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PubMed1989

[In vitro studies of the effect of flunitrazepam on cellular immune parameters].

We investigated in vitro the influence of flunitrazepam concentrations ranged between 10 and 140 ng/ml on immunological parameters by using the rosette-inhibition-test and the lymphocyte-transformation-test. After addition of 30 ng/ml flunitrazepam, which is in accordance with a threshold concentration of 1 mg flunitrazepam after intravenous injection, we saw a significant decrease of the positive cells in the rosette-inhibition-test. In higher concentrations no significant changes could be observed. By the lymphocyte-transformation-test no significant evidence of immunodepression could be demonstrated in concentration usually achieved during anaesthesia or possibly after long term application in intensive care unit, independent of the used mitogenes. Thus, flunitrazepam demonstrates no immunosuppressive effect in concentrations achieved during anaesthesia or in intensive care unit as could be observed by tests of cellular immune competence. However, one has to take into consideration that only parts of the immunesystem could be examined with these tests and in vivo-investigations have to verify these results.

Cells, Cultured↗
PubMed1987

[Effect of lormetazepam, triazolam and flunitrazepam on rapid eye movements, K-complexes and sleep spindles in normal probands].

"Equipotential" doses of lormetazepam, triazolam and flunitrazepam were tested regarding their influence on K-complexes, sleep spindles and rapid eye movements. The receptor affinity was used to determine the equipotency. In this respect triazolam, lormetazepam and flunitrazepam show a relationship of 1:2:4. Lormetazepam, however, showed only slight changes of the three neurophysiological parameters even when given as double dosage. Triazolam and flunitrazepam reduce K-complexes considerably, increase sleep spindles enormously and reduce REM activity markedly; both substances suppress the first REM period, flunitrazepam even the second one. All three of the benzodiazepines have the same effect on the dissociation of K-complexes and sleep spindles; epochs with K-complexes or sleep spindles are favored compared to epochs with K-complexes and sleep spindles. The general reduction of K-complexes and the increase in sleep spindles can be interpreted as a sleep protective function. When deciding on the dosage, however, REM-suppression should be used as a guide since it has the strongest effect on the cyclic structure of sleep which nowadays is considered to be the safest evidence of well balanced sleep behavior.

Adult↗
PubMed1987

[Ro 15-1788 antagonizes reliably the Benzodiazepine effect after Flunitrazepam combination anesthesias].

INTRODUCTION: The imidazobenzodiazepine Ro 15-1788 has been shown to block the central effects of benzodiazepines without severe side effects in animals studies and human volunteers. Benzodiazepine premedication and benzodiazepine/opioid combinations are often used in anesthesiology. A prolonged benzodiazepine action in combination with narcotics can cause problems in the postoperative period such as respiratory depression or aspiration of gastric contents due to reduced vigilance. Therefore, a reversal of the central effects of benzodiazepines can be of advantage postoperatively. This study was designed to compare the efficacy of Ro 15-1788 and placebo in reversing the central effects of flunitrazepam used to induce and maintain general anesthesia. METHODS STUDY DESIGN: double blind, parallel groups, randomized, placebo-controlled study. 60 patients of both sexes aged 20-65 years, ASA class I-II, who were to undergo elective surgery under general anesthesia with an estimated duration of 90-150 min. Study procedure: Evening premedication: 1-2 mg flunitrazepam orally. Morning premedication: 7.5 mg midazolam orally. Monitoring: blood pressure, heart rate, and ECG continuously. Induction of anesthesia: 0.2 mg fentanyl, 0.03-0.04 mg/kg flunitrazepam, 0.1 mg/kg pancuronium. Endotracheal intubation, mechanical ventilation. Maintenance of anesthesia: N2O/O2 = 2:1, fentanyl, pancuronium, and flunitrazepam depending on clinical response. At the end of surgery and after decurarization (neostigmine 2.5 mg and atropine 0.5 mg) and oxygenation the patients were extubated. Now Ro 15-1788 or placebo in a 5% glucose solution (in the case of Ro 15-1788: 1 ml = 0.1 mg active drug) were administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1980

A comparative study on the clinical effects of flunitrazepam and lorazepam.

The clinical effects of flunitrazepam and lorazepam as oral premedicants were tested in a double-blind study in 81 gynaecological patients. Flunitrazepam showed a higher sedative effect (p < 0.05), but in regard to other parameters tested, no significant differences were found (sleep, apprehension, excitement, dizziness, emetic effect, headache, increase or decrease in systolic blood pressure, increase in pulse rate, venipuncture). In 9 per cent of the patients treated with lorazepam, a prominent muscular relaxation with slurred speech was observed, but in none of the cases treated with flunitrazepam. Our results support the earlier claims of flunitrazepam's relatively specific sedative property, but on the whole the difference in the clinical effects of these benzodiazepine derivatives is not marked.

Adult↗
PubMed1981

[Clinical pharmacokinetics of midazolam, flunitrazepam and diazepam (author's transl)].

Diazepam, flunitrazepam and midazolam have different pharmacokinetic properties, their biological halflives for instance, being 24 to 48 hours, 4,5 hours and 2,5 hours respectively. Moreover, the total plasma clearances calculated for these drugs resulted in 30 ml/min for diazepam, 250 ml/min for flunitrazepam and 450 ml/min for midazolam. On the other hand, all three drugs were found to have nearly the same volumes of distribution (V1: 25 l, VdSS: 80-100 l). A tissue binding of over 90% of the drugs applied can further be computed from their high plasmaprotein binding action and their volumes of distribution. Of the 3 benzodiazepines investigated, diazepam reveals extremely complex pharmacokinetic effects which vary the duration of pharmacological responses very widely; besides drug interaction, enzyme induction and -inhibition it gives rise to the active metabolite N-desmethyl-diazepam (biological halflife 50 to 120 hours). In this respect however, the metabolic products of flunitrazepam and midazolam seem to be of minor clinical importance only. The pharmacokinetics of flunitrazepam will be presented as an example to discuss several modes of dosage.

Anti-Anxiety Agents↗
PubMed1981

[Pharmacoclinical competition between the benzodiazepines. Demonstration with diazepam and flunitrazepam in man].

While using a new benzodiazepines flunitrazepam by the intravenous route in ordinary anethesia a competitive action with another benzodiazepine which is being used for the last 15 years, namely diazepam, was demonstrated for the first time in man. This study on 170 patients operated for ear, nose and throat conditions demonstrated this phenomenon, confirmed it and it was possible to reproduce the effect. The interaction is mainly characterized by: - A reduction of the effects of flunitrazepam (less profound sleep, even wakefulness with a waking patient who could talk and could react to pain). This effect was obtained with injection of a normal clinical dose of diazepam. - There was a blocking action or a reduction in the pharmacological action normally expected of flunitrazepam by the previous administration of a clinical dose of diazepam, when given by the intravenous, intramuscular or oral routes. This suggests that there are common receptor sites for these two benzodiazepines at the cerebral level and this would explain this apparently paradoxical action. Even though flunitrazepam has a greater affinity for these receptor sites this molecule seems to be displaced, according to the law of mass action, by diazepam when used at a high dose. This interaction shown for these two benzodiazepines is also seen in other derivatives of the same chemicals series. This is important in therapeutics with the increasing use of these products in general medicine, and anesthetics and neuropsychiatry where they are quite often used in association.

Adolescent↗
PubMed1981

Effect of age on the pharmacokinetics and sedative of flunitrazepam.

Flunitrazepam (0.015 mg/kg) was injected i.v. into 20 patients, ages 19-79 years, as a sedative agent prior to epidural anesthesia. The concentrations of unchanged flunitrazepam in sea were determined by 63Ni-EC-GLC, and the pharmacokinetic parameters were calculated using the two-compartment open model. Age as such had no effect on the kinetics of flunitrazepam, but its sedative effect was clearly increased in the group over 60. No correlation between the serum level or elimination half-life and sedation was found. Generally, flunitrazepam's strong and rapid sedative effect renders it a useful adjuvant in connection with epidural anesthesia.

Adult↗
PubMed1983

A comparison of flunitrazepam and diazepam in the prevention of local anesthetic-induced convulsions.

The anticonvulsive effects of equivalent strengths (ED50) of flunitrazepam and diazepam were compared in 60 Sabra mice injected i.p. with median convulsive (CD50) doses of lidocaine or bupivacaine. Convulsions occurred in 40% of those pretreated with diazepam but were completely prevented in those injected with flunitrazepam. Mortality was much higher in those mice pretreated with diazepam, three having died after the administration of lidocaine and four after bupivacaine. With flunitrazepam pretreatment, there were no deaths after lidocaine and only one after bupivacaine. Flunitrazepam protected these mice against local anesthetic-induced convulsions more effectively than did diazepam.

Animals↗
PubMed1981

Reductions in retinal gamma-aminobutyric acid (GABA) content and in [3H]flunitrazepam binding after postnatal monosodium glutamate injections in rats.

Specific binding of [3H]flunitrazepam is found in the mammalian retina and its characteristics are similar in important respects to those in the cerebral cortex. Numerous reports have shown that monosodium glutamate (MSG) given neonatally to rats results in neuronal cell death with sparing of photoreceptor and glial cells. Sprague-Dawley rats were given MSG (3.2 mg/g i.p.) from day 2 to day 12 after birth; controls received equimolar injections of NaCl. At 8 to 9 weeks of age, the rats were killed and [3H]flunitrazepam binding was examined in the retinas are various brain regions. Histologic evidence showed the virtual absence of ganglion cells and a marked reduction of neurons in the inner nuclear layer of retinas from MSG-treated rats; photoreceptor and Muller cells appeared normal. In the retinas from MSG-treated rats, gamma-aminobutyric acid levels were decreased by 73% and the Bmax of [3H]flunitrazepam binding was decreased by 77%; there was no change in Kd. In the cerebellum, cerebral cortex and hypothalamus of MSG-treated rats, [3H]flunitrazepam binding was unchanged. These results strengthen the association of gamma-aminobutyric acid mechanisms with benzodiazepine binding and suggest a predominant neuronal localization of the binding sites.

Animals↗
PubMed1995

[The effect of flumazenil in reversing midazolam, flunitrazepam or diazepam].

In 31 adult patients who had undergone spinal or epidural anesthesia, we evaluated the effect of flumazenil in reversing midazolam, flunitrazepam or diazepam. The patients received midazolam 5 mg, flunitrazepam 1 mg or diazepam 5 mg 15 min after the spinal or epidural anesthesia. After the completion of operation, flumazenil (0.2 mg-1.0 mg) was administered until the patient became awake. Blood pressure, pulse rate and respiratory rate before and after administration of flumazenil showed no statistically significant changes in these groups. There were no significant differences in necessary amount of flumazenil among these groups. The time necessary for the patient to be awake in midazolam group was significantly shorter than that in flunitrazepam or diazepam group. Half of the patients in flunitrazepam and diazepam groups slept again after leaving the operating room, but they presented no clinical problems. In conclusion, we consider that flumazenil does not affect circulation and respiration, so it seems to be safe and effective for reversing benzodiazepins in clinical situation.

Adolescent↗
PubMed1993

[Treatment of insomnia related to depressive disorders. Effects of zolpidem versus flunitrazepam administration and withdrawal evaluated in a double-blind study].

The effects of a 15 day treatment with zolpidem (10 mg) and with flunitrazepam (1 mg) on Insomnia Disorders Related to Depressive Disorders (DSM-III-R) have been evaluated on 30 depressive in-patients (mean age 42.3 +/- 9.8). The trial has been carried out on double blind condition after 5 days of single blind placebo administration. Withdrawal effects have been evaluated in single blind condition on a 10 day period after drugs discontinuation. Patient's diagnosis was Major Depression or Dysthymia according to DSM-III-R; inclusion criteria were insomnia (total sleep time < or = 6 h, sleep latency > or = 30 min, wake after sleep onset > or = 30 min, No of awakenings > or = 3) refractory to clomipramine administration at constant dose (75-150 mg/day among patients). Both drugs have been followed by a rapid, significant diminution of insomnia as demonstrated by significant changes at Stanford Sleepiness Scale and Saint Mary Hospital Sleep Questionnaire and by a significant reduction of HDRS total scores. No clinical phenomena of rebound insomnia were detected after zolpidem and flunitrazepam withdrawal. Drug discontinuation however was followed by the slow increase of the score on insomnia items, approximating basal values at the end of the 10 day period after zolpidem and flunitrazepam withdrawal. A parallel increase of HDRS total score was also detected; HDRS changes were mainly due to the increase of the items anxiety somatic, general somatic symptoms, gastrointestinal somatic symptoms, hypochondriasis. The study confirms the therapeutic efficacy of zolpidem and of flunitrazepam in the treatment of insomnia resistant to antidepressant drugs in depressed patients. They also suggest that early drug discontinuation is frequently associated with clinical relapse of insomnia and of several other symptoms correlated with the affective pathology.

Adult↗
PubMed1993

Acute effects of zolpidem, triazolam and flunitrazepam on arterial blood gases and control of breathing in severe COPD.

Patients with severe chronic obstructive pulmonary disease (COPD) commonly complain of insomnia, but hypnotic drugs are generally not recommended due to their depressant effect on the respiratory centres. The aim of this study was, therefore, to compare the effects of a single dose of the benzodiazepine hypnotics, triazolam 0.25 mg and flunitrazepam 1 mg, and a new imidazopyridine compound, zolpidem 10 mg, in hypercapnic COPD patients. Twelve stable COPD patients (mean +/- SD arterial oxygen tension (PaO2) 9.3 +/- 0.8 kPa and arterial carbon dioxide tension (PaCO2) 5.9 +/- 1.9 kPa) were included in the study. The following measurements were performed before and 2 h after drug administration: PaO2 and PaCO2, minute ventilation (VE), mouth occlusion pressure (P0.1), rebreathing CO2 tests with ventilatory response to carbon dioxide stimulation (delta VE/delta PACO2) and mouth occlusion pressure response to carbon dioxide stimulation (delta P0.1/delta PACO2). The measurements were performed in a randomized, double-blind fashion, each patient receiving a single dose of each drug on three different days, separated by a one week interval. No difference was noted between control measurements and those taken 2 h after administration of zolpidem in the following parameters: PaCO2, PaCO2, VE, P0.1, delta VE/delta PACO2 and delta P0.1/PACO2. Two hours after administration of triazolam and flunitrazepam, a significant difference was noted in VE for triazolam and for flunitrazepam. After flunitrazepam administration, a significant decrease in PaCO2 (6 +/- 1.8 at baseline versus 7 +/- 0.4 kPa), and delta VE/PACO2 (0.44 +/- 0.20 at baseline versus 0.31 +/- 0.21 l.min-1 x kPa) were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Gas Analysis↗
PubMed1981

Effects of alcohol and flunitrazepam on mood and performance in healthy young men.

Alcohol and flunitrazepam did not have any pharmacokinetic interactions when ingested 30 minutes apart at night. Flunitrazepam, 2.0 mg, but not 0.8 Gm/kg alcohol had a strong deleterious effect on performance shortly after ingestion. The combination of flunitrazepam and alcohol impaired tracking in a divided attention task the following morning.

Adult↗
PubMed1988

Effect of after-dinner administration on the pharmacokinetics of oral flunitrazepam and loprazolam.

The pharmacokinetics of two benzodiazepine hypnotics, flunitrazepam and loprazolam, was determined on two occasions in two groups of eight healthy volunteers. Single 2-mg oral doses of either drug were given in the fasting state at morning on one occasion and after a standard dinner at night on another. Compared with administration of drugs in the fasting state, administration of the drugs after dinner decreased peak plasma concentrations, delayed the time to reach maximum concentration, and prolonged the absorption half-life. The extent of absorption was reduced for flunitrazepam but not for loprazolam. The elimination half-life of both flunitrazepam and loprazolam was not changed in the two conditions. These changes may be of clinical significance because they can delay and reduce the effects of the drugs.

Administration, Oral↗
PubMed2006

Commercial valerian interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes.

Valeriana officinalis extracts are used in folkloric medicine for their sedative, hypnotic and tranquilizer effects. Using [3H]flunitrazepam binding as an indicator, the interactions of commercial Valerian extracts with GABA(A) receptors were examined. There was considerable fluctuation among the different extracts, some mildly enhanced [3H]flunitrazepam binding, others had no effect and others had inhibitory effects, independent of standardization by valerenic acid. Central depression can also be accomplished by a reduction of excitatory transmission. Valerian extracts had modest inhibitory effects on [3H]MK-801 binding, an indicator of NMDA-Valerian interactions. Spectral analyses (UV region) did not show marked differences among the different extracts. The inhibitory effects of one of the extracts on [3H]flunitrazepam binding was somewhat stable, while on [3H]MK-801 binding the inhibitory effects were lost within months. These results suggest that particular care should be taken in analysing and interpreting results from commercial Valerian preparations.

Animals↗
PubMed2001

Characterization of [3H]flunitrazepam binding to melanin.

In both clinical and forensic toxicology, the analysis of hair for drugs is an important tool to determine drug use in the past or to verify abstinence from illegal drugs during extended periods. Melanin is proposed as one of the factors that influences drug incorporation to hair and we have characterized the binding of the drug flunitrazepam to melanin in vitro. The drug was 3H labeled and melanin granules from cuttlefish, Sepia officinalis, were used according to the suggested standard for melanin studies. We observed a rapid Langmuir-like binding followed by a slower diffusion-limited binding that may be interpreted as an initial surface binding followed by deeper bulk binding. From three concentrations of melanin, with a 60-min incubation time, a mean saturation value of 180 +/- 20 pmol/mg was calculated. The binding of a group of benzodiazepines and tranquilizers was compared to the binding of [3H]flunitrazepam by means of displacement experiments. These drugs showed binding characteristics similar to [3H]flunitrazepam except phenobarbital, which had a lower affinity to melanin. The method presented in this study allowed measurements with low melanin and drug concentrations and it has the strength of directly measuring the amount of drug bound to melanin, in contrast to previous indirect methods.

Animals↗
PubMed1988

Anterograde and retrograde amnesia after lormetazepam and flunitrazepam.

In a pharmacopsychological study, memory impairments after single oral doses of benzodiazepines or placebo were investigated in 40 healthy men aged 20-40 years. The study was designed as a double-blind and placebo-controlled trial. Four independent groups of 10 subjects randomly received either 1 mg lormetazepam, 2 mg lormetazepam, 2 mg flunitrazepam, or placebo. The tests consisted of word lists, picture tests, and syllable pairs (consonant-vowel-consonant trigrams). Tests were performed before drug ingestion, and 1, 2, 3, and 5 h after application. Different test versions were used on each occasion. The target variables were immediate recall (after presentation and a 10-s distraction task) and delayed recall and recognition (after 30 min). Recognition was also tested after 24 h for all five versions. A distinction must be made between anterograde amnesic effects and retrograde amnesic effects. The greatest anterograde memory impairments were observed after 2 mg flunitrazepam (p less than 0.05). Lormetazepam 2 mg produced less marked impairments than flunitrazepam. Results after 1 mg lormetazepam did not differ from those after placebo. Performance in the memory tests was better under benzodiazepines than under placebo as regards material learned before drug ingestion, i.e. the benzodiazepines had not negative retrograde amnestic effects, but rather "promnesic" effects. The results suggest that the extent of the benzodiazepines' amnesic effects--both negative (anterograde) and positive (retrograde)--depends on the dosage and type of substance.

Amnesia↗