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PubMed1994

[Trazodone versus flunitrazepam in premedication in day-care surgery].

A prospective single-blind study was conducted to compare flunitrazepam vs trazodone in the premedication of patients undergoing day-case surgery for termination of pregnancy, with particular regard to the degree of preoperative sedation, intraoperative analgesia and postoperative recovery. 86 patients were randomly allocated to receive orally 45 minutes before the surgical procedure either flunitrazepam 2 mg (group F) or trazodone 50 mg (group T). In both groups anaesthesia was achieved by i.v. fentanyl 2.5 micrograms/kg and ketamina 250 micrograms/kg. Patients in group F showed a deeper degree of preoperative sedation. There were no significant differences in intraoperative analgesia and in the immediate arousal time. In the postoperative period, the incidences of emetic symptoms and dizziness were similar in both groups; the incidence of drowsiness was significantly higher in group F at 120 minutes but not at 180 minutes of observation. Psychomotor performance was assessed preoperatively two days before the surgical procedure and 60, 120 and 180 minutes after surgery, using the Toulouse-Pieron test and the reaction time to a luminous stimulus with the aid of a computerized analogic tachystoscope (Neurometer). Trazodone allowed a more rapid recovery of psychomotor performance and it can represent a valid alternative to the use of benzodiazepines in the premedication of day-case surgical patients.

Abortion, Induced↗
PubMed1993

[Determination of benzodiazepines by thermospray liquid chromatograph-mass spectrometer. Part 1. Nitrazepam, estazolam, bromazepam, flunitrazepam].

Thermospray liquid chromatography mass spectrometric method is described for the determination of the benzodiazepines (Nitrazepam, Estazolam, Bromazepam, Flunitrazepam). Reversed-phase liquid chromatography was performed using a 15 cm Shim-pack CLC-ODS (Shimadzu) column, with acetonitrile-water (40:60) + 0.1 M ammonium acetate as mobile phase, at a flow rate of 1.0 ml/min. The temperature of the vaporizer, block and TH of the source block were 166, 270 and 275 degrees C, respectively. Positive ion thermospray mass spectra by thermospray ionization (TSP ionization) mode or thermospray on filament ionization (filament-on ionization) mode were obtained. Formation of the MH+ ion was observed as a base peak under TSP ionization and filament-on ionization conditions and fragment ions were very few. On both ionization mode, peaks representing nitrazepam as MH+ at m/z 282 at a retention time (R.T.) of 6.4 min, from estazolam as MH+ at m/z 295 at an R.T. of 6.4 min, from bromazepam as MH+ at m/z 316 at an R.T. of 4.5 min and from flunitrazepam as MH+ at m/z 314 at an R.T. of 8.8 min. The detection limit for all the benzodiazepines under investigation was less than 0.5 ng (S/N = 9.4 +/- 4.6) using selected ion monitoring.

Benzodiazepines↗
PubMedDate not supplied

[Storage stability of flunitrazepam, flurazepam, diazepam and metabolites in blood and plasma].

The stability of flunitrazepam, flurazepam, diazepam and some of their metabolites in spiked blood and plasma samples was studied bei GC-ECD analysis at defined time intervals up to 240 days. Validation data of the method are given. The blood or plasma samples were stored either at 22 degrees C or at 4 degrees C, and were exposed to global natural light irradiation or protected from light. All substances considerably decreased during the time interval studied. Flunitrazepam soon disappeared completely at room temperature (22 degrees C), while diazepam and flurazepam proved to be more stable, but a clear pattern of breakdown could not be established. The data obtained suggest a result from a long-term stored sample to be cautiously interpreted. Further investigation concerning the stability of drugs and the establishment of optimal storage conditions seem necessary.

Anti-Anxiety Agents↗
PubMed1991

Large dose of flunitrazepam attenuates baroreflex control of heart rate in man.

The effects of intravenous tranquilizers such as flunitrazepan, diazepam and droperidol on baroreflex control of heart rate were investigated using both pressor and depressor tests. The dose-dependency was also studied by the administration of the drugs at the usual or twofold dosage. The usual dosage caused no significant change in neuronal controlling mechanism of circulation. However, flunitrazepam at double the usual dosage produced a decrease in baroreflex sensitivity at depressor tests. The results suggest that flunitrazepam when given repeatedly might accelerate hemodynamic derangements induced by an acute decrease in blood pressure.

Journal Article↗
PubMed2004

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

Ameliorating effects of ginseng were observed on neuronal cell death associated with ischemia or glutamate toxicity. Ginseng saponins are transformed by intestinal microflora and the transformants would be absorbed from intestine. In the present study, we have investigated the effects of transformed ginsenoside Rg3, Rh2 and compound K on the modulation of NMDA receptor and GABAA receptor binding in rat brain. The NMDA receptor binding was analyzed by quantitative autoradiography using [3H]MK-801 binding, and GABAA receptor bindings were analyzed by using [3H]muscimol and [3H]flunitrazepam binding in rat brain slices. Ginsenoside Rg3, Rh2 and compound K were infused (10 microg/10 microl/h) into rat brain lateral ventricle for 7 days, through pre-implanted cannula by osmotic minipumps (Alzet, model 2ML). The levels of [3H]MK-801 binding were highly decreased in almost all regions of frontal cortex and hippocampus by ginsenoside Rh2 and compound K. The levels of [3H]muscimol binding were elevated in part of frontal cortex and granule layer of cerebellum by the treatment of ginsenoside Rh2 and compound K. However, the [3H]flunitrazepam binding was not modulated by any tested ginsenosides. Ginsenoside Rh2 and compound K induced the downregulation of the [3H]MK-801 binding as well as upregulation of the and [3H]muscimol binding in a region-specific manner after prolonged infusion into lateral ventricle. However, ginsenoside Rg3 did not show the significant changes of ligand bindings. In addition, ginsenoside Rh2 decreased the expression of nNOS in the hippocampus although Rg3 decreased the expression in the cortex. These results suggest that biotransformed ginsenoside Rh2 and compound K could play an important role in the biological activities in the central nervous systems and neurodegenerative disease.

Animals↗
PubMed1986

The inhibitory effect of endogenous convulsants quinolinic acid and kynurenine on the pentobarbital stimulation of [3H]flunitrazepam binding.

The metabolites of tryptophan-kynurenines with convulsant action quinolinic acid (QA) and l-kynurenine (l-KYN) antagonized the enhancing effect of pentobarbital (1 mM) on [3H]Flunitrazepam binding. IC50 for l-KYN were 35.9 +/- 14.8 microM and for QA 31.2 +/- 7.2 microM respectively. The inhibitory effect of KYN was stereoselective: IC50 of l-isomer was about two fold lower than IC50 of racemic form, d,l-KYN. Scatchard analysis revealed that inhibitory effect of QA and l-KYN on [3H]Flunitrazepam binding enhanced by pentobarbital is due to the decrease in affinity of benzodiazepine receptors. On the basis of these data it is proposed that QA and l-KYN possess their convulsant action interacting with barbiturate/picrotoxin sensitive sites of GABA-benzodiazepine-barbiturate complex.

Animals↗
PubMed1996

Does potency determine amnestic effects of benzodiazepines? A dose-response comparison of flunitrazepam and nitrazepam.

This study was designed to explore whether differences in the psychomotor, subjective and memory effects of different benzodiazepines (BDZ) relate to differences in their potencies. Two BDZs with similar kinetics but different potencies were compared. Flunitrazepam (0.5 and 1.0mg, nitrazepam (5 and 10mg) or placebo were administered to 50 healthy volunteers in a double-blind, parallel group design. Subjects completed a test battery before and 1.5h post-treatment. The higher dose of the more potent BDZ, flunitrazepam, impaired episodic memory in relation to placebo. In contrast, differences in psychomotor and subjective effects between BDZ were less clear. We conclude that a main caveat to the conclusion that potency plays a role in determining BDZ amnestic effects is the possible contribution of sedation and differential task sensitivities to apparent differential effects of BDZ compounds.

Journal Article↗
PubMedDate not supplied

Partitioning of flunitrazepam into model membranes studied by temperature controlled gel filtration chromatography.

The use of gel filtration chromatography with Sephadex as a separation medium was used in order to study flunitrazepam (FNTZ) partitioning into artificial model membranes consisting of dipalmitoyl-phosphatidylcholine (dpPC) vesicles, under controlled temperature conditions. In this system two phenomena are taking place simultaneously: the ligand-liposome interaction and the lipid self-aggregation to form the liposome. The liposome-FNTZ interaction was evidenced by the non-enantiography of the first derivative of FNTZ elution peak in frontal chromatography through Sephadex G-75. On the other hand, the presence of FNTZ reduced liposomes mean size and increased their size dispersion as evidenced by molecular filtration through Sephadex G-200. The dpPC-buffer FNTZ partition coefficient determined in zonal chromatography through Sephadex G-10 increased about 33% when the temperature rose above the temperature of dpPC transition from the liquid crystalline to the fluid phase. Gel filtration chromatography seems a suitable technique to study lipid liposome-FNTZ interactions at a qualitative level. In addition, this technique has the advantage over other methods of giving the possibility of observing the mutual effects exerted between the drug and the self-aggregating structure.

Chromatography, Gel↗
PubMed1992

Taurine allosterically modulates flunitrazepam binding to synaptic membranes.

Taurine is hypothesized to exert its inhibitory neuromodulatory effects, in part, by interaction with the GABAA receptor. Although taurine displaces GABA agonist binding to synaptic membranes, its allosteric effects on the benzodiazepine recognition site of the GABAA receptor complex is unsettled. We determined the effects of taurine on [3H]flunitrazepam (Flu) binding to well-washed, frozen-thawed synaptic membranes prepared from rat cortex. Comparative binding studies were conducted at 37 degrees C and on ice (0-4 degrees C). At 37 degrees C taurine increased Flu binding in a concentration dependent way by interaction with a bicuculline sensitive site, similar to GABA. Taurine increased Flu binding by causing a decrease in KD. The maximal effectiveness of taurine on Flu binding could not be increased further by addition of GABA. In contrast, the maximal stimulation of Flu binding by GABA was decreased by addition of taurine to the level attained by taurine alone. These mixed agonist/antagonist effects of taurine are pharmacologically specific and qualify taurine as a partial GABA agonist in this type of allosteric interaction. However, taurine causes opposite effects on Flu binding when measured at 0-4 degrees C: taurine interacts with a bicuculline insensitive site to inhibit Flu binding by increasing the KD. Taurine inhibition of Flu binding is not overcome by increasing concentrations of GABA. Although the mechanism of taurine inhibition of Flu binding at 0-4 degrees C is unclear, it may be an indirect effect of taurine interaction with membrane phospholipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Lack of correlation between melanin affinity and retinopathy in mice and cats treated with chloroquine or flunitrazepam.

Flunitrazepam (Rohypnol, Roche, Basel, Switzerland), which is similar to chloroquine, has an affinity to melanin in retinal cells. However, in contrast to chloroquine, it does not induce structural alterations in these cells or in adjacent tissues of pigmented mice and cats even after treatment for 6 and 12 months with respectively, 2000-times (mice, or 130-times (cats) the effective human daily dose. Treatment with chloroquine (with a dose similar to that used in human anti-rheumatic therapy) over the same period, resulted in the appearance of numerous membranous cytoplasmic bodies in the retinal ganglion cells of mice and cats. In addition, in cats, an augmentation of lysosomal structures in the pigment epithelium, chiefly in the melanin-free region, and destruction of the tapetal cells were observed. Moreover, the pigment epithelium with the highest concentration of melanin was unaffected in mice and only slightly affected in cats. It was concluded that the retinotoxic effect of chloroquine is not the result of its affinity to melanin-containing tissues. Consequently, the affinity to melanin-containing cells per se is not sufficient to class a substance as potentially harmful to vision.

Animals↗
PubMed1985

Further characterization of [3H] flunitrazepam binding sites on cultured mouse astroglia.

Astroglial cells in primary cultures bind [3H]flunitrazepam with a high affinity on a single type of site and on a number of binding sites which increased during astroglial growth and differentiation. These binding sites show a particular pharmacological spectrum characterized by an inhibition of high affinity by RO-5-4864 (4'-chlorodiazepam), an anticonvulsant of the benzodiazepine family and by an inhibition of binding of lower affinities by diazepam clonazepam and clobazam. RO-5-4864 and clonazepam compete for the same binding site in astroglia. The heat stability and the hormonal modulation by thyroxine are similar for astroglia and neuronal-cells. Benzodiazepines modulate the astroglial 5-HT receptor. Such an effect could be a possible physiological response to benzodiazepines for astroglial cells in primary cultures.

Animals↗
PubMed1983

Differential inhibition of brain specific [3H]flunitrazepam binding by several types of dyes.

Several dyes, representing different structural classes, inhibit [3H]flunitrazepam binding to brain specific receptors in the rat with 50% inhibition in the 1 to 100 microM range. Crystal Violet and Methyl Violet 2B inhibited more potently in the forebrain than in the cerebellum. Congo Red yielded a Hill number near 2.3, probably reflecting positive cooperativity between interacting binding sites in benzodiazepine receptor complexes. Toluidine Blue 0 was the most potent of the dyes tested (IC50 = 1 microM in cerebellum) and inhibited more potently in cerebellum than in forebrain.

Animals↗
PubMed1991

Purification of endogenous inhibitors of [3H]flunitrazepam binding from bovine brain.

Endogenous substances which inhibited the binding of [3H]flunitrazepam ([3H]FNZ) to bovine synaptosomal membranes have been purified from the hot acetic acid extracts of the bovine brain. Three peaks of inhibitory activity were obtained by Sephadex G-10 gel chromatography. Two of the peaks (Peak 2, and Peak 3) which had lower molecular weights than that of peak 1 were identified as inosine and hypoxanthine by TLC methods. Another peak (Peak 1) was further purified to homogeneity using both cation and anion ion-exchange chromatography and the following two-step reversed-phase HPLC. The purified substance inhibited the [3H]FNZ binding dose-dependently and competitively but did not have an effect on the binding of the peripheral-type BZ ligand [3H]Ro 5-4864. It was also shown that the substance was heat-stable and resistant to proteolytic degradation (trypsin, alpha-chymotrypsin, pronase). However, a significant loss of inhibitory activity to [3H]FNZ binding was observed after acid hydrolysis. Molecular weight estimates based on gel filtration methods were less than 500 dalton, and the maximal ultraviolet absorption peak was at 314 nm. These results suggest that this substance is a new endogenous ligand for the central BZ receptor and may play an important role in regulating the GABAergic tone in the central nervous system.

Animals↗
PubMed1994

Binding characteristics of [3H]flunitrazepam in pentobarbital-withdrawal rats.

The effects of chronic pentobarbital (PB) treatment on the binding characteristics of [3H]flunitrazepam (FLU) in rat brain were examined. Saline or sodium PB (500 micrograms/10 microliters/hr) was infused into the lateral cerebral ventricles of rats for 6 days using osmotic pumps. Immediately before withdrawal, there were no significant differences in [3H]FLU binding constants (KD and Bmax) between saline and PB groups. However, 24 hr withdrawal caused an increase in Bmax with no changes in KD. The enhancement of [3H]FLU binding by in vitro addition of chloride ions and PB was not affected after the PB infusion. The PB enhancement of [3H]FLU binding was inhibited by the convulsant, picrotoxinin. PB withdrawal did not cause significant differences in the binding constants of [3H]Ro 15-1788, a benzodiazepine (BZ) antagonist, between the saline and PB groups. Pretreatment of membranes with 0.02 mM of 3-[(3-cholamidopropyl)-dimethylammonio]-1- propanesulfonate (CHAPS), a zwitterionic detergent, caused decreases in both KD and Bmax in FLU binding in PB-withdrawal membrane, but not in the saline-treated membrane. The enhancement of [3H]FLU binding by chloride ions and PB was not affected by the CHAPS treatment. These results suggest that the change in BZ receptors induced by PB withdrawal is functionally linked to the GABA-BZ-barbiturate receptor complex and that PB withdrawal induces some conformational changes in BZ receptors.

Animals↗
PubMed1992

Muscimol and flunitrazepam binding sites in a subcellular fraction enriched in rat cerebellar glomeruli.

In the internal granular layer of the cerebellar cortex the polysynaptic complexes called glomeruli consist mainly of homogeneous populations of glutamatergic and GABAergic synapses, both located on granule cell dendrites. A subcellular fraction enriched in glomeruli was prepared from rat cerebellum, and the distribution of GABAA and of benzodiazepine binding sites between membranes derived from this fraction (fraction G) and from a total cerebellar homogenate (fraction T) was studied. The benzodiazepine and GABA binding sites were measured by the binding of agonists [3H]flunitrazepam and [3H]muscimol, respectively. The results indicate that both binding sites are present, but only slightly enriched, in the glomerular synapses. We found a muscimol/flunitrazepam binding site ratio of two, which is consistent with the enrichment of muscimol binding sites in the granular layer shown by both autoradiographic with radioactive glutamatergic ligands and in situ hybridization experiments respectively.

Animals↗
PubMed1990

Binding of flunitrazepam to differentiating neurons cultured in a chemically defined, hormone-supplemented medium.

[3H]Flunitrazepam (FNZ) binding to cortical neurons from fetal rat brain was investigated in vitro. The use of a synthetic medium specific for neurons made it possible to plot a developmental curve of 3H-FNZ binding in an almost pure neuronal culture. Detectable specific binding was present in vitro at time 0 (that is, the 16th gestational day). A progressive increase of binding, due to an increment in the number of recognition sites, was observed on the subsequent days. The affinity of the specific binding sites to 3H-FNZ was enhanced by the addition of exogenous GABA, whereas the density was not affected.

Animals↗
PubMed1978

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.

Administration, Oral↗