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PubMed1989

Effects of Ro 15-4513 on the motor impairment and hypnotic effects of ethanol and pentobarbital.

The selectivity of Ro 15-4513 in reversing the actions of sedative-hypnotic drugs was examined. The motor impairment induced by i.p. administration of 1.8 g/kg of ethanol was partially reversed by doses of Ro 15-4513 ranging from 2-8 mg/kg. Antagonism of the similar effect induced by 20 mg/kg of pentobarbital was observed only at the 8 mg/kg dose of Ro 15-4513. Treatment with 4 mg/kg of Ro 15-4513 shifted the dose-effect curve for motor impairment by ethanol to the right but did not affect the corresponding curve for pentobarbital. Ro 15-4513 also increased the onset latency and shortened the duration of sleep time induced by ethanol but not by pentobarbital. Blood ethanol and pentobarbital levels measured at 32 min after drug administration were not affected by Ro 15-4513. The selectivity of Ro 15-4513 and the mechanism(s) underlying its proconvulsant effect in reversing the actions of ethanol are discussed.

Animals↗
PubMed1996

N3-phenacyluridine, a novel hypnotic compound, interacts with the benzodiazepine receptor.

N3-Phenacyluridine (3-phenacyl-1-beta-D-ribofuranosyluracil) has potent sedative and hypnotic activities following intracerebroventricular injection in mice. To study the mechanism of action of N3-phenacyluridine, the interaction of this compound with the benzodiazepine receptor has been investigated. Results obtained showed that this compound inhibited specific binding of [3H]flunitrazepam to synaptic membranes of bovine cortex in a concentration-dependent fashion (IC50 = 129 microM). Scatchard analysis of [3H]flunitrazepam binding revealed that N3-phenacyluridine interacted with the ligand at the benzodiazepine receptor binding site in a competitive manner. Ro15-1788 (8-fluoro-3-carboethoxy-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a ]1, 4-benzodiazepine), a benzodiazepine receptor antagonist, also inhibited the specific binding of [3H]flunitrazepam in the presence of the compound. The results suggest that the pharmacological activity of N3-phenacyluridine may be partially mediated through the benzodiazepine receptor.

Analysis of Variance↗
PubMed1992

An isobolographic analysis of the hypnotic effects of combinations of dexmedetomidine with fentanyl or diazepam in rats.

The effects of the combinations of dexmedetomidine-fentanyl and dexmedetomidine-diazepam on the righting reflex were studied in rats. The doses that block the righting reflex for the agents given alone and for their combinations were determined with a probit procedure and compared with an isobolographic analysis. The interactions between dexmedetomidine and fentanyl or diazepam were found to be synergistic. In the dexmedetomidine-diazepam combination studies, less than one-fourth of the single drug dose (for each of two agents) was needed to produce the required effect. These data confirm synergistic interactions between dexmedetomidine and fentanyl or diazepam in producing hypnotic-anesthetic action.

Anesthetics↗
PubMed1982

Effects of a new benzodiazepine hypnotic (quazepam--SCH 16134) on EEG synchronization and sleep-inducing mechanisms in cats.

The sleep-inducing properties of a new benzodiazepine hypnotic (quazepam--SCH 16134) were evaluated in cats with transection at different levels of the brain stem structure. Effects observed after administration of doses ranging from 0.12 and 1 mg/kg given intravenously were compared with those of pentobarbital. In the encéphale isolé small doses of quazepam induced or increased the synchronized periods. The desynchronized electroencephalogram (EEG) pattern of midpontine pretrigeminal preparations was not modified by these small doses. Only larger doses induced a fast neocortical activity of high amplitude. In midpontine pretrigeminal hemisection the synchronization occurred exclusively or predominantly in the hemisphere contralateral to the lesion. In the cerveau isolé, quazepam did not influence the typical synchronized EEG pattern. The arousal threshold after mesencephalic and physiological stimulation was raised only in encéphale isolé animals. Pentobarbital provoked sustained synchronization in all preparations with a pattern quite different from that of the benzodiazepine. These results suggest that quazepam may act through facilitation of the EEG-synchronizing mechanisms localized in the lower brain stem which are involved in physiological EEG-synchronizing and sleep-inducing processes.

Acoustic Stimulation↗
PubMed1985

Antagonism of the hypnotic effect of ethanol in mice by an alpha-1 adrenoceptor agonist.

A lipid soluble alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587) antagonized the hypnotic effect of ethanol in C57Bl/6 and CD-1 mice. In Swiss-Webster mice the effect of St 587 was weak and in BALB/c mice this drug potentiated ethanol hypnosis. St 587 did not enhance the elimination of ethanol. Cirazoline, an alpha 1-adrenoceptor agonist which is more potent than St 587, was relatively more effective in antagonizing the ethanol-induced hypnosis. Though it appears that St 587 exerted its ethanol antagonism by virtue of its alpha 1-adrenoceptor agonistic effect, other contributing factors may also have to be considered. St 587 may prove to be of value in understanding the mechanism of action of ethanol and in the treatment of acute ethanol intoxication.

Adrenergic alpha-Agonists↗
PubMed1987

The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure.

The imidazopyridine zolpidem has previously been shown to displace benzodiazepines from their receptors, with a preferential activity at BZ1 sites, and to exert hypnotic activity in man. Zolpidem's pharmacological profile includes anticonvulsant, antipunishment and behavioral depressant actions. However, unlike benzodiazepines, zolpidem exerts sedative actions at relatively low doses. In drug discrimination experiments differences between the internal stimuli produced by chlordiazepoxide and zolpidem were identified. These differences appeared to be qualitative rather than quantitative with the stimulus properties of zolpidem being related to the drug's sedative action. In condition where tolerance developed rapidly to the depressant activity of benzodiazepines little tolerance was seen with zolpidem. The behavioral profile of consistent with the suggestion that this compound may have selective sedative action produced by activity at a sub-type of benzodiazepine receptor.

Animals↗
PubMed1993

Shifts and awakenings: valuable indicators of the quality of sleep: do these parameters react differently to hypnotics?

In order to test the assumption that the sleep stability increases as the number of shifts and awakenings decreases, all-night sleep recordings (registered at home) were reanalyzed. The registrations belong to 10 young good sleepers, 10 adult good sleepers, 10 insomnia patients without treatment, 10 treated with a benzodiazepine and 10 treated with a nonbenzodiazepine hypnotic, 10 patients with proven narcolepsy, and 10 with obstructive sleep apnea syndrome (OSAS). For each of the categories NREM-1-2, NREM 3-4, and REM sleep, indices were defined as the number of shifts and awakenings that occurred per hour. Our results show that the indices of awakenings for the good as well for the bad sleepers were similar, whereas the indices of awakenings were very group dependent. We interpreted these results as showing that awakenings are valuable indicators for studying the quality of sleep, whereas shifts are not.

Adolescent↗
PubMed1976

Effect of hypnotics on mice genetically selected for sensitivity to ethanol.

It was previously shown that the rate of disappearance of blood ethanol was identical for two lines of mice selectively bred for differences in sleep-time after ethanol administration. The ED50 values for the loss of righting response with ethanol were significantly different at 3.64 g per kg for the SS line and 1.65 g per kg for the LS line. In the present study the mean sleep time is 367 sec for SS mice and 9342 sec for LS mice. The ED50 values remain essentially the same as previously reported. Unchanged LD50 values for ethanol, however, are not different at 4.8 g per kg for the SS and 4.5 g per kg for the LS line of mice. The ED50 value for loss for righting response following administration of methanol, butanol and t-butanol is approximately 2 fold greater for the SS line of mice than for the LS line. The ED50 values for sodium pentobarbital or ether in the 2 lines of mice for loss of righting response are virtually identical. In addition, the sleep-time values obtained after the administration of pentobarbital, chloral hydrate, trichloroethanol and paraldehyde are not significantly different. These data indicate that while the SS and LS lines of mice differ in central nervous system sensitivity to ethanol, methanol, butanol and t-butanol it is implied that they do no differ in central nervous system sensitivity to other hypnotic agents tested. Proof of this latter suggestion awaits determination of metabolic rates, and brain levels of these other depressants.

Animals↗
PubMed1979

Hypnotic effect of tryptophan analog in rats.

The effects of DL 2-amino-3-(1-naphthyl) propanoic acid, a tryptophan analog, on sleep and brain chemistry were investigated in rats. Similar to previous findings with tryptophan, the tryptophan analog (30 mg/kg, IP) reduced slow-wave sleep (SWS) latency. The reduction in SWS latency occurred at a time when 5-hydroxytryptamine (5-HT) concentration was reduced in the cortex, pons-medulla and striatum-thalamus with no change in the concentration of 5-hydroxyindoleacetic acid, a major metabolite of 5-HT. At the same time, norepinephrine concentration was reduced in the cortex, hippocampus and striatum-thalamus with a marked reduction (40%) in cortical dopamine (DA). The reduction of cortical DA coincided with a 53% decrease in homovanillic acid, a major metabolite of DA. The behavioral effect of tryptophan analog for six hours, as monitored by the EEG, was an increase in SWS by 25 min and a decrease in waking by 29 min. These data suggest that the effects of the tryptophan analog on sleep may be due to the attenuation of the activity of brain catecholamines and imply that tryptophan may as well produce its hypnotic effect via a similar mechanism.

Animals↗
PubMed1982

Evidence for genetic correlation of hypnotic effects and cerebellar Purkinje neuron depression in response to ethanol in mice.

In the present study, we compared phenotypic differences in behavioral and neurophysiological responses to acute ethanol administration among eight inbred strains of mice. Genetic variation for behavioral sedation, as measured by loss of the righting reflex (sleep time) after a hypnotic dose of ethanol, was shown to be present among the inbred strain population. In addition, a large genetic component of variation in the depressant action of ethanol on the spontaneous discharge of cerebellar Purkinje neurons was found. Results from an analysis of covariance of the behavioral and electrophysiological phenotypes, measured on each mouse among the inbred strains, provided strong evidence for a high genetic correlation between sleep time and inhibition of cerebellar Purkinje neuron discharge in response to acute ethanol administration. Taken together with our previously reported data on ethanol-induced electrophysiological changes in selectively bred lines, the results described here strongly support the hypothesis that the cerebellar Purkinje neuron is one important locus for the acute soporific effects of alcohol.

Animals↗
PubMed1992

Dehydroepiandrosterone enhances the hypnotic and hypothermic effects of ethanol and pentobarbital.

Recent reports have indicated that the neurosteroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) interact with the GABAA receptor complex. Because many of the behavioral effects of ethanol and pentobarbital are due to activity at this complex, DHEA and DHEAS were tested for their ability to interact with the hypnotic and hypothermic effects of ethanol and pentobarbital. DHEA, but not DHEAS, causes a dose-dependent increase in the sleep time induced by either ethanol or pentobarbital. At 20 mg/kg, DHEA and DHEAS themselves cause a fall in body temperature. DHEA enhances the hypothermic effect of both ethanol and pentobarbital. DHEAS enhances the hypothermic effect of ethanol, but with pentobarbital it only delays the return of body temperature to baseline levels. Neither DHEA nor DHEAS affects the metabolism of ethanol.

Animals↗
PubMed1996

The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs.

Benzodiazepine anxiolytic and hypnotic drugs are some of the most widely prescribed drugs in the Western world. Despite this fact, the mechanisms that underlie the development of tolerance to, and dependence upon, benzodiazepines are poorly understood. The aim of this review is to summarize and critically evaluate the experimental evidence relating to the chronic behavioural and neuronal effects of benzodiazepines. Behavioural studies in animals generally indicate that tolerance gradually develops to the muscle relaxant, ataxic, locomotor and anticonvulsant effects of benzodiazepines. The evidence relating to the development of tolerance to the anxiolytic effects of benzodiazepines is less clear. The literature on the possible mechanisms of benzodiazepine tolerance and dependence is large, highly complex and difficult to interpret. The effect of chronic benzodiazepine treatment varies enormously as a function of the benzodiazepine used and the treatment schedule employed. Many studies have demonstrated a down-regulation of benzodiazepine binding sites, although affinity is usually unchanged. The evidence relating to the number and affinity of GABAA binding sites is unclear. Some studies suggest that chronic benzodiazepine administration results in a reduction in the number of Cl- channels associated with the GABAA receptor complex, although it is not clear that the efficacy of the GABA binding site in operating the Cl- channel necessarily changes. There is, however, substantial evidence to support the hypothesis that chronic benzodiazepine treatment results in a reduction in the coupling between the GABAA and benzodiazepine binding sites (the "functional uncoupling hypothesis"). Although some electrophysiological studies suggest that chronic benzodiazepine treatment results in a subsensitivity to GABA, this effect seems to be highly area-specific.

Animals↗
PubMed1982

Out-patient detoxification of patients addicted to sedative-hypnotics and anxiolytics.

Due to the risk of seizures and other potentially life threatening complications, it has been accepted practice to detoxify patients addicted to sedative-hypnotics or minor tranquilizers in an in-patient setting. Using the procedures for patient selection and management described below, we have been able to detoxify as out-patients approximately two-thirds of 69 patients who were found to be in need of detoxification. Out-patients experienced no serious complications during or immediately following detoxification and were not significantly less likely than in-patients to complete treatment. We present here some guidelines which will assist practitioners in identifying patients who are appropriate for out-patient detoxification and describe approaches to patient management that have proven effective.

Ambulatory Care↗
PubMed1991

Testing the abuse liability of anxiolytic and hypnotic drugs in humans.

This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.

Anti-Anxiety Agents↗
PubMed1985

Drug level monitoring: sedative hypnotics.

Barbiturates and other traditional non-barbiturate sedative hypnotics are still extensively prescribed for the treatment of insomnia. There are a number of situations where identification or quantitative determination of these agents in biological fluids is required. Gas-chromatography offers highly sensitive and specific procedures for the determination of these compounds. The use of a nitrogen-specific detector allows a relatively simple sample preparation for sensitive detection and the use of capillary columns with bonded liquid phase allows separation of barbiturates without derivatization. In recent years liquid chromatography has also been extensively applied to the determination of these compounds. Sensitivity and selectivity of detection of barbiturates have been improved with the use of an alkaline mobile phase. Immunoassays for the determination of therapeutic concentrations of phenobarbital are very popular as the assays can be rapidly performed automatically. Use of these techniques has been extended for emergency detection of barbiturate overdose and for monitoring high-dose pentobarbital therapy.

Barbiturates↗
PubMedDate not supplied

NMDA agonists and antagonists alter the hypnotic response to ethanol in LS and SS mice.

Involvement of glutamate neurotransmission in the differential response of long-sleep (LS) and short-sleep (SS) mice to acute ethanol was examined by measuring the effect of centrally administered glutamate receptor agonists and antagonists on blood ethanol concentration (BEC) at loss of righting response following intragastric administration of ethanol. NMDA coinjected with glycine, and quinolinic acid (QA), decreased sensitivity to ethanol in both lines of mice. SS mice were more sensitive to QA than were LS. The NMDA antagonists 2-amino-5-phosphonovaleric acid (APV), MK-801 and an inhibitor of glutamate synthesis, methionine sulfoximine, increased sensitivity to ethanol in both lines of mice. MK-801 effects were line dependent with SS being more sensitive. In addition, coinjection of APV, Mg++ or Zn++ with QA blocked the decrease in sensitivity seen with QA alone. These results demonstrate that NMDA agonists and antagonists alter the acute hypnotic response to ethanol in both LS and SS mice, and support the hypothesis that ethanol exerts its effects in part by altering glutamatergic neurotransmission.

Animals↗
PubMed2006

Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia.

OBJECTIVE: This paper reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of the nonbenzodiazepine cyclopyrrolone agent eszopiclone in the management of adult patients with insomnia. METHODS: Recent studies, abstracts, reviews, and consensus statements published in English were identified through searches of MEDLINE (1966-December 2005), International Pharmaceutical Abstracts (1970 December 2005), and PharmaProjects (1990-December 2005) using the search terms eszopiclone, cyclopyrrolone, insomnia, nonbenzodiazepine, and zopiclone enantiomer. Selected information provided by the manufacturer of eszopiclone was included, as were all pertinent clinical trials. RESULTS: Eszopiclone is rapidly absorbed after oral administration, with Tmax achieved within approximately 1 hour and a terminal-phase elimination half-life of approximately 6 hours. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Eszopiclone is extensively metabolized by oxidation and demethylation. In vitro studies have indicated that the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; therefore, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Eszopiclone is excreted in the urine as racemic zopiclone at <10% of the orally administered dose. Six Phase III clinical trials were identified that evaluated the safety profile and efficacy of eszopiclone, 1 in healthy subjects with transient insomnia and 5 in patients with primary chronic insomnia (3 in younger adults and 2 in the elderly). In the trials in younger adults, eszopiclone significantly improved sleep efficiency, sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened weekly, total sleep time, and quality and depth of sleep compared with placebo (P<0.05). In the trials in elderly patients, who received eszopiclone 2 mg or placebo for 2 weeks, eszopiclone was associated with significantly shorter sleep latency compared with placebo (P<0.004), as well as a significant decrease in the cumulative number of naps (P<0.05). The most commonly reported drug-related, dose-responsive adverse event in clinical trials of eszopiclone 2 and 3 mg was bitter taste (17% and 34%, respectively), followed by dizziness (5% and 7%) and dry mouth (5% and 7%). Somnolence occurred at an incidence of 4% to 9% with both doses. Tolerance or rebound insomnia was not reported. CONCLUSIONS: Eszopiclone represents an effective and well-tolerated option for the treatment of insomnia. In the absence of published studies comparing eszopiclone with similar hypnotic agents (eg, zolpidem, zaleplon, zopiclone), it is not yet possible to evaluate its efficacy relative to other agents used for insomnia.

Azabicyclo Compounds↗
PubMed2005

Design, synthesis and biological activity of acyl substituted 3-amino-5-methyl-1,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones as potential hypnotic drugs.

Among the known non-benzodiazepinic hypnotic drugs acting on the alpha1 subunit of the GABA-A receptor, Zolpidem, Zaleplon and Indiplon have showed high affinity and selectivity. Following a design methodology including pharmacophoric requirements and ADME-predicted properties, we have synthesized a library of 3-amino-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones and their N1-alkyl derivatives as new scaffolds for designing non-benzodiazepine BZ receptor ligands.

Animals↗