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PubMed1995

Double-blind comparison of zopiclone and flunitrazepam in elderly insomniacs with special focus on residual effects.

In a double-blind study of 102 patients with a mean age of 79 years, zopiclone was compared to flunitrazepam. The patients rated their sleep in a diary. There was no statistically significant difference between the relatively low dose of 5 mg zopiclone and 1 mg flunitrazepam for eleven out of the twelve variables measuring subjective sleep quality and quantity. There was no differences between the drugs as regards patients' feelings of being rested or alertness.

Aged↗
PubMed1997

A comparison of zopiclone and propiomazine as hypnotics in outpatients: a multicentre, double-blind, randomized, parallel-group comparison of zopiclone and propiomazine in insomniacs.

In a double-blind, parallel-group study of 135 patients with a mean age of 60 years, zopiclone 5 mg was compared with propiomazine 25 mg. The patients rated their sleep in a diary. There were statistically significant differences in favour of zopiclone for nine out of 13 variables measuring subjective sleep quality and quantity. Concerning side-effects, bad taste was reported more frequently in the zopiclone group and restless legs in the propiomazine group.

Adult↗
PubMed2004

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia.

OBJECTIVE: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia. RESEARCH DESIGN AND METHODS: Patients (n = 308) were randomized to receive placebo or eszopiclone (2 mg or 3 mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST). RESULTS: Eszopiclone 3 mg had significantly less time to sleep onset (p < or = 0.0001), more total sleep time and sleep efficiency (p < or = 0.0001), better sleep maintenance (p < or = 0.01), and enhanced quality and depth of sleep (p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2 mg had significantly less time to sleep onset (p < or = 0.001), more total sleep time (p < or = 0.01) and sleep efficiency (p < or = 0.001), and enhanced quality and depth of sleep (p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste. CONCLUSIONS: Patients treated with nightly eszopiclone 3 mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.

Administration, Oral↗
PubMed2026

Molecular determinants associated with resistance to imipenem and imipenem-relebactam in clinical Pseudomonas aeruginosa isolates.

BACKGROUND: Pseudomonas aeruginosa accounts for 10-20% of hospital-acquired infections and is a major pathogen in immunocompromised patients. Combination therapies with beta-lactam antibiotics and beta-lactamase inhibitors, such as imipenem-relebactam have improved treatment options, yet resistant strains have already emerged, with mechanisms still not fully elucidated. RESULTS: We sequenced and analyzed 10 clinical P. aeruginosa isolates resistant to imipenem-relebactam (IMI/REL) and compared them with publicly available genomes of imipenem-resistant (IMI-R) and imipenem-susceptible (IMI-S) strains. Resistance genes were identified using the RGI CARD database, while amino acid variations in core-genome proteins were evaluated through Gene Ontology overrepresentation analysis (GO), followed by GWAS. In total, 15,758 ARGs were detected, 25.85% associated with carbapenem resistance, but only 568 classified as beta-lactamases. Among IMI/REL isolates, 36.36% carried Ambler class A and 54.54% class B beta-lactamases, contrasting with much lower frequencies in IMI-R (5.4% and 3.6%) and IMI-S (0% and 0.73%). Core-genome analysis revealed 1,106 proteins with resistance-associated variations. Comparative analyzes identified 1,618 proteins differing between IMI/REL and IMI-R genomes, and 1,015 differing between IMI/REL and all other strains. GWAS highlighted candidate genes with strong statistical associations, including those involved in metal ion transport (e.g., tonB, foxA, phuR, pfeA) and efflux pumps (e.g., czcB), as well as regulators such as mexT and biofilm-related proteins. CONCLUSIONS: These findings suggest that, beyond classical beta-lactamases, resistance may be associated with multifactorial contributions from periplasmic and outer membrane proteins, metal ion homeostasis, efflux regulation, and biofilm-associated pathways. Our results expand current knowledge of P. aeruginosa resistome and highlight novel genomic signatures potentially driving resistance to imipenem-relebactam.

Imipenem↗
PubMed1985

Zopiclone: a non-benzodiazepine hypnotic. Controlled comparison to temazepam in insomnia.

Zopiclone, a non-benzodiazepine hypnotic, was compared with temazepam in the treatment of 36 patients suffering from insomnia; the trial period was two weeks, with cross-over of medications at one week and a randomised order of administration. There were highly significant improvements with both drugs, as compared to the control period in respect of: sleep latency, number of times waking during the night, and quality and duration of sleep. The incidence of side-effects was very low. No significant between-drug differences were found in respect to any of the assessment measures or of the incidence of side-effects.

Adult↗
PubMed2004

Sequential treatment for chronic insomnia: a pilot study.

This article explores the efficacy of sequential treatment involving medication and cognitive behavioral treatment (CBT) for insomnia. In a multiple baseline across-subjects design, 6 participants with primary chronic insomnia received 1 of the following treatment sequences: (a) concurrent combination of medication and CBT for the 10-week treatment duration (Combined); (b) medication for the first 5 weeks, with introduction of CBT at week 4 and medication withdrawal after the 5th week resulting in treatment overlap during weeks 4 and 5 (Overlapping: Medication --> Combined --> CBT); and (c) medication alone for the first 5 weeks followed by CBT alone for an additional 5 weeks (Medication --> CBT). Each sequence led to significant sleep improvements, but these improvements occurred at different times during the intervention. Participants in the Combined and in the Overlapping sequences improved their sleep during the 1st phase of treatment, whereas those in the Medication --> CBT sequence improved mostly during the 2nd phase of treatment. These preliminary results suggest that a sequential treatment is effective for chronic insomnia. In addition, the results suggest that sleep improvements are more likely to emerge when CBT is introduced, with an Overlapping sequence showing a slight advantage over the other sequences. Additional clinical trials should be conducted with larger samples to replicate these preliminary findings.

Adult↗
PubMed2002

Stereoselective distribution and stereoconversion of zopiclone enantiomers in plasma and brain tissues in rats.

Concentrations of (-)-zopiclone and (+)-zopiclone were determined in plasma and brain after oral administration, to investigate the stereoselectivity of distribution in rats. Zopiclone enantiomers were administered separately to rats and concentrations were determined by chiral HPLC in plasma and brain. In initial experiments, rats were treated with urethane before cannulation for blood sampling but as this drug modified zopiclone pharmacokinetics, it was not used in subsequent studies. This study showed that zopiclone pharmacokinetics after oral gavage in rats are stereoselective. After oral administration of (+)-zopiclone, no stereoconversion was observed in plasma. Conversely, after administration of (-)-zopiclone, both enantiomers were found in plasma and brain with (+)-zopiclone/(-)-zopiclone ratios of 1 and 8.4 in plasma and brain, respectively. Our findings suggest that zopiclone undergoes stereoconversion and that it is stereospecifically distributed to the brain.

Administration, Oral↗
PubMed1983

Effects of zopiclone and benzodiazepines on spinal reflexes, anemic decerebrate rigidity and benzodiazepine binding.

Whether or not zopiclone, a new sleep-inducing drug, exerted a similar effect to that of benzodiazepines was examined. The drug inhibited crossed extensor reflexes in chicks and augmented the dorsal root-dorsal root reflexes in rats without affecting the mono- and polysynaptic reflexes. The site of its action was considered to be located in the spinal cord since the effect on the dorsal root reflex was observed also in the spinal rats. Zopiclone selectively reduced the phasic responses of anemic decerebrate rigidity like benzodiazepines in rats. Despite the structural difference from the benzodiazepines, zopiclone dose-dependently inhibited [3H]flunitrazepam binding in rat brain membranes, although the potency was weaker. These results suggested that zopiclone exerts CNS actions via benzodiazepine receptors.

Animals↗
PubMed1987

Behavioral and electroencephalographic effects of zopiclone, a cyclopyrrolone derivative.

Behavioral effects of zopiclone were investigated in mice and rats and compared with the data on diazepam, nitrazepam and flurazepam. The electroencephalographic effect of the drug was also examined in unanesthetized rabbits with chronic electrode implants and compared with that of diazepam. The present results indicate that zopiclone possesses pharmacological properties qualitatively similar to benzodiazepines, which are characterized by potent anticonflict and antiaggressive effects and much weaker anticonvulsant, muscle relaxant, ataxiogenic, sedative and anesthesia potentiating effects; the properties of this drug were compared with those of diazepam, nitrazepam and flurazepam. Zopiclone suppressed the EEG arousal responses and inhibited afterdischarges induced by electrical stimulation of the hippocampus and amygdala. The effects of zopiclone on EEG and afterdischarges were approximately 1/10 those of diazepam.

5-Hydroxytryptophan↗
PubMed1988

The effect of agonists at the GABA-benzodiazepine-receptor-complex on the proconflict effect induced by beta-CCM and pentetrazol in rats.

The effect of anxiolytics, benzodiazepine (BZP), diazepam (DZP), non-BZP zopiclone (ZOP) and phenobarbital (PBT), on the proconflict effect induced by methyl-beta-carboline-3-carboxylate (beta-CCM) or by pentetrazol (PTZ) was investigated. The proconflict effect of beta-CCM and PTZ was reduced by these anxiolytics and aminooxyacetic acid (AOAA). In addition, isoniazid produced proconflict activity. Therefore, it is suggested that anxiolytics facilitate the GABA-ergic function, causing the inhibition of the proconflict effect. Although both propyl-beta-carboline-3-carboxylate (beta-CCP) and Ro15-1788 did not produce proconflict activity, they reduced the proconflict effect induced by beta-CCM but not by PTZ. These data clearly show that beta-CCM exerts the proconflict effect through interaction with BZP receptor and that there are behavioral similarities between beta-CCP and Ro15-1788. In this study, we additionally observed the time latency until the rat began to drink the water. beta-CCM and PTZ prolonged this latency in a dose-dependent manner. However, AOAA could not reduce the prolonged latency induced by beta-CCM and by PTZ, and anxiolytics and beta-CCP could not reduce the prolonged latency induced by beta-CCM. The mechanism of the prolongation of latency induced by beta-CCM and PTZ seems to be different from that of the proconflict effect.

Aminooxyacetic Acid↗
PubMed1989

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat.

Zopiclone is a new cyclopyrrolone derivative which exerts pharmacological activities similar to those of benzodiazepines in behavioral and biochemical studies. In order to clarify the discriminative stimulus properties of zopiclone, 8 rats were trained to discriminate the interoceptive stimulus induced by zopiclone (3.2 mg/kg, i.p.) from those of saline. Following discrimination acquisition, administration of zopiclone resulted in drug-appropriate responding with an ED50 of 1.3 (1.0-1.8) mg/kg. The zopiclone discriminative stimulus generalized to the benzodiazepines diazepam (1.8 mg/kg), nitrazepam (10 mg/kg) and alprazolam (10 mg/kg). A non-benzodiazepine, suriclone, at 3.2 mg/kg, generalized to the zopiclone stimulus in 5 out of 7 rats, but meprobamate, hydroxyzine, tracazolate and muscimol did not. The benzodiazepine antagonist Ro 15-1788 (1 mg/kg) completely blocked zopiclone stimulus. In contrast, however, bicuculline and pentetrazol failed to antagonize it. The serotonin antagonist cinanserin and ritanserin neither generalized to the zopiclone stimulus nor did they exhibit antagonism. These results suggest that the zopiclone discriminative stimulus is mediated by binding to benzodiazepine receptors and appears not to be related to GABAergic or serotonergic system.

Animals↗
PubMed1989

A key role of the mammillary body in mediation of the antianxiety action of zopiclone, a cyclopyrrolone derivative.

The present study was designed to elucidate the brain site of the anticonflict action of zopiclone (ZOP), a cyclopyrrolone derivative, using the rat conflict procedure. ZOP at 10 micrograms/microliters, bilaterally injected into the mammillary body (MB), produced a significant increase in the punished responses, with no change in the unpunished responses. There were no significant changes in these responses when ZOP was injected into the central amygdala, frontal cortex or dorsal hippocampus. Attention should be given to the possibility that the MB is the site of the anticonflict action of ZOP.

Animals↗
PubMed2003

Effect of zaleplon, a non-benzodiazepine hypnotic, on melatonin secretion in rabbits.

Melatonin, a major hormone secreted by the pineal gland, is known to play an important role in regulation of the circadian rhythm. (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon) is a non-benzodiazepine hypnotic that acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effect of zaleplon on melatonin secretion in rabbits using RIA and compared the effect to triazolam and zopiclone. Zaleplon increased a dose-dependent concentration of melatonin in rabbit plasma collected at 30 min after intravenous administration at doses of 1 and 2 mg/kg. The zaleplon-induced increase in plasma melatonin level was not blocked by flumazenil, a benzodiazepine-receptor antagonist. In contrast, triazolam and zopiclone failed to affect the plasma melatonin level. We also investigated the effect of zaleplon on intracellular cAMP in rat pinealocytes. Consequently, zaleplon had no effect on the intracellular cAMP levels in rat pinealocytes. These results of the present studies suggest that zaleplon may promote melatonin secretion and the elevation of plasma levels of melatonin may suggest an influence of zaleplon on chronobiology.

Acetamides↗
PubMed1998

Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia.

OBJECTIVE: To review the epidemiology, etiology, and classification of insomnia and provide an overview of the pharmacologic therapy of insomnia. Novel nonbenzodiazepine hypnotics including zolpidem, zopiclone, and zaleplon, as well as nonprescription products such as valerian and melatonin, are reviewed in detail. DATA SOURCES: A MEDLINE search was performed to identify relevant clinical studies, case reports, abstracts, and review articles published between April 1992 and December 1997. Key search terms included insomnia, benzodiazepines, zolpidem, zopiclone, zaleplon, Cl 284,846, melatonin, and valerian. Additional references were obtained from the lists of review articles and textbooks. DATA EXTRACTION AND SYNTHESIS: Data concerning the safety and efficacy of the hypnotic agents were extracted from all available clinical trials and abstracts. Background information regarding insomnia, benzodiazepines, and other hypnotics was extracted from the most current literature, including review articles and textbooks. CONCLUSIONS: New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. Over-the-counter agents such as valerian and melatonin may be useful in alleviating mild, short-term insomnia, but further clinical trials are required to fully evaluate their safety and efficacy.

Acetamides↗