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In 27 patients nitrazepam (Mogadon) taken in acute overdosage produced no untoward effects except drowsiness, even when 80 tablets were consumed. A double-blind trial in patients in general medical wards established that nitrazepam was as effective as butobarbitone as a hypnotic. It is concluded that nitrazepam is a safe and effective hypnotic.
The effects of acutely administered benzodiazepines have largely been validated in male animals, in spite of the fact that the majority of anti-anxiety drugs are prescribed for female patients. A study was carried out assessing the potential of female mice in the testing of the anxiolytic properties of drugs. Three doses (0.5, 1.0 and 2.0mg/kg) of the benzodiazepines diazepam and nitrazepam were given to individually-housed female Swiss mice before dyadic encounters with anosmic, group-housed males. Videotape analysis of the encounters, using an ethopharmacological technique, revealed suppressive effects of diazepam (1.0 and 2.0mg/kg) and nitrazepam (all doses) on avoidance/flee, confirming the anxiolytic properties of these drugs. However, some doses of diazepam (2.0mg/kg) and nitrazepam (1.0mg/kg), greatly increased immobility with little effect on active behavioural elements. It is suggested that "immobility" does not simply measure sedation.
The hydrolysis of nitrazepam involves a two-step sequential mechanism. The intermediate is the ring-opened compound resulting from scission of the azomethine bond. The final products are glycine and 2-amino-5-ni-robenzophenone. Recyclization of the intermediate to nitrazepam occurs at pH values above the pKa of the intermediate, in the pH region where the amino group of the intermediate is not protonated. As opposed to chlordiazepoxide and oxazepam, the initial hydrolysis step occurs at the 4,5-bond, not at the 1,2-amide linkage. This difference is attributed to a preferential activation for hydrolysis of the azomethine linkage by the nitro group. The hydrolysis involves an uncatalyzed reaction, specific acid-base catalysis, and general acid-base catalysis for acetate and phosphate buffers.
The daytime psychomotor performance of 12 healthy subjects of mean age 81.4 years was examined in a double-blind crossover study following single and repeated nightly doses of nitrazepam 5 mg, lormetazepam 1 mg, and placebo. Accuracy of performance on the Gibson spiral maze was unaffected by both drugs. On a reciprocal tapping task, speed was similarly unaffected. However, while neither drug significantly impaired accuracy on reciprocal tapping after the first dose, nitrazepam, but not lormetazepam, significantly reduced overall accuracy after seven consecutive doses, an effect consistent with drug accumulation.
The nocturnal sleep of eight healthy young volunteers was studied after placebo, Fosazepam 100 mg and Nitrazepam 10 mg. Overall results were very similar after the two drugs. During drug periods there was less of sleep Stages I, III + IV and REM, compensated by an increase in Stage II. The decrease in SWS (III + IV) persisted during the withdrawal periods. There was also an increase in Stage I during Fosazepam withdrawal, whereas the percentage of other sleep stages returned to normal. Sleep quality was reported to be slightly better and morning drowsiness, as well as hangover effects, were said to be less pronounced after Fosazepam than after Nitrazepam.
We applied micellar electrokinetic capillary chromatography to simultaneous separation and determination of nitrazepam and its major metabolites, 7-aminonitrazepam and 7-acetamidonitrazepam, in spiked urine. Prior to electrophoresis, the three compounds were successfully extracted from the spiked urine with commercial disposable solid-phase cartridges. The optimum running buffer for the separation was prepared by combining 85 parts of 60 mM sodium dodecyl sulphate-6 mM phosphate-borate, adjusted to pH 8.5, with 15 parts of methanol. The separation order, completed within 25 min, was 7-aminonitrazepam > 7-acetamidonitrazepam > nitrazepam, at an applied potential of 20 kV. We obtained reproducible electropherograms in successive repetitions, and few other peaks or interferences appeared in the electropherogram. The detection limits of the three compounds were 50-100 pg (0.1-0.2 microgram/ml of analyte in spiked urine), and the recoveries were 78.9-100.8% for 1 microgram/ml and 84.1-100.3% for 5 micrograms/ml. The application of this method to forensic or clinical samples is demonstrated.
The use of fifth order derivative spectra allows the direct determination of nitrazepam in urine at 388 nm with a limit of detection of 1 microgram ml-1. The determination of nitrazepam in blood plasma can be carried out directly by measurement at 402 nm in the fourth order derivative spectra with a limit of detection of 1.5 micrograms ml-1. Clonazepam can be determined directly in urine samples at 384 nm by using sixth order derivative spectra with a limit of detection of 1 microgram ml-1 and in blood plasma by using fourth order derivative spectra at 384 nm with a limit of detection of 0.5 ppm.
A method for the direct quantitative densitometry of nitrazepam and its main metabolites (7-aminonitrazepam, 7-acetamidonitrazepam and 2-amino-5-nitrobenzophenone) in urine was developed. The unchanged drug and its metabolites were extracted with benzene-dichloromethane (4:1), subjected to thin-layer chromatography, and determined by direct ultraviolet densitometry. Recovery experiments showed that the method was quantitative. The limit of detection was 5 ng/ml for 2-amino-5-nitrobenzophenone and 10 ng/ml for other compounds. The method was applied to the determination of nitrazepam and its metabolites excreted in human urine after administration of 10 mg of the drug.
A fatal case involving the suicidal ingestion of secobarbital, nitrazepam, and codeine is presented. The drugs were quantified using gas chromatography for codeine and high-performance liquid chromatography for the two other drugs. The blood concentrations of secobarbital, nitrazepam, and codeine were found to be 11.48, 1.72, and 0.036 microgram/ml, respectively. Results are discussed in the light of the existing literature.
This case report describes two cases of lethal poisoning caused by a combination of advanced chronic disease and an overdose of nitrazepam. In both cases, a relatively small blood concentration of nitrazepam was found postmortem.
A 50-year-old woman developed rhabdomyolysis and myoglobinuric renal impairment after an oral dose of 250 mg nitrazepam and 1,250 mg doxepin. Serum creatinine increased from 70 mumol/l to 472 mumol/l in two days. Serum creatine phosphokinase reached a maximal level of 391 mu kat/l (reference range less than 2.5 mu kat/l) on the third day and serum myoglobin was maximally 910 nmol/l (reference range less than 4.5 nmol/l) on the fourth day after the overdose. Passive and active movements of the knees and ankles became increasingly restricted, but the patient felt no muscle pain. Diuresis decreased to 20-22 ml/hour in spite of repetitive doses of furosemide, but was enforced to greater than 100 ml/hour by vigorous infusion of saline. Haemodialysis was avoided on this regimen. It is suggested that in patients intoxicated with nitrazepam and/or doxepin, rhabdomyolysis should be suspected when a rapidly increasing serum concentration of creatinine is found, even in the absence of muscle pain.
Some further results on the effects of the two hypnotic drugs, nitrazepam and flurazepam monohydrochloride, on mood state are described. An automated assessment and scoring system, Computer Assisted Psychometric System (C.A.P.S.), was used to assess mood state and showed that both hypnotics had a mild euphoriant effect even when administered to healthy volunteers during the daytime. This was most marked in the case of nitrazepam. It is argued that such euphoriant side effects should be further investigated as they can occur when hypnotics are administered on a long-term nightly basis, and there may therefore be a dependency aspect for those patients who habitually take such hypnotic drugs. The broad scope of the C.A.P.S. system is also discussed.
Efficacy and side effects of flurazepam 15 mg, fosazepam 60 mg, and nitrazepam 5 mg were studied in 17 psychogeriatric patients. The drugs were equipotent in maintaining sleep but nitrazepam had more side effects than the other hypnotics, and it induced a rebound insomnia after withdrawal. All hypnotics lost some of their efficacy towards the end of 7 days' administration. Patients with evident cerebrovascular disease were vulnerable to the side effects of the benzodiazepine hypnotics. The side effects did not correlate with the age of a patient. In addition, no correlations were found between the serum levels of fosazepam or its main metabolite and the side effects.
The short-acting hypnotic, triazolam 0.5 mg, was compared in a 7-day double-blind study with the longer acting drug, nitrazepam 5 mg. Of the 60 patients enrolled, 29 in each drug treatment group completed the study and were evaluated. All significant differences found favoured triazolam. On the first night, triazolam was found to be significantly more effective than nitrazepam in inducing and maintaining sleep and in increasing its overall duration. The patients' subjective preference, reflecting the depth of sleep experienced and the effect of the medication, reached highly significant levels in favour of triazolam. Later in the study the differences between the drugs disappeared although the depth of sleep as judged in the study was better with triazolam.
In a double-blind, cross-over trial, triazolam (0.5 mg) was compared with nitrazepam (5 mg) in patients with disturbed sleep. Each drug was given once, with a 48-h interval, to 40 outpatients. Quality, duration, and latency of sleep, and number of awakenings during the night, showed a significant difference in favour of triazolam. An overall evaluation of sleep also showed triazolam to be superior to nitrazepam. Both drugs seemed to reduce dream activity and to alter the character of the dreams. There was no significant difference in side effects.
The sleep of 10 volunteers with an average age of 57 years was recorded electrophysiologically before, during, and after nitrazepam 5 mg nightly for 10 weeks. Sleep was longer and less broken on the drug and no tolerance was obvious after two months' use. Withdrawal of the drug, however, caused sleep to be temporarily worse than before the drug had been taken. Slow-wave sleep was reduced by nitrazepam, but the accompanying secretion of growth hormone was not impaired.
In a group of patients with chronic bronchitis, repeated night sedation with 10 mg nitrazepam produced a fall in central respiratory drive and a steady rise in arterial carbon dioxide tension. The changes produced over a five-day period were not clinically important, except in two patients who were already hypercapnic before receiving nitrazepam. The use of this drug in patients with carbon dioxide retention should be avoided.
This investigation compares the effects of single and double doses of nitrazepam (5 and 10 mg) and zopiclone (7.5 and 15 mg) and placebo for 1 night in 40 psychiatric patients. The results indicate that zopiclone is an active hypnotic compound, comparable in its effects to those of nitrazepam, the higher dosage being best adapted to the type of patients included in the study.