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PubMed1994

Evaluation of the discriminative stimulus effects of the novel sedative-hypnotic CL 284,846.

CL 284,846, N-[3-(3-cyanopyrazolo[1, 5-a]pyrimidin-7-yl)phenyl)]-N- ethylacetamide, is a novel non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesired side effects. In an effort to further characterize its pharmacological activity, CL 284,846 (3.0 mg/kg, IP, 30 min pretreatment) was established as a discriminative stimulus (DS) in rats (n = 7). CL 284,846 (0.3-10.0 mg/kg) showed a dose-related increase in drug-appropriate responding up to the training dose and a dose-related decrease in response rate. The benzodiazepine agonist triazolam (0.1-1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3-3.0 mg/kg) and the triazolopyridazine CL 218,872 (1.0-3.0 mg/kg) substituted for CL 284,846 in all rats, whereas the imidazopyridines zolpidem (3.0-10.0 mg/kg) and alpidem (10.0-30.0 mg/kg), the benzodiazepine partial agonist bretazenil (0.03-10.0 mg/kg) and the novel putative anxiolytic CL 273,547 (10.0-56.0 mg/kg) substituted in most, but not all, rats. Ro 17-1812, bretazenil, and CL 218,872 had no effect on response rate while the other drugs showed a concomitant decrease in rate. The 5-HT1A agonist buspirone (1.0-10.0 mg/kg) and the barbiturate pentobarbital (3.0-17.0 mg/kg) failed to substitute for CL 284,846 up to rate-decreasing doses. The benzodiazepine antagonist flumazenil (3.0-10.0 mg/kg) blocked the DS effects of CL 284,846 in most rats with no effect on response rate. Taken together, these results suggest that the DS effects of CL 284,846 are mediated via benzodiazepine receptors; however, the DS profile of CL 284,846 remains distinct from both benzodiazepine and non-benzodiazepine sedative-hypnotic drugs.

Acetamides↗
PubMed1992

Rebound insomnia and hypnotic self administration.

Twenty-one (three groups of seven), men and women, 25-50 years of age were studied to determine whether or not rebound insomnia would increase the likelihood of self administering a benzodiazepine (triazolam 0.25 mg) hypnotic. The groups compared were patients with insomnia and disturbed sleep, insomnia and normal sleep, and healthy normals. Rebound insomnia, by both subjective and polysomnographic assessment, was induced. The experience of rebound insomnia did not increase the likelihood of self administering a benzodiazepine hypnotic in any of the groups. There were clear group differences in pill self administration with normals rarely and insomnia patients frequently, but not differentially (placebo versus active drug) self administering pills.

Adult↗
PubMed1996

Polysomnographic effects of hypnotic drugs. A review.

This review aims at providing a critical assessment of the effects of the most widely used benzodiazepine (flurazepam, flunitrazepam, temazepam, triazolam) and non-benzodiazepine (zopiclone and zolpidem) hypnotic drugs, based on the recording of polysomnographic variables. In the light of newly acquired neurophysiological data on the microstructure of sleep, this paper reconsiders the problem of insomnia and the current ideas on polysomnography and hypnotic drugs.

Adult↗
PubMed1981

Significance of hyperlactatemia in acute hypnotic drug poisoning.

Lactate concentration, fibrinogen and fibrin(ogen) -- degradation-products in central venous blood were analysed in 35 unconscious patient with acute hypnotic drug poisoning (HDP) and compared with the results in 13 healthy control persons undergoing the same degree of forced diuresis via central venous catheters. Blood samples were taken on admission and at 12 h intervals up to 36 h after admission. Patients with HDP were attributed to the categories of moderate intoxications (n = 17) and severe intoxications (n = 18) according to their clinical condition. On admission, blood lactate was significantly higher in severe intoxication (3.90 +/- 2.94 mmol/l) as compared to the control group (1.25 +/- 0.17 mmol/l). Blood lactate was less elevated in moderate poisoning (2.74 +/- 1.22 mmol/l). Thirty-six hours after admission blood lactate was completely normalised in patients with moderate intoxication (1.19 +/- 0.69 mmol/l) but still significantly elevated in severely poisoned patients (2.26 +/- 1.48 mmol/l). Lactate concentration was above normal in 15 out of 17 patients with moderate and in 17 out of 18 patients with severe poisoning. A statistically significant linear correlation existed between the duration of unconsciousness and the maximal lactate concentration within 12 hrs after admission. For fibrinogen concentrations statistically significant differences were observed neither between groups nor across time. Titers of FDP were elevated in 9 out of 11 patients with moderate and to a higher degree in all patients with severe poisoning, indicating low rate DIC. Hyperlactatemia is a frequent finding in acute hypnotic drug poisoning. Blood lactate estimations may improve the evaluation of the severity of poisoning and the efficacy of therapeutic interventions.

Adult↗
PubMed1998

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.

Adult↗
PubMed2000

Agranulocytosis induced by pyrithyldione, a sedative hypnotic drug.

OBJECTIVE: Pyrithyldione, a sedative-hypnotic drug with a poor clinical pharmacological development, was associated with anecdotal cases of agranulocytosis in the 1940s in the USA, in the 1960s and 1970s in the ex-Democratic Republic of Germany and in the 1980s in Japan. We describe the estimation of the risk of agranulocytosis associated with its use in Spain, which led to its withdrawal from the market. METHODS: In collaboration with the haematology units of all the hospitals in a defined area (3.3-3.9 x 10(6) inhabitants), all cases of agranulocytosis meeting strict diagnostic criteria were identified. Each case - defined as an episode of agranulocytosis - was reviewed by a haematologist without knowledge of previous drug exposures. Cases and age-, gender- and hospital-matched controls were interviewed with a structured questionnaire about previous drug exposures. In addition, in order to estimate the risk of pyrithyldione-associated agranulocytosis through a case-population approach, its consumption among the cases was compared with its consumption among the general population. RESULTS: After a follow-up of 66.5 x 10(6) person-years, 330 cases of agranulocytosis (230 community cases) were assembled. Reliable information on previous exposures was obtained for 204 cases. They were compared with 1314 controls. Eleven patients (14 cases, 6.9%) and zero controls had been exposed to pyrithyldione. The adjusted OR was 200.11 (CI 95% 22. 62-infinity). All patients were female; none had a fatal outcome; three exhibited positive rechallenge; and all had concomitantly taken other drugs. Although pyrithyldione was a prescription-only medicine, only 8% had been dispensed with medical prescriptions. Assuming the worst case, i.e. that all the exposed cases could be attributed to pyrithyldione, the incidence was 35.6 cases per 100, 000 patient-years (95% CI, 18.9-60.9), which gives a risk ratio estimate of 109.6 (57.5-191.5) if compared with the incidence of agranulocytosis among the non-exposed population [3.26 cases (CI 95% 2.83-3.71) per 10(6) inhabitants and per year]. DISCUSSION: Pyrithyldione was viewed by pharmacists as a mild hypnotic, and apparently this had conferred to this drug an unjustified image of safety. The National Commission of Pharmacovigilance recommended to the Ministry of Health its withdrawal from the market when eight cases of agranulocytosis had been identified. However, it took more than 2 years to withdraw it, and six additional cases occurred in the study area. This illustrates the need for quick regulatory action when pharmacoepidemiological data suggest an unfavourable benefit/risk ratio.

Adult↗
PubMed2005

Phorbol ester differentiates the levels of [3H]MK-801 binding in rats lines selected for differential sensitivity to the hypnotic effects of ethanol.

These studies addressed the possible involvement between sensitivity to the hypnotic action of ethanol and function of the NMDA receptor. The studies were carried out using high-alcohol sensitive (HAS) and low-alcohol sensitive (LAS) rats, two rats having differential sensitivity to the acute hypnotic action of ethanol. The animal models were developed by a selective breeding experiment. Using a quantitative autoradiograph technique, it was demonstrated that [3H]MK-801 binding to the NMDA receptor was highest in hippocampus in both HAS and LAS rats, but significant [3H]MK-801 binding was also detected in cortex, caudate-putamen, and thalamus of HAS and LAS rats. The density of [3H]MK-801 binding was lower only in cerebellar granule layers of untreated HAS rats as compared to the same brain area in untreated LAS rats. Activation of protein kinase C (PKC) by 100 nM PDBu, increased [3H]MK-801 binding in cortex, caudate-putamen, thalamus, central gray, and cerebellum of HAS rats but activation of PKC did not influence [3H]MK-801 binding in LAS rats. These activation of PKC differentiates between [3H]MK-801 binding of HAS and LAS rats in frontal cortex (layer II-IV and cingulate), caudate-putamen, and ventral lateral thalamic nuclei. The basal level of PKC-gamma mRNA was higher in HAS rats than that of LAS rats. These results suggest that the activation of PKC potentiates NMDA receptor function of the rat line which is more sensitive to alcohol (HAS) but does not affect [3H]MK-801 binding of alcohol resistant (LAS) rats.

Animals↗
PubMed1988

Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites.

Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.

Administration, Oral↗
PubMed1980

The quantitative measurement of changes in EEG frequency spectra produced in the cat by sedative-hypnotics and neuroleptics.

The sedative-hypnotic secobarbital and the sedative-anti-anxiety agent, chlordiazepoxide and two neuroleptics, chlorpromazine and halopridol, were treated for effects on the EEG of the cat using broad-band frequency analysis of 6 brain sites. Dose-related, 'drug-=specific' effects were abstracted from the data by the use of multivariate statistical techniques. These demonstrated that the two neuroleptic agents produced very similar alterations in the EEG frequency spectrum which were distinctly different from those resulting from the administration of the sedative-hypnotic and the sedative-anti-anxiety agent. The time-course of the central activity of the 4 compounds was also depicted.

Animals↗
PubMed1986

5-(2-Cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB): correlation of hypnotic and convulsant properties with alterations of synaptosomal 45Ca2+ influx.

Male ICR mice (20-35 g) were given either 5-(2-cyclohexylideneethyl)-5-ethyl barbituric acid (CHEB) alone (10-15 mg/kg i.p.) or CHEB (25-75 mg/kg i.p.) after a 1 h pretreatment with phenobarbital (75 mg/kg i.p.). CHEB alone (10 mg/kg) produced excitatory behavior but not convulsive seizures. Higher doses (11-15 mg/kg) produced convulsive seizures resulting in death. Pretreatment with phenobarbital prevented seizure activity. Following phenobarbital pretreatment, CHEB in doses of 50 and 75, but not 25 mg/kg, resulted in hypnosis of 53 +/- 16 and 64 +/- 9 min duration, respectively. In vitro, CHEB (10-200 microM) significantly inhibited 'fast-phase' (3 s) K+-stimulated 45Ca2+ uptake into cerebrocortical synaptosomes. CHEB (10 and 100 microM) also significantly increased basal 45Ca2+ uptake. The addition of CHEB (50 and 100 microM) or pentobarbital (100 microM) to striatal synaptosomes inhibited 'fast-phase' K+-stimulated 45Ca2+ uptake and endogenous dopamine release. CHEB (10-200 microM), but not pentobarbital (100 microM), produced a time- and dose-dependent increase in the resting release of endogenous dopamine from striatal synaptosomes. The results of this study show that CHEB possesses hypnotic activity if its lethal convulsant actions are blocked. The hypnotic actions of CHEB appear to correlate with inhibition of voltage-dependent calcium channels in brain synaptosomes.

Animals↗
PubMed1994

Sleep disorders in bipolar depression: hypnotics vs sedative antidepressants.

Ninety-six patients with bipolar disorder who attended a lithium clinic were reviewed in a retrospective study. Sleep disorders were studied in 85 depressive episodes. Eighty-one percent of the subjects presented with insomnia; the mixed type being the most frequent (49%) followed by early awakening (25%). The evolution of depression in the patients was compared according to the treatment received for insomnia: sedative antidepressants vs other anxiolytic or hypnotic drugs. Fifteen percent of patients shifted to mania, this group more frequently receiving sedative antidepressants (p < 0.05). Moreover, the patients who had received sedative antidepressants as therapy for insomnia (N = 61) showed a tendency to have a shorter asymptomatic interval before the following relapse (13 months vs 19 months; p = 0.06). In view of these results, we consider that the use of sedative antidepressants as a treatment for insomnia during depressive episodes in bipolar patients could be a factor contributing to worse prognoses; in these cases it appears that the use of other hypnotic drugs would be more advisable.

Adult↗
PubMed1992

Characterization of the hypnotic effects of triazolam microinjections into the medial preoptic area.

We have previously reported that microinjections of the benzodiazepine hypnotic triazolam into the medial preoptic area (MPA) of the hypothalamus enhance sleep in rats. The present study further characterizes this effect, by examining its anatomical specificity, determining whether it is mediated by interaction with central benzodiazepine receptors, and assessing whether sleep induction is associated with changes in core temperature. It was found that microinjections of 0.25 and 0.5 micrograms triazolam into two nearby structures, the lateral preoptic area and diagonal band of Broca, failed to alter sleep. Total sleep time was enhanced by microinjection of triazolam into the MPA, and this effect was blocked by co-administration of the benzodiazepine receptor blocker RO 15-1788. Sleep enhancement by triazolam was not associated with significant alterations in core body temperature. These observations continue to suggest that the MPA may be a site which mediates the hypnotic effect of triazolam, and add to the growing body of data emphasizing the importance of hypothalamic function in the regulation of sleep and waking.

Body Temperature↗
PubMedDate not supplied

Learned taste aversions induced by hypnotic drugs.

Taste aversions reflect the association of drug-produced noxious interoceptive stimuli with distinctive tastes. In the present experiments, taste aversions to sweetened condensed milk were induced in rats by a wide range of doses of the hypnotic drugs, hexobarbital, amobarbital, chloral hydrate, flurazepam and methaqualone and by anesthetization with ethyl ether. Observation of changes in motor behavior following drug administration could not be used to predict the development of taste aversions. Despite the fact that hypnotic drugs have punishing properties, which these paradox is discussed in terms of procedural differences between taste aversion and self-administration experiments.

Animals↗
PubMed1986

Preclinical evaluation of behavioral deficits following hypnotic drug treatment.

Most hypnotic medications result in performance decrements, or "hangover effects," the morning after bedtime ingestion. However, the severity of hangover effects with new compounds is difficult to predict prior to clinical trials. This paper describes a preclinical procedure that is predictive of human hangover effects following bedtime ingestion of hypnotic medication. Four cebus monkeys were shaped to discriminate between two levers such that rapid responses following the cue light maximized the probability of reinforcement. Subsequently, performance was evaluated one hr (immediate condition) and 8 3/4 hr (delayed condition) after the administration of flurazepam, triazolam, pentobarbital and placebo. All drugs caused dose-dependent performance decrements in both conditions. Significantly higher doses of triazolam were required to impair performance during the delayed condition as compared to the immediate condition, but no such differences occurred with either flurazepam or pentobarbital. These findings parallel human data which indicate that sleep-inducing doses of flurazepam and many barbiturates, but not triazolam, cause performance decrements the morning after bedtime ingestion.

Animals↗
PubMed1988

Zolpidem-polysomnographic study of the effect of a new hypnotic drug in sleep apnea syndrome.

Clinical studies have shown that zolpidem, an original imidazopyridine derivative, induces and maintains sleep and does not have daytime side-effects. Polysomnography has revealed that this drug has several interesting qualities that benzodiazepines do not possess: stages 3-4 increase, stage 2 is unchanged or slightly reduced and no abnormal changes are detected on the EEG tracing. Like benzodiazepines, zolpidem slightly reduces REM sleep. The Multiple Sleep Latency Test confirmed that the drug does not cause daytime drowsiness. All the hypnotic drugs studied up to now worsen heavy snoring and obstructive sleep apnea syndrome. A controlled double blind cross-over trial assessed the effects of a single dose of zolpidem 20 mg on nocturnal breathing in patients with mild forms of sleep apnea syndrome. The results indicate that, at this dose, the drug does not overcome the existing contraindications to the use of hypnotics in this syndrome.

Humans↗
PubMed1988

Zopiclone, a cyclopyrrolone hypnotic: review of properties.

Zopiclone is a non-benzodiazepine hypnotic with a pharmacological spectrum of activity which resembles that of the benzodiazepines (BZD), but it binds to the GABA complex at a site different from the BZD receptor. Pharmacokinetic properties class ZPC in the category of hypnotics with intermediate-short half-life (5-7 hours) and explain the low incidence of unwanted effects reported. The influence of zopiclone 7.5 mg on sleep architecture is minimal. In healthy volunteers, the amount of deep sleep is increased. No depressant effect on respiratory function and no rebound effect has been demonstrated.

Azabicyclo Compounds↗
PubMed1996

Possible involvement of alpha 2-adrenoceptor on the hypnotic action of flunitrazepam.

This study examined whether the pharmacologic manipulation of catecholaminergic systems would affect the hypnotic action of flunitrazepam in rats. Flunitrazepam, a potent hypnotic, was used alone or in combination with alpha-methyl paratyrosine (alpha MPT), an inhibitor of the synthesis of catecholamines, and clonidine (CLN), an alpha 2-adrenoceptor agonist. Flunitrazepam significantly increased the amount of slow-wave sleep and the latency of paradoxical sleep (PS) and decreased the amount of PS. Administration of flunitrazepam to alpha MPT-treated rats significantly increased the number of sleep cycles and PS episodes as compared with flunitrazepam alone. Clonidine decreased total sleep time and significantly decreased PS. The association of flunitrazepam with CLN induced a decrease in PS and waking as compared with flunitrazepam alone. The possible involvement of noradrenergic mechanisms in modulating the effect of flunitrazepam on the rat sleep-waking cycle is proposed.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1993

A review of the utilization of sedative-hypnotic drugs in a general hospital.

A retrospective review of 493 patients treated during a single month in a general hospital in mid-Michigan revealed that a majority (84.2%) of them received prescriptions for sedative-hypnotic drugs. These were p.r.n. in 66% of cases and routine prescriptions in the remainder. Prescriptions were equally distributed across the specialties: internal medicine 15%, surgery 23%, family practice 19%, psychiatry 22%, and OB/GYN 20%. Flurazepam was the most frequently prescribed drug (48.4%), followed by triazolam (24.6%) and temazepam (12.2%). Actual utilization rates were highest among psychiatric patients (85%) and lowest in obstetrics (33%). The therapeutic rationale for prescribing sedative hypnotic agents to hospitalized patients is discussed.

Drug Prescriptions↗