, and that Fm theta might be a useful tool in predicting the clinical efficacy of anxiolytic drugs in normal humans.
Adult↗