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N3-Phenacyl-N1-substituted uracils 3a-q were synthesized by introduction of substituents at the N1-position of N3-phenacyluracil 2, and their hypnotic and sedative activities were evaluated. Pharmacological activities of these N3-phenacyl-N1-substituted uracils were examined using hypnotic activity and synergistic effects with pentobarbital or diazepam for the hypnotic and sedative activities.
This paper reviews the available literature on the use of melatonin as a hypnotic in normal volunteers and in patients with noncircadian insomnias. Data are ordered in terms of studies of subject self-reports and polygraphic data and are seen in the context of generally accepted criteria for assessment of clinically used hypnotics. It is concluded that, at the present time, there is very little systematic evidence to suggest that melatonin has significant hypnotic efficacy in these populations.
The effects of an ultra-rapidly eliminated hypnotic (midazolam 7.5-15.0 mg; mean elimination half-life approximately 2 h) and a rapidly eliminated hypnotic (brotizolam 0.125-0.25 mg; mean elimination half-life approximately 5 h) were studied on transient insomnia induced by sleeping in a reclining seat. Rest in the seat did not lead to delay in sleep onset, but there was increased wakefulness and drowsy sleep and less REM sleep. There were no differences in wakefulness or drowsiness between sleep with drugs in the seat and with placebo in bed, but with midazolam, though not with brotizolam, there was a reduction in REM sleep less than or equal to 300 min after sleep onset. Ultra-rapidly and rapidly eliminated compounds used in the management of transient insomnia should be given in doses that are as free as possible from central nervous system depression as indicated by suppression of REM sleep during the early part of the night. Low doses of ultra-rapidly eliminated drugs are indicated for sleep-onset insomnia and for short periods of sleep, while rapidly eliminated hypnotics with elimination half-lives of approximately 5 h have the potential to sustain sleep free of residual effects.
UNLABELLED: Although clonidine has both hypnotic and analgesic actions, the dose relationship for each actions is still unknown in a clinical setting when clonidine is used as a premedication in children. We studied 80 ASA physical status I children (age range, 3-8 yr). Subjects were randomly divided into two groups (minimum alveolar anesthetic concentration [MAC]-Awake group, n = 40; MAC-Tetanus group, n = 40). Each patient received one dose of clonidine from 1 to 5 microg/kg orally, 100 min before arrival at the operating room. Anesthesia was induced and maintained with sevoflurane in oxygen and air. Before tracheal intubation, end-tidal sevoflurane was decreased stepwise by 0.2% at the start of 1.2%, a verbal command was given to the patients, and MAC-awake was determined in each patient. We also investigated MAC-tetanus, determined with transcutaneous electric tetanic stimulations, after tracheal intubation in each patient by observing the motor response to a transcutaneous electric tetanic stimulus to the ulnar nerve at a sevoflurane concentration decreased stepwise by 0.25% at the start of 2.75%. The initial reduction in MAC-tetanus was not as steep as that in MAC-awake. Clonidine reduced MAC-tetanus by 40% at the maximal dose of 5 microg/kg, whereas MAC-awake was already reduced by 50% at 2 microg/kg. We conclude that separate dose-response relationships for oral clonidine are present regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia. IMPLICATIONS: Separate dose-response relationships for oral clonidine were found regarding the hypnotic and analgesic effects in children undergoing sevoflurane anesthesia.
OBJECTIVE: To clarify whether tumor necrosis factor (TNF)-alpha modulates the inhibitory effect of clinically applied hypnotics and sedatives on neutrophil function. DESIGN: Prospective, randomized, controlled, dose response, in vitro study. SETTING: A university research laboratory. SUBJECTS: Neutrophils from healthy human volunteers. MEASUREMENTS AND MAIN RESULTS: Neutrophils were primed by incubation with TNF-alpha (25 ng/mL) for 15 mins. Subsequently, TNF-alpha-primed neutrophils were incubated with two concentrations of commercially available drug preparations and drug-free solutions, respectively. The following commercially available preparations of hypnotics and sedatives as well as their corresponding drug-free solutions were tested: methohexital, thiopental, midazolam, diazepam, etomidate, and propofol. The production of oxygen radicals was initiated by adding N-formyl-methionyl-leucyl-phenylalanine (FMLP) 10(-7) mol/L and detected by luminol-enhanced chemiluminescence measurements for 15 mins. Within the range of therapeutic plasma concentrations, only thiopental, diazepam, and propofol suppressed chemiluminescence of unprimed neutrophils. Additionally, propofol alone suppressed TNF-alpha-primed neutrophils. Hypnotics and sedatives were unable to suppress oxygen radical production of TNF-alpha-primed neutrophils below the level of their control activity, measured in FMLP-induced unprimed neutrophils in the absence of the respective drug or drug-free solution. However, the effect of etomidate could not be evaluated secondarily to effects mediated by its drug-free solution. In a cell-free chemiluminescence system, thiopental and propofol demonstrated scavenging of oxygen free radicals. CONCLUSIONS: Priming with TNF-alpha counteracts the inhibitory effect by certain drugs for oxygen radical formation by FMLP-stimulated neutrophils. Thus, TNF-alpha plus FMLP mediate additive effects in stimulating oxygen radical formation in neutrophils. The following drugs dose-dependently interfere with these activating pathways: thiopental, diazepam, and propofol. Additionally, thiopental and propofol have efficient oxygen-scavenging properties and may attenuate radical-mediated tissue destruction in hyperinflammatory syndromes.
In a double-blind, placebo-controlled crossover trial, propranolol 80 mg did not show any hypnotic properties and even increased the insomnia in a sample of 37 patients previously treated chronically with hypnotic medication (mostly benzodiazepines). This worsening of the insomnia is consistent with the observations of sleep disturbance at the beginning of treatment with beta-blocking drugs. This lack of efficacy suggests that the anti-stress or anxiolytic properties of propranolol do not apply to the rebound insomnia seen when stopping treatment with hypnotic drugs.
The effect of temazepam as a hypnotic was assessed with two different formulations, the solution-filled soft gelatin capsule and the more recently introduced elixir. Sixty psychiatric in-patients were included in the trial and 59 completed it. The study followed a double-blind crossover design for two consecutive nights. Patients took a capsule and elixir each night, but only one would contain the active ingredient (in a dose of 20 mg temazepam). In contrast to earlier work with volunteers, the elixir failed to reveal more of the characteristics of an ideal hypnotic. In fact, in those measures that were statistically significant, the balance favoured the capsule. We conclude that although there are many situations where an elixir is clearly clinically preferable, the essential hypnotic effect of the elixir is not conspicuously different to that of the capsule.
The appropriate use of hypnotics requires an understanding of the nature of the patient's insomnia and lifestyle. In the context of occupational medicine, the potential effects of these drugs on job skills and the persistence of such effects are also important considerations. This report reviews the factors that must be considered in the investigation of impaired performance due to hypnotics and the pharmacokinetic properties that determine the persistence of action of these drugs. Sleep disturbance associated with transmeridian flights (jet lag) is used to illustrate the place of hypnotics in the management of a transient form of insomnia.
BACKGROUND: Acute functional tolerance (AFT) to ethanol-induced hypnosis is one of the main factors that affect the duration of ethanol-induced loss of righting reflex (LRR: "sleep time"). Investigators who use duration of LRR as a measure of ethanol-induced sedation should consider the potential magnitude and time course of this neuroadaptation when interpreting their results. However, AFT to the hypnotic effects of ethanol has not been well characterized. The present study explored this form of AFT using a novel method of monitoring LRR in mice. METHODS: Genetically heterogeneous mice were used to study effects of dose and time on the development of AFT. Mice were treated with different dose regimens and tested for LRR after hypnotic doses using a cylindrical restrainer. Measures of initial sensitivity and AFT to ethanol-induced hypnosis were calculated and analyzed. Inbred strains of mice were then characterized for AFT magnitude after a single ethanol dose. RESULTS: Results showed that (a) AFT developed in a dose-dependent fashion but attained an apparent maximum value; (b) AFT to ethanol-induced hypnosis could develop partially after a small, subhypnotic dose; (c) AFT developed very rapidly and approached its maximum for a given dose by the 10th min after injection of ethanol; and (d) AFT has a strong genetic component. CONCLUSION: Although specific for AFT to the hypnotic effects of ethanol, the present findings expand general knowledge about acute tolerance and should also be useful for investigators who use loss of righting reflex as a measure of ethanol sensitivity.
The results of previous studies suggested that the sleep-time differential between long-sleep (LS) and short-sleep (SS) mice decreases for a series of sedative-hypnotic drugs as lipid solubility increases. Using the LS x SS recombinant inbred (RI) strains, we have tested whether this relationship arises because of common genetic influences on the sleep-time responses or was simply a fortuitous difference between LS and SS mice. Mice were sleep-time tested after intraperitoneal injections of a variety of sedative-hypnotic drugs that vary in lipid solubility including alcohols, barbiturates, chloral hydrate, and urethane. Sleep-time values from each of these drugs were compared with ethanol-induced sleep times in the LS x SS RI strains. Significant genetic correlations were observed between ethanol-induced sleep time and those responses elicited by butanol, propanol, and chloral hydrate, but not by pentobarbital or secobarbital. When the partition coefficient (log P) values were compared with the genetic correlations, a significant relationship (r = -0.85) was observed. These data suggest that common genes mediate sedative-hypnotic reactions to ethanol and some drugs resembling it in log P value, and that anesthetic agents with low lipid solubility may be working through different mechanisms than drugs with greater lipid solubilities.
The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n-propanol, and n-butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.
OBJECTIVES: Prescriptions of sedatives, hypnotics, and antianxiety medications have decreased over the past 15 years. However, racial differences have not been well investigated in controlled analyses. DESIGN: A prospective cohort study. SETTINGS AND PARTICIPANTS: The authors analyzed data from a community-based, biracial cohort of older adults (n = 4,000 at baseline) followed for 10 years to determine sociodemographic and health characteristics associated with the use of these medications between 1986 and 1996. MAIN OUTCOME MEASURES: Information about sedative, hypnotic, and antianxiety medication use and demographic and health characteristics was obtained from a race-stratified, probability-based sample of black and white community-dwelling older adults in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. RESULTS: A total of 13.3% of the subjects were taking these medications in 1986, with the frequency of use declining only to 11.8% in 1996 despite the cohort aging 10 years. Correlates of use at baseline were female gender, white race, depressive symptoms, poor self-rated health, impaired physical function, and health services use. These correlates persisted for each of the three follow-up waves of the survey. In 1996, the odds for being white and using these medications was 4.70 in controlled analyses. CONCLUSIONS: Despite the overall decline in the use of sedative, hypnotics, and antianxiety agents in the general population in recent years, over the 10 years of this survey, an aging cohort continued to use these medications at a frequency greater than the general population and did not demonstrate a significant decline in use. Factors unrelated to health status, specifically being white, were among the strongest correlates of use throughout the years of follow-up.
Expert bodies have long advised that use of hypnotic drugs should be limited to short courses for acutely distressed patients and should generally be avoided in elderly people. Despite this, more than 10 million prescriptions for hypnotics continue to be dispensed each year in England alone, mostly for benzodiazepines and drugs with similar actions such as zaleplon, zolpidem and zopiclone (so called 'Z-drugs'). Around 80% of all such prescriptions are for people aged 65 years or over, and many patients remain on the drugs for months or years. Such prescribing carries many potential hazards for patients, including risk of dependence, accidents and other adverse effects on health. Here we review how the risks from hypnotic drugs can be minimised.
Requests for night sedation and the use of placebo as first line drug management were studied prospectively in 1174 consecutive elderly hospital in-patients. Of the 390 (33.2%) patients requesting sleeping pills in hospital, 37 were subsequently satisfied without the prescription of additional medication. A further 216 patients were entirely satisfied with a placebo capsule during all of their hospital stay. An 'active' hypnotic drug was required by only 137 patients, many of whom were noisy and disturbing other patients in the ward. Most of the active hypnotic drugs prescribed to elderly hospital patients are unnecessary and a majority of those requesting hypnotics consistently respond to placebo. There remains a need for greater education of patients, nurses and doctors in the non-pharmacological management of sleep disorders.
Two ultrashort-acting hypnotics, triazolam 0.25 mg and zolpidem 10 mg, were studied for their effects on equilibrium function in humans. Eight healthy male subjects participated in a double-blind, placebo-controlled study after informed consent. They subjected to static equilibrium tests, oculomotor tests and an assay of drug concentrations in the blood. Zolpidem was statistically significant in postural sway in tandem stance test, as defined by parametric values of tracing sum length and polygonal area of foot pressure center measured by a gait analysis system. In the tandem stance test, triazolam was statistically significant in postural sway only as defined by the polygonal area. However, in the Romberg test, the only statistically significant difference in zolpidem use was observed in polygonal area values. Blood concentrations of triazolam and zolpidem were found to closely correlate with the extent of postural sway in both tandem stance and Romberg tests. In this study, zolpidem with minimal muscle-relaxant effect incurred imbalance more extensively than triazolam, which is known for its effect of muscle relaxation. In addition, gaze deviation nystagmus was observed only in zolpidem use in 5 of 8 subjects (62.5%). From these results, it is suggested that in the use of hypnotics, sway derives from the suppression of the central nervous system relevant to awakening rather than from muscle relaxation. The prior reference to blood concentrations of hypnotics should help improve safety care in minimizing loss of balance control and possible fall.
One hundred and forty-seven patients requiring a hypnotic, took soft gelatine capsules containing 10 mg temazepam (Euhypnos) 10-30 mg at night, for up to twelve weeks. One hundred and thirty-three patients (90-5%) completed twelve weeks on drug. Hypnotic performance was rated Good or Very Good in 90% of their assessments and 93-2% of the assessments recorded no hangover effect. Adverse reactions were occasional headaches and nausea. There were no drug-related accidents. One hundred and forty-two patients (96-6%) said there was no adverse effect on their work. Seven patients who did not complete twelve weeks resumed normal sleep patterns and had no further need for hypnotics.
In an open, multicentre study, the short-acting benzodiazepine hypnotic lormetazepam (Loramet) was administered nightly (1-2 mg p.o.) for a period of 7 nights to 665 out-patients with various types of sleep disturbances. The patients assessed the efficacy and acceptability of lormetazepam with the aid of a simple diary card and a set of visual analogue scales. The results showed that about 75% of the patients reported a significant improvement in their sleep pattern. The time to onset of sleep was decreased, the number of nocturnal wakings was reduced and the patients reported waking in the morning more refreshed and co-ordinated. The effects were significant after the first night and there were further significant improvements by the seventh night on the drug. In patients who had prior experience of other hypnotics, twice as many preferred lormetazepam to temazepam and three times as many preferred lormetazepam to nitrazepam. Nine patients withdrew from the study due to lack of efficacy and only fifteen patients dropped out following the occurrence of side-effects, mainly drowsiness and light-headedness. It was concluded that lormetazepam is an effective and highly acceptable hypnotic in patients with sleep disturbances.
BACKGROUND: Gamma-aminobutyric acid type A receptors (GABAA-Rs) are the major inhibitory receptors in the mammalian brain and are modulated by a number of sedative/hypnotic drugs including benzodiazepines and anesthetics. The significance of specific GABAA-Rs subunits with respect to behavior and in vivo drug responses is incompletely understood. The gamma2 subunit is highly expressed throughout the brain. Global gamma2 knockout mice are insensitive to the hypnotic effects of diazepam and die perinatally. Heterozygous gamma2 global knockout mice are viable and have increased anxiety-like behaviors. To further investigate the role of the gamma2 subunit in behavior and whole animal drug action, we used gene targeting to create a novel mouse line with attenuated gamma2 expression, i.e., gamma2 knockdown mice. RESULTS: Knockdown mice were created by inserting a neomycin resistance cassette into intron 8 of the gamma2 gene. Knockdown mice, on average, showed a 65% reduction of gamma2 subunit mRNA compared to controls; however gamma2 gene expression was highly variable in these mice, ranging from 10-95% of normal. Immunohistochemical studies demonstrated that gamma2 protein levels were also variably reduced. Pharmacological studies using autoradiography on frozen brain sections demonstrated that binding of the benzodiazepine site ligand Ro15-4513 was decreased in mutant mice compared to controls. Behaviorally, knockdown mice displayed enhanced anxiety-like behaviors on the elevated plus maze and forced novelty exploration tests. Surprisingly, mutant mice had an unaltered response to hypnotic doses of the benzodiazepine site ligands diazepam, midazolam and zolpidem as well as ethanol and pentobarbital. Lastly, we demonstrated that the gamma2 knockdown mouse line can be used to create gamma2 global knockout mice by crossing to a general deleter cre-expressing mouse line. CONCLUSION: We conclude that: 1) insertion of a neomycin resistance gene into intron 8 of the gamma2 gene variably reduced the amount of gamma2, and that 2) attenuated expression of gamma2 increased anxiety-like behaviors but did not lead to differences in the hypnotic response to benzodiazepine site ligands. This suggests that reduced synaptic inhibition can lead to a phenotype of increased anxiety-like behavior. In contrast, normal drug effects can be maintained despite a dramatic reduction in GABAA-R targets.