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PubMed2005

Insomnia.

The launch of eszopiclone by Sepracor Inc in April 2005 in the US has marked the long-anticipated advent of a new generation of hypnotics that promise safer treatment for chronic insomnia. Over the coming years more compounds are expected to be launched, offering improved daytime well being and fewer side effects compared with their predecessors that were launched in the early 1990s. This article examines the factors that will drive the uptake of the new insomnia drugs by the public, describes potential barriers to adoption of these drugs and provides ideas for future treatment approaches that may offer better targeting and management of possible underlying conditions rather than merely controlling a symptom.

Azabicyclo Compounds↗

PubMed2004

Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats.

The encephalographic (EEG) properties of zaleplon were investigated in comparison with those of other sedative hypnotics in conscious rats with chronically implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg), triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25 mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose-dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in particular, increased the slow wave deep sleep (SWDS), whereas triazolam, brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose-dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused no influence on fast wave sleep (FWS) at doses tested. The appearance of the sleep-inducing activity of zaleplon was more rapid than those of any compounds tested, and zaleplon significantly increased the relative EEG power density in the delta frequency band over that of triazolam at 20 and 30 min after the administration in the spectral analysis. Therefore, the present findings suggest that the non-benzodiazepine zaleplon can be expected to exhibit high practical potential as a hypnotic and is characterized by an increase in SWDS with rapid onset of hypnotic action.

Acetamides↗

PubMed1996

Development of a fluorescence polarization immunoassay for the routine detection of N-desmethylzopiclone in urine samples.

A polarization fluoroimmunoassay was developed for the detected of N-desmethylzopiclone in urine and the reagents were adapted for use on the Vitalab Eclair analyser. Therefore, N-fluoresceinthiocarbamyldesmethylzopiclone was synthesized as a fluorescent tracer and used in combination with an existing pool of antibodies, raised against the hemisuccinyl derivative of N-desmethylzopiclone. The optimization of the assay was performed on a semi-quantitative basis, relative to a cut-off value of 300 ng ml-1. No significant interference was observed from a selection of existing drugs and endogenous compounds. The minimum detectable dose of the immunoassay was calculated to be 30 ng ml-1 (pooled-variance t-distribution, p = 0.01, degrees of freedom = 10). Intra- and inter-assay relative standard deviations were < 10 and < 12%, respectively. For the confirmation of positive samples, an established reverse-phase HPLC technique, in combination with fluorescence detection, was used. The combined screening/confirmation procedure was applied to cumulative excretion samples, after ingestion of one tablet of Imovane (zopiclone, 7.5 mg).

Azabicyclo Compounds↗

PubMed1990

A comparison of the efficacy, safety and withdrawal effects of zopiclone and triazolam in the treatment of insomnia.

A double-blind study comparing zopiclone and triazolam, in 48 healthy, chronic insomniacs, was undertaken in two centers to compare the hypnotic and withdrawal effects of both compounds. Comparable doses of 7.5 mg zopiclone and 0.25 mg triazolam were given at bedtime for 21 nights after a 3 day wash-out period, followed by 4 placebo nights of withdrawal monitoring. During the investigation, a 17 item post-sleep questionnaire was completed daily, the Clinical Global Impression (CGI) scale weekly, and the Hamilton Anxiety Scale (HAM-A) at baseline and at the end of the study. Withdrawal effects were evaluated with a withdrawal symptom checklist and the CGI (withdrawal). Results indicated that both compounds improved sleep and were equally effective. However, a larger number of triazolam subjects withdrew from the study because of ineffectiveness or adverse side-effects. A greater number of zopiclone subjects experienced a transient modification of taste which disappeared with discontinuation of therapy. Significant deterioration in nearly all sleep parameters were noted after the first withdrawal night of triazolam; much fewer modifications of sleep parameters were observed following the discontinuation of zopiclone.

Adolescent↗

PubMed1985

Behavioral effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide.

Zopiclone and CGS 9896 are two nonbenzodiazepine compounds which have been shown to displace benzodiazepines from their binding sites. The present study compared the behavioral effects of these two compounds in rats with those of chlordiazepoxide. The three drugs produced dose-related increases in punished drinking as did pentobarbital and meprobamate but not PK 9084, which also acts at benzodiazepine binding sites, or buspirone. Rates of lever pressing suppressed by punishment were also increased by chlordiazepoxide and zopiclone. CGS 9896 exerted a similar although less marked effect. Lever pressing maintained by a differential reinforcement of low rate 18-sec schedule of milk presentation was increased by low doses of chlordiazepoxide and zopiclone and decreased by higher doses leading to dose-related reductions in numbers of reinforcers obtained. CGS 9896 also reduced number of reinforcers but without affecting rate of responding. In rats trained to discriminate a dose of chlordiazepoxide from saline, chlordiazepoxide, zopiclone, pentobarbital and meprobamate produced chlordiazepoxide-appropriate responding. CGS 9896 also produced chlordiazepoxide-appropriate responding at a wide range of doses although the stimulus properties of this compound appeared to be weaker than those of the other active drugs. Chlordiazepoxide and zopiclone produced dose-related increases in food intake in food-deprived rats. CGS 9896 had similar effects at low doses but its effects were less consistent at higher doses. Thus, zopiclone has a behavioral profile very similar to that of chlordiazepoxide. Although many of the effects of CGS 9896 were similar to those of chlordiazepoxide, a number of differences were also observed.

Animals↗

PubMed1997

Multidrug comparison (lorazepam, triazolam, zolpidem, and zopiclone) in situational insomnia: polysomnographic analysis by means of the cyclic alternating pattern.

Since homogeneous samples of insomniacs are difficult to recruit for pharmacotherapy studies, normal sleepers can be used to assess the protective effect of hypnotic drugs, under standardized nonconducive conditions. In particular, a noisy environment is a typical cause of situational insomnia that can be counteracted by a sedative-hypnotic agent. Six healthy middle-aged subjects (three men and three women), with no complaints about sleep, underwent a completely randomized double-blind series of 10 nocturnal polysomnograms with at least 72-h washout intervals. All subjects received a single dose of placebo, zolpidem 10 mg, zopiclone 7.5 mg, lorazepam 1 mg, and triazolam 0.25 mg both under basal and under perturbed conditions. For each individual, five recordings were carried out under basal conditions (sound pressure level not higher than 30 dB) and five recordings under acoustically perturbed conditions (continuous white noise at 55 dB). Sleep quality was assessed by means of a visual analogue scale (VAS). All recordings were scored according to conventional rules (macro-structure) and cyclic alternating pattern (CAP) methodology (microstructure). Statistical analysis was based on a repeated measures analysis-of-variance design integrated by Bonferroni adjusted probabilities. Under placebo, situational insomnia was confirmed by the significant increase in sleep fragmentation (intrasleep wakefulness) and by the significant enhancement of arousal instability (CAP parameters). In contrast to macrostructural information, CAP parameters were highly sensitive in detecting the perturbing effects of noise (mean CAP rate under placebo, 57%) and the protective action of hypnotic drugs during perturbation (mean CAP rate under active medication, 41%). Microstructural analysis enabled us to discriminate hypnotic drugs from placebo, nonbenzodiazepine compounds from benzodiazepine agents, and zopiclone from zolpidem. The latter, in fact, induced the lowest values of CAP rate both under basal (30%) and under noisy (39%) conditions and determined a significant decrease in electroencephalogram arousals. All CAP parameters were significantly correlated with the visual-analogue-scale scores for sleep quality. The use of CAP methodology in a highly standardized model of situational insomnia can be a valid alternative to conventional sleep scoring for the investigation of drug effects on disturbed sleep.

Adult↗

PubMed1997

Influence of zopiclone, a new generation hypnotic, on the intermediate stage and paradoxical sleep in the rat.

This study examined the influence of zopiclone, a third generation hypnotic, on the transition from slow wave sleep to paradoxical sleep (PS) which is increased at the expense of PS by barbiturates and benzodiazepines. The compound decreased sleep latency and increased the latency of the intermediate stage (IS) and PS at 2.5, 5 and 7.5 mg/kg IP. The amount of the IS was decreased because of the decrease in phase number up to 6 h at all doses. PS amount was decreased during 2 h at 2.5 mg/kg and during 4 h at 5 and 7.5 mg/kg also because of the decrease in phase number. The IS never substituted for PS. The IS spindle characteristics were not modified and the theta rhythm frequency slightly decreased at 5 mg/kg (IS) and 7.5 mg/kg (PS).

Animals↗

PubMed1980

A dose-response study in situational insomnia with zopiclone, a new tranquilizer.

Patients scheduled for next-day elective surgery were included in a randomized double-blind trial that compared the hypnotic and adverse effects of a placebo and four doses (3,5,6,9,13.5 mg) of a new compound, zopliclone. Sleep patterns were evaluated using a questionnaire; side effects were noted, and tests evaluating coordination and alertness were performed. Except for dreams and morning responses, there were significant differences in sleep indices at all dose levels. The 3.5-mg dose produced some significant differences compared with the placebo. All responses to the higher three doses were statistically significant; however, there was only a slight increase in effectiveness between 6 and 9 mg. Alertness, coordination tests, blood pressure, and adverse effects did not differ significantly among doses, except for the incidence of drowsiness and a bitter after-taste in the mouth.

Adolescent↗

PubMedDate not supplied

A method for the rapid detection of the zopiclone degradation product 2-amino-5-chloropyridine.

Zopiclone (Zimovane) is a cyclopyrrolone compound which exhibits hypnotic and sedative effects while also exhibiting anticonvulsant and muscle relaxant activities. The detection and quantification of zopiclone is difficult. It has a high molecular weight compared to most other commonly used drugs, therapeutic levels are not high, and it is unstable in nucleophilic solvents. A degradation product of zopiclone, 2-amino-5-chloropyridine (ACP) together with a method for its detection using high-performance liquid chromatography with diode array detection has been described previously. An account is presented of a simple method for the detection of ACP using gas chromatography with mass selective detection (GC/MS) which will facilitate detection of zopiclone use as part of a routine screen.

Azabicyclo Compounds↗

PubMed1994

A postmarketing surveillance study of zopiclone in insomnia.

Zopiclone, a novel cyclopyrrolone compound has recently become available for the treatment of insomnia in Singapore. Pharmacodynamic and pharmacokinetic studies have shown it to be an effective hypnotic with a good safety profile and minimal side-effects. The efficacy of Zopiclone was studied in a group of patients with insomnia (n = 40). The study group comprised patients with and without a psychiatric diagnosis. About two-thirds (65%) of the patients had been on hypnotics previously without relief of the insomnia. There was improvement in the various sleep parameters studied: sleep latency, sleep duration, night awakening, sleep quality, dreams, "day-after" effects. The drug was well-tolerated and only four patients experienced minor side-effects.

Adult↗

PubMedDate not supplied

Pharmacological properties and mechanism of action of the cyclopyrrolones.

We present the pharmacological properties of two cyclopyrrolones, zopiclone as a hypnotic and suriclone as an anxiolytic, and examine their mechanism of action. The effects of zopiclone on the amount of time spent at each vigilance level have been studied in freely moving rats. Zopiclone from 2.5 mg/kg i.p. extends the duration of slow wave sleep (SWS), concomitantly shortening the periods awake. This SWS inducing effect of zopiclone was more potent after 10 mg/kg i.p.; moreover, zopiclone did not depress REM sleep and no rebound of activity in wakefulness or REM sleep were observed the day after zopiclone treatment. In rats, at the cortical level, zopiclone increases the spectral energy in the delta band (0.5 to 4 hertz). This rise in energy appears at doses starting from 1.25 mg/kg p.o. and can also reach the fast frequencies (beta band: 12 to 16 hertz). This power spectrum is characteristic of a compound having tranquilizing-hypnotic potential. Taken together these EEG results corroborate the clinical studies. In man, zopiclone increased SWS, decreased SWS latency and respected sleep architecture in both healthy volunteers and insomniacs. This respect of sleep structure and the relative short duration of action of zopiclone minimized the residual effects seen upon waking (drowsiness, impairment of psychomotor performance). In the Geller-Seifter test, an operant conflict procedure, the minimal effective dose (MED) of suriclone in reversing the conflict-induced inhibition of drinking behavior was 2.5 mg.kg-1 p.o. in rats. Depression of unpunished responding is only seen at higher doses (20 mg.kg-1 p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1996

Development of a stereospecific radioimmunoassay for the analysis of zopiclone and metabolites in urine.

A sensitive and specific radioimmunoassay has been developed, allowing the stereospecific detection of nanogram amounts of (+)- and (-)-enantiomers of zopiclone and its major metabolites in urine, without prior extraction or purification. Antisera were obtained from two series of four rabbits, immunized with optically pure (+)- and (-)-N-hemisuc-cinyldesmethylzopiclone, conjugated to bovine serum albumin according to the active ester method. The assay was stereospecific, allowing discrimination between the two enantiomers of N-desmethylzopiclone with mutual cross-reactivities below 2%. Substantial cross-reaction was observed with the parent compound, although lower than expected, and to a lesser extent with the N-oxide metabolite. A selection of hypnotics, anxiolytics, antidepressants and some other widely used drugs did not interfere with the assay (< 0.1%), when tested at a concentration level of 10 micrograms/ml. The sensitivity of the assay was 50 pg/ml and 10 pg/ml for the (+)- and (-)-enantiomers, respectively. The binding assay described here was used to evaluate the stereoselective excretion pattern of zopiclone. Analysis of cumulative excretion samples from a volunteer revealed a mean metabolic excretion ratio (+)/(-) of 2.2, ranging from 1.7 (7 h) to 4.4 (36 h) A mean excretion ratio (+)/(-) of 2.5 +/- 1 was calculated after analysis of urine samples from 20 patients receiving zopiclone as a hypnotic daily.

Animals↗

PubMed2005

Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review.

The aim of this review is to establish the relationship between treatment with hypnotics and the risk of postural instability and as a consequence, falls and hip fractures, in the elderly. A review of the literature was performed through a search of the MEDLINE, Ingenta and PASCAL databases from 1975 to 2005. We considered as hypnotics only those drugs approved for treating insomnia, i.e. some benzodiazepines and the more recently launched 'Z'-compounds, i.e. zopiclone, zolpidem and zaleplon. Large-scale surveys consistently report increases in the frequency of falls and hip fractures when hypnotics are used in the elderly (2-fold risk). Benzodiazepines are the major class of hypnotics involved in this context; falls and fractures in patients taking Z-compounds are less frequently reported, and in this respect, zolpidem is considered as at risk in only one study. It is important to note, however, that drug adverse effect relationships are difficult to establish with this type of epidemiological data-mining. On the other hand, data obtained in laboratory settings, where confounding factors can be eliminated, prove that benzodiazepines are the most deleterious hypnotics at least in terms of their effects on body sway. Z-compounds are considered safer, probably because of their pharmacokinetic properties as well as their selective pharmacological activities at benzodiazepine-1 (BZ(1)) receptors. The effects of hypnotics on balance, gait and equilibrium are the consequence of differential negative impacts on vigilance and cognitive functions, and are highly dose- and time-dependent. Z-compounds have short half-lives and have less cognitive and residual effects than older medications. Some practical rules need to be followed when prescribing hypnotics in order to prevent falls and hip fractures as much as possible in elderly insomniacs, whether institutionalised or not. These are: (i) establish a clear diagnosis of the sleep disorder; (ii) take into account chronic conditions leading to balance and gait difficulties (motor and cognitive status); (iii) search for concomitant prescription of psychotropics and sedatives; (iv) use half the recommended adult dosage; and (v) declare any adverse effect to pharmacovigilance centres. Comparative pharmacovigilance studies focused on the impact of hypnotics on postural stability are very much needed.

Accidental Falls↗

PubMed1987

Modification of GABA turnover in the striatum and hippocampus of the rat after zopiclone.

The effects of zopiclone, a non-benzodiazepine compound that interacts with benzodiazepine receptors, on GABA turnover rate and GABA content in the rat striatum and hippocampus have been studied. Intraperitoneal administration of zopiclone reduced the GABA turnover rates in both the striatum and hippocampus, as estimated from the rate of GABA accumulation after inhibition of GABA transaminase by aminooxyacetic acid (AOAA). The effect of zopiclone on AOAA-induced accumulation of GABA in the hippocampus and striatum was blocked by the intraperitoneal injection of the benzodiazepine receptor antagonist Ro 15-3505. Furthermore, zopiclone slightly but significantly decreased GABA content in the hippocampus, the decrease being blocked by coadministration of the benzodiazepine receptor antagonist Ro 15-1788. Our results confirm that the GABAergic system plays a role in the mechanism of action of zopiclone.

Aminooxyacetic Acid↗

PubMed1990

Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics.

The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.

Animals↗

PubMed1992

Interactions and comparative effects of zopiclone, diazepam and lorazepam on psychomotor performance and on elimination pharmacokinetics in healthy volunteers.

A randomised, placebo-controlled, double blind single-dose cross-over study was arranged to investigate possible interactions between zopiclone (7.5 mg) and two widely used benzodiazepine (BZD) anxiolytics diazepam (5 mg) and lorazepam (1 mg) during the elimination phase of drugs. Psychomotor performance was tested before and 1, 6, 8, 12 and 24 hr after the drug administration. Simultaneously, blood samples were drawn for determination of plasma drug concentrations. The elimination of each compound was not altered by coadministration of other drugs. As expected, one hour after drug ingestion, psychomotor performance was impaired. The coadministration of drugs increased the effect. During the elimination phase, 6 and 8 hr after the drug intake, only zopiclone and lorazepam in combination slightly impaired performance as compared with the pretreatment levels, but there was no difference as compared with placebo. Adverse events after active treatments were not significantly different from those after placebo. At the recommended dose of 7.5 mg, zopiclone does not alter the elimination pharmacokinetics of the BZD anxiolytics diazepam (5mg) and lorazepam (1 mg), and neither is the elimination of zopiclone affected by these BZDs. Due to the rapid elimination of zopiclone, the increase in sedation seen after concurrent administration with BZDs is of short duration.

Administration, Oral↗

PubMed1985

Pharmacological and clinical studies of cyclopyrrolones: zopiclone and suriclone.

Among the non-benzodiazepine compounds which have been found to interact with the "GABA receptor-BZ receptor-chloride channel complex," the very chemically original cyclopyrrolone family has a special place. This has been demonstrated using selected pharmacological, biochemical and clinical data obtained with two cyclopyrrolones, zopiclone and suriclone, which, in addition to their capacity of displacing BZ from their sites, simultaneously possess the main pharmacological properties of BZ and well established therapeutic activities, as hypnotic and anxiolytic, respectively. However, although cyclopyrrolones recognize BZ receptor sites, their mechanism of action might not exactly fit with that of BZ. Indeed, using tritiated zopiclone and suriclone, it has been shown that they could act on sites distinct from those of BZ or could induce receptor conformational changes different from those induced by BZ.

Aggression↗

PubMed2006

Fast gas chromatography-negative-ion chemical ionization mass spectrometry with microscale volume sample preparation for the determination of benzodiazepines and alpha-hydroxy metabolites, zaleplon and zopiclone in whole blood.

Fast gas chromatography/negative-ion chemical ionization mass spectrometric (GC/NICI-MS) assay combined with rapid and nonlaborious sample preparation is presented for the simultaneous determination of benzodiazepines and alpha-hydroxy metabolites, zaleplon and zopiclone in whole blood. The compounds were extracted from 100 microl of whole blood by simultaneous multitube, microscale liquid-liquid extraction (LLE) and derivatized by N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), without the need for the time-consuming concentration stage. In the analytical separation, various parameters of fast GC/NICI-MS were applied, e.g. the use of hydrogen as a GC carrier gas, a high carrier gas velocity, a small film thickness of the analytical column, fast MS data acquisition, fast temperature ramping, and high initial and final temperatures of GC column. Sensitive identification, screening and quantitation of 18 compounds of interest were achieved in chromatographic separation in only 4.40 min. Accurate and reproducible results were obtained by using five different and carefully selected deuterated analogues on the basis of the chemical properties of the target analytes. Nevertheless, for alpha-OH-midazolam, and for bromazepam and flunitrazepam at low concentrations, the results can be considered only semiquantitative on the basis of the validation data. The extraction efficiencies ranged from 74.3 to 105.7% and the limits of quantitation (LOQ) from 1 to 100 ng ml(-1). Rapid sample preparation and fast chromatographic separation allowed cost-efficient, reliable and high sample-throughput analyses with a low amount of manual work. The method was fully validated and accredited according to EN ISO/IEC 17025 standards and is applicable for sensitive, reliable and quantitative determination of benzodiazepines, zaleplon and zopiclone, e.g. in clinical and forensic toxicology.

Acetamides↗