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PubMed1990

Kinetics of drug action in disease states. XXXIX. Effect of orally administered activated charcoal on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline administered intravenously to rats with renal failure.

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of phenobarbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Pharmacokinetics and anticonvulsant effect of a new hypnotic, CL 284,846, in rats.

PURPOSE: CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats. METHODS: CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection. RESULTS: Both the steady-state volume of distribution (1636 +/- 162 and 1804 +/- 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 +/- 7.1 and 22.2 +/- 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an Emax model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures. CONCLUSIONS: Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.

Acetamides↗
PubMed1998

Pilot evaluation of hypnotic medication during acute traumatic stress response.

Early intervention aimed at secondary prevention is a high priority for posttraumatic stress disorder (PTSD) research. Disrupted sleep may have a role in the initiation and maintenance of PTSD. Three of the participants were recruited from a surgical trauma service, and one had sought treatment in a psychiatric setting. All were within 1-3 weeks of trauma exposure and had acute PTSD symptoms that included disturbed sleep. Temazepam, a benzodiazepine hypnotic, was administered for 5 nights, tapered for 2 nights, and then discontinued. Evaluations 1-week after the medication had been discontinued revealed improved sleep and reduced PTSD severity. These observations suggest an approach that may be clinically useful and a need for more systematic trials.

Acute Disease↗
PubMed1985

Hypnotic efficacy of a modified triazolodiazepine, brotizolam.

Fifty-nine outpatients with insomnia were treated in a 3-week study to assess the safety and efficacy of a new triazolothienodiazepine with a short t1/2, brotizolam. Therapy was initiated with 0.25 mg at night, but by the end of the study all subjects who were receiving brotizolam were taking 0.50 mg. Results indicate brotizolam efficacy as measured by daily subject and weekly physician questionnaires in essentially all sleep parameters, including global subject and physician evaluation of treatment efficacy, sleep latency and sleep maintenance, and quality of sleep. Tolerance to the hypnotic action of brotizolam was not observed after 21 days of daily dosing.

Azepines↗
PubMed2003

Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data.

AIMS: The non-benzodiazepine hypnotics zolpidem and zopiclone, which are indicated for short-term treatment of insomnia, were considered originally by physicians as almost devoid of abuse and dependence potential. Several recent publications, however, have suggested that both agents carry a significant risk of abuse. To substantiate and re-evaluate this situation, the world literature was reviewed for cases of dependence of both agents; these cases were analysed in order to identify certain underlying patterns, if evident. METHODS: A systematic review based on a Medline literature search was conducted including the years 1966-2002 to assemble all available clinical case reports that were analysed for typical features of abuse and dependence according to prespecified criteria. Only case reports were of interest, and clinical studies were excluded. No limitations as to language or publication year were applied. The terms 'zolpidem', 'zopiclone' and 'abuse', 'dependence', 'addiction', 'withdrawal' and 'intoxication' were used to identify relevant publications. Potentially relevant citations were retrieved and assessed for inclusion independently by two authors. RESULTS: A total of 36 cases for zolpidem were identified, most of them reported in recent years, and 22 cases for zopiclone. Both sexes were involved to a similar extent; and cases were reported in all age groups. In extreme cases, dose increases reached a factor of 30-120 above the recommended doses. The majority of patients had a history of former drug or alcohol abuse and/or other psychiatric conditions. CONCLUSION: On the basis of world-wide prescription numbers, which are approximately twofold higher for zolpidem (1,338,774,000 tablets from June 2001 to June 2002 in Europe, Japan and United States) than for zopiclone (664,897,000 tablets during the same period in Europe and Japan), the relative incidence of reported dependence similar for both drugs and remarkably lower than that of benzodiazepines used for the treatment of disturbed sleep. The findings offer the conclusion that zolpidem and zopiclone are relatively safe drugs. However, as both drugs are psychotropic drugs, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse of these agents.

Adult↗
PubMed1976

[Treatment of severe hypnotic poisoning with extracorporeal haemoperfusion (author's transl)].

Four patients with severe hypnotic intoxication, twice after suicidal intake of barbital, once of barbital, methaqualone and carbromal, and once of carbromal, were treated with six activated charcoal haemoperfusions. Three patients showed rapid improvement in the level of consciousness followed by complete recovery. One female patient died in cerebral coma due to complete acute cerebromalacia following hypoxia. Serious complications due to the haemoperfusion did not occur. Correct use of activated charcoal haemoperfusion enriches the therapeutic spectrum of severe exogenous intoxications.

Adult↗
PubMed1977

[Radiological evidence and removal of tablet conglomerates in intoxication with bromide-containing hypnotics (author's transl)].

If large amounts of bromide-containing hypnotics are taken together, the tablets may conglomerate in the stomach. Because of the bromide, this is radiologically demonstrable. Conventional gastric lavage does not remove such conglomerates. In order to prevent long-term late absorption with serious complications such as hypothermia, shock-lung and renal failure, previously only gastrotomy had been an effective treatment. But using gastroscopy with lavage and aspiration, such conglomerates can be removed within one to three hours. Fifteen patients in whom this technique was used were rousable within 24 hours, significantly shortening the period of intoxication. At the same time, complications may be avoided. This is also true in instances where the tablet dosage would otherwise have been fetal.

Foreign Bodies↗
PubMed2002

Reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone, a new anticonvulsant and hypnotic drug, in mice. Fertility and peri- and post-natal studies.

The reproductive toxicity of gamma-ethyl-gamma-phenyl-butyrolactone (EPBL, CAS 53380-21-5), a new anticonvulsant and hypnotic drug, was investigated by performing fertility and peri- and post-natal studies in mice. In both studies, EPBL was administered by gavage at 0, 50, 10, or 200 mg/kg doses. The first study found parent toxicity as measured by reduced body weight at the higher dose. At the same dose, the number of live fetuses was decreased. However, neither male or female fertility nor the reproductive performance of mice were affected. The results of the second study showed that the only negative effects were a depression of maternal weight gain and a decrease in body weight of the litter at birth which was 200 mg/kg. A reduction in the survival rate was also seen. There was no evidence that treatment of F0 females from day 15 of pregnancy to day 21 post-partum affected either the reproductive capacity of the F1 offspring or the development of F2 progenies. The non observed effects levels (NOEL) for both studies can be estimated at 100 mg/kg.

4-Butyrolactone↗
PubMed1989

Can a rapidly-eliminated hypnotic cause daytime anxiety?

To test further the conclusions of preliminary reports that regular use of a rapidly-eliminated hypnotic might cause daytime anxiety, 82 women and 38 men, mean age 53, who claimed to be poor sleepers, took a capsule nightly for 45 nights. On 25 consecutive nights the capsule contained triazolam 0.5 mg (40 subjects), lormetazepam 2 mg (40 subjects) or continued placebo (40 subjects). Both drugs improved sleep, but compared with placebo or lormetazepam-takers, triazolam-takers became more anxious on self-ratings, were judged more often to have had a bad response by an observer, more often wrote down complaints of distress, and suffered weight loss. After about 10 days of regular triazolam they tended to develop panics and depression, felt unreal, and sometimes paranoid. The very short life of triazolam, leading to daytime withdrawal symptoms, may account for some of the observations, but enhancement of benzodiazepine inverse agonist activity is also hypothesized.

Adult↗
PubMed2001

Hormonal responses to exercise after partial sleep deprivation and after a hypnotic drug-induced sleep.

The aim of this study was to determine the hormonal responses, which are dependent on the sleep wake cycle, to strenuous physical exercise. Exercise was performed after different nocturnal regimens: (i) a baseline night preceded by a habituation night; (ii) two nights of partial sleep deprivation caused by a delayed bedtime or by an early awakening; and (iii) two nights of sleep after administration of either a hypnotic compound (10 mg zolpidem) or a placebo. Eight well-trained male endurance athletes with a maximal oxygen uptake of 63.5 +/- 3.8 ml x kg(-1) x min(-1) (mean value +/- s(x)) were selected on the basis of their sleeping habits and their physical training. Polygraphic recordings of EEG showed that both nights with partial sleep loss led to a decrease (P< 0.01) in stage 2 and rapid eye movement sleep. A delayed bedtime also led to a decrease (P < 0.05) in stage 1 sleep. Zolpidem had no effect on the different stages of sleep. During the afternoon after an experimental night, exercise was performed on a cycle ergometer. After a 10-min warm-up, the participants performed 30 min steady-state cycling at 75% VO(2-max) followed by a progressively increased workload until exhaustion. The recovery period lasted 30 min. Plasma growth hormone, prolactin, cortisol, catecholamine and lactate concentrations were measured at rest, during exercise and after recovery. The concentration of plasma growth hormone and catecholamine were not affected by partial sleep deprivation, whereas that of plasma prolactin was higher (P < 0.05) during the trial after an early awakening. Plasma cortisol was lower (P < 0.05) during recovery after both sleep deprivation conditions. Blood lactate was higher (P < 0.05) during submaximal exercise performed after both a delayed bedtime and an early awakening. Zolpidem-induced sleep did not affect the hormonal and metabolic responses to subsequent exercise. Our results demonstrate only minor alterations in the hormonal responses to exercise after partial sleep deprivation.

Adult↗
PubMed2006

Neighborhood social participation, use of anxiolytic-hypnotic drugs, and women's propensity for disability pension: a multilevel analysis.

AIMS: The increasing number of people on disability pension in Sweden is of concern for Swedish policy-makers, and there is a need for a better understanding of the mechanisms behind disability pension. We investigated (i) whether women living in the same neighborhood have a similar propensity for disability pension that relates to neighborhood social participation, and (ii) whether there is an association between anxiolytic-hypnotic drug (AHD) use and disability pension in women that is modified by the neighborhood context. METHODS: We used multilevel logistic regression with 12,156 women aged 45 to 64 (first level) residing in 95 neighborhoods (second level) in the city of Malmö (250,000 inhabitants), Sweden, who participated in the Malmö Diet and Cancer Study (1991-96). RESULTS: Both AHD use (OR = 2.09, 95% CI 1.65, 2.65) and neighborhood rate of low social participation (OR = 11.85, 95% CI 5.09, 27.58) were associated with higher propensity for disability pension. The interval odds ratio indicated that the influence of neighborhood social participation was large compared with the unexplained variance between the neighborhoods. The association between AHD use and disability pension was not modified by the neighborhood context. The median odds ratio was 1.44 after adjusting for individual characteristics and 1.27 after the additional adjusting for neighborhood social participation. CONCLUSIONS: Women living in the same neighborhood appear to have a similar propensity for disability pension, beyond individual characteristics, and this contextual effect seems largely explained by neighborhood social participation. In addition, AHD use might increase the propensity for disability pension in women.

Anti-Anxiety Agents↗
PubMedDate not supplied

Zolpidem involvement on memory and hypnotic effect of ethanol in chronically ethanol-treated rats.

Multiple (10x) treatment of zolpidem (1.0 or 2.0 mg/kg, orally, p.o.) led to different effects in chronically ethanol-treated and control rats. In control rats, after repeated zolpidem administration, a weaker, when compared to single administration, hypnotic effect of ethanol was observed, which may be the result of tolerance developed towards the inhibitory effect of zolpidem. However, in chronically ethanol-treated rats, the multiple zolpidem treatment led to prolongation of ethanol-induced sleep similar to the values observed in non-zolpidem-treated control animals. This suggests that zolpidem multiple administration may inhibit tolerance towards ethanol in chronically ethanol-treated rats. In the experiment with zolpidem, there were effects on performance in a memory test and the impairment of passive avoidance task after multiple drug treatment when compared to the effects after single administration in control rats. In contrast, in chronically ethanol-treated rats, amplification of latency (especially after 2.0 mg/kg) was observed. The possible relationship between ethanol-induced sedation and latency values would be consistent with a higher contribution of the inhibitory effect of zolpidem, than a direct influence on memory processes in chronically ethanol-treated rats.

Animals↗
PubMed1986

Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. A clinical study.

Patients receiving midazolam, temazepam or zopiclone by mouth as premedication for minor gynaecological surgery were pretreated with either ranitidine or an inert tablet. Pretreatment with ranitidine was associated with a greater degree of drowsiness at 20 and 40 min after midazolam, and a shorter mean time to peak hypnotic effect than in the non-pretreated group. Ranitidine did not affect the degree of drowsiness in the patients receiving temazepam or zopiclone.

Adolescent↗
PubMed2005

THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex.

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a selective GABA(A) receptor agonist with a preference for delta-subunit containing GABA(A) receptors. THIP is currently being tested in human trials for its hypnotic effects, displaying advantageous tolerance and addiction properties. Since its cellular actions in the neocortex are uncertain, we studied the effects of THIP on neurons in slices of frontoparietal neocortex of 13- to 19-day-old (P13-19) mice. Using whole-cell patch-clamp recordings, we found that the clinically relevant THIP concentration of 1 muM induced a robust tonic GABA(A)-mediated current in layer 2/3 neurons. In comparison, only a minute tonic current was induced by mimicking in vivo endogenous GABA levels. Miniature IPSCs were not affected by 1 muM THIP suggesting an extrasynaptic site of action. The EC(50) for THIP was 44 muM. In accordance with the stronger expression of delta-containing receptors in superficial neocortical layers, THIP induced a 44% larger tonic current in layer 2/3 than in layer 5 neurons. Finally, monitoring spontaneously active neocortical neurons, THIP caused an overall depression of inhibitory activity, while enhancing excitatory activity prominently. Our studies suggest that THIP activates an extrasynaptic GABA(A) receptor-mediated conductance in the neocortex, which may alter the cortical network activity.

Analgesics↗
PubMed1982

Characteristics of spindle activity and their use in evaluation of hypnotics.

The spindle activity of 10 healthy male adults, aged 20-24 years, was investigated over 7 consecutive nights. Spindle appearance showed a strikingly distinctive and reproducible pattern for each individual. There was no first-night effect and little night-to-night variation of spindle appearance rate per night. Eight male adults aged between 19 and 24 years were studied in an evaluation of methaqualone and flunitrazepam by an experimental schedule of 17 consecutive nights. Both drugs caused a significant increase of spindle activity expressed as appearance rate. By using spindle activity as a sleep parameter we could investigate in more detail the characteristics of hypnotics.

Adult↗
PubMed1997

Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?

Administration of alfentanil followed by propofol intravenously (IV) without neuromuscular blockade for induction of anesthesia provides adequate conditions for tracheal intubation. Other hypnotic drugs have not been thoroughly investigated in this regard. Accordingly, 140 ASA physical status I and II premedicated outpatients were randomly assigned to one of seven groups (n = 20/group). Patients in Groups I-VI received alfentanil 40 microg/kg followed by etomidate 0.3 mg/kg, propofol 2 mg/kg, or thiopental 4 mg/kg. One half of these patients (Groups II, IV, VI) also received lidocaine 1 mg/kg IV prior to the administration of the above drugs. Patients in group VII received d-tubocurarine 3 mg followed by thiopental 4 mg/kg and succinylcholine 1 mg/kg. Ninety seconds after induction, laryngoscopy and endotracheal intubation were attempted and graded. Patients in Group V (alfentanil/thiopental) were significantly (P < 0.05) more likely to have a clinically unacceptable response to intubation (55%) (e.g., vigorous coughing, purposeful movement, or requirement for succinylcholine to complete intubation) compared with patients who received propofol (35%) or etomidate (20%). Alfentanil/etomidate yielded intubation conditions comparable to those achieved with alfentanil/propofol and d-tubocurarine/thiopental/succinylcholine. Lidocaine appeared to improve intubating conditions, although this improvement did not reach statistical significance. The results suggest that healthy, premedicated patients with favorable airway anatomy who have received alfentanil 40 microg/kg can be reliably tracheally intubated 90 s after administration of propofol 2 mg/kg or etomidate 0.3 mg/kg.

Adult↗
PubMed1999

The hypnotic actions of oleamide are blocked by a cannabinoid receptor antagonist.

The unsaturated fatty acid amide oleamide (OA), which accumulates in the CSF of rats during sleep deprivation, induces electroencephalographically measured sleep when administered intracerebroventricularly. The mechanism of sleep induction by OA is unclear but may derive from enhancements of GABA or 5-HT receptor function, or alternatively from changes in the catabolism or uptake of the related fatty acid amide anandamide, an endogenous cannabinoid-1 (CB1) receptor ligand. The present study tests the latter hypothesis by administering OA alone and in combination with the CB1 receptor antagonist SR141716. As previously reported, 2.8 microg OA administered intracerebroventricularly significantly shortened electroencephalographic sleep latency. SR141716 in a dose of 3 microg had no effects on sleep by itself, but when co-administered with OA prevented its sleep-inducing effects. These data suggest that at least one aspect of the hypnotic action of OA involves interactions with the CB1 receptor system, possibly by blocking the metabolism of the endogenous CB1 receptor agonist anandamide.

Animals↗
PubMedDate not supplied

Multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the quinolizinone hypnotic Ro 41-3696 in elderly subjects.

The objectives of this double-blind, placebo-controlled study were to assess the multiple-dose tolerability, pharmacodynamics, and pharmacokinetics of the hypnotic agent Ro 41-3696 in elderly men and women (55-75 y of age). On day 1 and days 3-8, doses of 1, 3, 5, and 10 mg were administered sequentially to 4 groups of 10 subjects, 2 of whom received placebo. Psychomotor performance tests (tracking and attention) were conducted just before and at 1.5, 4, and 8 hours after drug intake on days 1, 4, 6, and 8. Memory was assessed at 24 hours after drug intake on days 1 and 8 by recall of a list of 10 words, which had been learned at 2 hours after intake. Ro 41-3696 was well tolerated at all dose levels. One subject dropped out of the study because of a hypersensitive skin reaction during treatment with 10 mg. Performance in both a tracking test and a memory search test was significantly affected by a dose of 10 mg and moderately affected by doses of 3 and 5 mg. The results of the 1-mg dose were indistinguishable from those of placebo. Long-term memory, as assessed by a word learning and recall test, showed the same pattern. Partial tolerance to the impairing effects in the psychometric tests developed over the course of treatment. Pharmacokinetics of both Ro 41-3696 and its O-desethyl metabolite Ro 41-3290 were dose proportional and time independent. Ro 41-3696 was absorbed and eliminated rapidly (time of maximum plasma concentration, approximately 1 hour; elimination half-life, approximately 2 hours). Plasma levels of Ro 41-3290 were higher than those of the parent drug, and it was more slowly eliminated (values for time of maximum plasma concentration and elimination half-life, approximately 2 and approximately 7 hours, respectively).

Aged↗