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PubMed2004

The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents.

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABAA receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABAA receptors containing alpha1 subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha1 subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.

Acetamides↗
PubMed2005

Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor.

Eszopiclone [Lunesta, Estorra] is a short-acting hypnotic agent that is a stereoselective isomer of the agent zopiclone, which has been available in Europe since 1992. Eszopiclone is structurally unrelated to the benzodiazepines, and Sepracor (the originator of eszopiclone) has stated that the drug acts rapidly, with the duration of effect lasting up to 6 hours. This may result in improved sleep maintenance, with less nocturnal awakening.Originally, racemic zopiclone was developed and marketed by Rhone-Poulenc Rorer, which merged with Hoechst Marion Roussel to form Aventis. Sepracor anticipates that eszopiclone will have equivalent efficacy to the racemic version with potential for an improved side effect profile. In October 1999, Sepracor exclusively licensed Aventis Pharma's preclinical, clinical and postmarketing surveillance data package for zopiclone, its isomers and metabolites. The company intends to use this information in addition to data from Sepracor's own studies as part of the regulatory package to gain approval of eszopiclone in the US. In July 2004, Sepracor announced terms of an additional agreement with Aventis under which it would have the right to read and reference Aventis' regulatory filings related to zopiclone outside the US for the purpose of development and regulatory registration of eszopiclone outside the US. Additionally, Aventis would assign Sepracor the foreign counterparts to the US patent covering eszopiclone and its therapeutic use. In August 2004, Paul Royalty Fund II, an affiliate of Paul Capital Partners, purchased from Sanofi-Aventis the royalty rights on US sales of eszopiclone. In exchange for the rights, Sanofi-Aventis will receive fixed and milestone payments totalling up to US$115 million. In December 2004 the US FDA approved eszopiclone (Lunesta) for the treatment of insomnia. It is indicated for patients who experience difficulty falling asleep as well as for patients who have sleep maintenance difficulty, and is approved for long-term treatment. The recommended dosing to improve sleep onset and/or maintenance is 2mg or 3mg for adult patients (aged 18-64 years) and 2mg for older adult patients (aged > or =65 years). The 1mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. The launch of eszopiclone in the US is expected to take place in the first quarter of 2005. The approval follows an NDA submission in January 2003, an approvable letter in February 2004, and a resubmission of the NDA in June 2004. The NDA contained data from 24 clinical trials that included >2700 adult and elderly subjects, as well as data from >60 preclinical studies. Six phase III trials in adult and elderly patients with chronic or transient insomnias were also included in the data submission. Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause. Sepracor has been granted a US patent for eszopiclone [S-zopiclone, (+)-zopiclone, Lunesta, Estorra], a single isomer of zopiclone.US patents (Nos. 6,319,926 and 6,444,673) have been issued covering the use of eszopiclone for the treatment of insomnia, eszopiclone and pharmaceutical compositions comprising eszopiclone.

Anxiety Disorders↗
PubMed1984

Effect of successive administration of zopiclone, a new class of minor tranquillizer, on mouse liver microsomal mono-oxygenase system.

Oral administration of zopiclone to mice (10 mg/kg daily) for 14 days had no significant effect on body weight, liver weight, hepatic microsomal protein or cytochrome P-450 contents but produced significant increases in the activities of NADPH-cytochrome c reductase, NADH-ferricyanide reductase, aniline hydroxylation and aminopyrine N-demethylation.

Aminopyrine N-Demethylase↗
PubMed1991

Zopiclone in the treatment of sleep abnormalities in fibromyalgia.

The clinical and polysomnographical effects of zopiclone were evaluated in 41 patients with fibromyalgia in a double blind controlled study. A significant improvement was observed regarding tiredness during the day and subjective sleep complaints, but no effects on pain or stiffness were observed. The sleep structure remained unchanged during treatment. Zopiclone seems to be of value in treating the sleep complaints in patients with fibromyalgia.

Aged↗
PubMed1996

Hypoglycemia associated with phenytoin intoxication.

BACKGROUND: Diphenylhydantoin, a widely used antiepileptic agent, can alter carbohydrate tolerance, and acute intoxication with diphenylhydantoin can be associated with hyperglycemia. CASE REPORT: We describe a patient who experienced a prolonged episode of hypoglycemia secondary to an acute voluntary intoxication with diphenylhydantoin 20 g and zopiclone 225 mg. This hypoglycemic episode was presumptively attributed to diphenylhydantoin and might be due either to an escape from the inhibitory effects of diphenylhydantoin on insulin secretion or an increased sensitivity of the tissues to insulin. Zopiclone was considered less likely since zopiclone overdoses have been only exceptionally associated with hyperglycemia.

Adult↗
PubMed2006

Practical considerations of new drugs: new choices for old problems.

As drug therapy experts, pharmacists are often called upon for facts and opinions about recently introduced drugs. New drugs are introduced at a rate that exceeds the reading time of many busy practitioners. This article is intended to provide an objective information and broad-based discussion about new drug options that have particular relevance for the elderly. Drugs that will be reviewed include: acamprosate, darifenacin, eszopiclone, exenatide, ibandronate, nitazoxanide, pramlintide, pregabalin, ramelteon, tigecycline, tinidazole, trospium, and solifenacin.

Advertising↗
PubMed1997

Zopiclone versus diazepam effects on EEG power maps in healthy volunteers.

EEG effects of zopiclone (7.5 mg), a cyclopyrrolone derivative with hypnotic action, were compared with effects of diazepam (10 mg). Multichannel EEG recordings, double-blind crossover trials with placebo, and oral single doses were used in healthy volunteers. Vigilance-controlled EEG before and after zopiclone (and placebo), and before and after diazepam (and placebo) were analyzed into FFT power spectra. Effects were assessed as placebo-referred pre-post-medication power differences in four frequency bands. Overall statistics showed significant (P < 0.007) global differences between medication effects in the delta frequency band (0.5-3.5 Hz). After zopiclone, fronto-central delta increased bilaterally, whereas after diazepam delta decreased over centro-parietal to right temporo-occipital regions. These spatially different brain electric effects show that different neuronal populations must have become active in response to zopiclone and diazepam.

Adult↗
PubMed1987

Azinomycins A and B, new antitumor antibiotics. III. Antitumor activity.

Azinomycins A and B, isolated from the culture broth of Streptomyces griseofuscus S 42227, were examined for antitumor activities against P388 leukemia, P815 mastocytoma, B-16 melanoma, Ehrlich carcinoma, Lewis lung carcinoma and Meth A fibrosarcoma. Azinomycin B was markedly effective against the intraperitoneally inoculated tumors such as P388 leukemia, B-16 melanoma and Ehrlich carcinoma. The intraperitoneal administration of azinomycin B showed 57% survivors for 45 days and 193% ILS against P388 leukemia. For Ehrlich carcinoma, azinomycin B gave 161% ILS and 63% survivors for 45 days, but solid tumors such as Lewis lung carcinoma and Meth A fibrosarcoma were not susceptible to repeated injection of this substance. Azinomycin A was somewhat less effective than azinomycin B for the tumor systems tested.

Animals↗
PubMed1999

Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism.

Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.

Azabicyclo Compounds↗
PubMed1999

[Detection of zopiclone in many drivers--a sign of misuse or abuse].

In 1998 zopiclone had a 42% share of the prescribed hypnotic drug market in Norway. The National Institute of Forensic Toxicology analyses all blood samples from suspected drugged drivers. The rise in zopiclone prescription was partly reflected in an increase in the number of drivers with zopiclone detected in the blood. We looked closer at the test results from 101 drivers with zopiclone detected in their blood in the January 1994 to April 1999 period. 60% had blood concentrations of zopiclone above the concentration observed after intake of therapeutic doses; 80% had higher blood concentrations than those expected 8 hours after intake of therapeutic doses. The majority of the drivers also tested positive for illegal drugs, prescription drugs with abuse potential, or alcohol. This indicates that zopiclone is misused or abused. Therefore the same caution should be applied when prescribing zopiclone as is applied when prescribing e.g. benzodiazepines.

Automobile Driving↗
PubMed2000

Zopiclone use during pregnancy.

QUESTION: One of my patients, whom I had treated with a 2-week course of zopiclone for insomnia, conceived while using the medication. She is concerned. How should I advise her? ANSWER: Based on available, albeit limited, evidence, zopiclone does not appear to be a major human teratogen.

Abnormalities, Drug-Induced↗
PubMed2000

The effect of zolpidem and zopiclone on memory.

The effect of 10 mg of zolpidem (ZLP) on memory function was evaluated in healthy male adults using word recall test, passage recall test, and Sternberg's memory scanning task. This study was carried out as a double-blind cross-over study with 7.5 mg of zopiclone (ZPC) and a placebo. No difference was noted between the active drugs and placebo in the number of words recalled from the word list presented before administration. No evidence of retrograde amnesia was suggested. However, encoding ability was slightly affected as indicated by a decrease in the number of words recalled from the list presented after administration. Slight impairment of a delayed recall was noted for both of the active drugs, but the effect disappeared the next morning. In the memory scanning task, ZLP prolonged a non-specific component of reaction time 1.5 h after administration, but the effect disappeared after 12.5 h. ZPC did not prolong the reaction time. The two active drugs showed no specific effects on either memory scanning or response-selection stage in short-term memory at any time. The findings suggest that residual effects did not reach clinical significance at the standard dosage, although the active drugs slightly affected encoding ability and retention soon after administration.

Adult↗