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[Anxiolytics and hypnotics use by psychiatric inpatients' children: preliminary study].

Psychotropic drugs are widely used in adulthood in France, and few studies have yet been made concerning children. Literature studies have shown an important consumption on their part, increasing with age and especially for girls. Certain family factors which may prove to determine such use have been pointed out like family habits of toxique use, maternal depression, mother's occupation and family troubles. This consumption also seems related to psychiatric symptomatology in children together with previous use in childhood. This feasibility study will attempt to research the forms of anxiolytics and hypnotics use by children aged 6 to 16, one parent being a psychiatric in-patient. 51 in-patients of the university section have been included, corresponding to 74 children. The investigator look down socio-demographic date as well as anxiolytics and hypnotics use in a lifetime and that of antalgics for the week prior to the interview. The parents' depressive and anxious symptoms were measured by the HAD and the children's psychopathological symptoms by the CBCL. A phone contact was proposed to teenagers 13 to 16 years old. One patient only refused the interview, 7 patients left without filling in the questionnaire. The parents more often than not refused to establish contact with the teenager. Only 5 teenagers out of 22 could actually be interviewed. Whereas 94.1% of parents use psychotropic drugs, only 16.2% of children have used them throughout their lifetime. The consumption of these drugs is not related to age or sex but rather seems to be linked with the children's symptomatology. The development of this study should confirm these results on a wider scale through a different approach of teenagers.

Adolescent↗

A comparison of three benzodiazepine hypnotics as oral pre-anaesthetic medication.

A comparative trial of nitrazepam, and triazolam (U-33,030) as pre-anaesthetic medicaments in patients allegedly not subject to insomnia, was undertaken the night before operation. The inclusion of placebo controls confirmed earlier findings that the majority of these patients suffer from transient insomnia. Nitrazepam and flurazepam are hypnotics, and in this study, triazolam also proved to be an hypnotic remarkably free of adverse effects.

Administration, Oral↗

[Prescriptions and consumption of hypnotic and anxiolytic drugs in the South University Hospital of Marseille].

An investigation of prescription and consumption of hypnotic and anxiolytic drugs in hospital was carried out and has associated a transverse prescription study and a prospective consumption study. The prescription study was undertaken on one day in several medical departments of Sainte-Marguerite Hospital in Marseille in February 1999. Of the 91 hospitalized patients included, 42 (46 per cent) had been prescribed a hypnotic or anxiolytic. Furthermore, the quantities of drugs taken out of the pharmacy during the month of February were 1.54 time more than those prescribed. This discrepancy was even more obvious in the case of certain benzodiazepines such as bromazepam (ratio from 1 to 4) and lorazepam (ratio from 1 to 8). Self-prescription and patients being supplied without a prescription are the hypotheses advanced to explain this phenomenon.

Anti-Anxiety Agents↗

Etomidate, a potent non-barbiturate hypnotic. Intravenous etomidate in mice, rats, guinea-pigs, rabbits and dogs.

Etomidate, R-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate was found to be a potent, short-acting and safe hypnotic; when given intravenously in single doses to mice, rats, guinea-pigs, rabbits and dogs. In rats of different body weight (50, 100, 200 and 300 g) two injection rates were used (2 sec and 2 min). By rapid iv injection in rats of 200 g etomidate (ED50 equal to 0.57 mg/kg) is about 6 times more potent than methohexital (ED50 equal to 3.51 mg/kg) and 25 times more potent than propanidid and thiopental (ED50's equal to 13.4 mg/kg). The safety margin (LD50/ED50) in these rats is 26.0 for etomidate, 9.5 for methohexital, 6.7 for propanidid and 4.6 for thiopental. Potency and toxicity of etomidate slightly increase with increasing injection rates without affecting the safety margin. The duration of hypnosis with etomidate is dose-dependent and the safety margin will therefore be widened when sleep of short duration is aimed at. Recovery after etomidate is very rapid. With lower body weights, higher doses in mg/kg are required for inducing hypnosis of comparable duration. No systematic differences were found after etomidate injection in incidence and duration of hypnosis nor in mortality between animals of different sex. ECG, blood pressure, haematological and biochemical analysis, urinalysis and histopathology did not reveal any drug-related adverse effect after daily injection of etomidate for 3 weeks in rats (highest dose 5.0 mg/kg) and 2 weeks in dogs (highest dose 1.50 mg/kg). No tolerance was observed after repeated administration. Etomidate is devoid of any teratogenic effect in rats (highest dose: 5.0 mg/kg daily from day 6 through day 15 of pregnancy), and in New Zealand white rabbits (highest dose: 4.5 mg/kg daily from day 6 through day 18 of pregnancy). The hypnotic effects of etomidate at very low dose levels in different laboratory animals are compared with the effects obtained in human subjects, in which successful induction of anaesthesia was obtained without producing any release of histamine and with only minimal effects on cardiovascular and respiratory functions.

Animals↗

Distribution, metabolism and excretion of etomidate, a short-acting hypnotic drug, in the rat. Comparative study of (R)-(+)-(--)-Etomidate.

Tritium-labelled (R)-(+) and (S)-(--)-etomidate was injected intravenously in male Wistar rats at four dose levels. Initial plasma clearance was high and the largest part of etomidate was rapidly distributed over those tissues, that had entered in equilibrium with plasma, such as brain, erythrocytes, heart, spleen, lung, kidney, muscle and intestines. Only in subcutaneous fat, testicles and stomach peak levels appeared after 28 minutes. The levels of etomidate, observed in all these tissues varied proportionally with the dose. Although the contents in brain of thw two isomers were comparable, only (R)-(+)-etomidate possesses hypnotic activity. The concentration in brain of (R)-(+)-etomidate, producing hypnotic activity in rats, was 1.50 +/- 0.35 mug/g tissues. Peak levels in liver appeared shortly after administration. Capacity-limited ester hydrolysis in the liver was the main metabolic pathway, yielding a single amphoteric metabolite. The rate of metabolization of (R)-(+)-etomidate was higher than that of the (S)-(--)-isomer. Excretion of the metabolite was mainly with the urine.

Animals↗

The 6-azauridine analogues possessing sedative and hypnotic effects.

Pharmacological effects of 6-azauridine (4) analogues were evaluated using hypnotic activity, pentobarbital (PB)-induced sleep prolongation and locomotor activity as indices. Compound 4, N3-benzyl- (10), N3-o-xylyl- (11), N3-m-xylyl- (12), N3-p-xylyl- (13), N3-alpha-phenylethyl-substituted 6-azauridine (14) exhibited hypnotic activity and PB-induced sleep prolongation, whereas N3-alkyl substituted analogues (methyl-, ethyl-, n-propyl-, n-butyl- and allyl-substitution) did not. Compound 4 and xylyl analogues (11-13) significantly decreased locomotor activity of mice by i.c.v. injection and produced motor incoordination. The results indicate that 4 and its benzyl related analogues, but not alkyl analogues have depressant effects on the central nervous system (CNS).

Animals↗

Glutethimide, a new nonbarbiturate hypnotic.

A new anticonvulsant, nonbarbiturate compound, Doriden (ethyl-a-phenyl-glutarimide) was studied for clinical activity as a hypnotic drug in mildly disturbed patients on the acute Psychiatric Service of Los Angeles County General Hospital. It was found to have approximately the same hypnotic activity as pentobarbital in the dosages recommended (1 gm. Doriden=200 mg. pentobarbital).

Anticonvulsants↗

[Effects of short-action hypnotics triazolam and zopiclone on simulated flight performance].

OBJECTIVE: To evaluate the effects of short-action hypnotics triazolam and zopiclone on simulated flight performance so as to provide experimental evidences for the use of these drugs in aircrew. METHOD: Six healthy young male volunteers served as the subjects. They were asked to take triazolam (0.25 mg), zopiclone (7.5 mg) or placebo at noon time (13:00) and sleep for 1 h. Simulated flight performances were tested in a simulator 1 h, 2 h, 3 h, 4 h, 6 b, 8 h, 10 h and 20 h (next morning 9:00) after taking the drugs. The experiments were done once a week for 3 weeks. RESULT: No significant difference was found between simulated flight performances before or after triazolam while simulated flight performances at 2 h and 3 h after taking zopiclone showed significant decrease (P<0.05), but restored to normal 4 h after taking the drug. CONCLUSION: Short-action hypnotics triazolam had no significant effect on simulated flight performance, while zopiclone had significant adverse effects on simulated flight performance at 2 h and 3 h after taking the drug.

Adolescent↗

[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes].

We examined the behavioral pharmacological properties of six benzodiazepine (omega) receptor ligands including brotizoram, nitrazepam, quazepam, rilmazafone, zolpidem and zopiclone and the binding of these drugs with omega receptor subtypes. Behavioral tests were performed at the time of the maximal effects induced by each drug following its oral administration to mice. All of these drugs dose-dependently induced impairment of motor coordination as rotarod performance and potentiation of thiopental-induced anesthesia as hypnotic effect. The hypnotic effects of rilmazafone, whose major metabolites were bound to both omega1 and omega2 receptors with high affinity, and omega1 selective quazepam were about 20 times more effective than the induction of motor impairments when compared with ED50 values. However, there was no difference between the ED50 values of omega1 selective zolpidem alone in these two tests. An antianxiety efficacy of zolpidem was relatively weak unlike that of other drugs in the elevated plus-maze. It has been reported that omega2, but not omega1, receptors are associated with motor impairment and anxiolytic effect. The weak anxiolytic effect of zolpidem supports the previous hypothesis. However, the strong motor incoordination of zolpidem suggests that not only omega2 but also omega1 receptors are related to motor impairment unlike the previous hypothesis.

Animals↗

[Actigraphic assessment of the effects of hypnotics on the night before surgery in relation with the severity of surgery].

BACKGROUND: Hypnotics have been used to provide adequate sleep on the night before surgery, but these effects have rarely been investigated. We investigated whether the preoperative hypnotic effects are related with the severity of surgery with quantitative evaluation using actigraph. METHODS: Sleep time on the night before surgery was evaluated after the administration of brotizolam 0.25 mg in 40 patients awaiting surgery; 20 patients for cardiovascular surgeries (Group I) and 20 patients for general surgeries (Group II). Sleep and awake state were identified by wrist activity measured with a motion-logger actigraph. Sleep time was assessed in total period from 22:00 to 6:00 and its 4 subdivided 2-hour periods (22:00-24:00, 24:00-2:00, 2:00-4:00, 4:00-6:00). RESULTS: The total sleep time in Group II (448 +/- 22 min) was significantly longer than that in Group I (409 +/- 44 min). Group I showed a significant reduction in sleep time in the period of 4:00-6:00 compared with other periods, whereas Group II did not show any difference among 4 periods. Group I showed significant shorter sleep time in the period of 4:00-6:00 compared with Group II. CONCLUSIONS: An actigraphic assessment of sleep time has demonstrated the possible influence of the severity of surgery on the sleep time on the night before surgery.

Aged↗

[Brotizolam--an easy to tolerate hypnotic. Broad application spectrum in general practice and the clinic].

Sleep disorders constitute one of the most common complaints of patients in general practice. Although drug therapy is not always necessary, a hypnotic is, for a limited time, indispensable in severe cases with strong subjective impairment. Among the numerous hypnotics available on the market, Brotizolam is one of the most effective and well-tolerated of these drugs to initiate and maintain sleep. In the following survey, pharmacological and clinical properties of Brotizolam are described in detail.

Azepines↗

[Anxiolytic agents and hypnotic drugs in Bretagne. Pharmaco-epidemiological study].

A pharmacoepidemiological survey was carried out in a rural region of France (Brittany) with the help of 54 general practitioners, all of whom belong to a clinical research group. The aim of the survey was 3-fold: to determine the frequency (incidence and prevalence) of anxiolytic and hypnotic drug prescriptions, the sociological characteristics of these drug consumers, and the indications and reasons for prescribing this class of drugs. The population of hypnotic drug and sedative consumers was strikingly dominated by women, 60 years old and over, retired or without a profession. Prescription analysis revealed that these drugs were essentially benzodiazepines whose prevalence and incidence were 17 and 1.76%, respectively. A high frequency of prescription renewals (78%) and an elevated percentage of long-term treatments (more than 9 years) were also noted. Insomnia and dependence are the two main "risk factors" for drug treatments lasting more than one year.

Adult↗

Criteria for selection of appropriate benzodiazepine hypnotic therapy.

The several benzodiazepine hypnotics currently marketed differ in onset and duration of action and in side effect profile. These differences are largely based on the varying pharmacodynamic properties of these agents. The selection of a drug for treating an individual patient should be based on consideration of these pharmacologic differences, as well as assessment of the sleep-wake disorder. The initial objective for the clinician who intends to manage a patient with insomnia is to determine which factors are contributing to the sleep disturbance and to decide on a treatment strategy. If medication is to be used, then the physician should select the most effective and safest hypnotic, prescribe it at the lowest effective dose and for the fewest number of nights. Individual patient response to the chosen medication should be monitored.

Anti-Anxiety Agents↗

Drugs acting at calcium channels can influence the hypnotic-anesthetic effect of dexmedetomidine.

The effects of chronic administration of the calcium channel antagonist verapamil on the anesthetic effects of a novel specific alpha 2-receptor agonist (dexmedetomidine) were studied in rats. It is presumed that this agonist acts on both pre- and postsynaptic alpha 2-adrenoceptors. To determine whether the central postsynaptic receptors are involved in the anesthetic interactions between these drugs, rats were treated with DSP-4 to deplete endogenous norepinephrine. Loss of the righting reflex was used to determine the presence of anesthesia and the duration of hypnosis. Chronic treatment with verapamil (1 or 5 mg/kg) significantly increased the duration of the hypnotic-anesthetic effect of dexmedetomidine. Neither acute treatment with verapamil nor the calcium channel agonist BAY K 8644 (0.5 or 1 mg/kg) influenced the dexmedetomidine-induced hypnosis after DSP-4 treatment. The results seem to support the idea that the hypnotic action of dexmedetomidine can be affected via modulation of the transmembraneous calcium movement in the central nervous system. Further, the data on catecholamine-depleted rats with DSP-4 suggest that the interactions between verapamil and dexmedetomidine may be mediated through presynaptic or homoreceptors on noradrenergic neurons.

Adrenergic alpha-Agonists↗

[Can the use of hypnotics be reduced? Systematic influence on attitudes and prescription practice in a psychiatric department].

Because of frequent use of hypnotics to treat insomnia in the population in general and in institutions especially, an alternative programme of treatment has been developed at the psychiatric hospital, Modum Bads Nervesanatorium. The programme includes different components and levels of treatment, wherein use of hypnotics is the last choice. The main focus is on sleep hygiene, which consists mainly of working on the patients' own attitude towards and experience of sleep problems. The pre-requisite for running such a programme is a systematic approach to these attitudes among the staff, and the prescribing patterns by physicians.

Attitude of Health Personnel↗

[Sleep problems and use of hypnotics in a nursing home. An inventory].

An inventory has been made on sleeping problems and the use of hypnotics in a nursing home. Contrary to general opinion, the results show that admission to a nursing home does not have to lead to an increase of hypnotics and neuroleptics used. One third of the total patient population revealed severe subjective sleeping problems, for which, however, a therapeutic intervention was not always necessary. In particular somatic revalidation patients showed high percentages of sleeping complaints and medical treatment. A communication hypothesis is presented as a possible explanation: somatic patients are able to ask for medication contrary to psychogeriatric patients, for whom the caregiving network often initiates therapeutic intervention. Attention is focussed on a few sleep disturbing stimuli that often occur in the setting of a nursing home. Prevention of these stimuli implicates changes in the nursing care organization.

Aged↗

Effect of alcohols and other hypnotics in mice selected for differential sensitivity to hypothermic actions of ethanol.

Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of an acute dose of ethanol were tested twice during the course of genetic selection for their hypothermic response to other alcohols and sedative hypnotics. The drugs administered were ethanol, propanol, n-butanol, t-butanol, pentanol, diazepam, phenobarbital, pentobarbital, methyprylon and ethchlorvynol, all of which have sedative effects on the central nervous system, and hydralazine, a peripheral vasodilator. All drugs decreased body temperature of both HOT and COLD mice. In mice selected for seven to nine generations, COLD mice were more sensitive than HOT mice to all sedative drugs. The longer-chain alcohols were more potent than ethanol in inducing hypothermia, but the magnitude of the response difference between HOT and COLD mice appeared to be smaller. The difference between HOT and COLD mice in hypothermic sensitivity to an acute dose of ethanol was greater after 11-15 generations of selection than after seven generations. Similarly, the differential effect of the other alcohols, phenobarbital, pentobarbital, and methyprylon, on HOT and COLD mice increased with more generations of selection but to a lesser extent than ethanol. These data demonstrate that selecting for sensitivity to acute ethanol hypothermia has produced mice that are also differentially sensitive to other sedative hypnotic agents. They also support the hypothesis that the drugs used in the present study share a common mechanism of action for inducing hypothermia, which may be regulated by a common set of genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗

In vivo and in vitro metabolic studies of N3-benzyluridine which exhibits hypnotic activity in mice.

The metabolism of N3-benzyluridine (N3-ByUd), which possesses hypnotic activity, was studied in mice. The decrease in brain concentration of N3-ByUd was faster than that of uridine (Ud) after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration. Liver and plasma concentrations of N3-ByUd were also lower than those of Ud after both i.c.v. and i.v. administrations. N3-Benzyluracil (N3-ByU) was identified as a metabolite of N3-ByUd in urine after i.c.v. administration. However, N3-ByUd was not metabolized in brain until 3 hr after i.c.v. administration. It was also not metabolized in the in vitro metabolic studies of N3-ByUd (brain and liver). The possible metabolites, e.g. Ud, uracil (U), N3-ByU and D-ribose, did not possess any hypnotic activity following i.c.v. administration. These results indicate that N3-ByUd itself, but not its metabolites, produced central nervous system (CNS) depressant activity.

Animals↗