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A comparison of the acute behavioral effects of flunitrazepam and triazolam in healthy volunteers.

Flunitrazepam is an hypnotic benzodiazepine marketed in different European countries. Epidemiological studies have shown that it is frequently abused by opioid addicts. In a survey, "liking" scores for flunitrazepam in methadone maintenance patients were higher than ratings for other benzodiazepines. A double-blind, placebo controlled, crossover clinical trial was conducted to assess the acute behavioral effects of flunitrazepam (0.50 and 2 mg) and triazolam (0.25 and 0.50 mg) in healthy male volunteers. Drug effects on physiological measures, psychomotor performance, and subjective rating scales, including specific questionnaires to evaluate abuse liability (e.g., ARCI or "liking" scores), were assessed before and 6 h after drug administration. Flunitrazepam 2 mg produced the most intense disruptive effects on all the performance tasks, triazolam 0.50 impaired performance except balance. All study drugs at all doses produced sedation symptoms in all or part of the subjective effects questionnaires. Only flunitrazepam 2 mg induced significative increases in some of the scales ("liking", "good effects", "high") that could be related to a possible abuse potential. The results seem to indicate that flunitrazepam, when administered to healthy subjects, produces some pleasurable subjective feelings, that could indicate a higher abuse liability of this drug as compared with other benzodiazepines.

Adult↗

Comparison of flunitrazepam and thiopentone for induction of general anaesthesia.

Forty female out-patients undergoing therapeutic abortion participated in a double-blind study comparing flunitrazepam 0.05 mg . kg-1 with thiopentone 6.0 mg . kg-1 as induction agents for general anaesthesia. Induction time, as measured by the time to loss of lid reflex and voluntary speech, was not only significantly longer in patients receiving flunitrazepam, but also much more variable and imprecise than with thiopentone. The Steward recovery room scores and psychomotor drawing test results revealed that recovery was significantly slower in the flunitrazepam group. Anterograde amnesia was observed in all patients who had received flunitrazepam and in one patient who had received thiopentone. No retrograde amnesia was found in either group. Flunitrazepam produced postoperative drowsiness, sedation, ataxia and nausea while with thiopentone discomfort from surgery and discomfort at the intravenous injection site were the main complaints. Because of the slowness of induction with flunitrazepam and marked individual variation, we do not feel that this drug can be considered a suitable agent for routine induction of general anaesthesia.

Abortion, Therapeutic↗

Action of pyrazolopyridines as modulators of [3H]flunitrazepam binding to the gaba/benzodiazepine receptor complex of the cerebellum.

The pyrazolopyridines etazolate (SQ 20009) and cartazolate (SQ 65396) have strong modulatory effects on the GABA/benzodiazepine receptor complex of rate cerebellum. Thus, etazolate and cartazolate directly stimulate [3H]flunitrazepam binding (with EC50 values of 1.2 microM and 0.3 microM respectively) by increasing the apparent affinity of [3H]flunitrazepam for its binding sites. Stimulation of [3H]flunitrazepam binding by pyrazolopyridines is dependent on the presence of certain anions like chloride, bromide, iodide, nitrite, nitrate but not fluoride, acetate, formate or sulfate. If is inhibited by bicuculline-methiodide, and by the "chloride channel drugs' picrotoxinin and IPTBO. isoTHAZ, a GABA analogue with GABA antagonist properties in vivo, fails to inhibit binding stimulated by etazolate but antagonizes [3H]flunitrazepam binding stimulated by GABA. The pyrazolopyridines have also indirect effects on benzodiazepine receptor binding since they enhance the apparent sensitivity of those GABA recognition sites which are coupled to benzodiazepine binding sites. Thus, in the presence of 10 microM etazolate, GABA and muscimol enhance [3H]flunitrazepam binding, with EC50 values of 109 nM and 12 nM respectively. This sensitization effect is partially dependent on the presence of chloride ions. The pyrazolopyridines facilitate also the stimulation of benzodiazepine receptor binding by beta-alanine and taurine and by the rigid and flattened GABA analogues THIP and piperidine-4-sulfonic acid. Taken together, these results suggest that the pyrazolopyridines modulate [3H]flunitrazepam binding by acting at a site closely related to GABA receptor-regulated chloride ion channels.

Animals↗

In vivo binding of (3H)Ro 15-1788 in mice: comparison with the in vivo binding of (3H)flunitrazepam.

Benzodiazepine binding sites have generally been labelled with benzodiazepine agonists: (3H)flunitrazepam and (3H)diazepam in vivo. We studied the in vivo binding of the antagonist (3H)Ro 15-1788 in mice and compared it to the in vivo binding of (3H)flunitrazepam. For this in vivo labelling, mice were injected with labelled and unlabelled ligands. Animals were then sacrificed and bound radioactivity was measured after homogenization of the excised brain and filtration of the homogenate. (3H)Ro 15-1788 is a better tool than (3H)flunitrazepam for in vivo labelling of benzodiazepine receptors since 1) it labels specifically the central type binding sites, 2) injection of 4 times less (3H)Ro 15-1788 (50 microCi/kg) than (3H)flunitrazepam (200 microCi/kg) produced the same amount of bound radioactivity, 3) 70-90% of the total (3H)Ro 15-1788 present in the brain is membrane bound instead of 45-55% with (3H)flunitrazepam, 4) maximal binding of (3H)Ro 15-1788 is reached within 3 min, 5) only 5% of the membrane bound (3H)Ro 15-1788 is nonspecific instead of 15% for (3H)flunitrazepam.

Animals↗

Self-injection of flunitrazepam alone and in the context of methadone maintenance in baboons.

Patients in methadone maintenance programs use benzodiazepines to "boost" methadone's subjective effects, and flunitrazepam has been prominent in this context. Self-administration of flunitrazepam (0.001-0.32 mg/kg i.v.) alone and during daily oral methadone administration was evaluated in three baboons. Flunitrazepam maintained self-injection as an inverted U-shaped function of dose at rates higher than those maintained by most other benzodiazepines under the same procedure. In the context of demonstrated physical dependence on 3.2 mg/kg/day p.o. methadone, flunitrazepam doses on the ascending limb of the dose-effect curve maintained greater rates of self-injection than before methadone in two baboons. When the methadone dose decreased to 1.8 mg/kg/day, self-injection remained higher for those baboons and became higher than before methadone for the third baboon. Self-injection remained higher when methadone decreased to 1.0 mg/kg/day, except self-injection of the lowest flunitrazepam dose returned to or below the pre-methadone rate for two baboons. After methadone was discontinued, the dose-effect curve shifted to the right in one baboon but remained to the left in two. Flunitrazepam thus served as a reinforcer alone and in the context of methadone maintenance. Lower doses maintained higher self-injection during and shortly after methadone maintenance. Further research should explore the duration of higher self-injection rates following methadone maintenance.

Animals↗

Simultaneous determination of flunitrazepam and its metabolites in plasma and urine by HPLC/DAD after solid phase extraction.

A high performance liquid chromatography (HPLC) assay was developed for the determination of flunitrazepam (FNZ) and its metabolites in urine and plasma. The analytes and the internal standard (triazolam, TRZ) were extracted by Sep-Pak C18 SPE-cartridge and separated utilizing a 5 microm ChromSpher C8 glass column with a gradient mobile phase containing methanol and 0.125% (v/v) of isopropylamine in water. Diode array detection (DAD) was carried out at a monitoring wavelength of 240 nm and a reference wavelength of 550 nm. Standard curves were linear from their quantitation limits until 200 ng ml(-1) urine or 250 ng ml(-1) plasma for 7-amino-desmethyl-flunitrazepam (ADF), 7-amino-flunitrazepam (AF), 7-acetamino-flunitrazepam (ACF) and until 400 ng ml(-1) urine or 500 ng ml(-1) plasma for FNZ, 1-desmethyl-flunitrazepam (DF), and 3-hydroxyl-flunitrazepam (HF). The intraday and interday coefficients of variation ranged from 2.04 to 9.07% and from 2.64 to 14.10%, respectively in urine and from 5.13 to 8.60% and from 7.27 to 10.46%, respectively in plasma. The developed method is used in forensic toxicology and is also applicable to pharmacokinetic studies in man.

Chromatography, High Pressure Liquid↗

[3H]Flunitrazepam binding to recombinant alpha1beta2gamma2S GABAA receptors stably expressed in HEK 293 cells.

The interaction of selected compounds with the binding of the benzodiazepine [3H]flunitrazepam to membranes isolated from human embryonic kidney (HEK) 293 cells, stably transfected with the aI( 2 2S subtype of GABAA receptors, was studied. This subtype of GABAA receptors is the most common type of GABAA receptor found in the brain, and benzodiazepines are drugs known to enhance the effects of the inhibitory neurotransmitter gamma-amino butyric acid (GABA) by binding to the benzodiazepine binding sites which are part of the GABAA receptor complex. Scatchard analysis of binding data revealed the existence of a single type of binding site for [3H]flunitrazepam. GABA and thiopental enhanced, while the antagonist of central benzodiazepine binding sites--flumazenil, benzodiazepines such as clonazepam, flunitrazepam and diazepam, and the triazolopyridazine CI 218,872--displaced with nanomolar potency the binding of [3H]flunitrazepam. A partial displacement was obtained with the antagonist of the peripheral benzodiazepine binding sites--PK 11195--and with the neurosteroid dehydroepiandrosterone sulfate. The potency of drugs to enhance or inhibit [3H]flunitrazepam binding mainly corresponded to that observed for the modulation of the binding of [3H]flunitrazepam to the native type 1 benzodiazepine binding sites. This, as well as a high density of expressed binding sites, makes the cell line under study a very reliable and economical model for the testing of effects of different compounds at the GABAA receptor.

Anti-Anxiety Agents↗

Comparison of diazepam and flunitrazepam for sedation during local anaesthesia for bronchoscopy.

Diazepam and flunitrazepam were compared as amnesic and sedative adjuncts to local anaesthesia for diagnostic bronchoscopy in 92 patients. After local anaesthesia of the pharynx, larynx and trachea with lignocaine, atropine plus diazepam of flunitrazepam was injected i.v. The co-operation of the patients and the technical circumstances under which the bronchoscopy was performed were good in each group. None of the treatments significantly modified arterial pressure or heart rate. Two hours after the injection, flunitrazepam 0.01 mg kg-1 more frequently caused amnesia for pictures shown to the patients during the first 15 min after injection (failure to recall 42--75%, and for bronchoscopy 67%), than did diazepam 0.125 mg kg-1 (failure to recall 21--67%; bronchoscopy 38%). Double doses of the drugs caused amnesic actions similar to those of flunitrazepam 0.01 mg kg-1. When failure to recall was assessed on the following day, 29% and 5% of the patients remembered bronchoscopy after flunitrazepam 0.01 and 0.02 mg kg-1 respectively; after diazepam 0.125 and 0.25 mg kg-1 the corresponding percentages was 59% and 30% (P less than 0.05% v. fluintrazepam). The ability to stand and walk on a stright line was similar after the smaller doses of both drugs, but after the larger doses recovery was slower after flunitrazepam. Psychomotor performance was still distinctly impaired 2 h after the injection of the larger doses.

Adult↗

Flunitrazepam versus placebo premedication for minor surgery.

The clinical effects of oral flunitrazepam (2 mg on the night before operation followed by 2 mg on the morning of operation) and placebo as premedicants were tested in a double-blind study in 81 gynaecological patients. The separate or total concentrations of flunitrazepam and its demethylated metabolite in plasma (measured by gas chromatography) were correlated with the clinical effects of flunitrapam premedication, assessed both sugjectively and objectively. In most parameters tested (sleep on the night before operation, sedation, apprehension, headache, pulse rate), there was a positive, significant difference between the flunitrazepam group (n = 44) and the placebo group (n = 37). No significant difference was found between the two groups in emetic effect, excitement, systolic blood pressure increase, and vene-puncture, but the patients receiving flunitrazepam felt significantly more dizziness. The temperature of the left forefinger before, during and after the anaesthesia did not vary significantly between the two groups. There was no correlation between the plasma concentration of flunitrazepam and its demethylated metabolite (separate or total concentrations) and any of the parameters tested before induction of anaesthesia. Flunitrazepam is a new oral premedicant with prominent sedative and anxiolytic actions. When the drug is given as a sedative on the night before operation, followed by a second dose on the morning of operation, the beneficial effects last for at least 8 hours after the second dose.

Adult↗

Autoradiographic localization of [3H]zolpidem binding sites in the rat CNS: comparison with the distribution of [3H]flunitrazepam binding sites.

The regional distribution of [3H]zolpidem, a novel imidazopyridine hypnotic possessing preferential affinity for the BZD1 (benzodiazepine subtype 1) receptor, has been studied autoradiographically in the rat CNS and compared with that of [3H]flunitrazepam. The binding of [3H]zolpidem to rat brain sections was saturable, specific, reversible, and of high affinity (KD = 6.4 nM). It occurred at a single population of sites whose pharmacological characteristics were similar to those of the benzodiazepine receptors labeled with [3H]flunitrazepam. However, ethyl-beta-carboline-3-carboxylate and CL 218,872 were more potent displacers of [3H]zolpidem than of [3H]flunitrazepam. The autoradiographic brain distribution of [3H]zolpidem binding sites was qualitatively similar to that previously reported for benzodiazepine receptors. The highest levels of [3H]-zolpidem binding sites occurred in the olfactory bulb (glomerular layer), inferior colliculus, ventral pallidum, nucleus of the diagonal band of Broca, cerebral cortex (layer IV), medial septum, islands of Calleja, subthalamic nucleus, and substantia nigra pars reticulata, whereas the lowest densities were found in parts of the thalamus, pons, and medulla. Comparative quantitative autoradiographic analysis of the binding of [3H]zolpidem and [3H]flunitrazepam [a mixed BZD1/BZD2 (benzodiazepine subtype 2) receptor agonist] in the CNS revealed that the relative density of both 3H-labeled ligands differed in several brain areas. Similar levels of binding for both ligands were found in brain regions enriched in BZD1 receptors, e.g., substantia nigra pars reticulata, inferior colliculus, cerebellum, and cerebral cortex lamina IV. The levels of [3H]zolpidem binding were five times lower than those of [3H]flunitrazepam binding in those brain regions enriched in BZD2 receptors, e.g., nucleus accumbens, dentate gyrus, and striatum. Moreover, [3H]zolpidem binding was undetectable in the spinal cord (which contains predominantly BZD2 receptors). Finally, like CL 218,872 and ethyl-beta-carboline-3-carboxylate, zolpidem was a more potent displacer of [3H]flunitrazepam binding in brain regions enriched in BZD1 receptors than in brain areas enriched in BZD2 receptors. The present data add further support to the view that zolpidem, although structurally unrelated to the benzodiazepines, binds to the benzodiazepine receptor and possesses selectivity for the BZD1 receptor subtype.

Animals↗

Characteristics of flunitrazepam binding to intact primary cultured spinal cord neurons and its modulation by GABAergic drugs.

The interaction of [3H]flunitrazepam and its modulation by various drugs was studied in intact primary cultured spinal cord neurons. In the intact cells, the [3H]-flunitrazepam binding was rapid and saturable. The benzodiazepine binding sites exhibited high affinity and saturability, with an apparent KD of 6.1 +/- 1.6 nM and Bmax of 822 +/- 194 fmol/mg protein. The association and dissociation of [3H]flunitrazepam binding exhibited monoexponential kinetics. Specifically bound [3H]flunitrazepam was displaced in a concentration-dependent manner by benzodiazepines like flunitrazepam, clonazepam, diazepam, Ro 15-1788, and beta-carbolines like methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3'-carboxylate. Specific [3H]flunitrazepam binding to intact cells was enhanced in a concentration-dependent manner by gamma-aminobutyric acid (GABA) agonists and drugs which facilitate GABAergic transmission like etazolate, (+)-etomidate, and pentobarbital. The enhancing effect of GABA agonists was antagonized by bicuculline and picrotoxinin. These results suggest that the intact cultured spinal cord neurons exhibit the properties of benzodiazepine GABA receptor-ionophore complex. Since these cells can also be studied in parallel for characterizing GABA-induced 36Cl-influx, they provide an ideal in vitro assay preparation to study GABA synaptic pharmacology.

Animals↗

Intravenous flunitrazepam in the treatment of alcohol withdrawal delirium.

Alcohol withdrawal delirium (AWD) requires treatment with an adequate sedative, anticonvulsant, and antipsychotic agent next to general intensive care measures. Optimal medication should have a rapid onset of action and the possibility of parenteral application. A specific antagonist should be available. Flunitrazepam is a benzodiazepine that fulfills all these criteria. Twenty five patients suffering from AWD (mean age 45 years) took part in an open trial and underwent treatment with infusions of flunitrazepam (concentration: 8 mg/250 ml NaCl; speed, 250 ml/hr). Psychopathological, vegetative, and vital parameters were assessed every hour. All patients survived. They were treated with a mean total dose (SD) of 83.9 (45.4) mg of flunitrazepam (1.3 mg/kg body weight), which induced sedation 13.2 (5.3) min after the initiation of intravenous treatment. The mean duration of AWD (85.1 +/- 39.4 hr) corresponded to other studies, whereas the frequency of preexisting and concomitant diseases was higher (92%) in our patients. A patient who suffered from bronchitis and had a nasopharyngeal tamponade showed severe respiratory depression after having received 4 mg of flunitrazepam. This complication remitted immediately when 0.5 mg of flumazenil was given intravenously. No epileptic manifestation was observed during the treatment or after discontinuation of flunitrazepam. Vegetative and psychopathological symptoms (tremor, sweating, hallucinations, confusion, and restlessness) remitted rapidly. Our data suggest that intravenous flunitrazepam can be an efficacious and safe alternative to traditional treatment strategies of AWD.

Adult↗

The passage of flunitrazepam into cerebrospinal fluid in man.

The passage of flunitrazepam into cerebrospinal fluid (CSF) was studied in 23 surgical patients (group 1), after a single 0.02 mg/kg intravenous injection, in 9 otherwise healthy patients undergoing neurological examination (group 2), after a single 2 mg oral dose, and in 9 chronically-ill neurological patients (group 3), after 2 to 4 successive 2 mg oral doses. Flunitrazepam in plasma and the CSF was determined by gas chromatography and its plasma protein binding by equilibrium dialysis. Uptake of flunitrazepam into human CSF was found to very fast: even 5 min. after intravenous injection the drug level in the CSF was 2.8% of the corresponding plasma concentration. CSF levels increased up to 77 min. after intravenous injection. In group 2 the mean percentage level in the CSF was 23.5 +/- 13.0 (S.D.) and in group 3 it was 16.7 +/- 3.1. In group 1, 22.9+/- 8.0% of flunitrazepam was not bound to plasma protein, in group 2, 12.1 +/- 8.3% and, in group 3, 30.3 +/- 14.1%. Groups 1 and 2 (P less than 0.01) and 2 and 3 (P less than 0.01) differ significantly from each other. In groups 2 and 3 there was no significant correlation between the percentage not bound to protein and CSF levels of flunitrazepam. The uptake of flunitrazepam by CSF provides an explanation for its rapid drug effects. Its binding to plasma protein is affected by disease and, possible, by other drugs.

Adult↗

Lack of interaction of buprenorphine with flunitrazepam metabolism.

OBJECTIVE: The authors' goal was to determine if the reported clinical adverse interaction of flunitrazepam and buprenorphine was caused by inhibition of drug metabolism. METHOD: Inhibition of flunitrazepam metabolism by buprenorphine and norbuprenorphine were determined in three human liver microsome preparations carrying the CYP2C19*1/*1 allele. Omeprazole metabolism mediated by CYP2C19 and CYP3A4 was used as a control reaction. Apparent K(i) values were determined. RESULTS: Norbuprenorphine did not inhibit the metabolism of flunitrazepam or omeprazole. Buprenorphine inhibited the formation of CYP3A4-mediated pathways of 3-hydroxyflunitrazepam and omeprazole sulfone formation (K(i) 118 and 16 microM) in human liver microsomes. Corresponding values were 38 and 90 microM in cDNA-expressed CYP3A4 microsomes. Projected in vivo inhibition of CYP3A4-mediated metabolism of flunitrazepam by buprenorphine is 0. 1%-2.5%. Estimated inhibition of buprenorphine N-dealkylation by flunitrazepam in vivo is 0.08%. CONCLUSIONS: The clinical interaction of flunitrazepam and buprenorphine is likely based on a pharmacodynamic mechanism.

Buprenorphine↗

Prevalence, patterns, and correlates of voluntary flunitrazepam Use.

OBJECTIVE: To determine prevalence, patterns, and correlates of voluntary flunitrazepam use in a sample of sexually active adolescent and young adult women 14 to 26 years of age. DESIGN: Cross-sectional survey. SETTING: University-based ambulatory reproductive health clinics. PATIENTS OR OTHER PARTICIPANTS: There were 904 women self-identified as white, African-American, or Mexican-American. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Lifetime, frequency, patterns, and physical effects of flunitrazepam use. RESULTS: Lifetime use was reported by 5.9% (n = 53) of subjects, with frequency of use ranging from 1 to 40 times. Flunitrazepam was taken most often with alcohol (74%), and 49% took this substance with other illicit drugs. Logistic regression analyses controlling for age and race/ethnicity found that users were significantly more likely than were nonusers to report lifetime use of marijuana (odds ratio [OR] = 3.6) or LSD (OR = 5.2), having a peer or partner who used flunitrazepam (OR = 21.7), pressure to use flunitrazepam when out with friends (OR = 2.7), and a mother who had at least a high school education (OR = 2.6). Finally, 10% of voluntary users reported experiencing subsequent physical or sexual victimization. CONCLUSIONS: Voluntary use of flunitrazepam is becoming a health concern to sexually active young women who reside in the southwestern United States. Young women who have used LSD or marijuana in the past or who have a peer or partner who used this drug appear to be at the greatest risk.

Adolescent↗

Low-dose flunitrazepam for conscious sedation for EGD: a randomized double-blind placebo-controlled study.

BACKGROUND: EGD with conscious sedation is a safe procedure, but complications such as hypoxia can occur. The efficacy and safety of low-dose flunitrazepam (0.25 mg) was compared with a standard dose of flunitrazepam (0.5 mg) for moderate sedation during EGD. METHODS: In a randomized, double-blind, placebo-controlled trial, 75 outpatients (40 men, 35 women, mean age 45 [11] years) undergoing screening EGD were randomly assigned to one of 3 treatment arms: 0.25 mg of flunitrazepam (F0.25 group), 0.5 mg of flunitrazepam (F0.5 group), or placebo (normal saline solution), each administered intravenously. Patient tolerance was scored by using self-assessment questionnaires with visual analogue scales. Cardiopulmonary complications were assessed by monitoring blood pressure, heart rate, oxygen saturation, and the electrocardiogram during the procedure. RESULTS: The patient tolerance scores in the F0.25 and F0.5 groups, respectively 2.1 (2.1) and 2.3 (2.5), were significantly lower than that for the placebo group (6.5 [3.0]); there was no significant difference between F0.25 and F0.5. Cardiopulmonary complications in the F0.25 group were significantly lower than in the F0.5 group. Oxygen desaturation (oxygen saturation < 90%) was noted in two of 25 patients in the F0.5 group. Post-procedure drowsiness was observed in two of 24 (8.3%) patients in the F0.25 group and 3 of 21 (14.3%) in the F0.5 group (p = 0.2438). CONCLUSIONS: Patient tolerance of EGD with low-dose flunitrazepam (0.25 mg intravenously) was similar to that with a standard dose (0.5 mg intravenously) and significantly better than in the placebo group. Oxygen desaturation was observed only in the group that received the standard dose, suggesting that sedation with low-dose flunitrazepam is efficacious and safe for EGD.

Anti-Anxiety Agents↗

Effect of heparin administration on flunitrazepam protein binding.

Non-esterified fatty acids have been shown to displace diazepam from its plasma binding sites both in vitro and in vivo. However, the binding of other benzodiazepines such as lorazepam is not affected in similar situations. Flunitrazepam exhibits a substantial degree of binding to plasma proteins, therefore it was deemed interesting to investigate the role of free fatty acids on flunitrazepam binding to human plasma proteins. Incubation of plasma with sodium oleate (1.5 and 3.0 microEq per ml) produced a decrease in the binding of flunitrazepam. The free fraction increased from 4.20 +/- 0.34 to 6.30 +/- 0.53 and to 22.18 +/- 1.28% respectively). Sodium heparin administration (10IU/kg, intravenously) increased free fatty acids levels and produced similar changes in the binding of flunitrazepam. After ten minutes of heparin administration free fatty acids increased from 0.16 +/- 0.03 mEq/l to 0.34 +/- 0.01 mEq/l and the free fraction of flunitrazepam in plasma increased from 3.70 +/- 0.22% to 6.20 +/- 1.24%. These binding data further support a relationship between increases in the concentrations of free fatty acids and decreases in the fraction of flunitrazepam bound to plasma proteins.

Adult↗

Distribution of central omega 1 (benzodiazepine1) and omega 2 (benzodiazepine2) receptor subtypes in the monkey and human brain. An autoradiographic study with [3H]flunitrazepam and the omega 1 selective ligand [3H]zolpidem.

The distribution of the central omega 1 (benzodiazepine1; BZD1) and omega 2 (BZD2) receptor subtypes has been studied autoradiographically in monkey and human brain sections using [3H]flunitrazepam (which binds indiscriminately to omega 1 and omega 2 subtypes) and [3H]zolpidem (which recognizes selectively the omega 1 subtype). Both ligands labeled an homogeneous population of binding sites (Kd values approximately equal to 1.5 nM and approximately equal to 5 nM, respectively) whose pharmacological characteristics were similar to those of central omega (BZD) receptors. Regional displacement studies in monkey brain showed that zolpidem was a more effective displacer of [3H]flunitrazepam from omega 1-than from omega 2-enriched areas. For example, it was 73-fold more potent in the cerebellum (omega 1-enriched) than in the dentate gyrus (omega 2-enriched). Zolpidem thus selectively recognizes omega 1 sites in primate brain. The autoradiographic distribution of [3H]flunitrazepam (omega 1 + omega 2) binding sites in primate brain was highly heterogeneous. Very high densities were observed in lamina IV of the neocortex (with higher densities in the occipital than in the frontal pole), the substantia innominata and molecular layer of the dentate gyrus. Intermediate densities were found in other neocortical laminae, cerebellum (molecular layer), claustrum, globus pallidus, caudate-putamen, nucleus accumbens, dentate gyrus (granular layer) and the majority of thalamic nuclei. Structures displaying low binding densities included the substantia nigra and the subthalamic nucleus. The regional distribution pattern of [3H]zolpidem binding sites was qualitatively similar to that of [3H]flunitrazepam but the relative density of the 3H-ligands differed in several brain regions. The relative density of omega 1 and omega 2 subtypes in each particular primate brain region was evaluated by measuring 1) the ratio of [3H]zolpidem to [3H]flunitrazepam binding; 2) [3H]flunitrazepam binding in the presence and in the absence of 100 nM zolpidem. With both approaches, a preferential enrichment in omega 1 sites was observed in lamina IV of sensorimotor cortical regions and in the extrapyramidal motor system (globus pallidus, ventral thalamic complex, subthalamic nucleus, substantia nigra and cerebellum). In contrast, omega 2 sites predominated in limbic areas (e.g., the dentate gyrus, amygdala, nucleus accumbens, cingulate and parahippocampal gyri) and in the anterior thalamic nucleus and caudate nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗