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At least 19 recordsLinked to original sources
PubMed1992

Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death.

Nitrazepam was used in the treatment of resistant myoclonic epilepsy in 38 children. After the occurrence of nitrazepam-associated swallowing incoordination, high-peaked esophageal peristalsis and related bronchospasm in one patient, we initiated a prospective study of esophageal manometry using a station pull-through technique with a pediatric 4-channel continuous perfusing system. Three more patients were found to have delayed cricopharyngeal relaxation and high-peaked esophageal peristaltic waves. The initial patient developed severe respiratory distress and bronchospasm necessitating ventilatory support while on nitrazepam and improved dramatically with subsequent normal manometric study following nitrazepam discontinuation. Nitrazepam was reintroduced for its anticonvulsant and cognitive benefits and was tolerated at a reduced dosage. We postulate a central nervous system effect of nitrazepam promoting parasympathetic overactivity or vagotonia which can cause potentially fatal respiratory distress. Care must be exercised in nitrazepam use and esophageal manometry may be helpful in defining patients at greater risk for sudden death.

Adolescent↗
PubMed1986

Influence of some dopaminoceptor agents on nitrazepam-induced sleep in the domestic fowl (Gallus domesticus) and rats.

The influence of apomorphine, levodopa and haloperidol was studied on nitrazepam sleep using young chicks and rats. In addition, the influence of dopamine and ADTN was studied in young chicks. Nitrazepam dose-dependently (0.4-51.2 mg/kg, i.p.) induced behavioural sleep in chicks. However, higher doses of nitrazepam (12.8-51.2 mg/kg, i.p.) were required to induce behavioural sleep in rats. Dopamine (12.5-100 mg/kg, i.p.) and ADTN (2.5-80 mg/kg, i.p.) delayed the onset but prolonged nitrazepam sleep in chicks: these effects were statistically significant. Levodopa (12.5-100 mg/kg, s.c.) and apomorphine (0.2-0.8 mg/kg, s.c.) profoundly delayed the onset and shortened the duration of nitrazepam sleep in both chicks and rats. Noradrenaline (20-80 mg/kg, i.p.) shortened the onset and prolonged nitrazepam sleep in chicks. Pimozide (1-8 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of dopamine, levodopa and ADTN on nitrazepam sleep in chicks. Similarly, haloperidol (0.5-1.0 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of levodopa and apomorphine on nitrazepam sleep in rats. The EEG synchronization and decreased EMG induced by nitrazepam (1.6 mg/kg, i.p., and 12.8 mg/kg, i.p., for chicks and rats, respectively) were antagonized by levodopa (12.5 mg/kg, s.c.). The behavioural and electroencephalographical results suggest that enhancement of dopaminergic neurotransmission may be involved in the mechanisms of wakefulness in both chicks and rats.

Aminooxyacetic Acid↗
PubMed1985

Influence of some agents that affect 5-hydroxytryptamine metabolism and receptors on nitrazepam-induced sleep in mice.

The effects of 5-hydroxytryptophan (5-HTP), citalopram, p-chlorophenylalanine (PCPA), cyproheptadine, lysergic acid diethylamide (LSD-25), metitepine and NSD 1034 on nitrazepam-induced sleep were investigated in mice. Nitrazepam (1.6-25.6 mg kg-1, i.p.) induced a dose-dependent sedative-hypnotic effect. 5-HTP (8-128 mg kg-1 i.m.) did not induce behavioural sleep but sedated mice and significantly potentiated nitrazepam-induced sleep. Similarly, 5-HTP (4-32 mg kg-1, i.m.) increased pentobarbitone sleeping time. Citalopram (2.5-10 mg kg-1, i.p.) significantly potentiated nitrazepam sleep. PCPA (300-400 mg kg-1, i.p.) completely abolished nitrazepam sleep; 5-HTP (32 mg kg-1, i.m.) reversed this effect. NSD 1034 (75-150 mg kg-1, i.p.) antagonized the potentiating effect of 5-HTP (32 mg kg-1, i.m.) on nitrazepam sleep. Cyproheptadine (5-10 mg kg-1, i.p.) and LSD-25 (2.5-10 micrograms kg-1, i.p.) partially antagonized nitrazepam sleep. Similarly, 5-HTP-induced potentiation of nitrazepam sleep was antagonized by cyproheptadine and LSD-25. Metitepine (4-8 mg kg-1, i.p.) induced behavioural sleep and significantly potentiated nitrazepam sleep. Ro15-1788 (10 mg kg-1, i.p.) effectively antagonized nitrazepam-induced sleep. These results indicate that enhancement of central 5-HT neurotransmission may underlie nitrazepam-induced sleep in mice.

5-Hydroxytryptophan↗
PubMed1977

Plasma nitrazepam concentrations after an acute intake and their correlation to sedation and serum growth hormone levels.

Concentrations of nitrazepam in plasma were determined by gas chromatography in healthy volunteers after an acute peroral administration of nitrazepam (5 and 10 mg). Placebo tablets were also used, and an assessement of subjective drug effects was made during each medication. In addition serum growth hormone levels were determined. The peak plasma nitrazepam concentration was achieved at 120 minutes (46.9 +/- 3.2 ng/ml, mean +/- S.E.M.) after 5 mg of nitrazepam and at 180 minutes (82.8 +/- 10.5 ng/ml) after the dose of 10 mg. The half-life of nitrazepam in plasma ranged from 16.5 to 48.3 (mean 28.8) hours. A significant positive correlation was seen between the subjective sedative effects and the magnitude of the peak nitrazepam concentrations in plasma. This drug effect was highly significant when the plasma levels of nitrazepam were rising. The subjective sedative effects were more prominent after 10 mg than after 5 mg dose of nitrazepam. The plasma nitrazepam concentration was not significantly correlated with the subjective sedative effect the next morning, 12 hours after the drug intake. Serum growth hormone levels rose significantly during the study both after 5 mg and 10 mg nitrazepam doses (peak levels 16.3 +/- 4.0 and 12.7 +/- 3.1 ng/ml) and were significantly higher than after placebo administration (3.7 +/- 0.7 ng/ml).

Administration, Oral↗
PubMed1991

Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction.

A study was undertaken to investigate the relationship between nitroreduction of nitrazepam and its teratogenic effects and the involvement of the intestinal microflora in Sprague-Dawley rats. Incubation of bacterial suspensions from rat cecal contents with nitrazepam resulted in extensive reduction to 7-aminonitrazepam. Rat liver homogenates also reduced nitrazepam but only under anaerobic conditions. Following oral administration of 300 mg/kg nitrazepam to pregnant rats, total excretion of reduced metabolites (7-aminonitrazepam and 7-acetylaminonitrazepam) in urine and feces accounted for approximately 30% of the administered dose. When antibiotics were administered to dams to deplete their intestinal microflora prior to administration to nitrazepam, the total excretion of the reduced metabolites in the urine and feces decreased to 2% of the dose. Nitroreductase activity of cecal contents was almost completely suppressed by antibiotic pretreatment, but the activity of liver homogenates was not significantly altered by the same treatment. The incidence of nitrazepam-induced malformations was markedly decreased by antibiotic pretreatment. These results suggest that the intestinal microflora plays an important role in the reductive metabolism of nitrazepam and that the teratogenicity of nitrazepam may be related to its nitroreduction by the microflora.

Animals↗
PubMed1979

Determination of nitrazepam and its main metabolites in urine by gas--liquid chromatography: use of electron capture and nitrogen-selective detectors.

Nitrazepam and its main urinary metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, free and conjugared, were determined from 24-h fractions of human urine after a single oral dose of 5 mg of nitrazepam. Nitrazepam and the metabolites were extracted before and after glusulase hydrolysis with benzene--dichloromethane (90:10) from a 1.0 ml sample. Methylnitrazepam and methylbromazepam served as internal standards. Recoveries were better than 90%. GLC analysis of nitrazepam was performed using a 63Ni electron-capture detector. The metabolites were measured by a dual flameless nitrogen selective detector. The detection limits were about 0.2 ng/ml for nitrazepam and 50 ng/ml for the metabolites. The nitrogen-selective detector responds similarly to all three compounds. The 63Ni electron-capture detector gives very poor response to 7-amino-nitrazepam but allows very sensitive detection of nitrazepam. Combined use of the two detectors gives valuable information about the metabolic profile of nitrazepam.

Adolescent↗
PubMed1975

Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance.

1 The residual effects of two benzodiazepines, nitrazepam (10 mg) and flurazepam hydrochloride (30 mg), and pentobarbitone sodium (200 mg) were studied by adaptive tracking and by reaction time. Performance was measured at 10 h, 13 h, 16 h, 19 h and 34 h after ingestion of each drug. Impaired performance on adaptive tracking was observed at 10 h, 13 h, 16 h and 19 h after nitrazepam and pentobarbitone sodium and at 10 h, 13 h and 16 h after flurazepam hydrochloride. Enhanced performance was observed at 34 h after nitrazepam and pentobarbitone sodium. 2 Increased reaction time persisted to 16 h after nitrazepam, flurazepam hydrochloride and pentobarbitone sodium and reaction time was also increased at 34 h after nitrazepam and pentobarbitone sodium. 3 During the morning immediately after ingestion, the subjects as a group were able to differentiate correctly between placebo and drugs, but they were not able to assess accurately the persistence of the residual effects of nitrazepam and pentobarbitone sodium. 4 Flurazepam hydrochloride would appear to be a more promising benzodiazepine than nitrazepam for use as a hypnotic by persons involved in skilled activity. There was a rapid recovery of performance during the afternoon and, unlike pentobarbitone sodium and nitrazepam, subjects retained the ability to recognize impaired skill.

Adult↗
PubMed1979

Long-term nitrazepam treatment in psychiatric out-patients with insomnia.

Psychiatric patients (N = 26) were treated chronically (from 1 week to 12 years) with nitrazepam, because of insomnia. The patients gave their subjective estimations of the effects and side effects of nitrazepam. The concentrations of nitrazepam in the plasma were measured by 63Ni-EC-gas-liquid chromatography. The pharmacokinetics of nitrazepam were compared between the psychiatric patients and healthy volunteers (N = 11). The steady-state concentrations and the half-life of nitrazepam in the psychiatric patients were comparable to those of the healthy volunteers. The subjective hypnotic effect of nitrazepam was mostly good or satisfactory and remained unchanged during long-term treatment. Only a few, mild side effects were reported. Nitrazepam does not seem to cause enzyme induction with lowered plasma levels and may therefore be of special value in the treatment of chronic insomnia.

Adult↗
PubMed1989

Effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in healthy volunteers.

We studied the effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in eight male volunteers aged 19-32. The hypnotic effects, effects on psychomotor performance, EEG activity and standing steadiness between BAHS 1000 mg and nitrazepam 5 mg were compared at regular intervals for 10 h. The serum levels of both drugs were also assayed. The hypnotic effects of BAHS were very weak compared to those of nitrazepam. BAHS did not exert any effects on psychomotor performance and standing steadiness during the test period. In contrast, nitrazepam impaired psychomotor performance and standing steadiness as the serum drug levels increased. Nitrazepam decreased the alpha activity and increased the beta activity in a concentration-dependent manner. BAHS did not change the alpha activity but increased beta-2 activity at Fz and Cz at 10 h of the post-drug period. BAHS was eliminated more rapidly than nitrazepam. These results indicated that BAHS, at the dose used, was less potent than nitrazepam and the effects on psychomotor performance and standing steadiness were minimal.

Acoustic Stimulation↗
PubMed1978

Toxicity of nitrazepam in the elderly: a report from the Boston Collaborative Drug Surveillance Program.

1 To assess the potential hazards of nitrazepam therapy of insomnia in the elderly, adverse reactions to nitrazepam were studied in 2111 hospitalized medical patients who received the drug. 2 Manifestations of unwanted central nervous system (CNS) depression (such as drowsiness or 'hangover') were reported in 49 nitrazepam recipients (2.3%), and signs of unwanted CNS stimulation (such as nightmares, insomnia, agitation, etc.) in 15 (0.7%). None of the adverse reactions were considered serious. 3 Physician-rated clinical efficacy of nitrazepam was not related to dose, but the frequency of both types of adverse reactions increased significantly at higher daily doses. CNS depression also was significantly more frequent in the elderly, being reported in 11% of those aged 80 years or older, whereas the frequency of CNS stimulation was not correlated with age. 4 The effect of age on the reported rate of unwanted CNS depression was most striking at high doses. Among patients aged 80 years or over whose daily dose averaged 10 mg or more, 55% experienced unwanted CNS depression attributed to nitrazepam. 5 Low doses of nitrazepam are safe for elderly individuals, but the elderly are readily susceptible to excessive CNS depression at high doses. The findings suggest that there is little reason to exceed 5mg doses of nitrazepam for most patients, particularly those who are elderly.

Aged↗
PubMed1990

Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects.

1. In a randomized study of 22 patients in a maternity ward, the residual concentrations of two hypnotics, midazolam 15 mg p.o. and nitrazepam 5 mg p.o., in early breast milk and plasma were measured 7 h after intake on day 2 to day 6 postpartum. Milk pH, milk fat and binding to plasma proteins were also investigated. Sleep variables were scored on questionnaires. 2. No measurable (less than 10 nmol l-1) concentrations of drug in milk were found in the group receiving 15 mg midazolam at night, either after the first night or after the fifth night. Additional investigations in two mothers demonstrated that midazolam and its hydroxymetabolite disappeared rapidly from milk with undetectable levels after 4 h. The mean (s.d.) milk to plasma ratio for midazolam was 0.15 (0.06) in six paired samples. It may be assumed that practically no midazolam is transferred via early milk to the baby if the baby is nursed more than 4 h after tablet intake. 3. Milk nitrazepam concentrations increased significantly from the first (30 nmol l-1) to the fifth morning (48 nmol l-1) in the group receiving 5 mg nitrazepam at night. The mean (s.d.) milk to plasma ratio of nitrazepam after 7 h was 0.27 (0.06) in 32 paired samples, and did not vary from day 1 to day 5. Plasma protein binding of nitrazepam in puerperal women was found to be lower than that in plasma of healthy controls. The average amount of nitrazepam received by the breast-fed baby in the morning was calculated to increase from 1 to 1.5 micrograms 100 ml-1 breast milk, from days 1 to 5. In the mothers nitrazepam was associated with better hypnotic effect, but a higher incidence of complaints than midazolam. 4. Milk pH, assuming anaerobic conditions, was found in 10 women to average 6.91 +/- 0.09 (s.d.) on days 2-6 postpartum, which is less than previously reported. 5. It is concluded that both hypnotics may be used safely for a few days in the maternity ward. However, possible long-term effects in the suckling infant of small doses of benzodiazepines ingested with breast milk remain to be investigated.

Adult↗
PubMed1979

Pharmacokinetics of nitrazepam in saliva and serum after a single oral dose.

The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni-EC-GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN-program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r = 0.472, P less than 0.001, n = 97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P less than 0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P less than 0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half-life of nitrazepam in serum was 30.5 hrs and in saliva 39.9 hrs, the difference being significant at P less than 0.05. The distribution phase parameters, poorly described before, were calculated. The clinical value of nitrazepam analysis in saliva seems to be negligible.

Administration, Oral↗
PubMed1975

Determination of nitrazepam in serum by gas-liquid chromatography. Application in bioavailability studies.

A gas chromatographic method with electron capture detection has been developed for the analysis of nitrazepam in serum. N-Desmethyldiazepam is used as internal standard. Nitrazepam isolated from serum is converted by acid hydrolysis into 2-amino 5 nitrobenzophenone, which is chromatographed. Metabolites of nitrazepam (7-amino and 7-acetamido compounds) are not included in the determination. Recovery experiments showed that the method is quantitative. The limit of detection is 5 ng/ml of nitrazepam in serum. The method has been used for measuring serum concentrations of nitrazepam in bioavailability studies on subjects given a single dose of nitrazepam tablets.

Biological Availability↗
PubMed1985

Age, sex, and nitrazepam kinetics: relation to antipyrine disposition.

Forty healthy men and women 19 to 80 years old received a single 10 mg oral dose of the 7-nitro benzodiazepine nitrazepam. Nitrazepam plasma concentrations were measured during the next 72 hours. Among men, the elderly had a larger volume of distribution (Varea) than did younger subjects (1.96 vs. 1.63 L/kg; P less than 0.05); because clearance did not change with age (0.84 vs. 0.95 ml/min/kg), the prolonged t1/2 in elderly men (28 vs. 20 hours; P less than 0.01) was a result of the larger Varea. Elderly and young women did not differ in nitrazepam Varea (2.58 vs. 2.55 L/kg), t1/2 (26 vs. 27 hours), or total clearance (1.19 vs. 1.09 ml/min/kg). The nitrazepam free fraction in plasma (18% to 19% unbound) was not related to age or sex. Among 18 subjects who also received antipyrine, the clearance of nitrazepam and antipyrine were not correlated (r = 0.23). Thus age minimally influences nitrazepam clearance (accomplished mainly by nitroreduction), which in turn is not significantly related to antipyrine oxidizing capacity.

Administration, Oral↗
PubMed1987

Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice.

The efficacy and tolerance of zopiclone were compared with nitrazepam and placebo in a multicenter double-blind parallel-group study in insomniac patients. Following a 7-day placebo washout period, 99 patients (age range 20 to 69 years) received oral capsules of 7.5 mg zopiclone or 5 mg nitrazepam or placebo for 2 weeks. During the fourth week all patients received placebo treatment. Sleep assessments by the patients showed that, compared with placebo, zopiclone and nitrazepam improved all sleep measures of efficacy from the first night and that effectiveness was maintained throughout treatment. The physicians global assessment of efficacy also favored zopiclone and nitrazepam over placebo treatment. Subjective morning drowsiness during treatment was significantly less for zopiclone than for either nitrazepam or placebo and represents a clear advantage for ambulatory patients. No rebound insomnia was evident during a 7 day post-treatment withdrawal period for either zopiclone or nitrazepam. Tolerance was good for all treatments.

Adult↗
PubMedDate not supplied

A comparison between chlormethiazole and nitrazepam as hypnotics in psycho-geriatric patients.

A double-blind crossover study was carried out in 68 demented elderly patients (mean age 77 years) to compare the hypnotic effects of chlormethiazole and nitrazepam. Chlormethiazole was administered as a 5% mixture (500 mg. chlormethiazole edisylate) in a 10 ml. dose: the corresponding single dose of nitrazepam was 10 mg. Treatment was discontinued in 6 patients and interrupted for from 1 to 3 days in a further 18 due to side-effects and 'hang-over' problems or because of intercurrent infections. Of these 24 drop-outs, 3 occurred during chlormethiazole treatment (1 severe 'hang-over'; 2 refused to take medication) and 21 during nitrazepam (15 severe 'hang-over' effects, including sleepiness and muscular weakness; 2 nausea; 4 intercurrent infection). Both preparations were equally effective as hypnotics, there being no noteworthy differences in time of onset or in duration of sleep. Of the 44 patients completing the trial without interuption, observations were carried out for 308 nights on each preparation. Chlormethiazole patients slept for more than 6 hours on 244 of the 308 nights without 'hang-over' effect the next day compared with 163 out of 308 nights of those on nitrazepam. The difference is statistically significant in favour of chlormethiazole. The high incidence of 'hang-over' effect during nitrazepam treatment indicates that a single 10 mg. dose is too large for use in the elderly. Overall assessment of treatment was made in 62 patients. Chlormethiazole was judged to be the most suitable drug in 37, nitrazepam in 11, and both preparations equally useful in the remaining 14 patients. This difference is statistically significant.

Aged↗
PubMed1992

Nitrazepam clearance unimpaired in patients with renal insufficiency.

Eight patients with mild to moderate renal insufficiency (mean serum creatinine: 2.4 mg/100 ml) and 9 matched control subjects with normal renal function received a single 5-mg oral dose of nitrazepam, cleared mainly by hepatic nitroreduction. Serum nitrazepam levels were determined by gas chromatography during the 72 hours after dosage. Renal patients and controls were well-matched for age (74 vs. 63 years), height (165 vs. 164 cm), and weight (68 vs. 64 kg). Patients and control subjects did not differ significantly in nitrazepam elimination half-life (32 vs. 24 hour) or volume of distribution (4.2 vs. 3.6 liters/kg). Clearance was higher in patients than in controls (4.2 vs. 1.7 ml/min/kg), but the difference was not significant. Nitrazepam free fraction in serum was increased in renal patients (16.8 vs. 15.0% unbound, p = 0.08). After correction for individual values of free fraction, the two groups still did not differ in kinetic variables for nitrazepam. Thus, mild to moderate renal insufficiency does not alter the kinetics of nitrazepam.

Adult↗