[Comparative evaluation of the hypnotic drugs under conditions of brain injury].

The effect of hypnotic drugs on the brain stability with respect to complete ischemia posttraumatic convulsive reactions and hypoxia has been studied in animals with model brain injury. It is established that zopiclone exhibits pronounced hypnotic effect during the first and second week after brain injury, while nitrazepam, zolpidem, and melaxen are effective in the first week. The neuroprotective effects of zopiclone and zolpidem are more pronounced than those of melaxen and nitrazepam.

Incorporation of five common hypnotics into hair after a single dose and application to a forensic case of drug facilitated crimes.

In order to obtain fundamental information on the disposition of hypnotics into hair after a single oral dose the quantitative hair analysis of triazolam (TZ), etizolam (EZ), flunitrazepam (FNZ), nitrazepam (NZ) and zolpidem (ZP) have been performed using a validated LC-MS/MS procedure. Hair specimens (straight, black) were collected from three subjects about one month and three months after a single 0.25 mg dose of TZ, 1 mg of EZ, 2 mg of FNZ, 5 mg of NZ and 10 mg of ZP tartrate. The subjects ingested just one out of five different hypnotics on each day, each of five days in turn. All ingested hypnotics have been detected in hair from each subject both one month and three months after intake, and their concentrations were in the range of 0.023-0.043 pg/hair strand (0.077-0.36 pg/mg) for TZ, 0.11-0.63 pg/hair strand (0.44-5.2 pg/mg) for EZ, 0.14-2.6 pg/hair strand (0.56-22 pg/mg) for FNZ, 0.33-1.7 pg/hair strand (1.3-17 pg/mg) for NZ and 20-40 pg/hair strand (120-270 pg/mg) for ZP. For FNZ and NZ, not only the parent drugs but also their metabolites, 7-amino-FNZ and 7-amino-NZ, were detected in the range of 2.3-9.2 pg/hair strand (9.2-82 pg/mg) and 2.4-9.1 pg/hair strand (8.0-55 pg/mg), respectively. The calculated incorporation ratios into hair against the dose were found to exhibit similarity between the four benzodiazepines. This finding suggests the ability to apply these quantitative data to approximately estimating the amounts of other benzodiazepines, which have similar chemical structures, in hair although it should be noted that the amounts of drugs in hair varies considerably depending on the hair color. On the other hand, the incorporation ratio of ZP showed 15-29 times higher than that of TZ, indicating that lipophilic ZP was more likely to incorporate into hair than benzodiazepines. In addition, the application of the present data to a drug-facilitated sexual assault was shown.

Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries.

BACKGROUND AND OBJECTIVES: Accurate assessment of medication impact requires modeling cumulative effects of exposure duration and dose; however, postmarketing studies usually represent medication exposure by baseline or current use only. We propose new methods for modeling various aspects of medication use history and employment of them to assess the adverse effects of selected benzodiazepines. STUDY DESIGN AND SETTING: Time-dependent measures of cumulative dose or duration of use, with weighting of past exposures by recency, were proposed. These measures were then included in alternative versions of the multivariable Cox model to analyze the risk of fall related injuries among the elderly new users of three benzodiazepines (nitrazepam, temazepam, and flurazepam) in Quebec. Akaike's information criterion (AIC) was used to select the most predictive model for a given benzodiazepine. RESULTS: The best-fitting model included a combination of cumulative duration and current dose for temazepam, and cumulative dose for flurazepam and nitrazepam, with different weighting functions. The window of clinically relevant exposure was shorter for flurazepam than for the two other products. CONCLUSION: Careful modeling of the medication exposure history may enhance our understanding of the mechanisms underlying their adverse effects.

Alterations in the thermic response to chlorpromazine in rats exposed prenatally to central nervous system depressants.

The thermic response to acute administration of chlorpromazine (5 mg/kg, i.p.) was assessed in rats exposed prenatally to haloperidol (0.1 mg/kg), phenobarbital (10 mg/kg), nitrazepam (2 mg/kg), propylene glycol (1 ml/kg) or saline, once daily from days 1-21 or 15-21 of gestation. The response in all animals was tested only once. The administration of chlorpromazine to 8- or 13-week-old male and female rats treated with saline (1-21 d) induced marked hypothermia for a 6-hr period of observation. Male and female rats treated with haloperidol (1-21 d) showed a delayed hyperthermic response to chlorpromazine at 8 weeks of age; the males showed an increase in rectal temperature at 3 hr and the females from 3 to 6 hr. Thirteen-week-old males but not females treated with haloperidol (1-21 d) showed a hyperthermic response to chlorpromazine during the first 2 hr. Eight-week-old male and female rats treated with phenobarbital (1-21 d) showed hypothermia, whereas 13-week-old male rats of another group treated with phenobarbital (1-21 d) showed significant hyperthermia after the administration of the chlorpromazine. The hypothermic response of the rats treated with nitrazepam (1-21 d) to chlorpromazine was similar to that in the vehicle (propylene glycol)-treated controls. The male rats treated with phenobarbital (15-21 d) responded to chlorpromazine with significant hyperthermia from 30 min to 1 hr. There was no alteration in thermic response to chlorpromazine in rats born to mothers treated with one tenth of the dose of phenobarbital, haloperidol or nitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Zopiclone versus nitrazepam: a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia.

A randomized, double-blind, comparative trial of zopiclone versus nitrazepam was conducted in 74 geriatric chronic insomniac patients. Following a 7-day wash-out period, two parallel groups, successively received a placebo for 7 days, then either 7.5 mg zopiclone or 5 mg nitrazepam for another 7-day period. Efficacy on sleep was assessed by a sleep analogue scale and the Spiegel Sleep Questionnaire, residual effects by psychometric tests and tolerance by a standardized question, as well as by clinical and laboratory tests. Zopiclone and nitrazepam were more active than placebo on all tests of efficacy. In contrast with nitrazepam, zopiclone was devoid of effect on neurological function. In addition, the condition on awakening was better with zopiclone.

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.

Chronic administration of zopiclone and nitrazepam in the treatment of insomnia.

The hypnotic effects of 7.5 mg zopiclone, as well as its unwanted and residual effects, were compared with those of 5 mg nitrazepam in a double-blind, randomized, multicenter, parallel group study. After an initial, 7-day, placebo wash-out period, insomniac out-patients under the care of general practitioners received either 7.5 mg zopiclone or 5 mg nitrazepam for 6 weeks. Everyday, the patients filled in a diary (analogue scales for sleep parameters and condition during daytime); a sleep questionnaire was filled in at baseline and at the end of active treatment period; every 2 weeks, a somatic complaint check-list inventory and a mood rating scale were filled in and psychomotor tests performed; and at the end of the study, a global evaluation of efficacy and acceptability was given by the investigator. Clinical laboratory tests were performed before and after the active treatment period. From the diary, sleep onset latency, as well as sleep quality, were similarly improved by both drugs throughout the whole study. From the sleep questionnaire, all sleep parameters measured were improved at the end of the 6-week treatment period in both groups. No statistical differences in the various psychomotor tests were observed between the two treatment groups, and a significant improvement in the working ability of patients was noted with both drugs. Some significant differences were observed in the mood rating scale and the somatic complaint check list, probably related to differences in pharmacokinetics of the two drugs.

Effects of repeated dose nitrazepam and lormetazepam on psychomotor performance in the elderly.

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.

Benzodiazepine effects on memory tests: dependence on retrieval cues?

Acute effects of oral flunitrazepam (0.5 and 1 mg), nitrazepam (5 and 10 mg) and placebo were assessed on direct (free recall of words and prose, stem-cued recall) and indirect (stem and fragment completion) memory tasks. Fifty health volunteers took part in this double-blind, independent group study. The relative effects of the two benzodiazepines (BZs) on memory revealed a different pattern from their effects on alertness, indicating that their amnesic effects are not totally secondary to their sedative effects. The higher dose of flunitrazepam impaired free recall of words and prose but not cued recall, while neither drug affected the two indirect tasks. Differences in drug effects on the direct and indirect memory tasks were discussed in terms of resource demands of the various tests. We conclude that whether BZs impair performance on memory tasks depends more on the cues given at retrieval than the retrieval instructions (direct/indirect). The implications for this in terms of BZ amnestic effects are drawn out for contextual encoding deficits induced by BZs.

The psychomotor effects of single and repeated doses of hypnotic benzodiazepines.

Benzodiazepine hypnotics are used for short periods in low doses in healthy people when stressed and in patients with insomnia. This study examined psychomotor impairment in healthy young males and females after 1 and 7 nights of flunitrazepam (1 mg), nitrazepam (2.5 mg) and temazepam (10 mg). There were substantial inter-individual variations. Results showed that no drug significantly affected psychomotor performance at these doses after single or repeated administration. The number and severity of side-effects were significantly greater after the first night with temazepam and 7 nights with nitrazepam, although this may reflect a statistical artefact rather than a significant clinical finding. The difficulties in performing adequately controlled psychopharmacological studies at low doses are highlighted. Given the large intra- and inter-subject variances, small drug effects would necessitate large sample sizes (21 to 600 subjects at the 95% level of chance of detection) depending on the variable. The study suggests there is minimal impairment with low dose hypnotic drugs and a need to individualize treatment.

Nitrazepam for refractory infantile spasms and the Lennox-Gastaut syndrome.

Infantile spasms and the Lennox-Gastaut syndrome are considered to be age-specific pediatric epileptic syndromes and together constitute a significant percentage of medically resistant seizures in childhood. Twenty children, ages 4 to 28 months (median, 12 months), with medically refractory infantile spasms or the Lennox-Gastaut syndrome, were treated with the investigational benzodiazepine nitrazepam in an open-label study. Daily dosage of nitrazepam ranged from 0.5 to 3.5 mg/kg, with a median dosage of 1.5 mg/kg, divided into two doses per day. Side effects included pooling of oral secretions (12 children) and sedation (six children); however, no serious side effects were seen. Responses to nitrazepam were as follows: five complete responses (cessation of all seizures), seven partial responses (greater than 50% reduction of seizures), and eight with no response. Median duration of response was 9 months (range, 4 to 16 months) in children with infantile spasms and 14 months (range, 8 to 26 months) in children with the Lennox-Gastaut syndrome. Nitrazepam is an effective anticonvulsant in this small cohort of children with medically refractory infantile spasms and the Lennox-Gastaut syndrome, resulting in a 25% response rate and only modest side effects.

Intermittent treatment of febrile convulsions with nitrazepam.

Intermittent oral or rectal administration of diazepam for the prophylactic treatment of febrile convulsions has given results comparable to the continuous use of phenobarbital while limiting side effects and risks of toxicity. Since we believe that nitrazepam is a better anticonvulsant than diazepam, we performed a study to evaluate the effectiveness of this medication in the prophylactic treatment of febrile convulsions. Nitrazepam was given only when the children had fever and almost exclusively in children with a high risk of recurrence (less than 12 months of age at first convulsion; atypical convulsion; one or several previous convulsions). Thirty one children with a high risk of recurrence received nitrazepam. The rate of recurrence in this group was 19.3% after a follow-up of 16 months, compared to 45.8% in 24 children who also had a high risk of recurrence but in whom the parents refused the medication or gave it inadequately (p less than 0.05). Fifty one children with a low risk of recurrence also were evaluated and followed for at least 12 months (mean 15.4 months). Six were treated with nitrazepam, mostly because of parental anxiety, and none had a recurrence; of the 45 untreated children in this group, 6 (13.6%) had another convulsion. These results show the efficiency of nitrazepam in the prophylactic treatment of febrile convulsions.

Carbamazepine and benzodiazepines in combination--a possibility to improve the efficacy of treatment of patients with 'intractable' infantile spasms?

Therapeutical efforts in epilepsies with infantile spasms (IS) often show unsatisfying results, especially if neurological impairments are found. In a clearly negatively selected group of 24 children with IS and 10 patients with symptomatic myoclonic-astatic epilepsies--pretreated without success with ACTH and/or benzodiazepines (BDZ) alone or combined with other anticonvulsants--we tried a two-drug therapy of BDZ with carbamazepine (CBZ). Dosage of both drugs was within the usual range. In a follow-up period of 1-5 years, 8 of the IS patients and 4 of those with myoclonic-astatic seizures became seizure-free; furthermore, 6 children showed a marked reduction in their seizure frequency: 3 more than 80%, 3 more than 50%. Besides the fact that the patients did not develop a so-called escape-phenomenon--as often seen in therapy with benzodiazepines--they also showed fewer and less intensive side-effects. Without optioning for antiepileptic polytherapy in general, we conclude that in cases of "intractable" IS the combination of BDZ with CBZ might be more successful than the single drug. To confirm these preliminary findings further controlled studies have to be carried out.

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.

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%).

Male reproductive toxicity study of nitrazepam in rats.

The main focus of this study is the optimal administration period concerning toxic effects on male fertility in rats. To assess functional and morphological changes induced in the testis by nitrazepam, male rats were administered the drug at doses of 0, 20, 40 or 80 mg/kg during pre-mating periods of 2, 4 or 9 weeks and then the 2 weeks of mating. At the end of the administration period the animals were sacrificed and sperm number, motility, abnormalities and histopathological changes in the testis were examined. Decreases in testis weight, epididymis weight, number of sperm in the testis and sperm motility were observed in the 40 and 80 mg/kg sections of the 2, 4 and 9 week pre-mating treated groups. Mating with untreated females revealed no adverse effects on copulation rate in any group; however, a remarkable decrease in pregnancy rate was noted in the 80 mg/kg section of the 2, 4 and 9 week treated groups. On histological examination, various degrees of localized necrosis in the seminiferous epithelium and Leydig cell hyperplasia were observed in the testis. No clear changes were observed in the 20 mg/kg section of the 2 week pre-mating administration group, but at the 4 week time point, necrosis of spermatogenic cells began to appear. The primary morphological event was evident in spermatocytes with necrosis of the cytoplasm observed from 4 weeks after administration of nitrazepam, although sperm motility and sperm head counts were unaffected. From these findings, examination of sperm characteristics and histopathological changes in the testis are important parameters for evaluation of drugs inducing testicular damage. We conclude that a 4 week administration period is sufficient to detect effects of nitrazepam on male fertility.

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.

Changes in hypnotic usage in residential homes for the elderly: a longitudinal study.

The use of hypnotic drugs in 25 local authority homes for the elderly was recorded on a 1-day point prevalence study following a 6-mth monitoring programme involving all new admissions. From a total population of 1114 residents 390 (35%) were taking hypnotics on the night of the survey, showing a slight increase from similar surveys carried out in 1980 and 1981. The proportion of residents receiving hypnotics within each home varied from 0.0 to 61.8%. Correlation with levels of usage in the previous surveys was low, suggesting that pattern of hypnotic usage may change considerably over time within individual homes. Of the 156 residents who were admitted as permanent residents during the 6-mth period preceding the survey, 56 (35.9%) had been taking hypnotics on admission. Both the results of the drug monitoring programme and the survey show an association between hypnotic usage and source of admission: residents admitted from hospital being more likely to be taking sleeping tablets. A considerable change was found in the type of hypnotic currently prescribed with an increased preference being shown for short half-life hypnotics. A higher proportion of residents also were prescribed lower doses of hypnotics than previously, suggesting an increased awareness of the risks associated with hypnotic use in the elderly.

Febrile seizures.

The definition, prevalence, characteristics, genetics, and causes of febrile seizures are discussed in this article. Acute management is outlined, including indications for lumbar puncture and treatment of the febrile child who is continuing to seize. The usefulness and limitations of the EEG are noted. Factors influencing the likelihood of further febrile seizures and the risk of later epilepsy are reviewed. The pros and cons of continuous and intermittent drug therapies for febrile seizure prophylaxis are summarized. A new double-blind randomized study of intermittent oral diazepam for the prevention of febrile seizure recurrences is described.

Infantile spasms. A retrospective study of 105 cases.

This paper is a summary of our observations on 105 cases of infantile spasms. The age of onset was around six months after birth, but the patients came for treatment mainly about one year after onset. Fever of unknown cause, asphyxia, birth injury, infection of the central nervous system, tuberous sclerosis, phenylketonuria and recent immunization etc. were complained. Clinically, it is characterized by head nodding, mental retardation, myoclonic jerks and various neurologic deficits. EEG findings showed classical or modified arrythmia or other epileptiform patterns. About one third of 22 cases examined had abnormal brain stem auditory evoked potentials. Among 42 patients who underwent CT scanning before ACTH treatment, 18 were normal and 7 abnormal; during ACTH treatment 3 normal and 4 abnormal; after completion of treatment, 4 normal and 6 abnormal, suggesting no further atrophy of the brain. Examination of trace elements of the hair by particle-induced X-ray emission (PIXE) method in 23 patients revealed a significant difference in lead, calcium and zinc contents between patients and 101 controls, but no statistical difference in iron and copper contents between the two groups. Sodium valproate, prednisone and ACTH appear to be effective in the treatment of infantile spasms. Eight patients fully recovered, and they can go to school without difficulty. Many patients derived various degrees of improvement to the satisfaction of their parents. Two patients were still amented and often attacked by myoclonus. The effects, side effects of these drugs, and the possible pathogenesis were discussed.