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PubMedDate not supplied

[Characteristics of the development of tolerance to nitrazepam and phenobarbital under experimental conditions].

Despite the similarity of the nitrazepam and phenobarbital spectra it was found that with their single usage the nature of tolerance for these substances differs quite substantially. With long-term introduction of nitrazepam to mice and rats in invariable and increasing doses there is seen a development of tolerance in the sense of the muscle relaxant and anticonvulsive action and in lethality without any marked attenuation of the tranquillizing effect. In contradistinction to this a long-term administration of phenobarbital is followed by a diminution of its tranquillizing action and by a slowly proceeding reduction of muscle relaxing manifestations. Crosswise tolerance among nitrazepam, diazepam and phenobarbital is marked but feebly. It is presumed that one of the possible mechanisms responsible for the nitrazepam tolerance in mice and rats may be a change in metabolic transformations and redistribution of metabolites.

Animals↗

PubMed1976

[The effect of long-term nitrazepam administration on sleep cycles in rats].

Single and chronic administration of a low dose of nitrazepam (1 mg/kg) had no effect on sleep cycles in rats. A single injection of a high dose (10 mg/kg) of nitrazepam resulted in prolongation of the total duration of synchronized sleep with a corresponding shortening of desynchronized (paradoxical) sleep. The number of sleep cycles was reduced. Chronic injections of nitrazepam (for 7-14 days) in a dose of 10 mg/kg evoked a gradual prolongation of the duration of paradoxical sleep and an increase in number of sleep cycles. After discontinuance of a long-term administration of nitrazepam (1 mg/kg or 10 mg/kg) prolongation of desynchronized sleep and an increase in the number of sleep cycles were more pronounced in comparison with the last day of chronic administration of the drug.

Animals↗

PubMed1990

Teratogenic effects of nitrazepam in rats.

The teratogenicity of nitrazepam, a benzodiazepine-type drug, was investigated in Sprague-Dawley rats. Nitrazepam was administered to pregnant females at levels of 100, 200 or 300 mg/kg in a single dose on one of gestation days 10-14. Fetuses were examined for external and skeletal malformations on day 20 of gestation. Nitrazepam was found to produce various types of malformations, i.e., exencephaly, cleft palate, micrognathia, short or kinky tail and limb reduction defects. The predominant malformation was limb reduction defects, which were produced at high frequency by treatment on day 12 or 13 of gestation. Microscopic examination of limb buds revealed hemorrhage and mesenchymal cell necrosis at 24 hours after nitrazepam treatment.

Animals↗

PubMed1978

[Studies on the interaction of Phenprocoumon with Diazepam and with Nitrazepam (author's transl)].

The influence of Diazepam and Nitrazepam on the anticoagulating activity of Phenprocoumon was studied in rats. It was found that the repeated oral application of Diazepam or Nitrazepam during the treatment with Phenprocoumon did not change the adjusted prothrombin time. The prothrombin time was considerably shortened when the application of Diazepam or Nitrazepam was stopped although Phenprocoumon was still applied. Furthermore, the influence of Chlordiazepoxid, Diazepam and Nitrazepam on the normal prothrombin time was studied. It was found that the treatment with benzodiazepine derivatives had no influence upon the prothrombin time, not only during the treatment, but also after the treatment was stopped.

4-Hydroxycoumarins↗

PubMed1982

Liquid-chromatographic measurement of nitrazepam in plasma.

In this simple and rapid "high-performance" liquid-chromatographic method for determining nitrazepam in plasma, serum, or whole blood, the sample at pH 7.4 is extracted into diethyl ether with an internal standard (prazepam), chromatographed, and detected at 280 nm with a fixed-wavelength ultraviolet detector. A specimen, together with standards and a quality control, can be analyzed in duplicate within 90 min. The limit of sensitivity is 5 micrograms/L (nitrazepam and 7-acetamidonitrazepam) and 50 micrograms/L (7-aminonitrazepam), and no interferents have been found. This method has the advantages of a small sample requirement and complete resolution of nitrazepam and the above-mentioned major metabolites. We have used this method for analysis of therapeutic and overdose concentrations of nitrazepam, and to investigate the stability of the drug in blood.

Chromatography, High Pressure Liquid↗

PubMed1980

Effect of nitrazepam and its combined administration with fenfluramine and cyproheptadine on explorative behaviour, muscle tone and coordination in normal mice and in mice with isolation syndrome.

The benzodiazepine nitrazepam, which has a marked hypnotic effect in human subjects and a myorelaxating effect in mice with aggressive behaviour, was applied in non-isolated and isolated non-aggressive and aggressive mice. The observed weaker inhibition of exploration behaviour is isolated mice (mice with isolation syndrome) compared with non-isolated mice suggests the significance of the functional activity of the serotoninergic system in the brain for the manifestation of the effects of the drug, since in mice with isolation syndrome the serotonin turnover is changed. The results obtained by combined application of nitrazepam with cyproheptadine suggest that nitrazepam exercises its influence partly by stimulation of the postsynaptic serotonin receptors. Combined application of nitrazepam with fenfluramine shows that serotonin and to a lesser extent the remaining neurotransmitters affected by fenfluramine play a considerable role in the mechanism of action of this benzodiasepine.

Aggression↗

PubMedDate not supplied

Effect of dimethyl-beta-cyclodextrin on nitrazepam stability.

Nitrazepam was found to form an inclusion complex with heptakis; 2,6 di-O-methyl-beta-cyclodextrin (DM-beta-CD) in solution. The phase solubility diagram was found to be AL type with no precipitation of the inclusion complex formed. The kinetic studies of nitrazepam hydrolysis in DM-beta-CD solution at 30, 40 and 50 degrees C was followed spectrophotometrically, as the degradation products of the drug did not interfere with such assay. It was found that the degradation of nitrazepam in acidic media followed the first order reaction kinetics at the temperatures studied. Inclusion complexation of nitrazepam in DM-beta-CD resulted in a relatively improved stability of the drug in solution at 30 degrees C. On the other hand, no appreciable stabilization was achieved at higher temperatures (40 and 50 degrees C).

Cyclodextrins↗

PubMedDate not supplied

[Distribution of nitrazepam and its metabolites in the subcellular fractions of several white rat organs].

After intraperitoneal administration into rats at a dose of 100 mg per kg of body weight nitrazepame (mogadone, eunoktine) was enzymatically reduced with the subsequent acetylation. Derivatives of nitrazepame were found in cellular fragments and nuclei, in mitochondrial, microsomal and soluble fractions of liver, lungs, heart and brain tissues. Reduction of the substrate was shown to occur in soluble and microsomal fractions of liver tissue and acetylation--in mitochondria of lungs and liver tissue. Nitrazepame metabolites were quite uniformly distributed over cell organelles of heart and brain tissues; this suggests that they originate in the organs from other tissues, where the processes of reduction and acetylation take place. Nitrazepame and its derivatives penetrated into brain very effectively; this phenomenon is considered as an essential one for their pharmocological activity.

Acetylation↗

PubMed1977

Effect of temperature and relative humidity on nitrazepam stability in solid state.

The decomposition of a 1% dilution of nitrazepam in microcrystalline cellulose was established by quantitative determination of the two main breakdown products, 2-amino-5-nitrobenzophenone and 3-amino-6-nitro-4-phenyl-2(1H)-quinolone, using in situ diffuse reflectance measurements on thin-layer chromatograms. The decomposition and formation rate constant of nitrazepam and of the breakdown products, respectively, were determined at four temperatures and six relative humidities. By means of a three-parameter regression equation, it was possible to correlate quantitatively the decomposition constant of nitrazepam to both temperature and relative humidity.

Chromatography, Thin Layer↗

PubMed1988

Decrease in [3H]flunitrazepam receptor binding in rats tolerant to the effects of nitrazepam.

Studies were performed to evaluate the binding of [3H]flunitrazepam to cell membranes from the brain cortex of rats that were made tolerant, by the i.p. administration of nitrazepam once daily, to the anxiolytic and sedative effects (after 14 days) and the anticonvulsant action (electroshock, after 28 days) of nitrazepam. A significant decrease in the number of specific [3H]flunitrazepam binding sites was found only in the group that was tolerant to the anticonvulsant effect. The same experiments were also carried out with oxazepam. Since there were no signs of tolerance, the administration of the drug, 10 mg/kg once daily i.p., was continued for 6 weeks. No tolerance occurred and there were no changes in [3H]flunitrazepam binding site density. We conclude that tolerance to the anticonvulsant effect of nitrazepam could be related to the down-regulation of the benzodiazepine receptors.

Animals↗

PubMed1977

Comparison of two gas-liquid chromatographic methods for the determination of nitrazepam in plasma.

Nitrazepam in plasma was determined by gas-liquid chromatography with a nickel-63 electron-capture detector, unchanged by a direct method and also by a hydrolysis method. The extraction in the direct method was carried out with benzenedichloromethane (90:10) and in the hydrolysis method with diethyl ether. The hydrolysis was performed with 6 N sulphuric acid. The hydrolysis product was extracted with toluene-n-heptane-ethyl acetate (80:20:5) directly from acid. Thus the commonly used change in pH was omitted. Nitrazepam concentrations in plasma were determined in 10 healthy volunteers after two oral doses (5 and 10 mg); 0.5 ml of plasma was used for each determination and clonazepam, methylbromazepam and methylnitrazepam were used as internal standards. The recoveries of the methods are almost quantitative (greater than 96%). The two methods are clinically comparable. The high sensitivity and specificity make these methods useful in clinical determinations of nitrazepam in plasma. Advantages and disadvantages of both methods are discussed.

Adult↗

PubMed2001

Study of partition of nitrazepam in bile salt micelles and the role of lecithin.

The effect of trihydroxy (sodium cholate and sodium glycocholate) and dihydroxy (sodium deoxycholate and sodium glycodeoxycholate) bile salt micelles on the spectrophotometric properties and on the solubility of nitrazepam in aqueous solution, at 25.0 degrees C and at ionic strength 0.1 M in sodium chloride, has been assessed. From the results obtained it was possible to calculate the partition coefficients (Kp) of nitrazepam between aqueous and micellar phases. The partition coefficients of nitrazepam have also been determined in mixed micelles of cholate or deoxycholate with lecithin (egg yolk phosphatidylcholine), which were used as a model of the gastrointestinal tract. Drug partition was found to depend on the bile acid (number of hydroxyl groups and conjugation with glycine), and our data indicate further that addition of lecithin to bile salt micelles decreases the values of the partition coefficients in the mixed micelles at physiological pH.

Bile Acids and Salts↗

PubMed2003

Nitrazepam for the treatment of Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a severe childhood epileptic syndrome with encephalopathy and multiple seizure types, which are often intractable to treatment. Most of these children will ultimately become mentally retarded and dependent on others for their daily care. Antiepileptic drugs are the mainstay of treatment, however, no particular drug is entirely effective. Apart from the use of antiepileptic drugs, nonpharmacologic treatments are also considered (i.e., callosotomy, ketogenic diet, and vagus nerve stimulation), which have proven to be partially effective. We prospectively studied 14 children (11 months-8 years of age) with medication-resistant Lennox-Gastaut syndrome, being treated with nitrazepam (open-label compassionate protocol). We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% (P = 0.001), with more than 50% seizure reduction in 60% of patients. Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rates, six patients had at least 25% seizure rate reduction, and one patient did not respond. No patient had any serious adverse effects. Side effects included sedation in six children (40%) and drooling in nine patients (60%).

Anticonvulsants↗

PubMed1977

Changes in reaction time and drug plasma concentrations after nitrazepam and glutethimide.

1 The effects of nitrazepam, glutethimide and placebo were assessed in a double-blind cross-over study with five healthy human subjects, using reaction time, and relating changes to drug concentrations in the plasma. 2 After glutethimide in all five subjects, and after nitrazepam in four subjects, larger doses led to higher concentrations in plasma and to greater changes in reaction time; one subject displayed the higher nitrazepam concentrations and the greater effect following the smaller dose. 3 The relationship between change in reaction time and concentration appeared to be mainly a within-subject dose-effect relationship, with the peak concentration in plasma as the 'dose' and the area under the reaction time curve as the effect.

Adult↗

PubMed1981

Triazolam compared with nitrazepam and with oxazepam in insomnia: two double-blind, crossover studies analyzed sequentially.

1 In two double-blind, crossover studies, general practitioners compared the hypnotic activity of triazolam 0.50 mg with that of nitrazepam 5 mg or oxazepam 50 mg in outpatient insomnias. 2 The patient's preferences served as the main criterion, and were processed by sequential analysis. 3 More patients (P less than 0.05) preferred triazolam to nitrazepam (triazolam 28; nitrazepam 11; no preference 9). 4 The numbers of patients who preferred triazolam or oxazepam did not differ significantly. 5 Triazolam and oxazepam affected sleep parameters similarly except for onset of sleep and feeling in the morning, for which triazolam seemed to be superior to oxazepam.

Adolescent↗

PubMed1985

The effect of repeated doses of temazepam and nitrazepam on human psychomotor performance.

The effects of six nightly doses of temazepam (20 mg), nitrazepam (10 mg) and placebo on saccadic eye movements, critical flicker fusion, choice reaction time and on subjective feelings were studied in a double blind cross-over study in eight volunteers. Testing was performed on nights 1 and 6 of treatment. Nitrazepam, a benzodiazepine with a long elimination half-life produced a residual performance impairment on night 1 that had disappeared by night 6, despite higher serum concentrations of the drug on the sixth night of treatment. Temazepam, with a shorter elimination half-life produced no significant performance impairment on night 1, but by night 6 a significant impairment of saccadic eye movements (P less than 0.05), was seen 1 h after drug intake. We conclude that tolerance developed to the sedative action of nitrazepam over the 6 night period of the study. No evidence of tolerance was seen with temazepam.

Anti-Anxiety Agents↗

PubMed1986

The effects of repeated doses of temazepam and nitrazepam on several measures of human performance.

The effects of six nightly doses of temazepam (20 mg), nitrazepam (10 mg) and placebo on saccadic eye movements, critical flicker fusion threshold, choice reaction time and mood were studied in eight volunteers. Performance was measured on nights 1 and 6 of each treatment. Nitrazepam produced a residual performance impairment on night 1 that disappeared by night 6, despite higher serum concentrations of the drug on the sixth night of treatment. Temazepam, with a shorter elimination half-life, produced no significant performance impairment on night 1, but by night 6 a significant impairment of saccadic eye movements (p less than 0.05) was seen 1 hour after drug intake. We conclude that tolerance to the sedative action of nitrazepam developed over the 6-night period of the study. No evidence of tolerance was seen with temazepam. No residual effects of temazepam (20 mg) were seen the morning after the night-time drug administration.

Anti-Anxiety Agents↗

PubMed1978

The effect of nitrazepam on manual skill, grip strength, and reaction time with special reference to subjective evaluation of effects on sleep.

The effects of 5 and 10 mg oral nitrazepam doses on manual skills, grip strength, and reaction time 8 hours after ingestion of the drugs were studied in 34 healthy female volunteers aged 19-22 years. 5 mg nitrazepam caused a slight but insignificant decrease in psychomotor skills. With 10 mg psychomotor skills were influenced significantly. Grip strength and reaction time were not influenced either by the 5 or 10 mg doses. The investigators corroborate the value of the established effects of nitrazepam as a hypnotic, but recommend that caution should be excercised in prescribing the drug as a hypnotic (especially in doses exceeding 5 mg) to work-aged subjects as there is a risk of significant effect on the psychomotor skills. Furthermore, the drug may cause fatigue.

Adult↗