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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↗

PubMed2006

[Effects of midazolam and estazolam as hypnotics in hypertensive patients with chronic insomnia: a multicentre, open labeled, randomized clinical trial].

OBJECTIVE: To compare the safety and efficacy of midazolam and estazolam in hypertensive patients with chronic insomnia. METHODS: In this multicentre, open labeled, randomized clinical trial, 217 adult (18 - 75 years) hypertensive patients (BP range 140 mm Hg or= 3 times/week for more than 1 month) were randomly divided into midazolam (7.5 - 15 mg before sleep, n = 113) or estazolam group (1 - 2 mg before sleep, n = 104). Patients took medication according to own need. Sleep diary should be completed within 15 minutes after getting up next morning. Follow-up analysis was performed in patients completed 8 sleep diaries or received midazolam or estazolam for 1 month. Patients' sleep diaries were evaluated, blood pressure and heart rate before and after therapy were measured and adverse events were recorded. RESULTS: (1) Blood pressure was equipotent reduced after both treatments (-11.8/7.3 mm Hg for midazolam group, and -9.1/5.6 mm Hg for estazolam group, all P < 0.05 vs. before treatment). (2) The total sleep score was also significantly decreased in both groups after medication (P < 0.01) and midazolam was significantly superior to estazolam in shortening sleep latency, reducing awakening frequency, improving objective sleep evaluation and decreasing daytime sleepiness, but there were no differences in dream frequency and total sleep time. (3) The adverse reactions such as dizziness, headache and nausea was similar in midazolam (3%) and estazolam group (7%, P > 0.05). CONCLUSIONS: It is safe to take midazolam or estazolam for hypertensive patients with chronic insomnia and both drugs reduced blood pressure. Midazolam is superior to estazolam in shortening sleep latency, reducing awakening frequency, improving objective sleep evaluation and decreasing daytime sleepiness.

Aged↗

PubMed2005

Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam.

To predict drug interactions with estazolam, the biotransformation of estazolam to its major hydoxylated metabolite, 4-hydroxyestazolam was studied in vitro using pooled human liver microsomes and individual expressed human cytochrome P450 (CYP) enzymes. Estazolam was metabolized to 4-hydroxyestazolam according to the Hill kinetic model in pooled human liver microsomes. The Km value for the 4-hydroxylation of estazolam was 24.1 microM, and the Vmax value was 52.6 pmol min(-1)mg(-1) protein. The formation of 4-hydroxyestazolam from estazolam in pooled human liver microsomes was significantly inhibited by itraconazole and erythromycin, specific CYP3A4 inhibitors, in a dose-dependent manner, with IC50 values of 1.1 and 12.8 microM, respectively. When estazolam was incubated with expressed human CYP enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4), it was metabolized only by CYP3A4. In conclusion, the biotransformation of estazolam to 4-hydroxyestazolam was catalyzed by CYP3A4.

Biotransformation↗

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↗

PubMed2002

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.

Administration, Oral↗

PubMed2002

Determination of estazolam in plasma by high-performance liquid chromatography with solid-phase extraction.

A high-performance liquid chromatography (HPLC) assay was developed for the determination of estazolam in human plasma. Estazolam and alprazolam as an internal standard were detected by ultraviolet absorbance at 240 nm. Estazolam in plasma was extracted by a rapid and simple procedure based on cyanopropyl bonded-phase extraction. Chromatographic separation was achieved with a reversed-phase C8-5 column using a mobile phase of 0.5% potassium dihydrogenphosphate(pH 4.5)-acetonitrile (70:30, v/v). The determination of estazolam was possible in the concentration range of 1.0 - 200.0 ng/mL. The mean recovery of estazolam added to plasma was 96.1 +/- 1.5% with coefficients of variation of less than 5.5%. This method is applicable for accurately monitoring the plasma level of estazolam in healthy subjects participating in scientific research.

Calibration↗

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↗