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PubMed2004

Over-expression of the fyn-kinase gene reduces hypnotic sensitivity to ethanol in mice.

Our previous work indicated a role for fyn-kinase in mediating several ethanol- and GABA(A) agonist-mediated behaviors. In the present work we investigate behavioral sensitivity to ethanol and several GABA(A) compounds in mice that over-express fyn-kinase in forebrain to further characterize the role of this non-receptor tyrosine kinase in the mediation of ethanol sensitivity. Transgenic mice over-expressing fyn-kinase were tested for sensitivity to ethanol-induced loss of righting reflex and ethanol preference drinking using a two-bottle choice drinking paradigm. Loss of righting reflex induced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; GABA(A) agonist) and etomidate (GABA(A) positive allosteric modulator) were also assessed. Fyn over-expressing mice exhibited shorter durations of ethanol-induced loss of righting reflex in the absence of differences in the rate of blood ethanol clearance, and exhibited reduced ethanol preference drinking. The genotypes did not differ in initial sensitivity to ethanol-induced loss of righting reflex suggesting development of greater acute tolerance to this ethanol action. Fyn over-expressing and wild-type mice also did not differ in sensitivity to loss of righting reflex induced by THIP and etomidate. The present results suggest regional specificity for fyn-kinase in the modulation of ethanol and GABAergic behavioral sensitivity. Fyn-kinase over-expression in forebrain structures modulates ethanol's hypnotic actions, as well as ethanol preference and consumption. Moreover, fyn over-expression in forebrain does not alter hypnotic sensitivity to THIP or etomidate, supporting data from fyn null mutant mice suggesting that cerebellar structures mediate the hypnotic actions of these GABAergic compounds.

Animals↗
PubMed2005

Melatonin as a hypnotic: con.

The physiological roles of melatonin are still unclear despite almost 50 years of research. Elevated melatonin levels from either endogenous nocturnal production or exogenous daytime administration are associated in humans with effects including increased sleepiness, reduced core temperature, increased heat loss and other generally anabolic physiological changes. This supports the idea that endogenous melatonin increases nocturnal sleep propensity, either directly or indirectly via physiological processes associated with sleep. The article "Melatonin as a hypnotic--Pro", also in this issue, presents evidence to support this viewpoint. We do not entirely disagree, but nevertheless feel this is an overly simplistic interpretation of the available data. Our interpretation is that melatonin is primarily a neuroendocrine transducer promoting an increased propensity for 'dark appropriate' behavior. Thus, it is our view that exogenous melatonin is only hypnotic in those species or individuals for which endogenous melatonin increases sleep propensity and is consequently a dark appropriate outcome. Evidence supporting this position is drawn primarily from studies of exogenous administration of melatonin and its varied effects on sleep/wake behavior based on dose, time of administration, age and other factors. From this perspective, it will be shown that melatonin can exert hypnotic-like effects but only under limited circumstances.

Animals↗
PubMed1998

Mortality hazard associated with prescription hypnotics.

BACKGROUND: The American Cancer Society's Cancer Prevention Study II was a large survey designed primarily to examine cancer risks such as cigarette smoking. From the same survey and methods, data on usage of "prescription sleeping pills" in 1982 were examined. METHODS: Standardized mortality ratios were computed. Because sleeping pill use could be a proxy for other risk factors, cox proportional hazards models were computed to control for possible confounding factors as extensively as the data permitted. RESULTS: Men and women who reported taking prescription sleeping pills 30+ times in the past month had standardized mortality ratios of 3.18 and 2.82, respectively; controlling for 10-year age groups (p < 0.001). The standardized mortality ratios for usage 1-29 times/month were 1.8 and 1.48, respectively (p < 0.001). In proportional hazards models that controlled for 30 other risk factors and comorbidities simultaneously, the excess mortality risk associated with usage 30+ times per month remained significant, but hazard ratios were reduced to 1.35 for men and 1.22 for women. CONCLUSIONS: Use of hypnotics was associated with excess mortality. This methodology could not determine if hypnotic compounds caused the risks associated with their use, nor could the risks of individual compounds be determined. Since millions of Americans are currently taking hypnotics, long-term controlled trials are urgently needed to further guide both patients and physicians.

Adult↗
PubMed2003

Predicting longer-term outcomes following psychological treatment for hypnotic-dependent chronic insomnia.

OBJECTIVES: To identify predictors of treatment adherence, patient dropout, and treatment response among long-term hypnotic users recruited into a randomized controlled trial of psychological treatment for insomnia. METHODS: Of 108 treatment and 101 control patients initially recruited, 37 treatment group patients (34.3%) failed to complete all 6 sessions (i.e., were nonadherent), while across both groups 61 (29.2%) patients failed to return postal assessments at 3-month follow-up (i.e., dropped out). Relationships between baseline characteristics and adherence (adherent vs. nonadherent) and attrition (dropout vs. nondropout) were examined in discriminant models. Relationships between baseline characteristics and treatment response (sleep quality, sleep latency, sleep efficiency, and hypnotic drug use) were examined in a series of multiple regression models. RESULTS: Adherent patients showed a significantly greater severity of pretreatment sleep disturbance, as measured by the Pittsburgh Sleep Quality Index (PSQI). Dropout at 3 months was associated with significantly lower perceived health status at baseline. In the regression models, lower Cure/Control subscale scores from the Illness Perception Questionnaire (IPQ) predicted greater posttreatment improvements in sleep efficiency and PSQI scores, while lower baseline anxiety scores predicted a posttreatment increase in hypnotic-free nights/week. CONCLUSION: In routine clinical practice settings, higher anxiety and a less positive attitude towards symptom control were associated with poorer treatment response. Adherence and attrition show a different pattern of associations, with greater need (as indexed by insomnia severity) predicting higher levels of service uptake and poorer general health predicting a higher likelihood of dropout.

Adult↗
PubMed2003

Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade.

The role of the adenosine A(2A) receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A(2A) receptor-deficient mice (A(2A)R KO) than for wild-type mice (A(2A)R WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A(2A)R KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A(2A)R WT but not in A(2A)R KO mice. SCH 58261, a selective A(2A) receptor antagonist, unlike DPCPX, a selective A(1) receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A(2A) receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A(2A) receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.

Adenosine A1 Receptor Antagonists↗
PubMed2000

Zaleplon: a pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia.

BACKGROUND: Insomnia is the subjective complaint of poor sleep or an inadequate amount of sleep that adversely affects daily functioning. For the past 4 decades, treatment of insomnia has shifted away from the use of barbiturates toward the use of hypnotic agents of the benzodiazepine class. However, problems associated with the latter (eg, next-day sedation, rebound insomnia, dependence, and tolerance) have prompted development of other agents. OBJECTIVE: This review describes the recently approved nonbenzodiazepine agent, zaleplon. METHODS: Studies of zaleplon were identified through a search of English-language articles listed in MEDLINE and International Pharmaceutical Abstracts, with no limitation on year. These were supplemented by educational materials from conferences. RESULTS: The efficacy and tolerability of zaleplon have been documented in the literature. Zaleplon has been shown to improve sleep variables in comparison with placebo. Like most hypnotic agents, zaleplon can be used for problems of sleep initiation at the beginning of the night, but its short duration of clinical effect may also allow patients to take it later in the night without residual effects the next morning. Zaleplon can be taken < or = 2 hours before awakening without "hangover" effects. It is generally well tolerated, with headache being the most commonly reported adverse event in clinical trials (15%-18%). Compared with flurazepam, a long-acting benzodiazepine sedative-hypnotic agent, zaleplon causes significantly less psychomotor and cognitive impairment (P < 0.001). Zaleplon has not been studied in pregnant women or children. The dose of zaleplon should be individualized; the recommended daily dose for most adults is 10 mg. CONCLUSIONS: Insomnia has a substantial impact on daily functioning. If pharmacologic treatment is indicated for insomnia, the choice of an agent should be guided by individual patient characteristics.

Acetamides↗
PubMed1990

Identification and differentiation of barbiturates, other sedative-hypnotics and their metabolites in urine integrated in a general screening procedure using computerized gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure is described for the identification and differentiation of sedative-hypnotics and their metabolites in urine. The following 24 barbiturates and thirteen other hypnotics could be detected: acecarbromal, allobarbital, amobarbital, aprobarbital, barbital, brallobarbital, bromisoval, (sec)butabarbital, butalbital, butobarbital, carbromal, clomethiazole, crotylbarbital, cyclobarbital, cyclopentobarbital, diethylallylacetamide, dipropylbarbital, glutethimide, guaifenesin, ethinamate, heptabarbital, hexobarbital, meprobamate, methaqualone, metharbital, methohexital, methylphenobarbital, methyprylone, pentobarbital, phenobarbital, propallylonal, pyrithyldione, secobarbital, thiobutabarbital, thiopental, vinbarbital and vinylbital. The procedure presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs detecting over 300 drugs and over 1000 of their metabolites. It includes cleavage of conjugates by acid hydrolysis, isolation by liquid-liquid extraction, derivatization by acetylation, separation by capillary gas chromatography, and identification by computerized mass spectrometry. Using mass chromatography with the selected ions m/z 83, 117, 141, 167, 169, 207, 221 and 235, the presence of barbiturates, other hypnotics and/or their metabolites was indicated. The identity of positive signals in the reconstructed mass chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The sample preparation, mass chromatograms, reference mass spectra and gas chromatographic retention indices are documented.

Acetylation↗
PubMed1991

[Benefits and risks of hypnotics].

Rationalisation of the war of hypnotics has recently been under discussion in France: a review of the benefits and risks of these substances may therefore be useful. Chronic insomnia is a result of multiple factors, among which individual characteristics of the personality play an important role. Hypnotic treatment is symptomatic; its beneficial influence on sleep progressively vanishes in few weeks, while some negative residual effects on daytime functioning (mood, alertness, performance, memory impairment) may persist. The main problems posed by hypnotic treatment with benzodiazepines are related to tolerance effects during the treatment period and to rebound insomnia and withdrawal phenomena after discontinuation. Practical issues for the treatment of insomnia, based on international consensus, are presented.

France↗
PubMed1988

[Reflections on the place of polygraphic recordings in the study of hypnotic drugs].

Polygraphic recordings are important for studying a new hypnotic molecule. Night recordings are used in the assessment of the objective hypnotic effect over short and long-term periods. They show sleep architecture modifications caused by the hypnotic drug and quantify rebound insomnia following abrupt withdrawal. The comparative usefulness of sleep laboratory recordings and ambulatory monitoring is discussed. Polygraphic recordings also allow to evaluate diurnal residual effect upon vigilance. Twenty-four-hour recordings as well as multiple sleep latency test (MSLT) are used.

Humans↗
PubMed2000

Mechanism of action of the hypnotic zolpidem in vivo.

Zolpidem is a widely used hypnotic agent acting at the GABA(A) receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to alpha 1-GABA(A) receptors, an intermediate affinity to alpha(2)- and alpha(3)-GABA(A) receptors and fails to bind to alpha(5)-GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying alpha1(H101R) mice, which possess zolpidem-insensitive alpha(1)-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by alpha(1)-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by alpha(1)-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on alpha(1)-GABA(A) receptors and not on alpha(2)- or alpha(3)-GABA(A) receptors.

Animals↗
PubMed2000

Small dose midazolam or droperidol reduces the hypnotic dose of propofol at the induction of anaesthesia.

We investigated the effect of a small dose of midazolam, ketamine, droperidol or lidocaine on the propofol dose required for hypnosis during induction of general anaesthesia. These drugs were randomly administered to 100 patients about to undergo scheduled surgery. Propofol was then infused at a rate of 250 microg kg-1 min-1 and the hypnotic dose to produce hypnosis was evaluated. Midazolam (20 microg kg-1) and droperidol (20 microg kg-1) significantly reduced the mean hypnotic dose of propofol (mean) S.D.) compared with the placebo (43.7 +/- 17.8 mg, 61.9 +/- 10.6 mg and 72.5 +/- 27.7 mg after pretreatment with midazolam, droperidol and placebo, respectively), whereas ketamine (0.1 mg kg-1) and lidocaine (1 mg kg-1) did not significantly affect the hypnotic dose of propofol (63. 1 +/- 25.6 mg and 65.1 +/- 24.8 mg, respectively). Only midazolam when compared with saline administration, (176 +/- 66 s and 298 +/- 126 s, respectively), shortened the time to achieve hypnosis. The changes in blood pressure (non-invasive) and heart rate were not significantly different in all groups during the induction of anaesthesia and oro-tracheal intubation. These results raise the possibility that new combinations of central nervous system drugs, such as droperidol and propofol, have a potential to reduce the dose of intravenous anaesthetics, including propofol, that produce hypnosis without significant adverse effects.

Adjuvants, Anesthesia↗
PubMed2002

Situation and problem of administration methods and the intermission of hypnotics.

The results of a questionnaire survey suggested four problems that might prolong the administration of benzodiazepine hypnotics without suspending the medication. First, psychiatrists did not actively consider the necessity of suspension of medication with hypnotics. Second, the period between improvement of insomnia and initiation of dose reduction was long, whereas the period between initiation of dose reduction and discontinuation was short. Third, to suspend medication of a hypnotic, every-other-day administration was used for the very short-acting and short-acting types, and substitution of the intermediate-acting or long-action type for the drugs with a short half-life were performed frequently. Finally, dose reduction and intermission of medication induced rebound insomnia, withdrawal symptoms, and recurrence of insomnia.

Adult↗
PubMed1998

The intermediate stage and paradoxical sleep in the rat: influence of three generations of hypnotics.

Paradoxical sleep in the rat, cat and mouse is preceded and sometimes followed by a short-lasting intermediate stage characterized by high-amplitude anterior cortex spindles and low-frequency hippocampal theta rhythm. Several neurophysiological arguments suggest that the intermediate stage corresponds to a brief functional disconnection of the forebrain from the brainstem. This paper is devoted to the review of quantitative and qualitative influences of three generations of hypnotics on the intermediate stage-paradoxical sleep couple. Barbiturates, first-generation hypnotics, extend the intermediate stage at the expense of paradoxical sleep. Three benzodiazepines are compared, two with a short half-life (triazolam and midazolam) and one with a long half-life (diazepam). They also decrease sleep occurrence latency and increase the intermediate stage at the expense of paradoxical sleep, except for midazolam, which increases both the intermediate stage and paradoxical sleep at low dose. Zolpidem and zopiclone, hypnotics of third generation, decrease paradoxical sleep but the intermediate stage never substitutes for paradoxical sleep. The results are discussed in relationship to the functional aspects of this turning-point period of sleep.

Animals↗
PubMed1999

Studies on the sedative and hypnotic effects of oleamide in mice.

The hypnotic and sedative effects of oleamide (CAS 301-02-0) were studied in mice. Intraperitoneal injection of oleamide showed a time-related inhibition of the locomotor activity with the maximum effect appearing 30 min after drug administration. Oleamide, at the dose range of 43.7-700 mg/kg, dose-dependently inhibited the locomotor activity in mice. Oleamide could promote the hypnotic action induced by sodium pentobarbital. The interaction studies showed that oleamide potentiated the inhibitory effect of diazepam (CAS 439-14-5) and antagonized the stimulatory effect of ethanol, methamphetamine, and caffeine, respectively. These results provide further evidence for the hypnotic and sedative effects of oleamide, suggesting a potential therapeutic usefulness of this fatty acid amide.

Animals↗
PubMed2001

High use of sedatives and hypnotics in ethnic minorities in Sweden.

OBJECTIVE: To study use of analgesics, and psychotropic drugs in relation to health indicators in four ethnic minorities in Sweden in comparison with Swedish-born. DESIGN: Cross-sectional study based on data from the Survey of Living Conditions and Immigrant Survey of Living Conditions in Sweden in 1996. STUDY POPULATION: Random samples of 1890 Swedish residents, in the age range 27-60 years, born in Chile, Poland, Turkey and Iran and 2452 age-matched Swedish-born residents. RESULTS: A two fold higher use of prescribed analgesics and antidepressants and a five to sixfold higher use of hypnotic and sedative drugs was demonstrated in members of ethnic minorities in Sweden in comparison with Swedish-born. In a multivariate analysis the higher use of prescribed analgesics and antidepressants was explained almost entirely by a higher morbidity in the minority study groups. A twofold higher use of sedatives and hypnotics was demonstrated in the minority study populations compared to the Swedish-born sample even after adjustment for extensive indicators of psychiatric and physical health in the multivariate analysis. CONCLUSIONS: The higher use of sedatives and hypnotics in relation to health in the minority samples in the present study indicates a differential treatment of minor psychiatric disorders of members of ethnic minorities in Swedish health services. Further studies that yield more qualitative data regarding the interaction of Swedish physicians with migrant patients are needed to explain these differences and to create a basis for intervention.

Adult↗
PubMed2002

Is there an interaction between self-rated health and medication with analgesics and hypnotics in the prediction of disability pension?

AIMS: Several studies have shown that self-rated health (SRH) is associated with drug use. The aim of this study was to investigate the possible interaction between SRH and use of analgesics and hypnotics and its ability to predict disability pension. METHODS: In 1974-78. complete birth-year cohorts of middle-aged male residents in Malmö, Sweden, were invited to a health screening, and the cohort in this study comprised 5,798 men with complete data followed up for 11 years. RESULTS: At inclusion, 27% rated their health as less than perfect, 11% used analgesics, 3% used hypnotics and, during follow-up. 12% received a disability pension. The adjusted hazard ratios of disability pension were 3.1 (CI: 2.6, 3.6) for those who had rated their health as less than perfect and 2.7 (2.3, 3.2) for subjects who used analgesics and/or hypnotics. For subjects with the combined risk of poor SRH and medication, the hazard ratio was 5.5 (4.6, 6.5). The granting of disability pension attributable to the interaction between poor SRH and medication was estimated at 47%, which was statistically significant. CONCLUSIONS: Disability pension among middle-aged men was associated with self-rated health as well as medication and clear evidence of synergism between the two factors was found, while there were no indications of medication acting as a causal link between poor SRH and disability pension. Several mechanisms may contribute to the findings, but the information gained may be used as means to identify those at risk for disability pension.

Adolescent↗
PubMed1990

Benzodiazepine hypnotics and insomnia.

In summary, it is proposed that the more frequent or severe side effects associated with the newer triazolo-benzodiazepines are related to an interaction of several factors, including rapid elimination, high receptor-binding affinity, and unique chemical properties. Among benzodiazepine hypnotics, triazolam has a unique side effect profile for CNS adverse reactions in regard to type, frequency, and severity. All of the three factors mentioned contribute to this side effect profile: rapid elimination (the shortest half-life among benzodiazepine anxiolytics and hypnotics); high receptor-binding affinity (the highest among benzodiazepine anxiolytics and hypnotics); and unique chemical properties as a triazolo-benzodiazepine. Given these three factors, the drug's side effects can be understood as follows: Hyperexcitability states (daytime anxiety during drug administration and rebound insomnia following withdrawal) are related primarily to its rapid elimination and secondarily to the other two factors, whereas cognitive impairments (amnesia, confusion, and psychiatric symptoms) are related to the high binding affinity and unique chemical properties as well as to its rapid elimination. In contrast, benzodiazepines that are slowly eliminated and have only relatively moderate receptor-binding affinity (flurazepam) are unlikely to produce daytime anxiety and rebound insomnia and CNS adverse reactions such as cognitive impairment. The most common side effect, daytime sedation, is easily recognized and can be managed by dose reduction and/or intermittent use. This safety profile combined with the drug's high degree of efficacy both initially and with continued use provides a high benefit-risk ratio in using the drug in the adjunctive pharmacologic treatment of insomnia. Similarly, temazepam, which has relatively weak receptor-binding affinity produces very few CNS adverse reactions. Furthermore, temazepam (15 mg) is more efficacious than triazolam (0.25 mg). However, temazepam is not as effective as flurazepam, because it is slowly absorbed and therefore has limited efficacy for sleep induction. On the other hand, triazolam's safety profile of frequent and severe adverse reactions combined with the lack of efficacy for the current dose of 0.25 mg limits the drug's usefulness. In fact, the 0.25-mg dose has such a poor benefit-to-risk ratio that there is a real question as to whether the drug should remain on the market.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Anxiety Agents↗
PubMedDate not supplied

A role for valproate in the treatment of sedative-hypnotic withdrawal and for relapse prevention.

In the human central nervous system, the gamma-aminobutyric acid (GABA) type A receptor complex undergoes changes with both acute and chronic exposure to sedative-hypnotic drugs. These changes contribute to both the acute effects of these drugs as well as the chronic effects of sedative-hypnotic dependence, withdrawal, and drug craving. Clinically these chronic effects are difficult to treat in patients dependent on ethanol or benzodiazepines. Valproate may return the GABA type A receptor function to a state more closely resembling its normal function. By this mechanism, it is possible to reduce the symptoms of sedative-hypnotic withdrawal and relapse.

Chronic Disease↗