Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic

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. Binding is thought to occur to the benzodiazepine receptor complex, or to a site closely linked to this complex. Although zopiclone exhibits anticonvulsant, muscle relaxant and anxiolytic properties in animals, it finds better use as an hypnotic because of marked sedating effects. In clinical trials, zopiclone (usually 7.5 mg) improved sleep in chronic insomniacs similarly to nitrazepam 5 mg, flurazepam 15 to 30 mg, triazolam 0.5 mg and temazepam 20 mg, but in a single study was slightly less effective than flunitrazepam 2 mg in some evaluation criteria. Sleep induction before surgical procedures in hospitalised patients is satisfactory with zopiclone, but when the drugs are administered a few hours before surgery, diazepam appears to be more effective in alleviating preoperative anxiety. Minimal impairment of psychomotor skills and mental acuity occurs in the morning after a bedtime dose of zopiclone, which has a short half-life of about 5 hours and no long acting metabolites. No serious side effects have been reported in the relatively small number of patients studied to date; the development of 'bitter taste' does not deter patients from continuing therapy. Thus, with its short duration of action zopiclone is a useful alternative to other hypnotics, especially in patients intolerant of residual effects the morning after taking an hypnotic.     

Synthesis of Sedative-hypnotic Zopiclone Analogues

本文根据环吡咯酮类催眠药佐匹克隆的构效关系及作用机制，合成了八个未见文献报道的环吡咯酮类新化合物，并进行了初步的药效研究。     

新型催眠镇静药佐匹克隆类似物的合成

本文根据环吡咯酮类催眠药佐匹克隆的构效关系及作用机制，合成了八个未见文献报道的环吡咯酮类化合物，并进行了初步的药效研究。     

Comparison of the clinical hypnotic effects of Zopiclone and Triazolam

Summary In a double blind crossover therapeutic trial the hypnotic effect of Zopiclone 7.5 mg and Triazolam 0.5 mg given orally at bedtime for 7 consecutive days have been compared. 5 of the items in Spiegel's questionnaire and 12 of the 18 items in Norris' visual analogue scale were significantly more improved by Zopiclone than by Triazolam. Both drugs caused few side-effects.     

Comparative neurologic effects of diazepam and suriclone, a cyclopyrrolone anxiolytic

Suriclone selectively displaces benzodiazepines from their binding sites but is structurally unrelated to benzodiazepines. Neurologic effects of suriclone were compared to those of diazepam in 54 subjects in a sequential, double-blind, single dose, randomized study (placebo; diazepam 10 mg; suriclone 0.2, 0.4, 0.6, or 0.8 mg). Data were collected on-line by microcomputer. Suriclone 0.2 mg did not differ from placebo. Suriclone 0.4 mg and 0.6 mg did not differ from diazepam 10 mg. Suriclone 0.8 mg caused significantly more decrement than diazepam 10 mg (p less than 0.05) in manual tracking, force platform stability, and Heath rail walking and in total severity of symptoms. Suriclone 0.8 mg caused nausea (p = 0.02), clumsiness (p = 0.02), and loss of balance (p = 0.01) more frequently than diazepam 10 mg. Suriclone 0.8 mg produced symptoms and signs qualitatively and quantitatively different from diazepam 10 mg, such as vomiting, unusual ocular movement effects, and difficulty walking. Possibly the differences in CNS drug binding for anxiolytics are associated with clinical differences in toxicity.     

The sedative-hypnotic properties of quazepam, a new hypnotic agent

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1, 4-benzodiazepine-2-thione (Sch 16134, quazepam) is a new hypnotic drug with demonstrated clinical efficacy. Quazepam has been shown in our laboratories to have potent hypnotic activity and fewer side effects at effective doses than flurazepam, which was studied concurrently. Hypnotic potency was estimated in mice via antagonism of electroshock-induced convulsions (ECS), potentiation of hexobarbital-induced sleeping time, and chlorprothixene potentiation. The respective oral ED50's (95% fiducial limits) in the 3 tests were 0.9 (0.4-2.0), 0.5 (0.3-0.8) and 0.05 (0.02-0.08) mg/kg for quazepam and 1.6 (1.1-2.3), 0.6 (0.4-1.0) and 0.11 (0.07-0.42) mg/kg for flurazepam. The duration of action of quazepam as measured by antagonism of ECS in mice was similar to that of flurazepam at equi-effective doses but quazepam had a faster onset. When potential tolerance to hypnotic efficacy was studied, quazepam did not show tolerance after dosing 20 mg/kg p.o. twice daily (b.i.d.) for 5 days, whereas tolerance was seen with flurazepam at equi-effective doses b.i.d. for 5 days. In conscious, unrestrained squirrel monkeys and cats, quazepam produced sedation with less ataxia and less evidence of CNS stimulant action than flurazepam. On the basis of the aforementioned studies, quazepam should be an effective hypnotic with less potential for ataxia, paradoxical excitation, and tolerance than flurazepam.     

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.     

The discriminative stimulus properties of zolpidem,a novel imidazopyridine hypnotic

Zolpidem is a non-benzodiazepine hypnotic drug which displaces benzodiazepines from their binding sites in different brain structures. Previous work has demonstrated several differences between zolpidem and benzodiazepines, including differences between the stimulus properties of zolpidem and chlordiazepoxide. In the present study the discriminative stimulus properties of zolpidem were analysed by training rats to discriminate between this drug and saline. It was found that stimulus control developed readily with 2 mg/kg but not with 1 mg/kg zolpidem. The effect was dose-related, had a short duration of action and was antagonised by Ro 15-1788. Furthermore, stimulus control produced by zolpidem was associated with marked reductions in rates of responding. Injections of chlordiazepoxide, triazolam, lorazepam, zopiclone, CL 218,872 and pentobarbital produced dose-related responding on the zolpidem-associated lever but haloperidol did not. However, in general, the doses of those drugs which produced drug-lever responding also reduced response rates. It is possible that the above mentioned differences between the discriminative stimulus produced by zolpidem in rats and those produced by other sedatives may be due to a selective action of zolpidem on a sub-type of benzodiazepine binding site. Offprint requests to: D.J. Sanger     

Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability

Zopiclone (7.5 mg) is frequently used as a positive control in studies that examine the residual effects of hypnotic drugs on driving ability and related skills. This review summarizes studies examining the effects of zopiclone, and discusses its usefulness as a comparator drug for investigations of residual effects of novel sleep medication. A literature review (Pubmed and Embase) was conducted searching for studies that tested zopiclone on driving. Cross references were checked for additional papers. Eight studies utilizing the standardized on-the-road driving test consistently showed that in the morning following bedtime administration zopiclone (7.5 mg) significantly impaired driving performance. A total of 191 healthy volunteers were tested after placebo and zopiclone (7.5 mg). Meta analyses showed no significant differences in driving performance after zopiclone (7.5 mg) between adult and elderly healthy volunteers. The combined effect size (ES) and 95% confidence interval (95%CI) for healthy volunteers was 0.782 (0.620, 0.944). Relative to placebo, an average increment of 3.0 cm in Standard Deviation of Lateral Position (SDLP) was observed when treated with zopiclone (7.5 mg). This deviation was higher than the increment in SDLP reported for drivers with a blood alcohol concentration of 0.05% (+2.4 cm). Results from driving simulators and psychometric tests are consistent with the on-road driving test results. In conclusion, zopiclone (7.5 mg) is a reliable positive control, that consistently shows significant and meaningful impairment on the on-the-road driving test.     

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.     

Brotizolam. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an hypnotic

Brotizolam is a new thienotriazolodiazepine derivative with a pharmacological profile similar to that of benzodiazepines. It is indicated for use as an hypnotic in the management of insomnia, although it also has anticonvulsant, antianxiety and muscle relaxant properties in animals. In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies. Brotizolam is an effective hypnotic for hospital patients awaiting surgery, in whom it also reduces anxiety. Brotizolam has an elimination half-life of about 5 hours, which is 'intermediate' compared with the shorter-acting hypnotic, triazolam, and longer-acting benzodiazepines. Consequently, it is able to induce sleep without producing early morning rebound insomnia, and can also maintain sleep throughout the night. Brotizolam at dosages below 0.5mg at night usually produced minimal morning drowsiness; no residual impairment of psychomotor performance occurs following dosages within the recommended range of 0.125 to 0.25 mg/kg. No serious side effects have been reported to date and the most frequently observed adverse experiences are drowsiness, headache and dizziness. Mild rebound insomnia may occur in some patients when treatment is stopped. Thus, brotizolam is a useful hypnotic which can be used in patients who have difficulty in falling asleep and also in patients who are troubled by night-time awakenings. Used in the recommended dosage it may be particularly useful for patients in whom daytime impairment of performance is unacceptable.     

Suriclone, a new anxiolytic of the cyclopyrrolone family: evidence for possible interference with GABAergic systems

The action of suriclone (R.P. 31,264), a new non-benzodiazepine compound of the cyclopyrrolone family with clinical anxiolytic activity was examined using biochemical and electrophysiological models supposed to be capable of revealing central GABAergic activity. Suriclone, which does not act directly on the gamma-aminobutyric acid (GABA) receptor (muscimol binding assay), markedly reduced the increase of striatal HVA level induced in the rat by a neuroleptic and decreased the cerebellar vermis cGMP content. Moreover, in the cat, suriclone was able to enhance dorsal root potential amplitude which reflects an increase of the presynaptic inhibition. In view of these results, a central GABAergic mechanism of action may be proposed for suriclone.     

新型安眠药加波沙朵的合成

目的合成新型安眠药加波沙朵。方法以甘氨酸乙酯盐酸盐、氯化苄和γ-丁内酯为原料,合成N-苄基甘氨酸乙酯和4-溴丁酸乙酯,经环合得到N-苄基-3-氧代-4-甲酸乙酯哌啶盐酸盐,该盐经氢化、基团保护,再与羟胺反应环合得到3-羟基-6-甲酸乙酯-4,5,6,7-四氢异唑[5,4-c]吡啶,最后去保护得到目标产物。结果与结论中间体及产物结构经IR、^1H-NMR和^13C-NMR确认。     

HPLC法测定佐匹克隆片的含量及有关物质

目的:用高效液相色谱法测定佐匹克隆片的含量及有关物质.方法:用C18柱;流动相:pH3.5缓冲溶液(取十二烷基硫酸钠8.1 g和磷酸二氢钠1.6 g,加水1 000 mL使溶解,用磷酸调pH3.5)-乙腈(55:45);检测波长:303nm.采用外标法测定含量,加校正因子的自身对照法测定已知杂质,自身对照法测定未知杂质.结果:佐匹克隆浓度在19.04～152.29mg·L-1范围内与峰面积呈良好的线性关系,r=0.9997.平均加样回收率为99.6%,RSD=0.8%(n=5).有关物质各杂质峰与主峰之间的分离度良好;结论:本方法灵敏度高,专属性强、准确可靠,适合于佐匹克隆片含量及有关物质的测定.     

Zopiclone,sleep and health-related quality of life

458 insomniac patients participated in a multinational, randomised, double blind, parallel groups study of zopiclone 7.5 mg versus placebo. Patients received the drug or placebo nightly for 14 days and for a further six weeks on demand. Sleep characteristics and Quality of Life measures were assessed at 14, 28 and 56 days after admission. Both groups of patients improved on these measures, but the active treatment showed significantly greater improvement compared to placebo, both after 14 days and at the end of the trial.     

Zopiclone misuse: an update from Dublin

The prevalence of zopiclone misuse in clients attending a methadone maintenance programme in Dublin through detection of its degradation product, 2-amino-5-chloropyridine (ACP) on urinalysis is outlined. Urine samples from all 158 clients were tested for the presence of ACP, opiates, benzodiazepines, cocaine, alcohol and cannabis. Of the 37 (23%) clients who tested positive for ACP, 23 (62%) were interviewed. A profile of zopiclone misusers is outlined, including details of demographics, drug history, viral status, recent urinalysis results and opinions on zopiclone. Of the 14 (38%) clients who were not interviewed, information was obtained from their clinical casenotes and documented urinalysis results. The prevalence of zopiclone misuse was reported as 23%. Benzodiazepines were the most popular drug of misuse with zopiclone followed by heroin/opiates. Zopiclone is being misused by drug users in Dublin in the context of many other drugs. Prescribing of zopiclone should be restricted, especially among drug misusers. [Bannan N, Rooney S, O'Connor J. Zopiclone misuse: an update from Dublin. Drug Alcohol Rev 2007;26:83 - 85]     

Brotizolam: a new short-acting hypnotic

A new short-acting thieno-diazepine compound, brotizolam, has been compared to nitrazepam in a double-blind trial. Following an initial 3-day control period with no treatment, insomniac patients were allocated to 2 weeks treatment with one or the other drug according to random selection. This was then followed by a further 3-day no-drug control period. Morning and evening questionnaires were used to assess various sleep parameters and possible daytime "hang-over" effects. The patients also made actual records of the periods awake during the night (somnography). Highly significant effects were shown for both drugs in comparison to both control periods, in relation to all of the sleep parameters. However, no significant differences from either control period were demonstrated for either drug on the daytime measures, with the exception of how the patients felt at work with brotizolam and how they felt with others on nitrazepam, on both of which measures the patients felt better whilst on the drug. Comparing the figures between the initial and final no-drug control periods, did not reveal any evidence to suggest a rebound effect with either drug.     

Lacosamide: a review of preclinical properties

Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.