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PubMed1982

A pharmacokinetic and pharmacodynamic study of flunitrazepam.

Flunitrazepam was given as an induction agent i.v. to 12 patients undergoing otologic operations. Pharmacokinetics were evaluated from serum samples at 5 min-72 h by 63Ni-EC-GLC. Pharmacodynamic characteristics were estimated subjectively by simple questionnaire and objectively by the anesthetist during and after anesthesia. The dose of flunitrazepam required for anesthesia varied from 14 to 33 (mean 21) micrograms/kg and was not related to age. The mean distribution volumes of flunitrazepam, calculated by the three-compartment open model, were Vd1 0.61 (SD = 0.36) l/kg, Vd2 1.4 (SD = 0.70) l/kg, and Vd3 3.6 (SD = 1.39) l/kg. The mean elimination half-life was 25 h and serum clearance was 94 ml/min. The maximum decreases in blood pressure during anesthesia correlated with the age of the patients. The general assessment of the anesthetist about this form of anesthesia was positive in 75% of the 12 cases. A clear anterograde amnesia was found.

Adult↗
PubMed1983

Etazolate (SQ20009): electrophysiology and effects on [3H]flunitrazepam binding in cultured cortical neurons.

The actions of etazolate (SQ20009) on cultured cortical neurons have been examined in electrophysiological experiments and in receptor binding studies. Etazolate (0.3 to 100 microM) prolongs the duration of spontaneously occurring IPSPs. Higher concentrations of etazolate produce an increase in membrane chloride conductance, an effect which is picrotoxinin and bicuculline sensitive. Etazolate potentiates the response to exogenously applied GABA and acts synergistically with diazepam to enhance GABA-mediated conductance. Etazolate does not increase glycine-mediated conductance changes. Etazolate increases [3H]flunitrazepam binding and stimulates the GABA enhancement of [3H]flunitrazepam binding. In addition, GABA stimulates the etazolate enhancement of [3H]flunitrazepam binding. The etazolate-mediated increases in binding are Cl- dependent and picrotoxinin and bicuculline sensitive. The dose response relationships for etazolate-mediated effects are similar in physiological experiments and in binding studies. These data suggest that etazolate interacts with the postsynaptic GABA receptor complex at a site distinct from either the GABA recognition site or the benzodiazepine binding site to enhance GABA-mediated inhibition and to increase benzodiazepine binding.

Animals↗
PubMed1983

Change in Bmax and Kd for [3H]flunitrazepam observed in the course washing rat brain tissue with distilled water.

A method for the removal of an endogenous inhibitor(s) of benzodiazepine receptor binding (extraction in distilled water at 20 degrees) was used to evaluate the possible influence of this inhibitor(s) on the affinity of the benzodiazepine receptor in vivo. The results indicate that the presence of an inhibitor(s) in the concentration which exists in the rat brain leads to a 30-fold increase in the Kd value as compared with the results obtained in vitro. The endogenous inhibitor(s) appeared to be a thermostable, proteinase K-resistant substance(s) with Mr between 500 and 10,000 daltons. Repeated washings of the brain tissue with distilled water were accompanied by a decrease in the Bmax for [3H]flunitrazepam. The [3H]flunitrazepam binding sites with Kd = 1.7 nM and Bmax = 61 fmoles/mg of protein were found in the supernatant collected after the second and third washings in distilled water. The presence of diazepam and the benzodiazepine antagonist Ro 15-1788 prevented in a dose-dependent manner the decrease in the Bmax value for [3H]flunitrazepam during the tissue washing with distilled water.

Animals↗
PubMed1983

A controlled trial of brotizolam versus flunitrazepam as a hypnotic.

Brotizolam, a new thieno-triazolodiazepine, was tested against flunitrazepam and placebo on patients the night before surgery. Flunitrazepam had a shorter onset of action while brotizolam caused longer and deeper sleep with no gastro-intestinal side-effects. It was preferred to flunitrazepam by the patients.

Anti-Anxiety Agents↗
PubMed1984

[Evaluation of the effect of flunitrazepam on the lower esophageal sphincter in man with intraluminal manometry].

The effect of Flunitrazepam on the human lower oesophageal sphincter is evaluated. Pressure in the LOS and GOR using the Acid Reflux Test was evaluated in 22 surgical cases at rest (after ingestions of a placebo and Flunitrazepam). The results obtained indicate that the LOS pressure variations induced by flunitrazepam significantly increase the probability of GOR.

Esophagogastric Junction↗
PubMed1983

[Premedication with flunitrazepam, lormetazepam or pethidine-promethazine. Psychometric study of subjective conditions].

In the course of a clinical study oral administration of two different diazepine derivatives as well as i.m. injection of pethidine and promethazine have been explored with a view to their anxiolytic, sedating and hypnotic action. The study involved 128 patients, randomized into four groups. Group 1 received flunitrazepam 1,5-2 mg p.o. only the evening before operation to group 2 flunitrazepam 1,5-2 p.o. was administered the evening before and the morning of the operation, group 3 were given lormetazepam 2-2,5 mg p.o. at the same time as group 2, in group 4 nitrazepam, 5 mg p.o. the evening before operation and pethidine, 50-100 mg combined with promethazine, 25 mg was given i.m. 60 min before surgery. In group 1 anxiolytic and sedating effect of flunitrazepam were not persistent enough to provide the patient with adequate premedication until the onset of surgery. Intensive sedation and fatigue as well as minimum recollection were observed under medication 2, however, increase in anxiety and depression as well as deterioration of mood were not prevented. Under medication 3 patients felt less exhausted and fatigued than under medication 2, but likewise anxiety and depression increased in the course of the operating day. Group 4 emerged as the last effective premedication both with regard to sleep during the previous night and the conditions of the day of the operation itself.

Adult↗
PubMed1984

[Comparative study of the oral administration of flunitrazepam with oral pentobarbital and intramuscular administration of atropine and pethidine (meperidine) as premedication].

Thirty-four patients were allocated at random to treatment with 1 mg of flunitrazepam, orally, the night before operation, and 1 mg on the morning of operation (Group 1), and another 34 to treatment with 100 mg of pentobarbital, orally, the night before operation, followed by intramuscular atropine (0.01 mg/kg)+pethidine (meperidine 1 mg/kg) on the morning of operation (Group 2). The patients in both groups slept equally well. As far as apprehension and excitement (= anxiolytic effect) just before induction of anaesthesia were concerned, oral flunitrazepam proved to be markedly better than i.m. atropine+pethidine. There were no significant differences in cardiovascular variables between the two groups. From the anaesthesiologist's point of view, atropine had beneficial antisecretory effects, but, from the patients point of view, it caused only a subjective unwanted effect (dry mouth). In our opinion, oral flunitrazepam is a useful alternative agent for routine premedication. However, when used without i.m. atropine, excessive salivary secretion in some patients may occur and be disturbing, especially during extubation.

Administration, Oral↗
PubMed1982

A comparative study of zopiclone and flunitrazepam in insomniacs seen by general practitioners.

A double-blind crossover trial was conducted in 42 outpatients of either sex in order to obtain information on the properties of 7.5 mg of zopiclone in a general practice setting compared with 2 mg of flunitrazepam. Each patient went through two periods of treatment, each period lasting 10 days. A comparison of the effect of the drugs showed a significant difference with regard to effectiveness and sleep latency favoring flunitrazepam. When patient's preferences were analyzed there was a highly significant difference favoring flunitrazepam both for effectiveness and tolerance. The side effects from both drugs were generally mild.

Adolescent↗
PubMed1994

Correlation of neuroactive steroid modulation of [35S]t-butylbicyclophosphorothionate and [3H]flunitrazepam binding and gamma-aminobutyric acidA receptor function.

Neuroactive steroids, including endogenously occurring metabolites of progesterone and deoxycorticosterone as well as their synthetic derivatives, are positive allosteric modulators of the gamma-aminobutyric acid (GABA)A receptor complex. They inhibit the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS), enhance the binding of [3H]flunitrazepam, and potentiate GABA-evoked chloride currents and agonist-stimulated 36Cl- uptake. The structure-activity relationship for 31 neuroactive steroids and related compounds was explored by examining their relative ability to inhibit [35S]TBPS binding in rat brain cortical membranes. A free 3 alpha-hydroxy group is necessary for high potency inhibition. Whereas hydroxylation in the 21-position and subsequent esterification maintain activity, 11 alpha- or 12 alpha-hydroxylation greatly reduces activity. The rank order of potency for 17-position substitutions in the 5 alpha-reduced series is 17 beta-acetyl > 17 beta-cyano > 17 beta-methoxycarbonyl > 17 alpha-acetyl > 17-one > or = 17-oxime > or = 17 alpha-cyano. Introduction of a double bond between the 9- and 11-positions reduces potency, whereas a double bond in the 4-position reduces the maximal extent of inhibition. Comparing the activities of these neuroactive steroids and related compounds in the [35S]TBPS and [3H]flunitrazepam assays, there is a strong correlation between potency (r = 0.90, n = 17) and magnitude of modulation (r = 0.95, n = 31), indicating that the neuroactive steroid binding site is similarly coupled to the TBPS and benzodiazepine sites in rat cortex. However, there is a weaker correlation (r = 0.74-0.78, n = 31) between the degree of modulation in either binding assay and potentiation of muscimol-stimulated 36Cl- uptake in rat cortical synaptoneurosomes. Using an electrophysiological approach, stronger correlations (r = 0.89-0.94, n = 15) were observed between the magnitude of modulation in the binding assays and potentiation of GABA-evoked chloride currents in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2L receptor complexes. Thus, neuroactive steroid modulation of [35S]TBPS and [3H]flunitrazepam binding is predictive of functional activity at the GABAA receptor complex.

Allosteric Regulation↗
PubMed1994

Regional changes in [3H]zolpidem binding to brain benzodiazepine receptors in flurazepam tolerant rat: comparison with changes in [3H]flunitrazepam binding.

Regional downregulation of brain benzodiazepine (BZ) receptors was studied in rats treated with flurazepam or diazepam protocols known to produce anticonvulsant tolerance. Zolpidem, a selective BZ1 receptor agonist, was used to detect BZ1 receptors; flunitrazepam, a nonselective BZ receptor agonist, was used to detect the total BZ receptor population. Rats were treated 4 weeks with flurazepam, then sacrificed immediately or 48 hr later. After flurazepam treatment, the maximal binding capacity of [3H]zolpidem binding decreased 22% in the cerebral cortex, 32% in the cerebellum and 25% in the hippocampus. The Kd increased in the cerebellum. The maximal binding capacity of [3H]flunitrazepam binding decreased by 13% in the cerebral cortex and 14% in the hippocampus, but did not change in the cerebellum. The Kd increased in the hippocampus. At 48 hr after flurazepam treatment, there was no significant difference in [3H]zolpidem binding between treated and control rats. In rats treated 3 weeks with diazepam released from s.c. reservoirs, there was no change in [3H]zolpidem binding. The data suggest that chronic flurazepam treatment causes downregulation primarily involving BZ1 receptors. The differing effects on [3H]-zolpidem and [3H]flunitrazepam binding, especially in the cerebellum in which more than 90% of the receptors are the BZ1 subtype, may indicate a shift in BZ receptor subtypes in flurazepam-tolerant rats, suggesting a change in the subunit composition or conformation of gamma-aminobutyric acidA/BZ receptors.

Animals↗
PubMed1993

[Oral premedication with clorazepate dipotassium. Comparison with oral premedication with flunitrazepam and intramuscular premedication with promethazine, pethidine and atropine in adults].

UNLABELLED: The purpose of premedication and the best form have been frequent subjects of controversy among anaesthetists in the past few years. Anxiolysis is now accepted as the main purpose. The preferred route of administration is by mouth. The intention of this study was to examine whether clorazepate dipotassium has the same sedative-hypnotic and anxiolytic effects as i.m. premedication with promethazine, pethidine and atropine. METHODS: A total of 100 patients aged 20-65 years and due to undergo arthroscopy took part in this study. Patients in group I were given 1 mg flunitrazepam p.o. on the evening before the operation and the i.m. premedication described above. The premedication for group II consisted in clorazepate dipotassium, 50 mg on the evening before operation and 25 mg on the morning of the day of the operation. The sedative-hypnotic effects were measured on a four-point scale. The Erlangen anxiety scale (EAS) and a visual analogue scale (VAS) were used to evaluate the anxiolytic effects according to the patient's own and the observer's evaluation of mood. In addition to this, we measured amnesia, heart rate and blood pressure. RESULTS: Clorazepate dipotassium or flunitrazepam p.o. significantly reduces anxiety 1 h after administration as measured by the EAS (P < 0.05) on the evening before the operation. This result was not, however, confirmed by the VAS for self-assessment. Patients who received premedication with clorazepate dipotassium are less anxious on the morning of the operation than patients given flunitrazepam the evening before the operation (P < 0.05); this, however, does not correspond to the VAS results. There were no differences in the other parameters compared. DISCUSSION: Oral premedication with clorazepate dipotassium has the same sedative-hypnotic, anxiolytic and amnestic effects as i.m. premedication with promethazine, pethidine and atropine. The results of this study are better than those obtained by Tolksdorf et al., owing to the higher dosage used in our study (50 mg as against 20 mg). Tolksdorf et al. [21] failed to show any improvement on a placebo. Our results correspond to those of Drautz et al. [2] who used 50 mg of clorazepate dipotassium on the evening before and 25 mg on the morning of the day of the operation.

Administration, Oral↗
PubMed2002

Microemulsion electrokinetic chromatography versus capillary electrochromatography-UV-mass spectrometry for the analysis of flunitrazepam and its major metabolites.

Benzodiazepines, namely flunitrazepam and its three major metabolites, were successfully separated by microemulsion electrokinetic chromatography. Separation was achieved using an untreated fused-silica capillary (48 cm (effective length 40 cm) x 50 num) at 25 kV; detection was performed by UV at 220 nm. The microemulsion system consisted of 70 mM octane, 800 mM 1-butanol, 80 mM sodium dodecyl sulfate (SDS) and 10 mM borate buffer, pH 9. Very high efficiencies (up to 400 000 plates) and resolution better than 3 were achieved. Since this technique is not compatible with mass spectrometry (MS) detection, a capillary electrochromatographic (CEC) method was developed to separate flunitrazepam and its metabolites. The effects of mobile phase composition and pH as well as voltage and temperature were systematically investigated. The optimized CEC method allowed the baseline separation of the investigated compounds. For the on-line coupling of CEC with electrospray ionization-mass spectrometry, the column was connected to a void fused-silica capillary using a Teflon connection. This configuration was found efficient and suitable for hyphenation of commercial CEC and MS instrumentation using commercially available CEC columns.

Anti-Anxiety Agents↗
PubMed2003

Stem-completion tasks (indirect, direct inclusion and exclusion) are differently affected by equipotent doses of lorazepam and flunitrazepam.

This study was designed to explore the effects on performance in stem-completion tasks of two benzodiazepines (BZ) in equipotent doses: lorazepam, a drug that atypically disrupts perceptual priming, and flunitrazepam, a compound with standard BZ effects. The study followed a placebo-controlled, double-blind, parallel-group design. Thirty-six young and healthy subjects carried out three completion tasks at theoretical peak-plasma concentrations of drugs: (a) indirect tasks, in which the subjects were instructed to complete stems with the first word that came to mind; (b) direct inclusion tasks/cued recall, in which the participants had to try to use words seen at study as completions; and (c) direct exclusion tasks, in which words seen at study were to be avoided. The PDP was applied to the results in the inclusion and exclusion tasks, to obtain indices of explicit/controlled (C) and implicit/automatic (A) memory. The C index was lowered by both BZs and A was equivalent in all treatments, confirming the general amnestic action of BZs. However, lorazepam led to decreases in completions in the indirect and inclusion tasks, while flunitrazepam impaired performance in the exclusion task. The qualitative differences between the drugs in their effects on performance suggest that these BZs may lead to differences in response bias.

Administration, Oral↗
PubMed1982

Efficacy and side effects of flunitrazepam and pentobarbital in severely insomniac patients.

One hundred thirty-seven current or prospective recipients of hypnotics were screened to obtain a sample of 12 severely insomniac patients for a study concerning efficacy and side effects of 2 mg flunitrazepam and 100 mg pentobarbital as hypnotics. During the baseline period, these 12 subjects showed wide intraindividual variability of sleep and performance. This variability was not reduced by the hypnotics, which on the average did not adversely affect performance. Flunitrazepam, but not pentobarbital, slightly reduced sleep latency. Neither hypnotic prolonged sleep duration or reduced the number of wakings. The generalizability of the results to the population of recipients of hypnotics is discussed.

Adult↗
PubMed1992

Monensin inhibits the binding of 3H-flunitrazepam to and reveals the intracellular passage of GABAA/benzodiazepine receptor.

Effects of monensin were examined on the intracellular processing of the GABAA/benzodiazepine receptor (GABAA/BZDR) in neuron cultures derived from embryonic chicken brain, using 3H-flunitrazepam as the probe for the benzodiazepine modulator site on the receptor. Incubation of cultures with 0.1 or 1 microM monensin for 3 h blocked the binding of 3H-flunitrazepam by about 18%. Loss of ligand binding was due to a reduction in the number of binding sites, with no significant changes in receptor affinity. The general cellular protein synthesis and glycosylation in the cells were inhibited by 26% and 56%, respectively, in the presence of 1 microM monensin, as detected by assaying the incorporation of 3H-leucine and 3H-galactose. In contrast, an increase was observed for mannose incorporation by the cultures in the presence of the drug. Moreover, the results from in situ trypsinization of the cultures following monensin treatment showed that monensin did not alter the distribution of intracellular and surface receptors. The data suggest that monensin induces the down-regulation of GABAA/BZDR by generating abnormal glycosylation of the receptor and interrupting its transport within the Golgi apparatus, as well as from the Golgi apparatus to the intracellular pool and cell membrane. The galactosylation of receptor proteins may be important for the maturation of the receptor.

Animals↗
PubMed1994

Lindane cytotoxicity in cultured neocortical neurons is ameliorated by GABA and flunitrazepam.

The effect of lindane (gamma-hexachlorocyclohexane) on [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding and GABA-stimulated 36Cl- influx was investigated in cultured cerebral cortical neurons. In addition, the cytotoxic action of lindane as well as a protection by GABA and flunitrazepam were studied together with the ability of lindane to increase the intracellular concentration of free Ca2+. Lindane was found to be toxic to the neurons, an effect that could be completely prevented by the simultaneous presence of GABA (0.1 microM) and flunitrazepam (100 microM) and reduced by GABA alone. An interaction with the GABA receptor-gated chloride channel was demonstrated by an inhibitory action of lindane on [35S]TBPS binding (IC50 188 +/- 51 nM) and on GABA-stimulated 36Cl- influx in the neurons. Lindane only marginally increased the intracellular Ca2+ concentration in the neurons. It is concluded that the cytotoxic action of lindane is mediated through interaction with GABA receptors in a manner essentially independent of changes in intracellular Ca2+ homeostasis.

Animals↗
PubMed1991

Kinetics of the acid hydrolysis of diazepam, bromazepam, and flunitrazepam in aqueous and micellar systems.

A kinetic study of the acid hydrolysis of aqueous diazepam, bromazepam, and flunitrazepam was carried out at 25 degrees C using a spectrophotometric method. For diazepam and flunitrazepam, the experimental pseudo first-order rate constant decreased as the acid concentration was increased. The contrary behavior was found in the case of bromazepam. A kinetic scheme that includes the hydrolysis reaction of both protonated and nonprotonated species of the drug can account for these results. Also, the kinetics of the acid hydrolysis of the same drugs in the presence of micellar aggregates [nonionic polyoxyethylene-23-dodecanol (Brij 35); cationic cetyl trymethyl ammonium bromide (CTAB); and anionic sodium decyl (SdeS), dodecyl (SDS), and tetradecyl (STS) sulfate] was studied at 25 degrees C. Negligible effects were observed in the cases of nonionic and cationic micelles. Anionic micelles produced an inhibitory effect in the reaction velocity. This effect increased as the hydrophobic nature of the surfactant increased. All these facts are interpreted quantitatively by means of a pseudophase model.

Bromazepam↗
PubMed2001

Changes of [3H]MK-801, [3H]muscimol and [3H]flunitrazepam binding in rat brain by the prolonged ventricular infusion of ginsenoside Rc and Rg1.

In the present study, we have investigated the effects of centrally administered ginsenoside Rc and Rg1 on the modulation of the NMDA receptor and GABA(A)receptor binding in rat brain. The NMDA receptor binding was analysed by quantitative autoradiography using [(3)H]MK-801 binding, and the GABA(A)receptor bindings were analysed by using [(3)H]muscimol and [(3)H]flunitrazepam binding in rat brain slices. Rats were infused with ginsenoside Rc or Rg1 (10 microg/10 microl h(-1), i.c.v.) for 7 days, through pre-implanted cannula using osmotic minipumps (Alzet, model 2ML). The levels of [(3)H]MK-801 binding were highly decreased in part of the parietal layers of the cortex and cingulated by ginsenoside Rc and Rg1. The levels of [(3)H]muscimol binding were strongly elevated in almost all regions of the frontal cortex by the treatment of ginsenoside Rc but decreased by ginsenoside Rg1. However, the [(3)H]flunitrazepam binding was not modulated by ginsenoside Rc or Rg1 infusion. These results suggest that prolonged infusion of ginsenosides could differentially modulate [(3)H]MK-801 and [(3)H]muscimol binding in a region-specific manner.

Animals↗