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PubMed1996

Flunitrazepam effects on human sleep EEG spectra: Differences in NREM, REM and individual responses.

Flunitrazepam (FNZ) (4mg), an intermediate type benzodiazepine (BDZ) hypnotic, was administered orally to five healthy male subjects (Ss) for seven consecutive nights. Sleep EEG from the baseline night (BLN), the initial drug night (IDN), the fourth and the seventh drug nights (4DN, 7DN) was subjected to fast Fourier transform (FFT) analysis. During NREM sleep of 4DN and 7DN the sigma band (11.0-12.5 Hz) activity was similarly enhanced in every S. In REM of 4DN and 7DN beta band (23.0-29.0 Hz) was enhanced, but with larger variations among Ss. High intra-individual consistency of the relative EEG power patterns on 4DN and 7DN was observed. These results suggest that 1) EEG responses to FNZ are different in sleep states; explorations of these differences may provide better understandings of sleep mechanisms, and 2) individual variations in EEG responses may reflect individual variations of the BDZ receptor system. These methods may be useful for exploring receptor changes in neuropsychiatric disorders.

Adult↗
PubMed1996

Flunitrazepam effects on human sleep EEG spectra. II: Sigma and beta alterations during NREM sleep.

Flunitrazepam (FNZ) is known to enhance the higher EEG frequencies, including sigma (10-15 Hz) and beta (20-28 Hz). Both sigma and beta frequency bands show an inverse relationship with delta (0.3-3 Hz) during NREM periods, as we have previously reported. It is not known whether generation of these two EEG frequencies is mediated by the same or different neuronal mechanisms. In this report, we compare alterations of delta, sigma and beta EEG induced by FNZ (4 mg) orally administered to five healthy male subjects for seven consecutive nights. Sleep EEG on the baseline night (BLN), and the fourth and seventh drug nights (4DN, 7DN) was subjected to fast Fourier transform (FFT) analysis. On drug nights, sigma was enhanced without regard to delta amount, but beta was enhanced only during epochs containing low delta. Thus, sigma and beta EEG were altered differently by the same pharmacological agent. These results suggest that sigma and beta EEG are mediated by different neuronal mechanisms.

Adult↗
PubMed1985

Pharmacokinetics of flunitrazepam in rats studied by a radioreceptor assay.

In rat the kinetics of flunitrazepam (FNZ) was evaluated by a radioreceptor assay (RRA) after i.v. administration of 1 mg/kg and after oral administration of 1 and 3 mg/kg. The i.v. kinetics is biexponential and the g.i. absorption is very rapid (with a plasma peak at 0.25 hour) with a good bioavailability (69%); the apparent distribution volume is high, 4.8 L/kg; the half-life is equal to 3.5 hours; the elimination constant is equal to 0.8 h-1; the urinary excretion of FNZ-equivalent is negligible; the plasma total clearance is equal to 3.9 (L/kg)h-1. The concentrations of FNZ-equivalents after oral administration of 1 mg/kg show a peak at the 2-nd hour with a very high concentration in the following organs (in decreasing order): brain, kidneys, heart, liver; after 8 hours no FNZ-equivalents are present in these organs except in the brain, which shows detectable concentrations at the 32-nd hour. The peak concentrations of FNZ-equivalent in brain, kidneys and heart are higher than the corresponding peak concentration in plasma.

Animals↗
PubMed1985

[3H]-Flunitrazepam binding in the presence of beta-phenylethylamine and its metabolites.

It has recently been reported that the concentration of beta-phenylethylamine (PEA) was elevated in the plasma of an individual experiencing convulsions because of an overdose of tranylcypromine. Also, high concentrations of PEA, injected into mice, were reported to induce convulsions. This convulsive effect was prevented by pretreatment with the benzodiazepines diazepam and chlordiazepoxide. In this study, PEA in concentrations from 0.5 to 100 microM failed to alter the binding of [3H]-flunitrazepam ([3H]-FLU) in membrane preparations from mouse rostral forebrain. The metabolites of PEA: phenylacetic acid, phenylethanolamine, octopamine and tyramine, also failed to affect [3H]-FLU binding. This suggests that although there are substances that act as convulsants by interacting with the benzodiazepine receptor sites, the convulsant effect of PEA and its metabolites is mediated elsewhere.

Animals↗
PubMed1993

Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents.

Progesterone is metabolized by ring-A reduction with subsequent oxidoreduction to 3 alpha-hydroxy-5 alpha-dihydroprogesterone (3 alpha-OH-5 alpha-DHP), a naturally occurring metabolite that has been shown to enhance [3H]flunitrazepam ([3H]FNZ) binding. Medroxyprogesterone acetate (MPA), a commonly prescribed progestational agent, is a synthetic progesterone derivative that has a metabolic profile similar to that of progesterone. In this study, the effects of MPA and its ring-A reduced metabolites DHMPA and THMPA on [3H]FNZ binding were investigated. While known modulators of specific [3H]FNZ binding demonstrated expected effects in frozen and fresh rat cortical tissue, 3 alpha-OH-5 alpha-DHP enhanced [3H]FNZ binding only in fresh, not frozen, tissue. Neither DHMPA nor THMPA affected binding, while MPA partially inhibited [3H]FNZ binding by 40%. In addition, five test drugs were used to assess the effect of gender and hormonal status on [3H]FNZ binding. Neither gender nor hormonal status influenced binding. Thus, ring-A reduced metabolites of progesterone but not of MPA enhance [3H]FNZ binding. The clinical implications of these in vitro results are currently under investigation.

Animals↗
PubMed1991

Determination of the membrane-buffer partition coefficient of flunitrazepam, a lipophilic drug.

The partition coefficient (P) of a benzodiazepine, flunitrazepam (FNTZ), was determined in a synaptosomal membrane/buffer system. A two component model was used, one of the components reflecting the drug partitioning into the membrane, and the other the amount of drug in the aqueous phase retained by the pellet after the centrifugation. The quantity of [3H]FTNZ measured as nonspecifically bound to the membrane includes both components so, the second one had to be discounted and in order to determined its magnitude a parallel experiment was performed using a non-partitioning hydrophilic drug (gamma-[3H]aminobutyric acid, [3H]GABA). The assay required previous determination of the fraction of the total volume of the incubation system that corresponded to membrane (fm). The fm value was calculated from the density value (delta) determined by a picnometer method. The results obtained were: delta = 1.66 +/- 0.02; fm = (1.6 +/- 0.2) 10(-3); P = 18.5 +/- 0.8. This P value could explain nonspecific effects of BZDs on some functions of the neuronal membrane.

Animals↗
PubMed1987

Benzodiazepine ([3H]flunitrazepam) binding in cat visual cortex: ontogenesis of normal characteristics and the effects of dark rearing.

[3H]Flunitrazepam (FNZ) binding sites were characterized in homogenates of cat visual cortex during normal postnatal development and following dark rearing from birth. In parallel experiments, the distribution and density of [3H]FNZ binding sites were examined by in vitro autoradiographic or 'scrape' methods. In homogenates, Bmax measurements showed low early values, rising to a peak in receptor density at about 60 days postnatal, followed by a decline in adulthood. At all ages, gamma-aminobutyric acid (GABA) altered the Kd, but not the Bmax of [3H]FNZ binding sites. Kd values showed a general increase with age, parallelled by an increased sensitivity to GABA. Receptor autoradiography revealed that the highest density of [3H]FNZ binding sites was in layer IV of cats of all ages. Deafferentation of extrinsic inputs to the visual cortex by surgical undercutting did not alter this pattern of laminar distribution, indicating that the receptors were associated with intrinsic cortical elements rather than subcortical inputs. Dark rearing had no effect on [3H]FNZ laminar distribution in the visual cortex. The Bmax was higher at 30 days postnatal, but did not differ significantly thereafter. Modulation by GABA was concomitantly higher at 30 days, but lower than normal in dark-reared animals at ages greater than 30 days postnatal. The results are discussed in relation to the normal and abnormal development of GABA receptors in the cat visual cortex.

Animals↗
PubMed1993

Effects of zopiclone, flunitrazepam, triazolam and levomepromazine on the transient change in sleep-wake schedule: polygraphic study, and the evaluation of sleep and daytime condition.

1. The effects of zopiclone 10mg (ZP), flunitrazepam 1mg (FN), triazolam 0.25mg (TZ) and levomepromazine 5mg (LP) on two models of sleep-wake schedule change-6 hours advanced shift: (A-shift), and 6 hours delayed: (D-shift)--were investigated in 6 healthy volunteers using polysomnography. 2. In A-shift with placebo, TST, SEI, %SR and REM/NREM decreased. ZP, FN and TZ shortened SL. All drugs increased TST and SEI. TZ and LP increased %SR and REM/NREM. 3. In D-shift with placebo, TST decreased, SWSL was prolonged, %S3+4 decreased, and %SR and REM/NREM increased. All drugs increased TST. ZP and LP shortened SWSL. All drugs increased %SWS. ZP, FN and TZ decreased %SR. ZP and FN decreased REM/NREM. 4. Daytime mental and physical conditions were worse than usual on more than half of the days in A- and D-shift. LP and FN caused some inadequate conditions on the following days. Significantly higher REM/NREM was observed in the nights before the days with worse mental conditions in D-shift, and lower REM/NREM in the nights before the days with worse physical conditions in A-shift. 5. It is concluded that TZ and ZP are superior to the others for A-shift and D-shift, respectively.

Adult↗
PubMed1980

The effect of temperature and chloride ions on the stimulation of [3H]flunitrazepam binding by the muscimol analogues THIP and piperidine-4-sulfonic acid.

THIP and piperidine-4-sulfonic acid (PSA) interact with [3H]GABA binding sites and have GABAmimetic efficacy in vivo, but fail to enhance benzodiazepine receptor binding performed at 0 degree C. However, when [3H]flunitrazepam binding is determined at elevated temperature (30 or 37 degrees C), THIP and PSA display potent chloride ion-dependent stimulatory effects. These results resolve apparent discrepancies between the properties of GABA receptors observed in vivo and in vitro, and they suggest that the modulation of benzodiazepine receptor binding investigated at physiological temperatures can be used as an experimental system for the characterization of GABA receptors.

Animals↗
PubMed1984

Enhancement of [3H]flunitrazepam binding by mianserin, in vivo.

Mianserin (5-20 mg/kg), like chlordiazepoxide (2.5-10 mg/kg), inhibits the shock-induced suppression of drinking (SSD) in rats. However, in contrast to chlordiazepoxide, the effect of mianserin is not blocked by the benzodiazepine antagonist, Ro 15-1788 (10 mg/kg). Although mianserin does not inhibit [3H]diazepam binding in vitro it has now been found to enhance [3H]flunitrazepam binding to mouse whole brain in vivo at 10-100 mg/kg p.o. These results suggest that mianserin does influence central benzodiazepine receptors, but the mechanism by which it does so differs from that of chlordiazepoxide.

Animals↗
PubMed1989

Superoxide dismutase treatment reduces [3H]flunitrazepam affinity in cortex and hippocampus of the rat.

Superoxide dismutases (SOD) are essential enzymes involved in the cellular defense against oxidative processes occurring with the generation of the superoxide anion. In this work, we have investigated in the rat the effects of a subchronic administration of liposomal SOD from bovine erythrocytes, on benzodiazepine (BZD) 'central-type' receptor sites in cortex and hippocampus. Animals were treated for 15 days with an i.p. injection of liposomal SOD, and binding parameters were determined using [3H]flunitrazepam. BZD receptor affinity was found decreased, while no change was observed in the maximal binding capacity. With regard to previously reported data, our results show that the superoxide anion radical is involved in the modulation and/or the stability of 'central-type' BZD receptor sites.

Animals↗
PubMed1993

Melatonin counteracts pinealectomy-dependent decreases in rat brain [3H]flunitrazepam binding through an opioid mechanism.

The effect of intracerebroventricular (i.c.v.) injection of melatonin and/or beta-endorphin on the [3H]flunitrazepam binding sites in the cerebral cortex of pinealectomized or superior cervical ganglionectomized rats was studied. Pinealectomy decreased the maximum concentration of benzodiazepine receptors (Bmax) without affecting the dissociation constant (KD), while melatonin, ineffective in control animals, counteracted the effect of pinealectomy. Intracerebroventricular injection of beta-endorphin increases Bmax in both control and pinealectomized animals, the effect being significantly higher in the latter. Simultaneous i.c.v. injection of melatonin + beta-endorphin did not further increase Bmax in any group, whereas i.c.v. injection of naloxone significantly blocked the effects of melatonin and/or beta-endorphin administration. Pineal sympathetic denervation produced a significant increase in Bmax and KD, whereas i.c.v. injection of melatonin further increased the former, restoring KD to control values. Neither i.c.v. administration of beta-endorphin or melatonin + beta-endorphin significantly modified the ganglionectomy-dependent increase in Bmax, although both treatments restored KD to control values. Naloxone administration had no effect on beta-endorphin- and melatonin + beta-endorphin-treated ganglionectomized groups, but counteracted the increased effect of melatonin on Bmax in ganglionectomized animals.

Animals↗
PubMed1984

Benzodiazepine ([3H])-flunitrazepam) binding sites in cerebellar and cerebral cortical slices of mouse brain.

We have characterized and quantified the specific binding of [3H]-flunitrazepam ( FNZ ) to thick (230 micron) slices of mouse brain. The binding site has the characteristics of a benzodiazepine receptor, i.e., binding of FNZ is reversible, stereospecific, saturable and of high affinity. Clonazepam, but not R05 -4864, readily displaces the label. In contrast to results from homogenate assays, neither GABA nor bicuculline has any effect on [3H]- FNZ binding. However, as previously reported, the slice assay confirms the lower number of benzodiazepine receptors in "emotional" mouse brain. In addition, we have confirmed that the neurotoxin DSP4 can modify [3H]- FNZ binding though in our hands this compound elevates rather than reduces binding. The speed, simplicity and minimal tissue preparation involved suggests that this slice assay could be a valuable addition to neurochemical studies of neurotransmitter receptors.

Animals↗
PubMed1991

[3H]-flunitrazepam binding after morphine treatment and under abstinence syndrome.

Chronic morphine treatment produced increases in [3H]-flunitrazepam binding in some hippocampal areas of the rat brain. The differences in binding were statistically significant in some cases. Both morphine-dependent and morphine-deprived (abstinence syndrome) animals showed an identical response in binding, which confirms a real, although small, increase in benzodiazepine binding sites in the hippocampus after morphine treatment, that is not affected by a naloxone-induced abstinence syndrome under the conditions studied. These findings support the hypothesis of a morphine-induced up-regulation of benzodiazepine binding sites in the hippocampus. A possible different response in benzodiazepine binding sites 1 and 2 could explain the different findings reported in the literature. Our data suggest that the detected increase in benzodiazepine binding would be mainly due to type 2 binding sites, since the hippocampus has a higher density of this type of benzodiazepine binding sites.

Animals↗
PubMed1995

Flunitrazepam and nordiazepam slowly released from silastic capsules induce physical dependence in rat.

The rates of in vitro release of flunitrazepam (FN), nordiazepam (ND) and diazepam (DZ) from silastic capsules were compared and found to be in the following order: DZ > FN > ND. Rats that were implanted subcutaneously with capsules filled with FN or ND for 5 to 7 weeks before administering flumazenil (FLU) (40 mg/kg, i.v.) showed precipitated abstinence as measured by the Precipitated Abstinence Score (PAS) which included a rapid onset of clonic and tonic-clonic convulsions. Rats implanted with DZ also demonstrated significant PAS and seizures. Implantation of similar doses of DZ, FN and ND resulted in different plasma levels of parent benzodiazepines and their metabolites that corresponded with their in vitro release: DZ > FN > ND. These data indicate that, as for DZ, the capsule implantation is an effective method of producing physical dependence on FN and ND in the rat.

Animals↗
PubMedDate not supplied

High doses of penicillin decreases [3H]flunitrazepam binding sites in rat neuron primary culture.

Penicillin (PC) neurotoxicity (convulsions and encephalopathy) is considered to be due to GABAergic inhibition. The effects of penicillin G(PCG) on [3H]flunitrazepam (FNZ) binding in rat neuron-enriched primary cultures was examined to assess the role of the benzodiazepine (BDZ) receptor in the neurotoxicity. PCG application for 24 h induced a significant decrease in [3H]FNZ binding activity at 10(-3) M, and a decrease in available receptor number (Bmax) at 10(-2) M, without obvious cell damage. Pre-application of the BDZ receptor antagonist, Ro-15-1788, prevented the PC-induced decrease in [3H]FNZ binding activity. Therefore, PC seems to reduce the number of BDZ receptors through a direct effect on this receptor, which is a part of the major inhibitory system in mammalian brain; the GABAergic macromolecular receptor complex. This decrease in BDZ receptors may play a role in PC-induced neurotoxicity, especially encephalopathy.

Animals↗
PubMedDate not supplied

Flunitrazepam for sleep disturbance in children with intractable epilepsy.

Add-on therapy with flunitrazepam (FNZ) was performed in 5 children with marked sleep disturbance and intractable seizures. Correction of the sleep disturbance was attained immediately after the start of FNZ administration in all patients. Furthermore, a significant decrease in the seizure frequency (3 patients) and improved quality of life (4 patients) were concomitantly observed. There was no adverse effect or interaction with conventional AEDs on long-term use.

Child↗