Disease relevance of zopiclone

• Zopiclone is the first of the cyclopyrrolones, a new class of psychotherapeutic agents possessing a pharmacological profile of high efficacy and low toxicity similar to that of the benzodiazepines [1].
• Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency [2].
• On the basis of these findings, a reduction of the initial zopiclone dose from 7.5 to 3.5 mg/day is recommended for patients with severe liver insufficiency and patients over 70 years of age with liver insufficiency [2].
• None of the doses of zopiclone (ZPC) influenced uterine and adrenal weights or body weight, but it increased ovarian weight at 10 mg/kg [3].
• Long-term administration of zopiclone in 6 patients with severe chronic obstructive respiratory insufficiency with stable ventilatory function did not demonstrate any depressant action on respiratory blood gases recorded during the daytime and in ambient air [4].

Psychiatry related information on zopiclone

• Although the available data on rebound insomnia and dependence liability are encouraging, potential differences between zopiclone and the benzodiazepines in these respects may have little clinical relevance in the context of short term intermittent use of hypnotics, as it currently recommended [5].
• STUDY OBJECTIVES: To compare residual effects of zaleplon 10 mg, zopiclone 7.5 mg, and placebo, and a social dose of alcohol on car driving, memory, and psychomotor performance [6].
• Two performance tests (eye-hand coordination test and choice reaction time test) showed a highly significant impairment (p less than 0.01) at 0000 h with 7.5 mg zopiclone; one test (eye-hand coordination test) showed a significant impairment (p less than 0.05) at 0800 h also with 7.5 mg zopiclone and none at 1200 h [7].
• INTERVENTIONS: Participants received either a manualized treatment package based on cognitive-behavior therapy and sleep management or hypnotic-drug treatment (7.5 mg zopiclone) for 6 weeks (these findings are reported elsewhere) [8].
• NREM sleep stages 3 and 4 increased significantly after 3.75 mg and 7.5 mg zopiclone (p less than 0.05) [7].

High impact information on zopiclone

• Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study [9].
• After photoaffinity labeling with flunitrazepam, receptors in rat cerebellar membranes showed differentially reduced affinity for flunitrazepam and zopiclone by 50- and 3-fold, respectively [10].
• Rifampin (INN, rifampicin) is a potent inducer of many cytochrome P450 enzymes, and it greatly reduces the plasma concentrations and effects of, for example, midazolam, triazolam, and zopiclone [11].
• With the beta 2 gamma 2 subtype, the type 1 ligands zolpidem, alpidem, and Cl-218872 showed no or very low levels of potentiation, whereas less selective ligands such as diazepam, zopiclone, U-78098, and U-90167 displayed levels of Cl- current potentiation comparable to those observed with the subtypes containing the alpha 1 and gamma 2 subunits [12].
• Their geometries, as obtained by X-ray crystallography, are discussed and missing crystal and molecular structures of two of them (zopiclone and CL 218-872) are reported [13].

Chemical compound and disease context of zopiclone

• Zolpidem and zopiclone, hypnotics of third generation, decrease paradoxical sleep but the intermediate stage never substitutes for paradoxical sleep [14].
• On each of the 3 study nights a sleep EEG was registered from 10 p.m. to 6.30 a.m. and cognitive performance tests were applied at 8 p.m., 2 a.m. (when subjects were awake for 30 min), 7 a.m. and 9 a.m. RESULTS: After zopiclone treatment, sleep continuity had significantly improved and sleep stage 4 was increased compared to temazepam and placebo [15].
• The cognitive function and psychomotor performance of 10 healthy male volunteers were measured following single oral doses of: zopiclone (7.5 mg), flurazepam (15 mg), lormetazepam (1 mg), triazolam (0.25 mg) and placebo [16].
• Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone [17].
• While there was no noticeable difference in the Choice Reaction Time (CRT) for any of the drug-ethanol combinations and ethanol alone, the zopiclone combination appeared to be initially more sedative in the Critical Flicker Fusion test (CFF) [18].

Biological context of zopiclone

• 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 [19].
• Clinical pharmacokinetics of zopiclone [20].
• The subjective response to the prescription drug zopiclone, an hypnotic agent belonging to the cyclopyrrolone family, was assessed under the usual conditions of prescription of an hypnotic in general practice [21].
• Further, suriclone binding sites are recognized by BZDs or zopiclone, similarly in the two regions [22].
• After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80% [20].

Anatomical context of zopiclone

• Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk [20].
• The anticonflict effects of diazepam and zopiclone injected into the amygdala were completely reversed by Ro15-1788 and beta-CCM but not by bicuculline, while the anticonflict effect of phenobarbital was reversed by beta-CCM but not by Ro15-1788 or bicuculline [23].
• Modification of GABA turnover in the striatum and hippocampus of the rat after zopiclone [24].
• Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease [25].
• 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) [26].

Associations of zopiclone with other chemical compounds

• The effects of equipotent, single intravenous doses of zopiclone (7.5 mg) and diazepam (10 mg) on ventilatory responses in healthy volunteers (aged 40 to 60 years) were investigated in a randomized, double-blind cross-over study [27].
• Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors [28].
• Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone [29].
• 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 [30].
• Together with results from earlier studies, subsequent clinical trials have shown that zopiclone is generally at least as effective as the benzodiazepines (regardless of duration of action) in the treatment of insomnia, although comparisons between zopiclone and flurazepam have produced inconsistent results [5].

Gene context of zopiclone

• Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism [26].
• Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4 [26].
• CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation [26].
• Triazolam-treated patients presented significantly more day-time-interdose anxiety than zopiclone as assessed by the weekly HARS and Clinical Global Assessment of Anxiety. Although daytime-interdose anxiety was observed with both drugs, this treatment emergent symptom was more frequent and severe with triazolam [31].
• OBJECTIVE: Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro [32].

Analytical, diagnostic and therapeutic context of zopiclone

• A double-blind, randomized, cross-over study has been conducted with zopiclone (Imovane), a new cyclopyrrolone hypnotic in ten healthy volunteers [33].
• Dynamics of slow-wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone [34].
• For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available [20].
• Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantitation of zopiclone and its 2 main metabolites in biological samples [20].
• The agreement between both strategies, visual and computer analysis, was tested using data from a pharmacological sleep study with 16 elderly insomniacs, which was aimed at comparing the effects of lormetazepam and zopiclone on polysomnography [35].

References