Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled,active comparator crossover studies in healthy volunteers

ABSTRACT

Objective: To assess the effects of post-bedtime dosing with indiplon on next-day function in adults and the elderly.

Research design and methods: Two randomized, double-blind, placebo-controlled crossover studies were conducted in two groups of healthy volunteers: an adult study (18–45 years) and an elderly study (65–80 years). In adults, a single post-bedtime dose of indiplon 10?mg and 20?mg was compared to placebo, with zolpidem 10?mg and zopiclone 7.5?mg included as controls. In the elderly, a single post-bedtime dose of indiplon 5?mg and 10?mg was compared to placebo, with zopiclone 3.75?mg included as a control. Next-day residual effects were evaluated in the morning at 4 and 6?h post-dose in adults, and 4, 6, and 8?h in the elderly, by a Visual Analog Scale of sleepiness (VAS-sleepiness), Digit Symbol Substitution Test (DSST), and the Symbol Copying Test (SCT).

Results: In adults, there were no statistically significant differences between indiplon and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint for either dose. In contrast, a significant increase versus placebo in VAS-sleepiness was observed for both zopiclone (at 4 and 6?h post-dose; p < 0.0001 and p = 0.002, respectively) and zolpidem (at 4?h post-dose; p = 0.042). In the elderly, there were no statistically significant differences between indiplon 5?mg and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint. DSST was significantly reduced for indiplon 10?mg versus placebo at 4?h only (?p = 0.022), compared with a significant reduction in DSST for zopiclone at both 4 and 8?h post-dose (?p = 0.002 and p = 0.003, respectively). In adults, the overall incidence of adverse events was higher on zopiclone compared to indiplon, zolpidem, and placebo. In the elderly, the incidence of adverse events was similar for indiplon, zopiclone, and placebo. Potential limitations of the current study include recruitment of healthy volunteers and the use of a limited pharmacodynamic battery.

Conclusions: Indiplon, at doses of 10?mg in adults and 5?mg in the elderly, was not associated with next day residual sedation or impairment in simple cognitive and psychomotor tasks when administered during the night 4?h prior to awakening.     

Flunitrazepam (Ro 5-4200) and sleep cycle in insomniac patients

The action of flunitrazepam (Ro 5-4200), a benzodiazepine derivative, was assessed on the sleep cycle of insomniac patients by means of all-night reeordings. Baseline placebo nights were compared with the drug (2–8 mg p.o.) and with the placebo post-drug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and a disappearance of sleep stages 3 and 4 while stage 2 was increased. In 10 out of 12 studied insomniacs the compound was effective in inducing and maintaining sleep (decrease in NREM sleep latency, wake time and number of wakes) throughout the drug administration period. Both NREM and REM sleep were increased, the latter most likely in relation to a blockade of processes precluding NREM emergence.The hypnotic action of flunitrazepam was still present during the first withdrawal night, pointing out to a carry over effect.Supported by a grant from Hoffman-La Roche.     

A polysomnography study of eszopiclone in elderly patients with insomnia

ABSTRACT

Objective: To evaluate the safety and efficacy of eszopiclone 2?mg in elderly patients (aged 64-86 years) with chronic insomnia.

Methods: This was a randomized, double-blind, placebo-controlled 2‐week study. Patients meeting DSM-IV criteria for primary insomnia and screening polysomnography criteria (wakefulness after sleep onset [WASO] ≥ 20?min and latency to persistent sleep ≥ 20?min) were randomized to 2 weeks of nightly treatment with eszopiclone 2?mg (n = 136) or placebo (n = 128). Efficacy was assessed using polysomnography (Nights 1, 2, 13, and 14) and patient reports (Nights 1–14); safety was assessed using adverse events, clinical labs, physical examination, and vital signs. The mean of all efficacy results during the double-blind period was used for the efficacy analysis.

Results: Results indicated that eszopiclone was associated with significantly shorter sleep onset, less WASO, higher sleep efficiency, more total sleep time, and greater patient-reported quality and depth of sleep scores than placebo (?p < 0.05 for all) with a trend in patient-reported morning sleepiness (?p = 0.07). Other measures of daytime functioning (ability to function, daytime alertness, and sense of well-being) were not significantly different between the two treatment groups. Among patients who napped, eszopiclone patients reported fewer naps (?p = 0.03) and less cumulative naptime (median: 98?min placebo, 70?min eszopiclone, p = 0.07). Unpleasant taste, dry mouth, somnolence, and dizziness were higher in the eszopiclone group (12.5%, 8.8%, 6.6%, and 6.6%, respectively) than in the placebo group (0%, 1.6%, 5.5%, and 1.6%, respectively).

Conclusion: In this study, eszopiclone was well tolerated and produced significant improvements in both polysomnographic and patient-reported measures of sleep maintenance, sleep induction, and sleep duration in elderly patients with chronic primary insomnia.     

In vivo apparent pA2 analysis in rats treated with either clocinnamox or morphine

Experiments tested the hypothesis that loss of agonist potency or effectiveness following irreversible antagonist or chronic agonist treatment may result from affinity changes at opioid receptors. Apparent affinity of naltrexone or nalbuphine for opioid receptors was measured in vivo in rats treated with either a single dose of the irreversible antagonist clocinnamox or repeated doses of morphine. Apparent affinity of each antagonist was estimated from its potency as an antagonist of discriminative stimulus or rate-decreasing effects of morphine in rats trained to discriminate 3.2 mg/kg morphine and saline. In control rats, apparent pA₂ values for naltrexone and nalbuphine were 7.5–7.6 and 5.3, respectively. In clocinnamox-treated rats, apparent pA₂ values for naltrexone were 7.2–7.7, suggesting that clocinnamox treatment did not alter affinity of naltrexone for sites through which morphine exerts behavioral effects. In rats treated repeatedly with morphine, apparent pA₂ values for nalbuphine were 5.1–5.3, suggesting that repeated morphine treatment did not alter affinity of nalbuphine for these sites. The observation that neither clocinnamox nor repeated morphine treatment altered in vivo affinity estimates for naltrexone or nalbuphine, respectively, suggests that the reductions in agonist potency produced by these treatments do not result from changes in affinity at opioid receptors.This work was supported by US Public Health Service Grant DA03796 and NIDA Research Scientist Development Award K02 DA00132 to A.M. Young. A portion of this work is presented in abstract form [Walker EA, Richardson TM, Young AM (1995) Apparent affinity estimates for opioid antagonists in rats treated with clocinnamox or chronic morphine. In: Harris LS (ed) NIDA Res Monogr 153: 450]     

Use of in vivo apparent pA2 analysis in assessment of opioid abuse liability.

Abuse liability testing of opioid drugs was originally motivated by attempts to separate the analgesic effects of opioids from their likelihood for abuse. It has become apparent that the human population group likely to abuse opioids has little overlap with the population group requiring opioids to treat pain, therefore there is no longer a need to separate these two properties of opioids. This is fortunate, since, as reviewed here by Jim Woods and colleagues, the results of the plethora of studies that have attempted to distinguish these two properties in known opioids strongly indicate that they are inseparable. Evaluation of the abuse potential of novel opioids remains, however, critically important in deciding on governmental restrictions on their accessibility. In addition, opioid abuse liability testing contributes enormously to our understanding of the behavioral mechanism of action of these drugs, and in surprising and helpful ways has increased our appreciation of the various test systems used to garner information about them.     

Effects of thalidomide and pentobarbital on neuronal activity in the preoptic area during sleep and wakefulness in the cat

To test the hypothesis that sleep produced by thalidomide, unlike that of pentobarbital, is associated with increased neuronal activity in the preoptic area (POA), the spontaneous activity of 96 POA neurons was recorded in chronically prepared cats during alert wakefulness (W), deep slow-wave sleep (SWS), and REM sleep in a drug-free preparation and after administration of thalidomide (4mg/kg) and pentobarbital (4 or 8 mg/kg). Thalidomide, unlike pentobarbital, at a dose that significantly increased the amount of SWS, failed to depress neuronal activity in the POA compared to drug-free controls. Mean discharge rates during thalidomide treatment were similar to drug-free rates. In contrast, rates during low-dose pentobarbital treatment were significantly less than those of drug-free and thalidomide-treated animals. Rates during high-dose pentobarbital treatment were significantly less than those in all other groups. Thalidomide, compared with the other groups, in addition to increasing the amount of SWS, significantly increased the total amount of REM sleep as well as REM sleep as a percent of total sleep, but did not produce ataxia or behavioral excitement. These results do not confirm the initial hypothesis, but suggest that hypnotic drugs that do not depress neuronal activity in the POA may be devoid of some of the unwanted side effects often associated with the more commonly prescribed hypnotic medications.     

Schild (apparent pA2) analysis of a kappa-opioid antagonist in Planaria

Previous investigators have provided radioimmunological and immunocytochemical evidence for an enkephalinergic (opioid) system in Planaria and described naloxone-sensitive qualitative behavioral responses to κ-opioid receptor agonists. We report the application of Schild-analysis to the antagonism of a selective κ agonist (U-50,488H) by a selective κ antagonist (nor-BNI) in a quantitative in vivo endpoint. The results provide further evidence of a κ-opioid-like receptor in planarians.     

Pharmacological profiles in vivo of benzodiazepine receptor ligands

Since the discovery of specific binding sites for benzodiazepines in the brain, a range of compounds have been discovered that do not have the benzodiazepine structure but that do interact with the benzodiazepine receptors. Classical benzodiazepines were considered to be agonists at these receptors. Some compounds only possess part of the profile of classical benzodiazepines and antagonise benzodiazepines in those test procedures in which they are totally inactive. Such compounds are regarded as partial agonists. The discovery of methyl and ethyl β-carboline-3-carboxylate opened a new vista in the pharmacology of benzodiazepine receptors. These agents and now several other compounds act on the benzodiazepine receptors to induce effects functionally opposite to those of classical benzodiazepines (proconvulsant and convulsant) and have been called inverse agonists. Both agonists and inverse agonists can be blocked by compounds with affinity for the receptors but little intrinsic activity (antagonists). A recent increase in the number of benzodiazepine receptor ligands with in vivo activities allows comparison of a range of compounds from several different structral groups. Their pharmacological profiles suggest that these compounds all fit onto a continuum of behavioural effects related to activation of benzodiazepine receptors.     

A translational,caffeine-induced model of onset insomnia in rats and healthy volunteers

Rationale Insomnia is a common and disabling complaint for which there is a need for improved treatments. Successful drug discovery relies on the use of appropriate animal models to assess likely outcome in the clinic. Objectives The purpose of this study was to develop a translational, caffeine-induced model of insomnia in rats and healthy volunteers. We used sleep onset latency (SOL) as a comparable sleep measure between the two species. The model was validated by two effective sleep-promoting agents with different pharmacology, zolpidem and trazodone, which have GABA-ergic and serotonergic mechanisms, respectively. Materials and methods In rats, radiotelemetry transmitters with electroencephalogram and electromyogram electrodes were implanted for sleep recording. Animals were administered with caffeine alone (10 mg/kg) or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg), or vehicle, in crossover experiments. Home polysomnography was performed in 12 healthy male volunteers in a randomised, placebo-controlled, 4-week crossover study. Subjects received placebo, caffeine (150 mg) or caffeine in combination with zolpidem (10 mg) or trazodone (100 mg). Subjective sleep effects in volunteers were assessed using the Leeds Sleep Evaluation Questionnaire. Results Caffeine caused a significant prolongation in objective SOL in rats and humans. This effect was sensitive to zolpidem and trazodone, both of which attenuated the caffeine-induced increase in SOL. Furthermore, both hypnotics restored the disruption in subjective measures of sleep onset caused by caffeine in volunteers. Conclusions This model therefore provides a promising paradigm in which we can study novel treatments for sleep disorders and an opportunity for direct comparison of results between rodents and humans.     

In vivo Schild regression analyses using nonselective 5-HT2C receptor antagonists in a rat operant behavioral assay

RATIONALE: Although competitive antagonism experiments are critical tools in the classification of potential pharmacotherapies, no studies have quantitatively compared the potencies of 5-HT(2C) receptor antagonists using the Schild regression analysis in vivo. OBJECTIVES: To evaluate the behavioral effects of 5-HT(2C) receptor agonists and antagonists, a series of nonselective 5-HT(2C) receptor antagonists, the 5-HT(2A/2C) receptor antagonist ketanserin, the 5-HT(2B) receptor antagonist SB 204,741, the 5-HT(2B/2C) receptor antagonist SB 200,646, and the peripherally acting 5-HT(2C) receptor antagonist RS102,221 were evaluated for their capacity to competitively antagonize the agonists MK212, mCPP, or BW723C86 in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats (N = 28) were trained to respond under a fixed ratio 10 schedule of food reinforcement. A multiple-trial, cumulative-dosing procedure was used to evaluate the capacity of the compounds to suppress response rates. RESULTS: MK212, mCPP, and the 5-HT(2B) receptor agonist BW723C86 dose-dependently decreased response rates. Only metergoline, mianserin, and methysergide produced a dose-dependent antagonism of the rate-decreasing effects of both mCPP and MK212. Apparent pA(2) analysis indicated that metergoline, mianserin, and methysergide were approximately equipotent as antagonists overall. Metergoline and mianserin failed to block the rate-decreasing effects of BW723C86. Ketanserin, SB 200,646, SB 204,741, and RS102,221 failed to block either mCPP or MK212, suggesting that 5-HT(2A), 5-HT(2B), or peripheral 5-HT(2C) receptors do not play a primary role in the rate-decreasing effects of these two agonists. CONCLUSIONS: Taken together, these antagonism profiles suggest that the agonists MK212 and mCPP produce their rate-decreasing effects through a combination of 5-HT receptors with the 5-HT(2C) receptor playing a prominent but not exclusive role.     

Effect of a single dose (10 mg) of zolpidem on visual and spectral analysis of sleep in young poor sleepers

Four non-consecutive nights of sleep were recorded in eight young volunteers complaining of chronic poor sleep. The subjects received a placebo or a 10 mg zolpidem dose prior to bedtime according to a Latin square double-blind design. All-night spectral analyses of the Cz-Pz lead were associated to the standard polysomnography. According to the visual scoring performed with the Rechtschaffen and Kales criteria, zolpidem significantly increased the stage 4 amount and reduced waking. Compared to placebo no difference in sleep stages was observed when the scoring was based on the power in the 0.7 to 4-Hz band. In zolpidem nights power was significantly reduced in the 4 to 8-Hz band during NREM (stages 2, 3 and 4) and was increased in the 2 to 4-Hz band during REM sleep. A significant reduction of fast activities over 12 Hz was observed during the first 3 h of sleep. Concerning slow wave activity, the only change noted was a significant slowing of its build-up rate at the beginning of cycle 1.     

Ethanol and the peripheral benzodiazepine receptor: in vivo and in vitro experiments.

1. The effect of chronic ethanol exposure on rat peripheral benzodiazepine receptors (PBR) was studied. 2. The binding of 3H-RO 5-4864 to PBR was increased (35.4%) in the kidneys of rats treated with 10% (v/v) ethanol for 12 weeks, but not in renal membranes isolated from rats exposed to ethanol 30% (v/v) during the same period. 3. Similarly, short-term administration of ethanol (4 weeks) did not alter the binding of 3H-RO 5-4864 to renal membranes. 4. To examine the possibility of a direct interaction of ethanol with PBR, in vitro experiments were carried out. Only high concentrations of ethanol (> 100 mM) caused a significant inhibition of 3H-RO 5-4864 binding in kidney, testis and cerebral cortex. 5. The results presented indicate that chronic ethanol exposure causes a time and dose-dependent increase in renal PBR.     

Effect of zolpidem on sleep and sleep EEG spectra in healthy young men

A single 10 mg dose of zolpidem, an imidazopyridine hypnotic, was administered to young, healthy male volunteers prior to bedtime. The drug reduced REM sleep but did not significantly affect other sleep stages and subjective sleep parameters. All-night spectral analysis of the EEG revealed that power density in nonREM sleep was reduced in the low-frequency range (1.25–2.5 Hz; 5.25–10.0 Hz) and increased in the spindle frequency range (12.25–13.0 Hz). Significant changes in the EEG spectrum were present in the first 4 h of sleep. The pattern of the spectral changes was similar to those induced by other hypnotics that bind to the GABA_A/benzodiazepine receptor complex. There were no residual effects of zolpidem on psychomotor performance in the morning, on the self-rated state in the morning and at noon, and on sleep and EEG parameters in the subsequent drug-free night.     

The effects of substituting zopiclone in withdrawal from chronic use of benzodiazepine hypnotics

Twenty-four volunteers (19 women and five men) with insomnia and a history of chronic use of benzodiazepine hypnotics participated in a randomized, double blind, controlled clinical trial. The study was designed to assess the effects of substituting zopiclone (ZOP) – as an hypnotic – among chronic users of flunitrazepam (FLU), and to compare the subsequent withdrawal of ZOP with placebo controlled withdrawal of FLU. During the 5 weeks of a withdrawal protocol, sleep and physiological parameters were assessed by polysomnographic measures for 11 nights and by nightly actigraphic recordings for weeks 1, 3, and 5. Subjective effects of the withdrawal process were evaluated with daily sleep diaries, and with various weekly self-report symptom checklists. Paired t-tests performed on differences in objective sleep parameters between baseline and the last weeks of the withdrawal program showed a significant decrease in sleep quality within the FLU group, but not in the ZOP group. Subjective sleep diaries consistently reflected the objectively measured changes in sleep throughout the withdrawal program, indicating significant changes in sleep parameters only in the FLU group. The results obtained from the self report inventories aimed at assessing withdrawal symptoms, however, revealed no differences between the baseline week and the termination week of the program in any of the groups. After completing the pharmacological withdrawal, all subjects received a short-term cognitive behavioral intervention focused on improving their coping strategies with symptoms of insomnia; they were evaluated immediately after concluding the intervention, and at 3 and 12 month follow-ups. Received: 19 December 1997/Final version: 11 May 1998     

Differences in enhancing effects of zolpidem and benzodiazepine drugs on recurrent inhibition in rat hippocampal slices

It has been reported that the clinical and electroencephalographic profiles of zolpidem, a non-benzodiazepine drug which binds preferentially to the ω₁ benzodiazepine recognition sites located within the GABA_A receptor complex, are different from those of benzodiazepine drugs, which bind non-selectively to the ω₁ and ω₂ sites. In order to clarify the electrophysiological mechanism underlying the unique profile of zolpidem, the present study compared the enhancing effects of zolpidem and two benzodiazepine drugs, triazolam and diazepam, on recurrent inhibition. This inhibition was expressed as suppression of the orthodromically induced population spikes by the preceding antidromic stimulation of the alveus in the CA1 region of rat hippocampal slices. The rank order of potency for enhancing recurrent inhibition was triazolam > diazepam > zolpidem. From the present results and previously reported findings that zolpidem has a lower affinity for the ω₂ sites than diazepam while both have the same affinity for the ω₁ sites, we concluded that the hippocampal recurrent inhibition appears to be enhanced mainly by activation of the ω₂ sites, but not by that of the ω₁ sites. Furthermore, the lower potency of zolpidem for enhancing recurrent inhibition may underlie its unique profile in terms of its clinical and electroencephalographic effects. Received: 1 November 1996/Final version: 22 January 1997     

Dissociation between the effects of benzodiazepine receptor agonists on behavioral vigilance and responsivity

The effects of benzodiazepine receptor (BZR) full agonists chlordiazepoxide and midazolam, and the partial agonist-carboline ZK 91 296 on the rat's performance in a simple reaction time paradigm were examined. This task required the animals to respond to a rarely and unpredictably occurring brief (50 ms) visual stimulus. Non-parametric measures of signal sensitivity and response bias derived from signal-detection theory were used as a basis for the dissociation between the effects of these drugs on attentional abilities and general responsivity. The dose-dependent effects of midazolam (0.1–3.13 mg/kg) on signal sensitivity and general responsivity occurred in parallel. In contrast, the effects of chlordiazepoxide (1.56–12.5 mg/kg) on signal sensitivity were largely independent from effects on response bias. The partial agonist ZK 91 296 (0.39–25 mg/kg) in general had little effect on performance. The effects of the highest doses of chlordiazepoxide and midazolam were reversed by the co-administration of the BZR antagonist Ro15-1788 (15 mg/kg). Additionally, extension of the stimulus presentation time to 500 ms decreased the magnitude of the effect of chlordiazepoxide on signal sensitivity. These results support the hypothesis that BZR agonist-induced disruption of attentional abilities is not necessarily confounded by effects on general responsivity or sedation, and thus may represent a discrete pharmacological property of BZR-agonists.     

Ovarian steroids modify the behavioral and neurochemical responses of the central benzodiazepine receptor

The effect of ovarian steroids on the benzodiazepine receptor was assessed in the elevated plus-maze and, after restraint stress, in benzodiazepine receptor binding assays. Vehicle-treated proestrous rats displayed anxiolytic behavior, relative to diestrous or estrous rats. Anxiolytic behavior was observed after 1 or 2 mg/kg diazepam in diestrus and estrus. However, whereas 4 mg/kg increased open arm exploration in diestrus, a decrease in the same measure was found at estrus. At proestrus, a decrease in anxiolytic behavior was observed after 2 and 4 mg/kg. In ovariectomized vehicletreated rats, restraint stress increased NaCl-induced potentiation of³H-flunitrazepam binding in cortical and cerebellar, but not in hippocampal membranes. Estradiol benzoate (2 µg) prevented the potentiation of flunitrazepam binding by NaCl in nonstressed and stressed animals, whereas progesterone (0.5 mg) increased the NaCl-induced potentiation of flunitrazepam binding in both nonstressed and stressed animals. Combined estradiol benzoate and progesterone treatment produced effects that were intermediate to those seen after injection of either steroid alone. The potentiation of flunitrazepam binding by NaCl observed in vehicle-treated stressed or progesterone-treated nonstressed animals was mimicked in vitro by addition to reaction test tubes of the neuroactive metabolite of progesterone, 3-hydroxy-5-pregnan-20-one (allopregnanolone). These results point to a significant role of ovarian hormones in modifying the stress response of the benzodiazepine receptor.     

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

Summary

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.     

脾胰耳穴磁珠贴压法对2型糖尿病伴失眠患者的影响

目的 观察脾胰耳穴磁珠贴压对2型糖尿病伴失眠患者的影响.方法 选取2型糖尿病并伴有失眠患者99例,中途流失9例,最终收集病例数为90例,按照进入研究的先后顺序随机分为五点耳穴组(选取脾、胰、神门、心和神经衰弱点5个耳穴点,每日按压4次,每次每穴按压3 min)、三点耳穴组(选取神门、心和神经衰弱点3个耳穴点,每日按压4次,每次每穴按压3 min)和对照组(不给予耳穴磁珠贴压),各30例.疗程为1个月.治疗期间检测每周固定一天的空腹血糖(FPG),记录匹茨堡睡眠质量指数量表(PSQI),并观察试验前后各组睡眠中医症状量化表积分变化.结果 干预后,五点耳穴组主观睡眠质量因子得分低于三点耳穴组和对照组[1(1,2)分比1(1,2)、2(2,2)分,P＜0.05];五点耳穴组口苦咽干得分低于三点耳穴组和对照组[1(0,1)分比1(0,1)、1(1,2)分,P＜0.05];五点耳穴组FPG值低于三点耳穴组和对照组[(6.1±1.0) mmol/L比(7.0±1.4)、(7.3±1.8) mmol/L,P＜0.05].结论 脾胰耳穴磁珠贴压可辅助改善2型糖尿病伴失眠患者的主观睡眠质量、口苦咽干症状和FPG,为改善2型糖尿病伴失眠患者的睡眠质量和控制FPG提供了一种新疗法.