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At least 19 recordsLinked to original sources
PubMed1982

[Alterations of sleep stage patterns in humans and carry-over effects under estazolam / 1st comm.: effects of estazolam on sleep disturbed by jet fly-over noise (author's transl)].

Effects of the benzodiazepine derivative 8-chloro-6-phenyl-4H-s-triazolo(4,3-a)-(1,4)benzodiazepine (estazolam, BAY k 4200) on sleep stage patterns of 10 subjects were studied in the laboratory under double-blind conditions during quiet and noise-disturbed nights. The noise of 17-20 jet fly-overs was presented during sleep. The mean peak level of the noise was 97 dB(A) measured indoors near the sleeper's head. Intermittent wakefulness, stage 1 and movement time (MT) increased during noise-disturbed nights. Estazolam suppressed the phases of intermittent wakefulness during the quiet night and reduced stage 1 and MT. Arousal reactions by jet noise were milder and shorter under estazolam. Both effects resulted in equal amounts of intermittent wakefulness, stage 1 and MT during the noise-disturbed night under estazolam and during the quiet night under placebo. The dosage of 2 mg estazolam had no significant effect on stage REM, but delta-sleep decreased. Hints of carry-over effects were found in the sleep stage patterns. Effects of estazolam were seen in the estimations of sleep quality and mood by the subjects in the morning after awakening.

Adult↗
PubMed1986

Metabolism of 14C-estazolam in dogs and humans.

14C-Estazolam (2 mg) administered orally to dogs and human subjects was rapidly and completely absorbed with peak plasma levels occurring within one hour. In humans, plasma levels peaked at 103 +/- 18 ng/ml and declined monoexponentially with a half-life of 14 h. The mean concn. of estazolam in dog plasma at 0.5 h was 186 ng/ml. Six metabolites were found in dog plasma at 0.5 and 8 h, whereas only two metabolites were detected in human plasma up to 18 h. Metabolites common to both species were 1-oxo-estazolam (I) and 4-hydroxy-estazolam (IV). Major metabolites in dog and human plasma were free and conjugated 4-hydroxy-estazolam; the concn. were higher in dogs. After five days, 79% and 87% of the administered radioactivity was excreted in dog and human urine, respectively. Faecal excretion accounted for 19% of the dose in dog and 4% in man. Eleven metabolites were found in the 0-72 h urine of dogs and humans; less than 4% dose was excreted unchanged. Four metabolites were identified as: 1-oxo-estazolam (I), 4'-hydroxy-estazolam (II), 4-hydroxy-estazolam (IV) and the benzophenone (VII), as free metabolites and glucuronides. The major metabolite in dog urine was 4-hydroxy-estazolam (20% of the dose), while the predominant metabolite in human urine (17%) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam. The metabolism of estazolam is similar in dog and man.

Administration, Oral↗
PubMed1990

Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia.

A multicenter, double-blind placebo-controlled clinical trial was designed to compare the safety and efficacy of estazolam compared with flurazepam as hypnotics. Outpatients complaining of insomnia were randomized to receive either estazolam 2 mg, flurazepam 30 mg or placebo for 7 consecutive nights. The analysis of efficacy was based on the patients' daily assessments of sleep and the investigators' global evaluations. Adverse events which were considered by the investigator to be attributable to, or of unknown relationship to the test medication were analyzed. The patient subjective questionnaire indicated that estazolam and flurazepam significantly improved all parameters (P less than .05) as compared to placebo. A marked or moderate improvement in sleep was reported by 81% (58/72), 78% (63/81) and 36% (27/76) of estazolam, flurazepam, and placebo recipients, respectively. There were no significant differences in hypnotic effect between estazolam and flurazepam. All efficacy parameters of the investigators' global evaluation improved significantly more (P less than .05) for patients receiving estazolam or flurazepam (except quality of sleep) than for those receiving placebo. The percentage of patients reporting any adverse experience was greatest for flurazepam (72%), followed by estazolam (59%), and placebo (43%). Somnolence and hypokinesia were the most commonly reported adverse events. An analysis of the global evaluation of side effects showed that flurazepam had a significantly worse side effect profile than estazolam (P less than .05) or placebo (P = .001). Estazolam and flurazepam effectively, and comparably, relieved insomnia when administered for 7 nights in adult patients complaining of insomnia. Estazolam demonstrated a more favorable side effect profile than flurazepam.

Ambulatory Care↗
PubMed1983

Comparative study on the effects of haloxazolam and estazolam, new sleep inducing drugs, on the alpha- and gamma-motor systems.

The pharmacological actions, in vivo, of estazolam and haloxazolam were comparatively studied. Spontaneous discharges of spinal motoneurons in cats were markedly suppressed by estazolam (3 mg/kg, i.d.), but unaffected by similarly administered haloxazolam. The facilitatory effect of stimulation of the posterior hypothalamus on the gamma-activity was suppressed by both haloxazolam and estazolam (3 mg/kg, p.o., for each). The stimulus threshold was raised 1.7 times by haloxazolam and 1.6 times by estazolam. The facilitation of the gamma-activity induced by stimulation of the mesencephalic reticular formation was also depressed by both drugs. The stimulus threshold was raised 6 times by estazolam, but unchanged by haloxazolam. The spinal monosynaptic reflex was unaffected by haloxazolam, while its amplitude was depressed to a half by estazolam (3 mg/kg, p.o., for each). The facilitation of the monosynaptic reflex induced by conditioning stimulation was depressed by both drugs (3 mg/kg, p.o.), but estazolam showed a stronger suppressive action. The seizure-like responses of spinal motoneurons, which were induced by stimulation of the gastrocnemius nerve following strychnine administration, were unaffected by 30 mg/kg of haloxazolam, while they were suppressed by estazolam of the same dose. Thus, the results of all experiments in the present study indicate that estazolam blocks the descending activating functions of both alpha- and gamma-motor systems, whereas the blockade by haloxazolam is limited only to the gamma-system, and also that the suppressive actions of estazolam on both alpha- and gamma-motor systems are stronger than that of haloxazolam.

Animals↗
PubMed1991

Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia.

Estazolam is a new benzodiazepine hypnotic agent with an intermediate half-life of 12 to 15 hours. The authors designed an investigation to compare its hypnotic efficacy to that of flurazepam, generally considered the reference standard. The hypnotic efficacy of estazolam at two doses (1 mg and 2 mg) was compared with that of flurazepam (30 mg) in a double-blind, placebo-controlled, multicenter, 7-night study that involved 223 outpatients with insomnia. On subjective assessments of the patients, no differences were noted between estazolam 2 mg and flurazepam 30 mg on any of six sleep parameters. Patients who were receiving estazolam 1 mg rated their sleep significantly better than did patients who were receiving placebo on all parameters except sleep latency. Global evaluation of the physicians indicated significant improvement in quality of sleep, sleep depth, sleep duration, and nocturnal awakenings in all three active treatment groups; estazolam 2 mg and flurazepam also decreased sleep latency significantly. The percentage of patients who reported any adverse experience was 68% for flurazepam, 58% for estazolam 2 mg, and 54% for estazolam 1 mg; the incidence of adverse events in the placebo group was 43%. In conclusion, estazolam 2 mg was found to be as effective a hypnotic as flurazepam 30 mg. Estazolam 1 mg is also effective in the treatment of outpatients with insomnia, but to a lesser degree.

Adolescent↗
PubMed1991

Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study.

Estazolam, a triazolobenzodiazepine with an intermediate elimination half-life, has been shown previously to be an effective and safe hypnotic in insomniacs without concomitant psychiatric illness. Our study of the efficacy of estazolam in patients with insomnia associated with generalized anxiety disorder began when 108 patients meeting criteria for generalized anxiety disorder (mean total score of Hamilton Rating Scale for Anxiety [HAM-A] = 22.0 +/- 3.1 [SD]) and insomnia were given single-blind placebo for 7 nights. Nine patients whose anxiety and/or insomnia improved were dropped as placebo responders. The remaining 99 patients were randomly allocated (1:1) to double-blind treatment with either estazolam 2.0 mg or matching placebo for 7 nights. Hypnotic efficacy, as determined by patient-completed sleep questionnaires, was statistically significant for estazolam 2.0 mg versus placebo for all sleep indices (p less than 0.01). Patients treated with estazolam 2.0 mg showed significantly greater improvement in anxiety than those receiving placebo on the mean total score of HAM-A ([placebo, -3.4; estazolam, -7.1; p less than 0.001] and without the insomnia item [placebo, -2.7; estazolam, -5.5; p less than 0.001]). Anxiety scores on the State-Trait Anxiety Inventory showed greater improvement in the estazolam group, but without statistical significance (p = 0.237). Estazolam 2.0 mg is an effective hypnotic in patients with generalized anxiety disorder and appears to have a favorable anxiolytic action.

Adult↗
PubMed1990

Ventilatory response to single, high dose estazolam in healthy humans.

The purpose of this study was to determine the effect of oral estazolam at two and three times the usually recommended dosage (2 mg) on ventilation and respiratory drive during wakefulness. Sixty healthy subjects were randomized to receive a single oral dose of either: 1) estazolam 4 mg; 2) estazolam 6 mg; 3) placebo; or 4) morphine 0.15 mg/kg. Predrug and postdrug measurements were obtained for ventilation, respiratory cycle timing, metabolic rate, temperature, and ventilatory and mouth occlusion pressure (P0.1) responses to exogenous CO2. No difference between placebo and the study drugs was noted during eupneic breathing. During administration of exogenous CO2, morphine caused a decrease in the slope of the ventilatory (-0.4 +/- 0.1 L/min/mm Hg, P = .008) and P0.1 (-0.22 +/- 0.06 cm H2O/mm Hg, P = .015) responses. Estazolam (4 and 6 mg) had no effect on the ventilatory response to exogenous CO2. However, estazolam (6 mg) caused the P0.1 at a PCO2 of 57 mm Hg to decrease (-0.67 +/- 0.30 cm H2O, P = .005). The preservation of ventilation with the highest dose of estazolam, despite the decrease in P0.1, indicates that a compensatory strategy independent of respiratory center drive may have been activated. Sedation was a common side effect of estazolam reported in 13% and 53% of subjects at the 4 mg and 6 mg doses, respectively. We conclude that a single, high dose of estazolam does not cause ventilatory depression during wakefulness in healthy subjects.

Administration, Oral↗
PubMed1985

Kinetic and pharmacological studies on estazolam in mice and man.

After i.v. and oral doses of estazolam (5 mg/kg) to mice, the drug was rapidly cleared with a beta half-life (t1/2 beta) of 0.7 h. The active metabolite, 1-oxo-estazolam, was present in traces in mouse plasma and brain. Its elimination t1/2 (beta), determined after i.v. injection of 1-oxo-estazolam (5 mg/kg) to mice, was similar to that of the parent drug in both plasma and brain. After a single oral dose of estazolam (4 mg) to four human volunteers the drug was rapidly absorbed and reached maximum plasma concentrations in one to three hours. Elimination t1/2 of estazolam in humans was 19 h. The metabolite was undetectable in human plasma after either single or multiple doses of estazolam. These results, together with the finding that 1-oxo-estazolam was less effective than estazolam, in terms of ED50 and brain concentrations necessary to antagonize leptazol convulsions and disrupt rota-rod performance in mice, indicate that the metabolite does not contribute significantly to the pharmacological effects of its parent drug.

Administration, Oral↗
PubMed1992

The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs.

Insomnia, a common complaint among the elderly, is generally treated with benzodiazepines. Long-acting benzodiazepines (e.g., flurazepam) often produce daytime somnolence and performance deficits, whereas short-acting drugs (e.g., triazolam) have been associated with marked rebound insomnia and anterograde memory loss. The authors designed a pilot study to evaluate the efficacy of an intermediate-acting benzodiazepine, estazolam (e.g., ProSom), as well as its side effects. The parameters studied were sleep, daytime performance, and memory. Ten geriatric patients (greater than 60 years of age) with insomnia participated in the study. They received placebo nightly for 2 weeks (baseline), estazolam 1 mg nightly for the next 4 weeks (treatment phase), and placebo again for 2 weeks (withdrawal period). Sleep was monitored by polysomnography the first two nights of each week in a sleep laboratory. Estazolam significantly decreased sleep latency, nocturnal awakenings, and wake time after sleep onset. Total sleep time increased an average of 63 minutes the first night of treatment. Significant improvements in wake time after sleep onset and total sleep time also were observed in the fourth week of estazolam treatment. Rebound insomnia occurred on the first withdrawal night only for wake time and total sleep time. By the next night, these sleep parameters returned to baseline. Neither day-time performance nor anterograde memory was adversely affected by estazolam treatment or its withdrawal. A 1-mg dose of estazolam appears to be a safe and effective hypnotic for elderly patients with insomnia.

Aged↗
PubMed1982

Effect of the benzodiazepine derivative estazolam in patients with auditory hallucinations. A multicentre double-blind, cross-over study.

The main aim of this study was to test the effect of the triazolobenzodiazepine, estazolam, on auditory hallucinations. Fifty-eight patients (28 male, 30 female) with auditory hallucinosis that had responded poorly to neuroleptics alone, were included; most patients were chronic schizophrenics, and most patients were maintained on previous neuroleptic treatment during the trial. Each patient was treated for three consecutive 3-week periods, and randomly allocated to receive estazolam (1 + 1 + 4 mg) either in the first and third, or in the second period. Similar-looking placebo tablets were given in the control periods. These were seven drop-outs, three of them due to somnolence on estazolam. In both treatment groups there was a significant (but not significantly different) improvement during the first 3-week period, with regard to both global clinical state and auditory hallucinations. During the second and third periods, however, the two groups differed significantly, in that improvement of global state and hallucinosis was seen on estazolam, and deterioration on placebo. It is concluded that estazolam (as an addition to neuroleptics) had a significantly better effect than placebo on the global clinical state, on the frequency of, and attitude towards the hallucinations, and also on the single symptoms "Compulsive thoughts" and "Visual hallucinations" (items in the Comprehensive Psychopathological Rating Scale). There were few side effects except drowsiness. Possible pharmacokinetic and pharmacodynamic interactions between benzodiazepines and neuroleptics are discussed briefly.

Adult↗
PubMed1987

[Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions].

In order to study the efficacy of estazolam versus triazolam in preoperative patients, two groups of 49 patients each were treated with 2 mg estazolam and 0.5 mg triazolam in a single dose, the night before surgery. This controlled study was designed to evaluate sleep patterns, emotional status on awakening and side effects, by the administration of a questionnaire either in the morning of the day before (baseline) or on the morning of surgery. The results show better sleep patterns after estazolam excepting the duration of sleep that was the same for the two drugs. The better emotional status upon awakening in the morning before surgery and the lower incidence of side effects in the patients treated with estazolam, lead to the conclusion that estazolam is clearly better than triazolam in the treatment of preoperative patients.

Adult↗
PubMed1983

Dose-related effects of estazolam on sleep of patients with insomnia.

The dose range of estazolam for hypnotic effects was studied in seven men and eight women (mean age 30.3 +/- 8.6 years) who complained of insomnia and had polysomnographic evidence of disturbed sleep. Patients slept in the laboratory and were monitored using standard polysomnographic techniques. Four consecutive nights in the laboratory with placebo, which served as baseline and screening nights, were followed by five 2-night drug administration periods separated by 5-day drug washout periods spent at home. Each of the patients received a sequence of four doses (0.25, 0.5, 1.0, and 2.0 mg) of estazolam and placebo administered according to a Latin square design and in a double-blind manner. Estazolam significantly increased total sleep time and reduced time awake during sleep in a dose-dependent manner. Sleep latency parameters were reduced systematically with increasing doses of estazolam, but these effects on sleep latency were not statistically significant. Increasing doses of estazolam had systematic and statistically significant effects on sleep stages. Subjective estimations of sleep were consistent with the polysomnographic findings bur were not statistically significant.

Adult↗
PubMed1979

Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine.

The pharmacokinetic properties of estazolam, a triazolo benzodiazepine hypnotic agent, were assessed in a series of healthy volunteers following single and multiple doses. After single oral doses of 2--16 mg, peak plasma concentrations were reached within 6 h. Values of elimination half-life ranged from 8.3--31.2 h (mean 17.0 h) and did not vary significantly with dose. During 3 weeks of therapy, steady-state plasma concentrations increased approximately in proportion to increasing doses. and accumulation was essentially complete within 3 days of each dose change. The mean observed accumulation ratio was 1.84, which was slightly larger than the predicted ratio of 1.53. Exposure to multiple-dose estazolam therapy had no significant influence on the kinetics of a single dose of antipyrine, suggesting that estazolam neither stimulates nor inhibits enzyme activity in humans. Thus the accumulation and elimination kinetics of estazolam can be classified as intermediate to those of the short-acting (such as oxazepam) and the long-acting (such as diazepam) benzodiazepine derivatives.

Adult↗
PubMed1990

Efficacy of estazolam. The United States clinical experience.

The hypnotic efficacy of estazolam, a triazolobenzodiazepine, has been established in well-controlled sleep laboratory and outpatient clinical trials. Estazolam 1.0 mg and 2.0 mg significantly improves sleep latency, total sleep time, number of nocturnal awakenings, depth of sleep, and sleep quality in adults with chronic insomnia. Long-term studies indicate that estazolam 2.0 mg remains an effective hypnotic for at least six weeks of continuous nightly administration with no evidence of clinically significant tolerance. Estazolam is an effective treatment for situational insomnia and significantly improves sleep in patients with insomnia associated with moderately severe anxiety or depression.

Adolescent↗
PubMedDate not supplied

Effects of estazolam and flurazepam on cardiopulmonary function in patients with chronic obstructive pulmonary disease.

Benzodiazepine drugs have been shown to suppress respiratory function in patients with chronic obstructive pulmonary disease (COPD). We designed a placebo-controlled crossover study to compare the effects of a new benzodiazepine, estazolam ('ProSom'), with those of flurazepam ('Dalmane') on cardiopulmonary function in COPD patients. 29 patients completed all treatment phases (estazolam 2 mg, flurazepam 30 mg or placebo). Respiratory and cardiovascular function were assessed in awake patients on days 1 and 5 (acute and cumulative effects). Eight patients were also assessed during sleep in each period. The effects of estazolam and flurazepam on ventilatory response to CO2 and mouth occlusion pressure were no different from those of placebo. However, acute administration of flurazepam lowered tidal volume and increased inspiratory flow. Although no clinical signs of respiratory depression were observed with any long term treatment, flurazepam decreased oxygen saturation and inspiratory time and increased respiratory frequency. Neither drug altered breathing control during sleep. Our results indicate that estazolam 2 mg is equally as safe a hypnotic agent as flurazepam for patients with mild COPD.

Estazolam↗
PubMed1986

Comparative efficacy of estazolam, flurazepam, and placebo in outpatients with insomnia.

The efficacy and safety of estazolam, an investigational triazolobenzodiazepine, and flurazepam were compared in 65 insomniac outpatients. Patients completed sleep questionnaires each morning. Global evaluations demonstrated that both treatments were significantly superior to placebo. However, estazolam was preferred over flurazepam in a global rating that reflected how well rested and refreshed the subjects felt on arising. Improvement in complaints of difficulty in going to sleep showed only a trend toward significance favoring estazolam and flurazepam over placebo. Residual daytime drowsiness and fatigue accounted for approximately 70% of all side effects with both active treatments. Significantly more side effects occurred with flurazepam than with estazolam. Flurazepam-treated patients had a significantly more severe rating of adverse reactions than did placebo-treated patients.

Adult↗
PubMed1990

Safety of estazolam. The United States clinical experience.

The safety profile of estazolam, a new triazolobenzodiazepine hypnotic medication, has been developed in 1,320 normal volunteers and patients with insomnia. No clinically significant effects of estazolam on vital signs or laboratory values were detected. Drug-specific adverse effects such as somnolence, dizziness, hypokinesia, and abnormal coordination occurred, but these are expected extensions of benzodiazepine pharmacologic activity. No consistent effects on psychomotor performance, including memory, were seen at the recommended hypnotic doses in insomniac subjects. These data, combined with the evidence for hypnotic activity, indicate that estazolam is a safe and effective treatment for insomnia.

Adolescent↗
PubMed1984

Carcinogenic evaluation of estazolam via diet in CD strain Sprague-Dawley rats and B6C3F1 mice for 2 years.

A comparative toxicity and carcinogenicity study was carried out for 2 years with estazolam, a benzodiazepine, via diet in Sprague-Dawley rats (0.5, 2, and 10 mg/kg/day) and in B6C3F1 mice (0.8, 3, and 10 mg/kg/day). In rats, no biologically significant changes were seen with respect to mortality, clinical signs, food consumption, or occurrence of palpable masses. Body weight gain in females (10 mg/kg/day) was depressed 12.6% and reflected a maximum-tolerated dosage (females). Spontaneous and incidental nonneoplastic lesions were consistent with aging in this species and unrelated to drug treatment. No biologically significant differences in tumor incidences occurred. Mice were more responsive to estazolam as suggested by (1) increased mortality (males) at 10 mg/kg/day, (2) increased food consumption and body weight gains (females), (3) withdrawal signs characterized by hyperactivity/aggressiveness and convulsions, and (4) appearance of dose-related nodular hyperplasia of the liver due to the relatively high dosages used coupled with the propensity of benzodiazepines to enhance liver enzyme induction. Several spontaneous benign and malignant tumors observed in all groups were not considered to be drug related. Based on the findings in these studies, estazolam was not considered to be carcinogenic when administered via diet to either rats at 0.5, 2, and 10 mg/kg/day or to mice at 0.8, 3, and 10 mg/kg/day for 2 consecutive years.

Animals↗