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PubMedDate not supplied

[A specific domain (the omega 1 site) of the GABA(A) receptor may be implicated in the hypnotic effects of zolpidem].

Zolpidem (Stilnox) is a new hypnotic belonging to the imidazopyridine series. In animals, in contrast to the benzodiazepines which alter sleep architecture, zolpidem induces a physiological pattern of deep sleep. Zolpidem also differs from the benzodiazepines by its hypnoselective profile (its sedative effects are seen at doses much lower than those needed for anticonvulsant or myorelaxant effects). In this review, the authors analyze the hypothesis that the hypnoselective profile of zolpidem is linked to its interaction with a specific domain, the omega 1 site, of the GABAA receptor complex. This hypothesis is supported by: 1) the high selectivity of zolpidem for omega 1 as compared to omega 2 sites and its high intrinsic activity, 2) autoradiographic studies of the regional distribution of omega 1 and omega 2 sites in the human and non-human primate brains showing that omega 1 sites are located preferentially in sensorimotor cortical regions whereas omega 2 sites predominate in the limbic system and spinal cord. The selectivity of zolpidem for omega 1 sites could also account for the fact that in contrast to the benzodiazepines, this compound does not alter memory functions at hypnotic doses.

Animals↗
PubMedDate not supplied

[Transcerebral electrostimulation in hypnotic drug withdrawal].

This preliminary study attempted to test the efficacy of electrosleep therapy on hypnotic drug withdrawal. Among 89 outpatients complaining of chronic insomnia and receiving a heavy hypnotic drug treatment, an efficient withdrawal associated with a marked improvement of self-reported sleep was observed in 78% of cases, especially when insomnia was not related to medical aetiologies or to major psychiatric disorders. These results suggest further controlled studies to determine the magnitude of the placebo component in the effect observed.

Adult↗
PubMed1987

Calcium channels. Interactions with ethanol and other sedative-hypnotic drugs.

Biochemical and electrophysiological studies have shown that ethanol potently inhibits voltage-dependent calcium channels in presynaptic nerve terminals in brain. The ability of ethanol to inhibit calcium channels appears to vary from one brain region to another. Chronic ethanol administration results in adaptation of the calcium channels in certain brain regions such that they become tolerant to the inhibitory actions of ethanol. Other sedative-hypnotic drugs, such as barbiturates and benzodiazepines, also inhibit calcium channels but may differ from ethanol in their brain regional potency. These studies suggest that the pharmacological actions of ethanol and other sedative-hypnotic drugs may be linked with alterations in calcium channel function.

Animals↗
PubMed1989

[Daytime sedation measured after intake of nitrazepam and lorazepam, respectively, as hypnotics for 10 days].

A prospective double-blind cross-over investigation was undertaken among 46 geriatric patients (62-92 years) in which either 5 mg nitrazepam or 1 mg lorazepam were administered as hypnotics for two periods of ten days. No significant differences were observed in the quality of sleep but the objective psychomotor tests and the patients' subjective experience of hang-overs showed that there were significant differences in the frequencies of side effects in favour of lorazepam. It is concluded that daytime sedation after repetitive administration of a benzodiazepine preparation depends upon the half-life and that side effects are revealed better by psychomotor tests than by intellectual, cognitive tests and that lorazepam should be given preference to nitrazepam as a hypnotic for elderly patients.

Aged↗
PubMed1989

Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat.

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v. and p.o. administration of 2.63 mg.kg-1 of [14C]zolpidem (dose expressed as the base). Autoradiography was used to examine the regional distribution of the compound and the metabolic profile of zolpidem in the plasma and brain was also investigated. The pharmacokinetic data were related to electrocorticogram power spectral analysis. After i.v. administration, the disappearance of zolpidem from plasma fitted a biexponential model with a rapid phase of 0.2 to 0.3 hr and a slower phase of 1.3 to 1.5 hr. After p.o. dosing, peak plasma concentrations where already attained at 15 min (first sampling time). Independent of the route of administration, the concentrations of zolpidem in the brain at shorter times were 30 to 50% those of the plasma values. Furthermore, up to 1 hr, zolpidem accounted for 80 to 90% of brain radioactivity. The rate of disappearance from brain paralleled that from plasma. Autoradiographic studies confirmed the rapid absorption and elimination of zolpidem as well as the relatively homogenous distribution throughout the brain. Electrocorticogram analysis in immobilized rats after i.v. administration of zolpidem showed a rapid onset and a short-acting sedative effect compatible with the kinetic profile of the parent compound. Metabolites of zolpidem displayed a poor penetration into the brain and no significant hypnotic activity. At the dose of zolpidem used, no alteration of the sleep pattern was observed.

Animals↗
PubMed1979

[A simple gas chromatographic method for the determination of hypnotics in the serum (author's transl)].

In the extract of the serum, prepared as described by Külpmann (1979) (this J. 17, 89-96), other hypnotics, in addition to the barbiturates can be determined by gas chromatography; these are: carbromal, 2,2-diethylallylacetamide, ethinamate, glutethimide, methyprylone and pyrithyldione. Methaqualone can be detected qualitatively. The coefficient of variation for the precision in the series is dependent on the hypnotic investigated and ranges from 2.1 to 8.5%, the recovery from 76 to 92%; the detection limit is estimated to be 1.6 up to 4.6 mumol/l. The specificity was proved by comparison 1) of analyses of sera from poisoned patients or animals before and after the additional purification of the extract by thin-layer chromatography, 2) with the retention times of about 100 drugs under the gas chromatographic conditions that were used. The method allows the determination of 18 barbiturates and 7 non-barbiturates within one to two hours.

Carbamates↗
PubMedDate not supplied

[Interactions between hypnotics and psychotropics. Various aspects of experimental pharmacology].

Fourteen french pharmacologists working for the pharmaceutical industry were asked about the tests they used for the primary screening and the study of hypnotic drugs. They were also asked about the tests using interactions between hypnotics and the studied drugs, either psychotropic or not. The results of survey are presented. A systematic study was performed concerning the interaction of psychotropic drugs with either barbital or pentobarbital in mice. The utilization of these two tests is useful for the research of possible inductory or inhibitory effect on hepatic enzymatic systems. For a complete study of drugs with a profile of psychostimulant or antidepressant.

Antidepressive Agents↗
PubMed1979

The pharmacological profile of a potential hypnotic compound RU 31158.

RU 31158, 6-(orthochlorophenyl)-1, 2-dihydro-2 (N-methylpiperazine-1-yl) methylene-8-nitro-IH, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1-one methanesulphonate, demonstrated potent hypnotic activity compared to diazepam when examined in the mouse and rat. RU 31158 potentiated minimal hypnosis in mice induced by both hexobarbital and chlorprothixene with ED50 values of 2.15 (1.53-3.01) and 0.69 (0.46-1.02) mg/kg p.o. respectively; these compared to values for diazepam of 17.00 (11.25-25.67) and 3.60 (2.25-5.76) mg/kg p.o. RU 31158 also potentiated hexobarbital in the rat with an ED50 value of 1.2 (0.7-2.0) mg/kg p.o. as compared to 32.0 (27.5-38.5) mg/kg p.o. for diazepam. Sleep studies in the rat confirmed the hypnotic properties of RU 31158, and also showed that the duration of action at 8.0 and 16.0 mg/kg p.o. was not longer than 9 hours. RU 31158 also showed potent minor tranquilizer, anxiolytic, and anti-convulsant properties in a series of pharmacological tests.

Animals↗
PubMed1966

A clinical trial of four hypnotic drugs.

A CLINICAL TRIAL OF FOUR HYPNOTIC DRUGS WAS CARRIED OUT: Ro 4-5360, 10 mg. (Mogadon), methyprylon, 200 mg. (Noludar), Ro 4-5360, 5 mg. (Mogadon), secobarbital sodium, 100 mg. (Seconal), and a placebo. The study was on the usual double-blind basis, and all observations were made by a full-time nurse. Capsules were given at 10 p.m. for five successive nights, with two nights free from medication or observation. There were five such periods. The nurse carried out her observations right through the night, determining whether the patients were awake or asleep. Each of these drugs was statistically significantly different from the placebo, in terms of length of sleep. Differences between the individual drugs were not significant. The length of action of the various drugs appeared to be similar, with a somewhat longer period of activity for the Mogadon in both dosages. The major side effect was some drowsiness: this was more marked with Mogadon 10 mg. With the hypnotics, the patients had, on the average, about one hour more sleep than on the placebo.

Adult↗
PubMed1983

Midazolam and triazolam: hypnotic action and residual effects after a single bedtime dose.

The hypnotic action and residual effects of a single bedtime dose of 8-chloro-6(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) (7.5 or 15 mg) or 8-chloro-6(o-chlorophenyl)-1-methyl-4H-S-triazolo[4,3-a] [1,4]benzodiazepine (triazolam) (0.25 or 0.5 mg) were investigated in young, healthy adults. Motor activity was continuously recorded by a wrist-worn activity monitor. In comparison to placebo, all compounds reduced night-time motor activity in the first half, but not in the second half of the night. Subjects rated their sleep as more quiet. Neither the spontaneous daytime motor activity nor the self-rated state in the morning and at noon was affected by drug intake in the preceding night. Performance in the morning as measured by a psychomotor test was significantly impaired only after triazolam 0.5 mg. There was no evidence for rebound insomnia in the 3 nights following drug intake. The results indicate that midazolam 15 mg and triazolam 0.25 mg have a reliable hypnotic action without significant residual sequelae.

Adult↗
PubMed1984

Hypnotic action and residual effects of a single bedtime dose of temazepam.

The hypnotic action and residual effects of a single bedtime dose of 7-chloro-3-hydroxy-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)one (temazepam, Planum) were investigated in young, healthy adults. Two different doses of the drug (20 or 30 mg) or placebo were administered as soft-gelatin capsules 30 min before bedtime. Motor activity was recorded by a wrist-worn activity monitor. In comparison to placebo both doses of temazepam reduced night-time motor activity, an effect that was significant only for the first half of the night. After temazepam subjects rated their sleep as deeper and more quiet. A dose of 30 mg caused increased ratings of "grogginess" in the morning and at noon. There was no evidence for rebound insomnia in the 3 nights following drug intake. The results indicate that temazepam 20 mg in young adults has a reliable hypnotic effect without significant residual sequelae.

Adult↗
PubMed1982

Pharmacology of hypnotics.

Sedative hypnotics belong to several chemical classes and thus have heterogeneous pharmacodynamic properties. Among various ways of approaches, conventional pharmacology using animal models allows one to define a common pharmacological profile. It still remains the best predictive tool of hypnotic efficacy in man. The study of discriminative properties is a useful extension of these conventional models. Electrophysiological and biochemical studies allow primarily to approach the problems of the sites and mechanisms of action, but only begin at the moment to lead to practical applications.

Aggression↗
PubMed1984

Interactions of cholinesterase inhibitors and corticosteroids with the hypnotic effect of benzodiazepines in mice.

Interactions of cholinesterase inhibitors or dexamethasone with the hypnotic effect of benzodiazepines appear to be strongly dependent on the dose of the cholinesterase inhibitor used and to a lesser extent on the dose of the hypnotic. The duration of the loss of righting reflex caused by the benzodiazepines, diazepam or chlorodiazepoxide, is markedly prolonged by 500 micrograms/kg, significantly antagonized both diazepam and chlorodiazepoxide. Relatively higher doses of physostigmine have no significant effect on either diazepam or chlorodiazepoxide. Dexamethasone, in relatively low doses of 250 and 500 micrograms/kg or 500 micrograms/kg respectively, significantly reverses the effect of diazepam and chlorodiazepoxide, while in relatively high doses of 1000 micrograms/kg the hormone significantly potentiates the hypnosis produced by the benzodiazepines. It is suggested that the interactions described may be the result of a modification of possible changes in cholinergic activity caused by the benzodiazepines. Although as yet no unequivocal explanation can be offered for the different effects, the observations described in this paper may explain the highly contradictory findings of other authors in both animal and human studies.

Adrenal Cortex Hormones↗
PubMed1983

Relationship of sedative-hypnotic response to self-injurious behavior and stereotypy by mentally retarded clients.

Groups of clients exhibiting both self-injurious behavior (SIB) and stereotypy, stereotypy alone, SIB alone, or neither of these types of behavior were rated in terms of response to sedative-hypnotic medication. Sixty-eight percent of the clients with both SIB and stereotypy maintained wakefulness and were either resistive, combative, restless, uncooperative, or abusive after treatment with sedative-hypnotics. Thirty-nine percent of the clients with only SIB and 35 percent of the clients with only stereotypy evidenced such "paradoxical" responses to these medications. None of the matched control clients displayed paradoxical responses. This result suggests that an impaired endogenous opiate system characterized by increased levels of beta-endorphin may mediate and maintain a type of syndrome of SIB that involves the presence of stereotypy, implying the need for a new diagnostic classification and treatment of these aberrant behavioral disorders.

Adolescent↗
PubMed1993

[Abuse potential during use and withdrawal psychosis after treatment with the hypnotic zolpidem (Stilnoct)].

Three cases are presented. Withdrawal symptoms and ultimately psychosis developed in two cases following cessation of the hypno-sedative zolpidem. Two cases involve dependence upon and abuse of the drug; in one, a well-known alcoholic, it was abused in combination with alcohol, the other had prior well-known dependence on sedative hypnotics. One patient had chronic dysphoria and one encephalopatia toxica. Adverse effects such as withdrawal symptoms, dependence and abuse have not previously been reported in relation to zolpidem. Chemically unrelated to benzodiazepines, zolpidem is thought to have fewer adverse effects, but shares a pharmacokinetic profile with the benzodiazepine triazolam. It is advised that normal criteria for the prescription of benzodiazepines also be used when prescribing non-benzodiazepine sedatives and hypnotics, as they act upon the same receptor, namely the benzodiazepine-GABA-chloride complex.

Adult↗
PubMedDate not supplied

Effect of hypnotic drugs on sleep architecture.

It is widely accepted that the conventional polysomnographic parameters (macrostructure of sleep) supply only rough information for clinical purposes. In particular, they often appear inadequate to support a diagnosis of insomnia or the effectiveness of a hypnotic compound. In the past years, attention has been focused on the microstructure of sleep, and especially on the periodic distribution of arousal-related phasic events known as Cyclic Alternating Pattern (CAP). This microstructural rhythm is not only a physiological component of normal NREM sleep, but it also appears highly sensitive in the detection of disturbing factors and drug manipulation. Regardless of the specific context, CAP always translates a condition of arousal instability during sleep. Accordingly, the higher the amount of CAP, the poorer the subjective quality of sleep. In young adults, the physiological amount of CAP Rate (percentage ratio of CAP time to NREM sleep time) ranges around 25%, while CAP Rate rises to 55% when sleep is perturbed by continuous white noise (situational insomnia). The analysis of CAP Rate within this framework of situational insomnia is recommended for evaluating the effects of hypnotic drugs under controlled experimental conditions. Therapeutical doses of zolpidem preserve the regular course of sleep both at the macro- and at the microstructural level, when sleep is recorded under basal conditions. In contrast, during acoustic perturbation, zolpidem reduces the pathological amounts of arousal instability by lowering the values of CAP Rate to 38%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Sedative and hypnotic activities of pyrimidine nucleoside derivatives.

N3-Substituted pyrimidine nucleoside and their related compounds were synthesized. The central nervous system (CNS) depressant effect of the compounds such as hypnotic activity and synergistic effect with pentobarbital have been evaluated. N3-Phenacyl derivatives of uridine (2), thymidine (3), deoxyuridine (4), 6-azauridine (5) and arabinofuranosyluracil (6) exhibited the hypnotic activity, whereas N3-phenacyl-2',3'-O-isopropylideneuridine did not. Compound 2, 3, 4 and 6 significantly enhanced pentobarbital-induced sleep. The results indicate that CNS depressant effect of pyrimidine nucleoside derivatives might relate to functional group at the N3-position on oxopyrimidine ring and stereospecificity of sugar moiety at the N1-position.

Animals↗
PubMed1996

[Dynamics of the hypnotic effect of 0.125 mg and 0.250 mg brotizolam. The lower dosage is adequate for treatment of sleep disorders].

BACKGROUND: Although observations have shown that half a tablet (0.125 mg) of brotizolam develops an adequate sedative effect in patients who cannot get to sleep, confirmatory pharmacodynamic studies are lacking. METHOD: In a comparative double-blind, randomized, placebo-controlled study, the hypnotic effects of 0.125 mg and 0.250 mg brotizolam, a short-acting benzodiazepine-like hetrazepine, were investigated. The concept underlying the study was that both doses are equally rapid in action onset, but differ in duration of effect. The study included 49 healthy women aged between 23 and 44 years. The nocturnal tests lasted until 2.30 am, and a concluding examination took place after breakfast. The test subjects were asked to estimate their state of well-being on visual analog scales at half-hour intervals, while concentration was tested hourly using the digit symbol substitution test (DSST) tried and tested in numerous studies on benzodiazepines. RESULTS: Both doses proved to be equally effective after 0.5, 1.5 and 2.5 hours. While the hypnotic effect of the lower dose no longer differed from that of placebo after 3.5 hours, the larger dose still had a greater effect than both placebo and the lower dose after 4.5 hours. A hangover effect in the morning was not observed with either dose. The pharmacodynamic results indicate that the effect of the substance is readily controllable, and that half a tablet of brotizolam is an effective treatment of difficulty in getting to sleep initially or after waking prematurely. CONCLUSION: The results of the present study demonstrate for the first time that a half-tablet of brotizolam is an effective treatment of difficulty in getting to sleep initially or after premature wakening.

Adult↗