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PubMed1982

[Effects of flunitrazepam on intraocular pressure (author's transl)].

Though ophthalmologists operate upon patients that are in a debilitated state, a general anesthesia has to be employed with increasing frequency. Flunitrazepam, known to possess good cardiovascular tolerance, was studied to evaluate its effects on intraocular pressure in 34 unselected patients undergoing 41 operations under general anesthesia, usually 41 operations under general anesthesia, usually for retinal detachment or cataract. Ocular pressure was normal in all cases before surgery, but a history of chronic respiratory insufficiency was obtained in 8 cases and of cardiovascular disease in 18. After premedication with 0.02 mg . kg-1 of flunitrazepam and 0.01 mg . kg-1 of atropine, anesthesia was induced by 0.04 mg . kg-1 i.v. of flunitrazepam alone. No marked alterations in cardiac of respiratory functions were observed. Intraocular pressure was measured with a Schiötz tonometer, just before and 5 minutes after the i.v. injection of flunitrazepam. Results showed -- before: 1.61 +/- 0.51 kPa (12.1 +/- 3.8 mmHg); after: 1.09 +/- 0.36 kPa (8.2 +/- 2.7 mmHg) -- a statistically reduction of 32 p.cent. The precise mechanism of action of flunitrazepam on intraocular pressure is not known, but cannot be related to the reduction in aqueous humor secretory flow or the marked diminution in arterial or venous pressure. A probable explanation is the lowering of resistance to aqueous humor flow exterior to the ocular globe as a result of the muscle relaxant properties of the product. Flunitrazepam appears to be a narcohypnotic of choice in ophthalmological surgery on these inherently debilitated patients.

Adolescent↗
PubMed1983

Association of proteins irreversibly labeled by 3H-flunitrazepam with different benzodiazepine.

Studies of the regional distribution of proteins irreversibly labeled by 3H-flunitrazepam indicate that the contribution of the individual proteins to total irreversible binding of 3H-flunitrazepam was different in different brain regions and varied independently from each other. Study of the inhibition by Cl 218 872 of 3H-flunitrazepam binding to the individual benzodiazepine binding proteins in cerebellum and hippocampus revealed that inhibition by Cl 218 872 of total irreversible binding of 3H-flunitrazepam to proteins was closely similar to that of reversible binding to membranes. However, when inhibition by Cl 218 872 of 3H-flunitrazepam binding to individual benzodiazepine binding proteins was measured, it was found that this substance had different affinity for the various individual proteins. The present results are consistent with the hypothesis that the protein P51 is associated with the BZ1-benzodiazepine receptor subtype and that the individual proteins irreversibly labeled by 3H-flunitrazepam are independent from each other and associated with different benzodiazepine receptors.

Anti-Anxiety Agents↗
PubMed1984

In vitro and ex vivo inhibition by flutoprazepam of [3H]flunitrazepam binding to mouse brain receptors.

The ability of flutoprazepam, a new antianxiety drug of the benzodiazepine class, to inhibit [3H]flunitrazepam binding to mouse brain receptors was investigated in vitro and ex vivo (measurement of [3H]flunitrazepam binding in vitro after in vivo treatment of animals with unlabelled drugs). The Ki values for [3H]flunitrazepam binding in vitro were as follows: flutoprazepam (13.0 nM), diazepam (2.7 nM), nitrazepam (5.3 nM), prazepam (68.5 nM) and chlordiazepoxide (234 nM). Two metabolites of flutoprazepam, N-desalkyl-flutoprazepam (Ki = 3.1 nM) also inhibited [3H]flunitrazepam binding in vitro with higher potencies than that of flutoprazepam. Flutoprazepam was found to be more active in inhibiting [3H]flunitrazepam binding ex vivo and in preventing pentetrazol convulsions than predicted from Ki values. The ID50 values for inhibiting [3H]flunitrazepam binding ex vivo were 0.32 mg/kg, p.o. (flutoprazepam), 0.89 mg/kg, p.o. (diazepam), 0.94 mg/kg, p.o. (nitrazepam), 1.98 mg/kg, p.o. (prazepam) and 23.3 mg/kg, p.o. (chlordiazepoxide), respectively. The correlation between ID50 values ex vivo and ED50 values for preventing pentetrazol convulsions was highly significant (r = 0.929). These results suggest that flutoprazepam can exert its pharmacological activities by itself and that two metabolites also play an important role in the effects of flutoprazepam in vivo.

Animals↗
PubMed2003

Effect of ergot alkaloids on 3H-flunitrazepam binding to mouse brain GABAA receptors.

In vitro effects of dihydroergotoxine, dihydroergosine, dihydroergotamine, alpha-dihydroergocriptine (ergot alkaloids), diazepam, methyl-beta-Carboline-3-carboxilate (beta-CCM), flumazenil (benzodiazepines), gamma-amino butyric acid (GABA) and thiopental (barbiturate) were studied on mouse brain (cerebrum minus cerebral cortex) benzodiazepine binding sites labeled with 3H-flunitrazepam. Specific, high affinity (affinity constant, Kd = 57.7 8.6 nM) binding sites for 3H-flunitrazepam on mouse brain membranes were identified. All benzodiazepine drugs inhibited 3H-flunitrazepam binding with nanomolar potencies. In contrast to benzodiazepines, all ergot drugs, GABA and thiopental produced an enhancement of 3H-flunitrazepam binding to its binding site at the GABAA receptor of the mouse brain. The rank order of potency was: neurotransmitter (GABA) > dihydroergotoxine > thiopental > alpha-dihydroergocriptine > dihydroergosine > dihydroergotamine. The results suggest that dihydrogenated ergot derivatives do not bind to the brain benzodiazepine binding sites labeled with 3H-flunitrazepam. However, an enhancement of 3H-flunitrazepam binding by all ergot drugs tested, clearly identifies an allosteric interaction with the benzodiazepine binding sites of GABAA receptors.

Animals↗
PubMed1989

Effects of flunitrazepam on cognitive functions.

The effects of various oral doses (1, 2, 4 mg) of flunitrazepam on vigilance, attention, immediate memory, short-term memory, learning, non-consolidated and consolidated long-term memory were determined. Twelve healthy young male volunteers were given placebo or flunitrazepam in a double-blind, random latin-square sequence, crossing over every 2 weeks. Volunteers completed a battery of tests at night, 3.5 h after drug administration, and in the morning, 10 h after drug administration. Flunitrazepam 1 mg did not significantly impair any of the functions tested at night, while 4 mg impaired vigilance, attention, immediate memory, short-term verbal memory and learning. The impairments of immediate and short-term memory seem to be related and proportional to reductions in vigilance and attention. Doses of 2 mg and 4 mg impaired the speed of learning but did not decrease the amount of material learned. Flunitrazepam caused dose-related impairment of long-term memory, both consolidated and not. This reduction of long-term memory does not seem to be related to the impairments of vigilance, attention or learning. The lowest dose did not modify vigilance and learning in any subject, improved attention in half of the subjects but reduced long-term memory in a similar number of subjects. Therefore, our results indicate selective impairment of long-term memory. Since there were no differences between the effects on consolidated and non-consolidated memory, the amnesic effect of flunitrazepam seems to be due to a decrease in the storage of memory traces. There were no clear generalized residual effects in the morning after administration.

Adult↗
PubMed1987

Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine.

Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.

Animals↗
PubMed1995

A specific immunoassay for the detection of flunitrazepam.

The development of an immunochemical procedure for the determination of flunitrazepam in whole blood is described. Flunitrazepam was derivatized in position 3 of the benzodiazepine ring to a hapten which was coupled to a carrier protein. To obtain antibodies, rabbits were immunized with these immunogens and the collected antisera were tested in a heterogeneous, competitive RIA. The antibodies showed a very specific reaction with flunitrazepam and hardly any cross-reactivity with related 1,4-benzodiazepines. Because of its high specificity the antiserum has the advantage of a definite determination of low levels of flunitrazepam without the risk of false-negative results obtained by using the commercially available group-specific test systems. The drug was extracted from whole blood in a simple batch process with a polystyrene suspension and the extracts were measured by RIA. The advantages of an immunochemical system, such as short analysis time and simple sample preparation, and the exactness of a drug-specific method are combined in this procedure, which allowed the specific and very sensitive determination of flunitrazepam in the low therapeutic range.

Animals↗
PubMed1995

Precipitated withdrawal in squirrel monkeys after repeated daily oral administration of alprazolam, diazepam, flunitrazepam or oxazepam.

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam consistently to induce loss of righting reflex in squirrel monkeys or vehicle was orally administered to monkeys on 18 consecutive days: 2 mg/kg alprazolam (n = 4), 30 mg/kg diazepam (n = 4), 1 mg/kg flunitrazepam (n = 4), 280 mg/kg oxazepam (n = 5), or vehicle (n = 4). Tolerance developed rapidly for loss of righting reflex, more slowly for sleep and only minimally for muscle relaxation observed during the period immediately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg i.v.) 5 h after the ninth daily oral treatment produced signs of precipitated withdrawal (tremor, vomiting and/or convulsions) in one alprazolam-, four diazepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intravenously several days later under these same experimental conditions failed to provoke a precipitated withdrawal reaction. When flumazenil-induced precipitated withdrawal was again evaluated after the 18th daily oral treatment, withdrawal signs were observed in all alprazolam- and all diazepam-treated monkeys, as well as in three flunitrazepam- and three oxazepam-treated monkeys, but not in the vehicle-treated monkeys (convulsions were observed in one alprazolam-, two diazepam-, one flunitrazepam- and two oxazepam-treated monkeys). No signs of spontaneous withdrawal were observed in any of the monkeys during a subsequent 3-week drug-free period. Thus, repeated administration of approximately equieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occurrence of a precipitated withdrawal reaction).

Administration, Oral↗
PubMed1984

Oral flunitrazepam in the prevention of local anaesthetic-induced convulsions in mice.

The present study determined whether oral flunitrazepam was effective reducing CNS toxicity of lidocaine and bupivacaine. Pretreatment of mice with flunitrazepam, 0.065-0.25 mg X kg-1, significantly reduced or prevented convulsions and mortality induced by lidocaine 106 and 209 mg X kg-1 or bupivacaine 58 and 90 mg X kg-1 injected intraperitoneally. The doses of flunitrazepam used did not cause measurable sedation in mice. The efficacy of oral flunitrazepam in preventing local anaesthetic-induced convulsions is similar to that previously reported by intraperitoneal or intramuscular injections in mice. Flunitrazepam could be useful for oral premedication of patients before regional anaesthesia.

Administration, Oral↗
PubMed1999

Residual effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades.

RATIONALE: Studies report contradictory results concerning the residual effects of zolpidem and zopiclone. Moreover, residual effects of these compounds on healthy subjects have not yet been simultaneously assessed. OBJECTIVE: The present study with healthy subjects investigated the residual effects of zolpidem 10 mg and zopiclone 7.5 mg on driving performance and on ocular saccade and compared them to those under flunitrazepam 1 mg and placebo. METHODS: The study involved 16 subjects divided into two groups, a 9:00 a.m. group and a 11:00 a.m. group, in a balanced, double-blind, cross-over design. RESULTS: In the 9:00 a.m. group, zolpidem had no residual effects while zopiclone and flunitrazepam both impaired driving performance (P < 0.001 for both) and increased saccadic latency (P < 0.005; P = 0.052, respectively). Zopiclone impaired driving performance 5 times less than did flunitrazepam. In the 11:00 a.m. group, zolpidem and zopiclone had no residual effects, while flunitrazepam increased saccadic latency (P = 0.065) but did not impair driving performance. CONCLUSIONS: Zopiclone and flunitrazepam had residual effects in the first part of the morning, whereas zolpidem had no residual effects. The hierarchical character of the effects of the molecules differed according to the test administered. This is probably linked more to drug-induced specific alterations than to different sensitivities of the tests.

Adult↗
PubMed1983

Binding of [3H]flunitrazepam to the LM cell, a transformed murine fibroblast.

LM cells have a saturable, high affinity binding site for [3H]flunitrazepam with a KD of 13 nM and a Bmax of 19 pmoles/mg protein. The IC50 values for Ro 5-4864, flunitrazepam and clonazepam against [3H]flunitrazepam were 6, 23 and 2800 nM, respectively, indicating that this receptor is of the peripheral type. A decrease of 37, 26 and 26% in Bmax was associated with substituting dimethylethanolamine, monomethylethanolamine or ethanolamine, respectively, for choline in the cell culture medium. These treatments did not change either the KD of [3H]flunitrazepam binding or the IC50 values of the different benzodiazepine drugs. Metastatic cell lines of the LM cell obtained from either athymic or C3H/Hef mice exhibited alterations in the binding parameters of [3H]flunitrazepam. There was a reduction in the Bmax values of the athymic (34%) and the C3H/Hef (44%) cell lines compared to the LM cell. In both groups there was a 90% increase in the KD. In the C6 astrocytoma, the peripheral type receptor appears to regulate plasma membrane mediated synthesis of phosphatidylcholine from phosphatidylethanolamine. However, this was not observed in the LM cell. Nor did it modulate cyclic AMP metabolism as assessed by measurement of cyclic AMP levels in whole cells after drug treatment.

Animals↗
PubMed1991

Hypnotic action of flunitrazepam is reversed by proglumide in rats.

1. Caerulein, an analogue of cholecystokinin (CCK-8), like CCK-8, has been shown to produce hypnotic effects similar to those of benzodiazepine (flunitrazepam). 2. Proglumide antagonizes the action of CCK-8 and of its analogue. 3. The aim of the present study was to demonstrate whether proglumide would affect the potent hypnotic action of flunitrazepam in rats. 4. The association of proglumide with flunitrazepam suppress the increase of total sleep time and slow wave sleep seen after flunitrazepam alone. Proglumide alone has no effect on sleep stages. The authors report here for the first time that the hypnotic action of flunitrazepam is antagonized by proglumide in rat.

Animals↗
PubMed1988

Effects of in vivo estradiol and progesterone on tritiated flunitrazepam binding in rat spinal cord.

Tritiated flunitrazepam binding was measured in autoradiograms of lumbar spinal cord from control ovariectomized female rats and from ovariectomized females treated with either estradiol-silastic implants or one subcutaneous injection of 500 micrograms progesterone 4-5 h before being killed or both estradiol and progesterone. Four areas of spinal cord were analyzed: the substantia gelatinosa, the region leading to and around the central canal, the remainder of the dorsal horn and the ventral horn. Specific flunitrazepam binding was greatest in the substantia gelatinosa and in the region around the central canal and was weakest in the ventral horn. Estradiol had no effect on flunitrazepam binding in the spinal cord despite estradiol concentrating cells in the substantia gelatinosa and around the central canal. In vivo progesterone enhanced flunitrazepam binding in the substantia gelatinosa while 10(-8) M progesterone in vitro was without effect. One day after spinal transection flunitrazepam binding in endocrine controls and estradiol-treated animals was unchanged but a progesterone injection 4-5 h before being killed had no effect on binding in the substantia gelatinosa.

Animals↗
PubMed1995

Long-term and regional specific changes in [3H]flunitrazepam binding in kindled rat hippocampus.

The binding of the GABAA/benzodiazepine receptor agonist [3H]flunitrazepam was studied in the hippocampus of rats kindled by daily stimulation of the Schaffer collaterals, using semi-quantitative autoradiography. Two kindled stages were investigated: (i) 24 h after the last generalized tonic-clonic seizure (fully kindled) and (ii) 28 days after the last generalized seizure (long-term). The binding of [3H]flunitrazepam was determined at two concentrations, 3 and 16 nM. In the CA1 area, we found a small but significant decrease (ca. 10%), both in the 3 and 16 nM [3H]flunitrazepam binding at the fully kindled stage. In contrast, there was a significant increase in the 3 nM binding (c. 15%) at the long-term stage. The 16 nM binding was not significantly different from control binding at this stage. In the granular and molecular layers of the fascia dentata, we found at both kindled stages a significantly increased 3 nM (ca. 9 and 19%, respectively) and 16 nM (ca. 19 and 14%, respectively) binding. Furthermore, we found that muscimol was still able to enhance the [3H]flunitrazepam binding in kindled animals, indicating that the GABAA receptor agonist binding site and benzodiazepine agonist binding site are still functionally coupled. The changes in [3H]flunitrazepam binding at the fully kindled stage are in agreement with the recently observed kindling-induced changes in [3H]muscimol binding in the hippocampal formation of the same animals [Titulaer M. N. G. et al. (1994) Neuroscience 59, 817-826] and extend these observations to the benzodiazepine modulatory site of the GABAA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Allosteric modulation of [3H]flunitrazepam binding to recombinant GABAA receptors.

The allosteric modulation of [3H]flunitrazepam binding by gamma-aminobutyric acid (GABA), pentobarbital, (+)-etomidate, etazolate, alphaxalone, propofol and chlormethiazole was investigated in cerebellar membranes and membranes from human embryonic kidney (HEK) 193 cells transfected with alpha 1 beta 3 gamma 2 or alpha 1 gamma 2 subunits. Results obtained indicate that [3H]flunitrazepam binding to recombinant GABAA receptors consisting of alpha 1 beta 3 gamma 2 subunits could be modulated by these compounds in a way and with a potency similar to that observed in cerebellar membranes. In addition, it was demonstrated that not only receptors consisting of alpha 1 beta 3 gamma 3, but also those consisting of alpha 1 gamma 2 subunits exhibited [3H]flunitrazepam binding which could be stimulated by GABA. In contrast to alpha 1 beta 3 gamma 2 receptors, however, [3H]flunitrazepam binding to recombinant alpha 1 gamma 2 receptors was inhibited by pentobarbital, (+)-etomidate, etazolate, alphaxalone, propofol and chlormethiazole. This seems to indicate that binding sites for these compounds are present on alpha 1 gamma 2 receptors, but that their allosteric interaction with [3H]flunitrazepam binding sites is different from that of alpha 1 beta 3 gamma 2 receptors.

Allosteric Regulation↗
PubMed2007

Effects of gamma-hydroxybutyric acid and flunitrazepam on ethanol intake in male rats.

Both gamma-hydroxybutyric acid (GHB) and flunitrazepam are often used illicitly in combination with ethanol. Nevertheless, the effects that these and other drugs of abuse have on the reinforcing effects of ethanol remain inconclusive. To test the effects of GHB and flunitrazepam on contingent ethanol intake, twelve male Long-Evans rats were trained to orally consume ethanol using a saccharin-fading procedure. After training, all animals preferentially consumed ethanol instead of water at each of five ethanol concentrations (0-32%) when tested with a two-bottle preference test in the homecage. Animals then received a noncontingent dose of ethanol (0.32, 0.56, 1, and 1.33 g/kg), flunitrazepam (0.032, 0.1, and 0.32 mg/kg), or GHB (100, 180, 320, and 560 mg/kg) prior to each subject's daily access to ethanol (18% v/v). Noncontingent doses of ethanol decreased ethanol intake, however, the subjects consumed enough ethanol to maintain a consistent total ethanol dose in g/kg. Flunitrazepam did not affect ethanol intake at any dose tested, whereas GHB only affected intake at the highest dose (560 mg/kg), a dose that also produced sedation. These data suggest that there are perceptible or qualitative differences between GHB, flunitrazepam, and ethanol in terms of their capacity for modulating oral ethanol intake in outbred rats.

Alcohol Drinking↗
PubMed1998

Propofol modulation of [3H]flunitrazepam binding to GABAA receptors in guinea pig cerebral cortex.

Binding of the radioligand [3H]flunitrazepam to membranes prepared from the cerebral cortex of adult, male guinea pigs under equilibrium and non-equilibrium conditions was used to investigate the allosteric interaction between the intravenous general anesthetic propofol and the benzodiazepine site of the GABAA receptor. Propofol induced a potentiation of [3H]flunitrazepam binding with an EC50 of 9+/-4 microM. Propofol increased the affinity for [3H]flunitrazepam binding with no change in maximal binding. Propofol did not change the rate constant of association for [3H]flunitrazepam binding to cerebral cortical membranes. In contrast, the rate constant for dissociation of [3H]flunitrazepam was significantly decreased in the presence of propofol. These data demonstrate that propofol increases the affinity of the benzodiazepine site of the GABAA receptor via a selective decrease in the rate constant for dissociation, and suggest a mechanism for the allosteric interaction between propofol and benzodiazepines at the GABAA receptor.

Anesthetics, Intravenous↗
PubMed1987

[Effects of flunitrazepam on the baroreflex control of heart rate and on adrenergic activity].

The effects of intravenous flunitrazepam (25 micrograms . kg-1) on the baroreflex control of heart rate and plasma catecholamine levels were determined in ten ASA 1 unpremedicated patients. Plasma concentrations of flunitrazepam were also measured. The data was obtained before and 5, 10 and 15 min after flunitrazepam administration. The baroreflex gain was significantly decreased at 5 min, the time of the highest flunitrazepam plasma concentration. Catecholamine plasma levels were decreased at each study time. It was concluded that flunitrazepam induced a transient depression in baroreflex function and a sustained decrease in adrenergic activity.

Adult↗