[Zopiclone (imovane)--a new sedative agent].
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Azabicyclo Compounds↗
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Discriminative-stimulus effects of midazolam in squirrel monkeys: comparison with other drugs and antagonism by Ro 15-1788.
Squirrel monkeys were trained to respond on one of two levers depending on whether midazolam (0.3 mg/kg) or saline had been injected. After i.v. injections of midazolam 10 consecutive responses on one lever either produced food or terminated a stimulus associated with electric shock, whereas after i.v. injections of saline 10 consecutive responses on the other lever either produced food or terminated the stimulus. The discriminative-stimulus effects of drugs were determined by administering cumulative doses i.v. during timeout periods that preceded sequential components of the experimental session. The benzodiazepines midazolam, chlordiazepoxide, diazepam and N-desmethyldiazepam, the cyclopyrrolone zopiclone and the triazolopyridazine CL 218,872 had qualitatively similar stimulus effects regardless of the type of consequence (food presentation or stimulus-shock termination) that maintained responding. Administration of each of these drugs resulted in greater than 90% of responses on the midazolam-associated lever at cumulative doses that did not severely suppress the overall rate of responding. The order of potency was: midazolam = diazepam greater than or equal to N-desmethyldiazepam greater than or equal to zopiclone greater than CL 218,872 greater than or equal to chlordiazepoxide. Administration of the 5-hydroxytryptamine antagonists cyproheptadine and cinanserin also resulted in greater than 90% of responses on the midazolam-associated lever in about half the subjects, although these effects were observed only with cumulative doses that markedly reduced the overall rate of responding. Administration of pentobarbital, barbital, clozapine, muscimol, buspirone, diphenhydramine, tripelennamine, caffeine and Ro 15-1788 did not result in substantial responding on the midazolam-associated lever at doses up to those that reduced or eliminated responding.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Comparison of the effects of zopiclone and triazolam on the sleep of normal subjects].
Zopiclone 7.5 mg and triazolam 0.50 mg have been compared in a double-blind randomized cross-over sleep laboratory study. After a 6-day placebo, 12 healthy male volunteers aged 20-35 years received 2 active treatment sequences of 6 days separated by a 8-day placebo period and followed by a withdrawal period with placebo for 8 days. 22 polygraphic sleep recordings have been performed. The duration of nocturnal awakenings decreases at the beginning of treatment. Sleep onset latency is significantly decreased as well as the number of awakenings during sleep at the end of treatment. Both drugs improve the sleep efficiency index. Zopiclone increases total sleep time at the beginning and at the end of treatment. Triazolam increases this parameter at the end of the study only. Zopiclone, unlike triazolam increases the duration of deep NREM sleep-stages 3 and 4--at the beginning of treatment. No significant changes in sleep parameters were seen with zopiclone nor triazolam at the end of treatment. In sleep questionnaires, sleep onset latency is shorter under zopiclone than under triazolam and daytime drowsiness is less frequent with zopiclone.
Adult↗
Behavioral effects of the pyrazoloquinoline CGS 9896: agonist and antagonist actions in squirrel monkeys.
The behavioral effects of 2-p-chlorophenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9896) were compared with those of lorazepam and zopiclone in squirrel monkeys. Two groups of monkeys were trained to respond under a fixed-interval schedule of food presentation. In one group, responding was suppressed (punished) by superimposing a fixed-ratio schedule of response-produced shock. Dose-effect curves were determined for all three drugs by administering cumulative doses i.v. during timeout periods that preceded sequential components of the fixed-interval schedule. Low and intermediate doses of CGS 9896 (0.03-3.0 mg/kg), lorazepam (0.03-0.3 mg/kg) or zopiclone (0.1-1.0 mg/kg) produced dose-related increases in the rates of both suppressed and nonsuppressed responding. The maximal increases in response rates produced by CGS 9896 were usually less than those produced by either lorazepam or zopiclone. Pretreatment with the benzodiazepine antagonist Ro 15-1788 antagonized the increases in suppressed and nonsuppressed response rates produced normally by intermediate doses of CGS 9896, lorazepam or zopiclone, suggesting that the rate-increasing effects of the three drugs are mediated similarly. CGS 9896 was studied additionally for antagonist activity by administering selected doses before lorazepam or zopiclone. Pretreatment with a high dose of CGS 9896 (5.0 mg/kg) antagonized the rate-increasing effects of both lorazepam and zopiclone, suggesting that CGS 9896 has antagonist effects in addition to its agonist effects at benzodiazepine recognition sites.
Animals↗
Residual effects of zopiclone (Imovane).
A double-blind, randomized, cross-over study has been conducted with zopiclone (Imovane), a new cyclopyrrolone hypnotic in ten healthy volunteers. Hypnotic efficacy has previously been demonstrated at a dose of 7.5 mg. The present study was designed to determine the overnight residual effects of different doses of the drug ranging from 2.5 to 10 mg. Measurement of complex reaction time was used as an objective test of impairment of psychomotor function. To supplement this, the volunteers were asked to report, by means of visual analogue scales, any perceived changes in their performance in the complex reaction time test, in their mood, and in the onset and quality of sleep. Complex reaction time testing revealed no significant impairment except at 12 h after the 10 mg dose. Subjective assessments of onset of sleep showed a dose-dependent shortening of sleep latency, confirming the hypnotic action of the drug. Volunteers were aware of a decline in psychomotor performance, of some sleepiness on awakening, and decreased alertness after previous night doses of 7.5 and 10 mg. It is concluded that a dose of 7.5 mg is optimal, producing significant hypnotic effect with minimal residual impairment.
Adult↗
Chronic administration of zopiclone and nitrazepam in the treatment of insomnia.
The hypnotic effects of 7.5 mg zopiclone, as well as its unwanted and residual effects, were compared with those of 5 mg nitrazepam in a double-blind, randomized, multicenter, parallel group study. After an initial, 7-day, placebo wash-out period, insomniac out-patients under the care of general practitioners received either 7.5 mg zopiclone or 5 mg nitrazepam for 6 weeks. Everyday, the patients filled in a diary (analogue scales for sleep parameters and condition during daytime); a sleep questionnaire was filled in at baseline and at the end of active treatment period; every 2 weeks, a somatic complaint check-list inventory and a mood rating scale were filled in and psychomotor tests performed; and at the end of the study, a global evaluation of efficacy and acceptability was given by the investigator. Clinical laboratory tests were performed before and after the active treatment period. From the diary, sleep onset latency, as well as sleep quality, were similarly improved by both drugs throughout the whole study. From the sleep questionnaire, all sleep parameters measured were improved at the end of the 6-week treatment period in both groups. No statistical differences in the various psychomotor tests were observed between the two treatment groups, and a significant improvement in the working ability of patients was noted with both drugs. Some significant differences were observed in the mood rating scale and the somatic complaint check list, probably related to differences in pharmacokinetics of the two drugs.
Adolescent↗
Zopiclone and sleep research.
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Azabicyclo Compounds↗
Comparison of zopiclone pharmacokinetics in patients with impaired renal function and normal subjects. Effect of hemodialysis.
Maximal blood concentration (Cmax), time to concentration peak (Tmax), area under the serum concentration-time curve (AUC infinity) and half-life (t1/2) after the oral administration of zopiclone 7.5 mg were compared in patients with severe renal failure (group I), with moderate renal insufficiency (group II), and in healthy volunteers (group III) over a 72-h period. Cmax did not differ from one group to the other but Tmax was significantly longer in group II. Half-lives were longer in renal patients than in healthy volunteers and AUC infinity s tended to increase with the degree of renal failure. Hemodialysis of the severely ill renal patients did not increase the plasma clearance of zopiclone. Finally, only small amounts of drug were found in urine in the three groups. Overall, results allow the conclusion that zopiclone may be safely used in patients with various degrees of renal impairment.
Adult↗
Pharmacodynamic effects of the sleep inducer zopiclone.
Pharmacodynamic effects of [6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin -5- yl]-4-methyl-1-piperazine-carboxylate (zopiclone, RP-27267), chemically unrelated to benzodiazepines and a potential new sleep inducer, on the peripheral system were investigated in several species of animals. The drug was dissolved in the vehicle of 0.01 mol/l HCl solution for intravenous administration or for addition to the bath medium and was suspended in 0.25% carboxymethylcellulose solution for oral administration. In unanesthetized rabbits, zopiclone, 0.5 mg/kg i.v., exerted no action and at 1 mg/kg slightly decreased respiration and heart rate without affecting blood pressure and ECG. Zopiclone at 10(-6) g/ml had no action in the isolated guinea-pig atria but at 10(-5) g/ml it produced a gradual and slight decrease in heart rate without affecting the contraction. In the isolated small intestine of rabbits and guinea-pigs, zopiclone at 10(-6) g/ml had no action but produced a slight inhibition in a dose of 10(-5) g/ml. Zopiclone, 10(-5) g/ml, did not affect the stimulatory effects of acetylcholine, serotonin, histamine and barium in the isolated guinea-pig intestine. Zopiclone, 1, 5 and 10 mg/kg i.v., exerted no action on rabbit intestinal movement in vivo. Zopiclone, 5, 10, 20 and 50 mg/kg p.o., had no effect on the propulsive motility of the mouse intestine. Zopiclone, 10(-5) g/ml, did not affect contractile movement of the uterus isolated from rabbits and did not influence the contractile response to epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Zopiclone: a new nonbenzodiazepine hypnotic used in general practice.
Ninety-one insomniacs completed a four-week study of the efficacy and safety of zopiclone (Z), 7.5 mg. Patients were randomly allocated to one of two groups, each of which received placebo (P) during one week of the study. Forty-six subjects received medication in the sequence of ZPZZ, and 45 received it in the sequence of ZZPZ. Twice each week, patients filled out presleep and postsleep questionnaires and reported their morning complaints. Compared with placebo, zopiclone produced statistically significant improvements (P less than 0.05) in sleep induction time, duration of sleep, number of awakenings per night, quality and soundness of sleep, morning state of rest, and daytime sleepiness. Headache, dizziness, nausea, and bitter taste were the predominant complaints. Zopiclone can be considered an efficient and safe hypnotic for chronic insomnia.
Adult↗
[Effect of hypnotics on daytime function].
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Adult↗
Influence of zopiclone on male reproductivity in rats.
The influence of zopiclone, a non-benzodiazepine hypnotic, on male reproductivity and the recovery of the influences were examined in rats since it was found that oral administration of zopiclone to male rats produced sperm death and infertility at doses of 50 mg/kg or more. In the present study, zopiclone was administered orally by gavage at doses of 50 and 250 mg/kg once daily for 6 weeks to male rats of 8 weeks old. The rats were paired with untreated female rats at the end of the 2nd, 4th, and 6th weeks of administration and of the 2nd, 4th, and 6th weeks after termination of the administration. As the results, the copulation rates were 100% in the 50 mg/kg group, but the rate was low in the 250 mg/kg group at the end of the 2nd week of administration. The pregnancy rates of 0% and low motility and morphological abnormalities of the sperm were observed in the zopiclone-treated groups at the end of the 2nd week of administration. In the histological examination of the male reproductive organs, such changes as arrest of spermatogenesis and dilation of the epididymal ducts filled with the sperm were observed in the 250 mg/kg group at the end of the 2nd week of administration. In the recovery observation, the ability to impregnate female rats and the condition of the sperm recovered in the 50 mg/kg group at the end of the 2nd week of recovery. In the most rats of the 250 mg/kg group the ability to impregnate female rats and the condition of the sperm recovered at the end of the 4th and 6th weeks of recovery. However, in some rats of the 250 mg/kg group the ability to impregnate female rats and the condition of the sperm were still not recovered at the end of the 6th week of recovery.
Animals↗
Zopiclone in the treatment of insomniacs of family practice.
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Adolescent↗
A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane).
Eleven volunteers were dosed once daily for 14 days with zopiclone (7.5 mg/day). The peak plasma zopiclone concentration (65 ng/ml) occurred at 1.4 h after dosing and thereafter declined by a biexponential process, with half-lives of 2.0 and 6.5 h, to 3 ng/ml by 24 h after dosing. Repeated once daily dosing did not markedly alter the peak plasma zopiclone concentration or the pharmacokinetic parameters of absorption or elimination.
Adult↗
Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepine receptors.
The interactions of zopiclone and suriclone, representatives of nonbenzodiazepine cyclopyrrolone anxiolytics, with central-type benzodiazepine receptors have been characterized in rat and bovine brain. While zopiclone potently (IC50 approximately 50 nM) inhibits [3H]Ro-15-1788 binding in an apparent mass action fashion, suriclone and its metabolite 35,489 RP are extremely potent (IC50 approximately 350 pM and 1 nM, respectively) and display Hill coefficients of approximately 2.0. Like classical benzodiazepines, none of the cyclopyrrolones studied display selectivity for type I or type II benzodiazepine receptors. Using [3H]suriclone, saturable high affinity sites for cyclopyrrolone anxiolytics were directly labeled in rat and bovine brain. The regional distribution and pharmacologic specificity of [3H]suriclone and [3H]Ro-15-1788 binding sites are similar, suggesting that [3H]suriclone recognition sites reside on the benzodiazepine receptor complex. Unlike classical benzodiazepine agonists, such as diazepam, the binding of [3H]suriclone is not modulated by GABA, Cl-, pentobartibal, or tracazolate. Unlike those of [3H]diazepam, [3H]suriclone-binding sites are only minimally affected by photoaffinity labeling with flunitrazepam. Whereas the binding affinities of [3H]Ro-15-1788, [3H]flunitrazepam, and [3H]ethyl beta-carboline 3-carboxylate increase at lower temperatures, [3H]suriclone binds with higher affinity at higher temperatures. Scatchard analysis of [3H]flunitrazepam, [3H]ethyl beta-carboline 3-carboxylate, and [3H]Ro-15-1788 binding in the presence of all cyclopyrrolones studied reveals an apparent noncompetitive pattern of inhibition of binding in each case; by contrast, inhibition of [3H]suriclone binding by Ro-15-1788 flunitrazepam, methyl beta-carboline 3-carboxylate and all of the cyclopyrrolones studied appears competitive. The dissociation kinetics of [3H]Ro-15-1788 indicate that cyclopyrrolones, but not benzodiazepines, increase the dissociation rate of [3H]Ro-15-1788 from its membrane receptors; the converse is true for [3H]suriclone dissociation kinetics. The association kinetics of [3H]suriclone suggest that suriclone induces a conformational change upon binding to receptors. Taken together, these results indicate that [3H]suriclone labels a site on the benzodiazepine receptor complex allosteric to the recognition site for benzodiazepines. A model is proposed to describe the interaction between benzodiazepines and cyclopyrrolones.
Allosteric Regulation↗
Comparison of the reinforcing properties of zopiclone and triazolam in former alcoholics.
The reinforcing properties of zopiclone (3.75 mg) and triazolam (0.25 mg) and their side effects were studied in a double-blind crossover design, followed by forced choice in 40 volunteers taken from a population of chronic alcoholic inpatients who had just completed withdrawal from alcohol. After initial interview when the physician checked if the inclusion and exclusion criteria were met, patients were submitted to the following assessments: profile of mood states (POMS), ARCI subscales (items of scales No. 452, 129, 125, and 52), drug record form and vital signs, SESI (side effect checklist), preference form, subjective effect scale (subscale 220 of the ARCI), and withdrawal assessment. No difference between the drugs could be found on the POMS, ARCI or in the drug intake. There was a difference in patients' drug preference for triazolam in comparison to zopiclone. Zopiclone, like triazolam, may induce some feelings similar to those obtained with alcohol. Side effects noticed by patients were of mild to moderate degree and harmless.
Adult↗
Pharmacological studies on zopiclone.
Zopiclone (RP 27 267) is an hypnotic with a chemical structure different from that of the benzodiazepines (BZD) or barbiturates. Studies of zopiclone in classical psycho-pharmacological tests, in comparison with BZD and barbiturates, have shown that it exhibits the five main types of activity considered as characteristic of the pharmacological profile of BZD and partly of that of barbiturates (anticonvulsant, myorelaxant, antiaggressive, sedative-hypnotic and 'anticonflict'). However, like BZD, zopiclone differs from barbiturates by a high safety margin. Electrophysiological studies performed in cats have shown that zopiclone induces modifications in sleep-wakefulness pattern which are close to those observed with BZD, specially with nitrazepam. Moreover, zopiclone increases the threshold for arousal by reticular formation stimulation, rather more than nitrazepam, but with a shorter duration of action. The short duration of action of zopiclone has been demonstrated in other species using different tests.
Aggression↗
Brain receptors and zopiclone.
Zopiclone (ZPC; RP 27,267), which is chemically unrelated to benzodiazepines (BZD), was found to have a similar pharmacological profile and to possess in man hypnotic activity similar to that of some BZD such as nitrazepam. It was, therefore, interesting to study the interaction of ZPC with rat brain receptors and specially with the so-called 'BZD receptors'. ZPC possesses in three rat brain regions a high affinity for BZD receptors: its Ki values measured against [3H]-flunitrazepam are 24 nM in the cerebral cortex, 31 nM in the cerebellum, and 36 nM in the hippocampus. No other brain receptors such as gamma-aminobutyric acid receptor, dopamine receptor, serotonin and noradrenergic receptors are reached by ZPC. Moreover, ZPC seems to bind only to brain BZD receptors and, contrarily to some BZD such as flunitrazepam, it does not reach the peripheral renal BZD-binding sites. The synthesis of [3H]-ZPC has permitted a more in-depth study of the interaction of ZPC with brain receptors. The high affinity of ZPC has been confirmed by equilibrium-binding studies (KD = 13 +/- 4 nM in rat hippocampus) and the study of the modulating effect of gamma-aminobutyric acid and barbiturates on ZPC binding has revealed some differences between ZPC and BZD. It could, therefore, be postulated that ZPC might bind in rat brain to sites which do not correspond exactly to BZD sites.
Animals↗