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Barbitone-induced tolerance to the effects of sedative-hypnotics and related compounds on operant behaviour in the rat.

1 Pretreatment doses of barbitone, pentobarbitone, ethanol, and phenytoin (diphenylhydantoin) in non-tolerant rats produced increases in operant responding at low doses and at higher doses resulted in decreases in responding.2 Daily barbitone injections (100 mg/kg, i.p.) resulted in the development of functional tolerance to both the stimulant and depressant effects of barbitone on responding.3 Barbitone tolerance development did not result in any change in the brain or plasma pharmacokinetics of barbitone.4 Barbitone-tolerant rats were cross-tolerant to the behavioural effects of pentobarbitone, ethanol, and phenytoin. The dose-effect curves for all of these drugs were shifted to the right in tolerant rats, compared to non-tolerant rats.5 Comparison of the brain and plasma levels of these drugs in non-tolerant and tolerant rats provided a means of separating functional cross-tolerance from dispositional cross-tolerance. Barbitone-tolerant rats appeared to be functionally cross-tolerant to ethanol in that there was no change in the brain and blood ethanol levels at times when the degree of behavioural impairment was substantially reduced. In contrast to ethanol, cross-tolerance to phenytoin appeared to be due to a decrease in the brain and plasma levels (dispositional tolerance). Cross-tolerance to pentobarbitone appeared to be comprised of both functional and dispositional cross-tolerance.6 The usefulness of a multidisciplinary approach in the analysis of sedative hypnotic tolerance and cross-tolerance is discussed. It is concluded that without the concurrent determination of both brain and plasma drug levels it would not be possible to distinguish between functional and dispositional tolerance.

Animals↗

Has sodium valproate hypnotic effects?

Eight fasting normal subjects were given a single dose of sodium valproate, 400 mg, phenobarbital, 60 mg, or the two drugs in combination, in a double-blind placebo-controlled study. The effects were assessed behaviorally and by a standard 30-min EEG, begun 1 hr after the treatments had been given. The recording was rated for the amount of drowsiness and sleep, independent of which drug had been given. The scores obtained indicated that valproate intself has hypnotic action, and there is a tendency for this to be increased by the simultaneous administration of phenobarbital.

Adult↗

Classical genetic analyses of responses to sedative-hypnotic drugs in crosses derived from long-sleep and short-sleep mice.

A classical (Mendelian) genetic analysis of responses to eight sedative-hypnotic compounds (ethanol, urethane, trifluoroethanol, chloral hydrate, barbital, paraldehyde, methyprylon, pentobarbital) was conducted in crosses derived from mouse lines that were selectively bred for differential duration of anesthesia following ethanol. The sleep-time responses of these mice, the long-sleep (LS) and short-sleep (SS) mouse lines, as well as the F1, F2 and backcross (F1 x LS, F1 x SS) generations were measured. Generally, differences in responses among the generations were greater for water soluble compounds than were differences for more lipid soluble compounds. Also, the inheritance of responses to water soluble compounds could be explained primarily by additive effects of alleles while the inheritance patterns for more lipid soluble compounds were more complex. Genetic correlation with ethanol response decreased with increasing lipophilicity. These results suggest that the selection of the LS-SS mouse lines was specific for water soluble anesthetic agents. Because several of these agents are known to act at GABA receptors, examination of the interactions of compounds which differ in lipid solubility at GABA receptors from LS and SS mice may prove useful in elucidating the mechanism of the anesthetic actions of ethanol and other drugs.

Alcohol Drinking↗

Comparison of oxazepam, flurazepam and chloral hydrate as hypnotic sedatives in geriatric patients.

In a four-week study, a comparison was made of oxazepam, flurazepam and chloral hydrate as hypnotic sedatives in 17 geriatric patients. Each drug was given alone for six nights, with a two-night placebo interval following each phase. Each patient completed an additional placebo phase (up to six nights) before each drug phase. The number of awakenings per night and the sleep latency (time required to fall asleep) were determined from the patients' reports and from the reports of a nurse-observer. Only for oxazepam was the number of patient-reported awakenings per night significantly less than for placebo, although with both oxazepam and flurazepam the awakenings were fewer than with chloral hydrate. According to the patient-reports, sleep latency was significantly lower with flurazepam than with placebo; for oxazepam and chloral hydrate the latencies were not significantly different from those for flurazepam or placebo. Only for oxazepam were the patients' ratings of sleep quality significantly greater than for placebo. The objective assessment of sleep by the nurse-observer usually confirmed the patients' assessments. Morning drowsiness was the most common side effect, reported equally for placebo and for the active drugs. Drowsiness during the day was reported less frequently for oxazepam than for flurazepam, chloral hydrate or placebo. It is concluded that oxazepam is safe and efficacious for the short-term management of insomnia in the elderly.

Aged↗

Sedative-hypnotic use and increased hospital stay and costs in older people.

OBJECTIVE: To assess the relationship between sedative-hypnotic (S/H) utilization, severity of illness, length of stay, and hospital costs among older patients admitted to a tertiary care university hospital. DESIGN: Retrospective review of computerized hospital and pharmacy data bases. SUBJECTS: A total of 856 older consecutive medical and surgical admissions from November 1993 to March 1994. MEASUREMENTS: Sedative/hypnotic utilization in accord with the Health Care Financing Administration (HCFA) guidelines for S/H use in nursing homes. Jefferson Disease Staging to estimate severity of illness. Hospital records to obtain demographic characteristics, length of stay, and hospital costs. RESULTS: Patients whose S/H use exceeded HCFA guide lines, compared with those within the guidelines and those receiving no drugs, had longer lengths of stay (21.5 days vs 12.3 days vs 6.7 days, P < .001), increased hospital costs ($29,245 vs $15,219 vs $7,516, P < .001). and greater severity of illness (245.8 vs 189.5 vs 148.5, P < .001). S/H use exceeding and within HCFA guidelines were associated with increased length of stay (both P < .0001) and hospital costs (both P < .0001). CONCLUSIONS: Older hospitalized patients receiving S/H have greater severity of illness, longer lengths of stay, and higher hospital costs compared with other patients. S/H use, and, in particular, S/H use exceeding the HCFA guidelines, are associated with increased hospital stay and cost.

Aged↗

Purchases of hypnotics, sedatives and minor tranquillizers among 2,566 individuals in the county of Jämtland, Sweden. A 6-year follow-up.

Data from a continuous recording of drug prescriptions to 16,600 individuals in the county of Jämtland, Sweden, revealed that 2,566 patients (15.5%) obtained prescriptions for hypnotics, sedatives and minor tranquillizers in 1970. Occasional use (one purchase only, Group A) was seen in 7.4% of the population, intermediate use (two to six purchases, Group B) in 6.9% whereas 1.2% were regular users (seven purchases or more, Group C). For each group as a whole there was 5 years later a highly significant intraindividual reduction in the purchases of these drugs as well as of other psychotropic drugs. In all groups 10-23% had increased their purchases, most of them insignificantly. Fifteen of 30 patients with a marked increase in consumption developed a regular purchase pattern, but signs of overuse or abuse were seen in only four persons. During the studied period the benzodiazepines increased their share of the total from 45 to 60%. Antihistamines also increased in all groups while the proportion of barbiturates and combined preparations decreased markedly.

Anti-Anxiety Agents↗

Comparative evaluation of hypnotic efficacy of flunitrazepam in psychiatric in-patients.

Flunitrazepam in 2-mg and 4-mg doses was compared with flurazepam 30 mg and nitrazepam 10 mg for hypnotic efficacy in a double-blind, multiple cross-over trial involving 41 psychiatric in-patients. In the vast majority of comparisons involving a number of sleep parameters differences did not reach significance level. Flunitrazepam 4 mg tended to produce the shortest latency time and the longest duration of sleep but also the most side-effects. Nitrazepam 10 mg appeared to have a slight advantage over the other drugs in terms of patient preference. For severe sleep disturbance flunitrazepam 2 mg tended to be the most satisfactory drug in terms of efficacy and paucity of side-effects.

Adult↗

History and current status of sedative-hypnotic drug use and abuse.

Sedative-hypnotic drug use and abuse increased in Europe after World War II and peaked about 1972. Clinical and follow-up descriptions of abusers support the concept of a psychiatric addiction syndrome, different from a low-dose withdrawal syndrome. Although these drugs may be prescribed unnecessarily, large portions of the general population with pathological psychic distress and insomnia do not receive psychotropic treatment, in spite of findings pointing to genetic and biochemical factors in the genesis of these. Research on underlying mechanisms and the rationale for maintenance therapy is needed.

Anti-Anxiety Agents↗

Saccadic eye movements as a measure of residual effects: temazepam compared with other hypnotics.

Eye movements are classified into two categories: quickly running saccades and smooth pursuit movements. Saccades are fast conjugate eye movements with a preprogrammed direction, amplitude, and speed course; their purpose is to register new objects in the visual field. The duration and velocity of saccadic eye movements are very much dependent on vigilance. Comparisons were made with a number of psychometric tests [d 2 Durchstreichtest (cross out test), Viennese determination apparatus, and flicker fusion frequency] and the velocity of fast eye movements. The results of three separate investigations are presented. Standardization was undertaken in 100 healthy volunteers, 50 male and 50 female subjects aged between 20 and more than 50 years were included. In an open parallel group study, comparisons were made between various hypnotics with different half-lives (temazepam, flunitrazepam, flurazepam, and phenobarbital). There were 10 healthy volunteers in each group, and medication was taken as a single night-time dose for 7 nights. In a double-blind study, temazepam (20 mg/day) was tested against flunitrazepam (2 mg/day). Dosing lasted 7 days. A marked impairment of the saccadic eye movements was observed with flunitrazepam but not with temazepam. Of all the benzodiazepines tested, only temazepam had no influence on the parameters of the saccade test. These results can be explained by temazepam's short half-life and also by the fact that no active metabolites are formed.

Adult↗

Drug and ethanol effects on the clinical test for drunkenness: single doses of ethanol, hypnotic drugs and antidepressant drugs.

The clinical test for drunkenness has been used in Finland to detect alcohol-induced impairment of driving fitness. Since the data about the effects of psychotropic drugs on the clinical test for drunkenness are limited, this test was administered in two randomized double-blind cross-over trials with 12 subjects in each. The clinical tests were done at 2 hr and 5 hr after drug intake. For comparison, the representative laboratory tests used were digit symbol substitution, simulated driving (tracking+reaction time) and "global psychomotor performance". In Trial I, 15 mg of diazepam, 50 mg of amitriptyline and 15 mg of mirtazepine, each drug administered alone, had minor effects on the clinical tests. Compared to the placebo, mirtazepine, and diazepam, diazepam+mirtazepine impaired performance on the motor subtests at 2 hr. The tracking error percentage was increased by amitriptyline, diazepam+amitriptyline, and diazepam+mirtazepine up to 4.5 hr. In Trial II with 7.5 mg of zopiclone, 0.25 mg of triazolam and 0.8 g/kg of ethanol, ethanol alone and hypnotic-ethanol combinations impaired performance on the motor and vestibular subtests, whereas single drug intake had minor effects. Tracking was more sensitive to drugs than to ethanol. In conclusion, the clinical test for drunkenness detected impaired performance following single doses of ethanol or drug-ethanol combinations better than it detected impaired performance following moderate doses of drugs or drug-drug combinations, respectively.

Adult↗

4-Methylpyrazole alters phenobarbitone hypnotic concentrations in rats.

The liver alcohol dehydrogenase inhibitor, 4-methylpyrazole, has been tested for its ability to change the hypnotic concentrations of phenobarbitone (phenobarbital) in rats. Following a single dose of 1 mmol kg-1 i.v., administered 60 min before phenobarbitone, 4-methylpyrazole shortened the onset time and reduced the dose of phenobarbitone required to produce loss of righting reflex. Consistent with this, phenobarbitone concentrations in serum (both total and free), brain and in cerebrospinal fluid at onset of hypnosis were about half in 4-methylpyrazole compared with saline-treated rats. These results suggest that acute 4-methylpyrazole pretreatment increases the central nervous system sensitivity to phenobarbitone and presumably other barbiturates; an effect apparently distinct from its inhibition of liver alcohol dehydrogenase.

Animals↗

Neighbourhood social participation and women's use of anxiolytic-hypnotic drugs: a multilevel analysis.

STUDY OBJECTIVES: To identify and quantify a hypothesised collective effect of the neighbourhood on individual use of anxiolytic-hypnotic drugs (AHD). To analyse the general impact of neighbourhood social participation on use of AHD, adjusting for individual characteristics. DESIGN: Cross sectional analysis performed by multilevel logistic regression with women at the first level and neighbourhoods at the second level. SETTING: Malmö (250 000 inhabitants), Sweden. PARTICIPANTS: 15 456 women aged 45 to 73, residing in 95 neighbourhoods in Malmö, who took part in the Malmö diet and cancer study (1991-1996). MAIN RESULTS: The prevalence of AHD use was 5.5% in the study sample. Overall, 1.7% of the total individual differences in the propensity for using AHD were explained by the neighbourhood level. This percentage, however, differed between different individuals. Low level of social participation in the neighbourhood was associated with higher probability of AHD use (OR = 3.10 (95% CI 1.51 to 6.41)), independently of individual age, low social participation, low educational level, and living alone. This association was reduced (OR = 2.01 (95% CI 0.97 to 4.14)) after the additional accounting for individual disability pension, low self rated health, stress, and medication for somatic disorders. CONCLUSIONS: The neighbourhood level of social participation seems to affect individual use of AHD, possibly through individual characteristics. However, neighbourhood boundaries play a minor part in understanding individual AHD use in the city of Malmö.

Aged↗

Effect of p-chlorophenylalanine on the acquisition of tolerance to the hypnotic effects of pentobarbital, barbital, and ethanol.

Rats were given pentobarbital by daily intubation. Sleeping times and blood levels of drug at awakening, after intraperitoneal test doses of ethanol, pentobarbital, or barbital, were measured at various times during chronic treatment in order to assess the degree of tolerance developed. No central nervous system (CNS) tolerance to pentobarbital or cross-tolerance to barbital or ethanol occurred on treatment with sodium pentobarbital, 50 mg/kg, daily. However, when the size and frequency of pentobarbital treatment doses were increased (50-80 mg/kg, three times daily) a clear CNS tolerance to barbital occurred. Chronic administration of p-chlorophenylalanine (p-CPA), in a dose previously shown to maintain more than 95% depletion of brain serotonin (5-HT), enhanced the acute hypnotic effect of barbiturates and ethanol. Independently of this effect, p-CPA treatment also resulted in a reduction in the development of CNS tolerance. These results are consistent with earlier findings that brain 5-HT depletion retards tolerance development to central depressant drugs as measured by a variety of unrelated tests.

Animals↗

Enhanced neuronal K+ conductance: a possible common mechanism for sedative-hypnotic drug action.

It is commonly thought that central nervous system depressant drugs exert their actions through enhancement of gamma-aminobutyrate (GABA)-mediated mechanisms. Recently, the cellular electrophysiological evidence from this laboratory and others suggests that both sedative hypnotics and general anaesthetics inhibit central neurons by increasing potassium conductance (GK). We have utilized the mammalian in vitro hippocampal and cerebellar slice preparations at 34-36 degrees C. Intracellular recordings from CA1, CA3, and cerebellar Purkinje cells were obtained. Low dose (sedative) concentrations of ethanol (less than or equal to 20 mM), two different benzodiazepines (midazolam and clonazepam in low nanomolar concentrations), and pentobarbital (10(-6) to 10(-4) M) were applied by pressure ejection or were bath perfused. All drugs caused a hyperpolarization with decreased spontaneous activity, and enhanced post spike afterhyperpolarizations (AHPs). These long-lasting AHPs are presumably due to enhanced calcium-mediated GK. Increased responsiveness to focally applied GABA was only seen at higher doses (ethanol, 100 mM; midazolam, 10(-7) M; pentobarbital, 10(-4) M). These data suggest that the above neurodepressant drugs, when applied at sedative doses to hippocampal pyramidal cells, enhance GK and not the actions of GABA.

Animals↗

Effect of benzodiazepine hypnotic triazolam on relationship of blood pressure and Paco2 to cerebral blood flow during human non-rapid eye movement sleep.

We sought to clarify the effect of short-acting benzodiazepine hypnotic on the relationship of arterial blood pressure and arterial partial pressure of carbon dioxide (Paco2) to regional cerebral blood flow (rCBF) during human non-rapid-eye-movement (non-REM) sleep. Nine young normal volunteers were treated in a randomized, crossover design with triazolam or placebo and underwent positron emission tomography at night. During wakefulness and stage 2 and slow wave (stages 3 and 4) sleep, we measured mean arterial blood pressure (MAP), Paco2, and absolute CBF. With triazolam compared to placebo, MAP reduced gradually. During stage 2 sleep, Paco2 increased and whole-brain mean CBF decreased. With triazolam, relative rCBF of the left orbital basal forebrain decreased more during stage 2 than slow wave sleep, whereas absolute CBF of the occipital cortex and cerebral white matter remained constant. During triazolam-induced stage 2 sleep, absolute CBF of the cerebral white matter correlated more strongly to both MAP and Paco2 than during placebo sleep and also correlated more strongly to both MAP and Paco2 than absolute CBF of the occipital cortex. In the frontal white matter, during triazolam-induced stage 2 sleep compared to wakefulness, absolute CBF was significantly better correlated to MAP, but not to Paco2. During triazolam-induced stage 2, the cerebral white matter may receive a modulated CBF regulation having the strengthened relationship of Paco2 to CBF and, more locally, the frontal white matter may depend precariously on CBF regulation.

Adult↗

Low doses of brotizolam and nitrazepam as hypnotics in the elderly.

0.125 mg brotizolam and 2.5 mg nitrazepam proved to be equipotent in promoting and maintaining sleep in 29 elderly patients used to long-term hypnotics. These drugs were superior to placebo and they were excellently tolerated. The drugs were administered in a random order, double-blind, for 7 nights each.

Aged↗

Relationship between the effects of a hypnotic drug, zopiclone, on polysomnography and on daytime EEGs.

The correlation between the effects of zopiclone (ZPC), a nonbenzodiazepine hypnotic drug, on sleep polysomnograms and on daytime EEGs was examined in 12 healthy adult male volunteers. Sleep polysomnograms were recorded after a single oral administration of ZPC 10 mg or placebo according to the double-blind crossover method. Daytime EEGs were recorded after the administration of ZPC, 7.5 mg, or placebo in the same manner, and recorded for 3 min with closed eyes at rest. Then, square roots of the absolute power (amplitude) of the delta-, theta-, alpha-, and beta-activities were calculated from the power spectrum obtained by the fast Fourier transform method. As a result, ZPC decreased the percentage of stage 1 sleep in total sleep time, while it increased the percentage of stage 2, total sleep time, and time of slow wave sleep in the first and second sleep cycles (SWS 1 and 2). Changes in SWS 1 and 2 correlated positively with the amplitude changes in daytime resting delta-activity. This indicates that the increase of SWS due to ZPC could be related to the change of delta-activity in the daytime resting EEG.

Adult↗

Zopiclone to geriatric patients. A parallel double-blind dose-response clinical trial of zopiclone as a hypnotic to geriatric patients - a study in a geriatric hospital.

Zopiclone was given for 14 nights to 68 geriatric patients (mean age 81 years) with sleep problems. The patients were randomly allocated to four treatment groups: 3.75 mg, 5.0, 7.5, or 10.0 mg of zopiclone. Sleep quantity and quality, side effects, and influence on psychomotor performance (digit symbol substitution and letter cancellation test) were studied before treatment, during active treatment, and after withdrawal of the drug. All patients slept better on zopiclone compared to placebo. There were only slight differences between the different dose levels as regards quantity and quality. No influence on psychomotor performance could be shown. The side effects were mild. Zopiclone showed a good hypnotic efficacy, and 7.5 mg is probably the best dose for elderly patients.

Aged↗