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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↗
PubMed1980

Sedative and cardiovascular effects of clonidine and nitrazepam.

Five healthy male subjects, aged 26 to 35 yr, received single oral doses of clonidine 0.3 mg, nitrazepam 20 mg, or placebo double-blind with an interval of at least 1 wk between each treatment. Clonodine induced a maximal fall in systo9lic blood pressure from 104.2 +/- 1.6 to 84.7 +/- 1.4 mm Hg (mean +/- SEM) after 3.5 hr and nitrazepam from 102.9 +/- 1.9 to 90.3 +/- 2.6 mm Hg after 1.0 hr while after placebo blood pressure rose steadily from 102.5 +/- 2.9 to 109.6 +/- 3.5 mm Hg at the end of the 8-hr study. Total sleep time increased from 90.3 +/- 2.5. min after placebo to 256.2 +/0 21.0 min after clonidine (p < 0.001) and 281.0 +/- 40.3 min after nitrazepam (p < 0.001). Stage I sleep increased from 49.7 +/- 11.2 to 76.9 +/- 10.2 min after clonidine and to 76.3 +/- 25.2 min after nitrazepam (p < 0.0), while the greatest increase was observed in stage II: 230.7 +/- 25.6 min after clonidine and 236.6 +/- 35.4 min after nitrazepam compared with only 48.5 +/- 15.8 min after placebo (p < 0.001). Plasma norepinephrine did not change after placebo but fell after nitrazepam from 0.28 +/- 0.04 to 0.14 +/- 0.02 ng/ml after 3 hr (p < 0.05) and after clonidine from 0.23 +/- 0.07 to 0.07 +/- 0.02 ng/ml after 2 hr (p < 0.01). Clonidine and nitrazepam both induced similar hypnotic and hypotensive effects with some evidence that this might be due to a reduction in sympathetic tone.

Adult↗
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↗
PubMed1982

A comparison of the effects of chlormezanone and nitrazepam on sleep.

1 Twelve volunteers, of mean age 60 years, took part in a double-blind, balanced cross-over study, to compare effects of chlormezanone 400 mg and nitrazepam 5 mg on electrophysiologically-recorded and subjectively-rated sleep. 2 In the first week of administration nitrazepam caused a significant shortening of the time to fall asleep, but following withdrawal subjects took longer to fall asleep than during the baseline period. 3 Both chlormezanone and nitrazepam initially caused increase of sleep duration and less interruption of sleep by wakefulness. By the third week, for chlormezanone this effect was no longer significant, and for nitrazepam there was a significant decline in the effect. There was no statistically significant difference between the two drugs for these measures. 4 The drugs differed little in their effects on the amount of the various sleep stages, except that nitrazepam significantly reduced the duration of slow wave sleep, whereas chlormezanone had no significant effect on slow wave sleep. Both drugs reduced the amount of REM sleep in the first 6 h of sleep but only nitrazepam reduced the percentage of the time spent in REM sleep of the whole night. 5 Subjects' own ratings of sleep quality showed that both of the drugs improved sleep, but following withdrawal it was only after nitrazepam that there was impairment of the quality of sleep. Neither drug affected subjective alertness in the morning.

Adult↗
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↗
PubMed1995

Potential parameters of male reproductive toxicity: reproductive performance, histopathology and sperm evaluation in SD rats given nitrazepam.

The present study was designed to elucidate the correlation between findings from reproductive performance testing and those from histopathological examination of the testis and sperm analysis in rats given a benzodiazepine derivative, nitrazepam, for 2 and 4 weeks. The mechanisms of toxicological action of nitrazepam on the male reproductive organs were also investigated. Nitrazepam was given orally to Sprague-Dawley male rats (6-week-old) at a daily dose of 80 mg/kg for 2 weeks or at daily doses of 20, 40 or 80 mg/kg for 4 weeks. Treated males were mated to examine reproductive performance with untreated females after each dosing period, and after 4 and 9 week of recovery periods. Necropsy was performed for histopathological examination of the testis and epididymis and for sperm analysis after each dosing period and the final mating trial (total of 11 weeks recovery). In the findings from reproductive performance testing, significant decrease in the fertility index was observed in the 80 mg/kg group even after 2 weeks dosing and thereafter until 4 weeks recovery, though the mating index did not significantly differ from that of controls through the experiment. In the histopathological examination and sperm analysis, testicular signs of toxicity, decrease in number of sperm heads in the testis and increase in number of sperm with abnormal heads in the seminiferous tubules were noted in the 80 mg/kg group after 2 weeks dosing and in the 40 and 80 mg/kg groups after 4 weeks dosing. Concentrations of plasma testosterone and content of testis testosterone in nitrazepam-treated groups were not significantly different from those of controls. Plasma FSH concentration was significantly elevated in the 80 mg/kg group through the experiment, although significant elevation of plasma LH was observed only after 2 weeks dosing. These results indicate that histopathological examination is the most reliable approach to detect male reproductive adverse effects induced by nitrazepam rather than using parameters from mating trials. The four-week-dosing period is appropriate for their detection. Hypospermatogenesis induced by nitrazepam is suggested to be caused by direct action of nitrazepam on germ cells and/or Sertoli cells rather than by indirect action through inhibition of testosterone secretion.

Animals↗
PubMed1984

Investigation of the muscle relaxant activity of nitrazepam.

Administered intravenously in decerebrate cats nitrazepam or diazepam (0.0625 to 0.5 mg/kg) produced dose-related inhibition of the ipsilateral extensor reflex. Nitrazepam (0.25 mg/kg i.v.) produced a significantly greater (P less than 0.001) inhibition than that produced by diazepam (0.25 mg/kg i.v.). Nitrazepam or diazepam (0.0625-4 mg/kg i.v.) had no effect on the contractions of directly stimulated (120 V, 5 msec, 0.1 Hz) quadriceps femoris muscle and on the contractions of tibialis anterior muscle produced by stimulating the cut peripheral end of the lateral popliteal nerve (8 V, 1.5 msec, 0.1 Hz). Nitrazepam or diazepam (0.125-0.5 mg/kg i.v.) produced dose-related depressor responses in cats anaesthetized with chloralose or pentobarbitone. Nitrazepam produced a depressor response at 0.0625 mg/kg dose while diazepam did not. The drugs did not appear to have any deleterious effect on the veins removed 6 hr after the first exposure to the drugs as evidenced by lack of histological changes. It is concluded that nitrazepam and diazepam produce central muscle relaxation by inhibiting polysynaptic pathways in the spinal cord. The potency of nitrazepam appears to be greater than that of diazepam. Definitive evidence has been provided that the peripheral neuromuscular or direct muscular actions are not involved in the muscular relaxation produced by the two drugs.

Anesthesia↗
PubMed1980

Reversible ring-opening reactions of nimetazepam and nitrazepam in acidic media at body temperature.

Hydrolytic reactions of nimetazepam and nitrazepam in acidic solutions at body temperature were studied spectrophotometrically. The open-ring compounds produced by hydrolysis were in equilibrium with the corresponding closed-ring compounds (protonated nimetazepam and nitrazepam). Forward-reaction rate constants of both drugs were greater than the rate constant of diazepam. In nimetazepam, the forward-reaction rate constant was smaller than the reverse-reaction rate constant; in nitrazepam, the reverse-reaction rate constant was much smaller than the forward-reaction rate constant, and possible amide bond cleavage was indicated. The activation energies of the forward and reverse reactions of nimetazepam and the forward reaction of nitrazepam were calculated from Arrhenius-type plots, whereas no clear temperature dependency was observed in the reverse-reaction rate constant of nitrazepam. The effect of pH on these reactions also was examined. In addition, the pKa values of nimetazepam and nitrazepam were calculated to be 2.53 and 2.77, respectively.

Acids↗
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↗
PubMed1983

Determination of nitrazepam and temazepam in plasma by high-performance liquid chromatography.

A rapid and simple high-performance liquid chromatographic analysis of nitrazepam in plasma with temazepam as an internal standard is described here. Alternatively, this assay method can also be used to determine temazepam plasma concentrations with nitrazepam as the internal standard. Chloroform was used as an organic solvent for the extraction process. The percentage recoveries of nitrazepam and temazepam were 79% and 85%, respectively. The coefficient of variation of the within-day precision of the assay procedure at a concentration equal to 50 ng/ml of nitrazepam was 2.4% (n = 5), and that for day-to-day precision at the same concentration was 4.7% (n = 5). Calibration curves for nitrazepam and temazepam were linear over their therapeutic ranges. Pharmacokinetic parameters obtained with this method after a single oral dose of 5 mg of nitrazepam in five normal subjects were comparable to results obtained in previous studies.

Anti-Anxiety Agents↗
PubMed1983

Pharmaco-EEG and Psychometric study of the effect of single doses of temazepam and nitrazepam.

A double-blind, daytime, placebo-controlled study was carried out in 12 healthy volunteers to investigate the effects of single doses of 5, 15 and 30 mg temazepam and of 5 and 10 mg nitrazepam on the EEG, psychomotor performance, subjective mental and emotional status, blood pressure and heart rate. Each subject received all 6 treatments in a random sequence at intervals of 1 week. The EEG tracings were evaluated quantitatively by spectral analysis. Psychomotor performance was assessed by means of the tapping test. Subjective mental and emotional status were assessed using the Bond and Lader analogue self-rating scale. Procedures were carried out before and at 1/2, 1, 2, 4, 6, 7, 8 and 9 h after drug administration, with the exception of the tapping test, which was carried out before and, again, after 2 and 7 h. EEG estimates of equipotency, based on magnitude of peak effect, were as follows: 15 mg temazepam approximately 5 mg nitrazepam; and 30 mg temazepam greater than or equal to 10 mg nitrazepam. At these approximately equipotent doses, temazepam had a somewhat earlier onset of action on the EEG, a clearly shorter duration of EEG action, and lesser impairment of psychomotor performance than nitrazepam. Qualitatively, both drugs had similar effects on the subjective mental and emotional states of the subjects. There were no clinically relevant changes in mean or individual sitting and standing blood pressure values. After temazepam, but not after nitrazepam, heart rate increased (maximal mean change 10 bpm) as part of a normal startle response to arousal. The results suggest that temazepam has less hangover potential than nitrazepam.

Adult↗
PubMed1994

Changes in mouse hippocampal EEG characteristics after oral administration of Ro 41-3696, nitrazepam, or zopiclone alone and in combination with ethanol.

Ro 41-3696, a benzoquinolizinone derivative, is a partial agonist to the benzodiazepine (BDZ) receptor and is expected to be a nonsedative hypnotic. The present comparative study was performed to examine the effects of the oral administration of Ro 41-3696, nitrazepam or zopiclone alone and in combination with a 'social' dose of ethanol on mouse hippocampal EEG. Ro 41-3696 (1-10 mg/kg), nitrazepam (0.1 and 1 mg/kg), and zopiclone (1 and 10 mg/kg) each alone caused an increase in the drowsy EEG pattern associated with a decrease in the duration of hippocampal rhythmic slow-wave activity (RSA). On the other hand, nitrazepam markedly lowered, while Ro 41-3696 and zopiclone slightly lowered the RSA frequency during waking mobility. In combination with a noneffective oral dose (1 g/kg) of ethanol, the reductions in both total duration and peak frequency of RSA caused by nitrazepam, unlike those by Ro 41-3696 and zopiclone, were significantly potentiated. In addition, only nitrazepam produced motor impairment. These results suggest that Ro 41-3696 acts more selectively than nitrazepam to promote the drowsy EEG pattern, and the partial agonistic properties may minimize the residual effects during waking mobility similar to the short-acting agent zopiclone.

Animals↗
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↗
PubMed1982

Influence of food and of age on nitrazepam kinetics.

The influence of food intake and of age on the kinetics of nitrazepam was examined in eight young and eight elderly healthy volunteers after single-dose administration of the drug. Serial blood samples were obtained during 0-24 hr, and the serum concentrations of nitrazepam were determined by gas chromatography. Concomitant food intake had no apparent influence on the absorption rate or on the bioavailability of nitrazepam in the young subjects, and there was no significant difference in nitrazepam kinetics between young and elderly subjects. Accordingly, nitrazepam may be taken together with food as well as on an empty stomach, at least in young subjects, and the increased nitrazepam sensitivity often seen in elderly subjects does not seem secondary to age-dependent pharmacokinetic differences.

Adult↗