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PubMedDate not supplied

Binding characteristics of 3H-flunitrazepam and CL-218,872 in cerebellum and cortex of C57B1 mice made tolerant to and dependent on phenobarbital or ethanol.

The influence of chronic phenobarbital (PB) or chronic ethanol administration on binding characteristics of 3H-flunitrazepam (3H-FLU) in cerebellum and cortex of C57Bl mice was examined. Chronic PB treatment for six days decreased the number of binding sites (Bmax) for 3H-FLU, whereas no change in the affinity (KD) was found. Further kinetic analysis revealed that the overall decrease in Bmax was due to a reduced number of high affinity (Type 1) benzodiazepine (BDZ) binding sites in the cerebellum, but to a decreased number of low affinity (Type 2) BDZ binding sites in the cortex. Furthermore, a marked reduction in the pentobarbital-produced enhancement of 3H-FLU binding was observed in the cerebellum of the PB-treated animals. Following chronic ethanol administration for seven days, no change in the Bmax or in the KD could be demonstrated. However, in chronically ethanol-treated mice, the pentobarbital-induced stimulation of 3H-FLU binding was reduced in the cerebellum of mice 24 hours after discontinuation of the ethanol treatment. The significance of the present findings for the development of tolerance to and dependence on barbiturates and ethanol is discussed.

Alcoholism↗
PubMed1996

Estimation of the binding affinity constants of soluble ligand-receptor complexes by a rapid filtration technique: [3H]-flunitrazepam-bovine serum albumin as an example.

A method for determining the equilibrium dissociation constant (KA) of a soluble ligand (L) from a soluble receptor (A) in the presence of another solid phase receptor (R) for the same ligand was developed. The total and nonspecific binding of L to R was measured in the presence and in the absence of A. The separation of bound and free L was done by a rapid filtration technique so that only the complex RL, but not AL, was recovered. An apparent dissociation constant (KR,app) was calculated from the saturation curve obtained in the presence of A. The magnitude of KA could be determined from this KR,app and the value of the equilibrium dissociation constant of the complex R-L (KR) calculated from the saturation curve in the absence of A. The equality of the Bmax values obtained in the presence and in the absence of A assured the accuracy in the determination of KA so that the fulfillment of this condition could be used as an internal control. For the correct definition of nonspecific binding, the displacement agent (L1) should be used at concentrations within the range 10(2).KR < L1 < 10. K4. This fact constraints the applicability of the method to systems where KA/KR > 10(3). The highest sensitivity of the method can be attained when 0.33 < [At]/KA < 3. The equilibrium binding constant of [3H]-flunitrazepam to non-delipidized bovine serum albumin determined by the present approach (31 +/- 7 mumol/L) did not differ significantly from the literature.

Binding Sites↗
PubMed2005

Characterization of benzodiazepine binding site on human alpha1-acid glycoprotein using flunitrazepam as a photolabeling agent.

The binding of flunitrazepam (FNZP) by human alpha1-acid glycoprotein (hAGP) and the relationships between the extent of drug binding and desialylation and the genetic variants of hAGP were examined. The photolabeling specificity of [3H]FNZP was confirmed by findings in which other hAGP-binding ligands inhibited the formation of covalent bonds between [3H]FNZP and hAGP. The photolabeling of asialo-hAGP suggested that sialic acid does not involve in the binding of [3H]FNZP. No difference in the labeling could be found between the F1*S variants and A variant. Similarly, FNZP did not show a difference in binding affinity to the two genetic variants of hAGP. Sequence analysis of the photolabeled peptide indicated a sequence corresponding to Tyr91-Arg105 of hAGP.

Amino Acid Sequence↗
PubMed2006

Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths.

BACKGROUND: The magnitude and the characteristics of the use of methamphetamine, MDMA (Ecstasy), LSD (d-lysergic acid diethylamide), ketamine, GHB (gamma-hydroxybutyrate), and flunitrazepam (Rohypnol) were examined in a probability sample of the U.S. civilian population that included multiethnic urban, suburban, and rural youths aged 16-23 (N=19,084). METHODS: Data were drawn from the National Survey on Drug Use and Health (NSDUH). Logistic regression analyses were conducted to identify the characteristics associated with the use of each of these drugs and of multiple drugs. RESULTS: Approximately 20% of youths aged 16-23 reported having ever used one or more of these drugs. Less than 1% of club drug users used club drugs only, and 82% of them had ever used three or more drug classes. Females were more likely than males to report using multiple club drugs. Recent users of methamphetamine were most likely to be females and adolescents aged 16 or 17. Recent users of MDMA tended to be young adults aged 18-21 and residents of metropolitan areas. Most recent users of LSD were adolescents aged 16-19 and those in low-income families. Ketamine users were primarily employed youths. Staying in school and getting married were associated with decreased odds of club drug use. Club drug use was highly associated with the presence of criminal behaviors and recent alcohol abuse or dependence. CONCLUSIONS: Adolescents are more likely than young adults to use multiple drugs. The clustering of multidrug use and alcohol use disorder is a cause of concern.

Adolescent↗
PubMed2004

Perinatal flunitrazepam exposure causes persistent alteration of parvalbumin-immunoreactive interneuron localization in rat prefrontal cortex.

GABA regulates proliferation via GABAA receptors during development of the neocortex. We recently demonstrated that the endogenous GABAA receptor modulator allopregnanolone plays a role in regulating normal neurodevelopment in prefrontal cortex. Benzodiazepine exposure during early development produces marked behavioral changes in adult rats. To determine if exposure to benzodiazepines during development alters GABAergic interneurons in prefrontal cortex (PFC), rat pups were exposed to flunitrazepam (2.5 mg/kg) on postnatal day (P) 2 and assayed for parvalbumin- and calbindin-immunoreactivity on P80. The ratio of parvalbumin labeled cells in deep vs. superficial layers increased five-fold; calbindin-immunoreactivity and total cell number were not altered. These data are consistent with altered distribution of a subset of interneurons after benzodiazepine exposure and suggest a role for GABAA receptor modulation in normal development of GABAergic systems in PFC.

Animals↗
PubMed2004

Effects of single and repeated phencyclidine administration on [3H]flunitrazepam binding in rat brain.

Repeated administration of phencyclidine (PCP) induces behavioral sensitization to dopaminergic neural transmission. This phenomenon has been implicated in the pathophysiology of schizophrenia. Recently, GABAergic agonists have been shown to reduce behavioral activity induced by enhanced dopaminergic neural transmission, which is mediated by the GABA(A)/benzodiazepine (BZD) receptor complex. Thus, to investigate the role of BZD receptors during induction and expression of behavioral sensitization in PCP-sensitized animals, the effects of both single and repeated PCP administration on BZD receptors in rat brain were examined using in vitro quantitative autoradiography. Repeated PCP administration failed to significantly alter levels of [3H]flunitrazepam (FNZ) binding in any of the regions examined. However, significant increases in levels of [3H]FNZ binding were found in the nucleus accumbens and ventral pallidum 1 h after single administration of PCP. These results suggest that BZD binding sites may not play important roles in the development of PCP-induced sensitization at several sites of GABA(A)/BZD receptor complex, while changes in GABA function in the nucleus accumbens differ from other areas following single administration of N-methyl-D-aspartate (NMDA) antagonist.

Animals↗
PubMed2000

Flunitrazepam partitioning into natural membranes increases surface curvature and alters cellular morphology.

In recent studies, we showed that flunitrazepam (FNTZ) and other benzodiazepines interact with artificial phospholipid membranes locating at the polar head group region, inducing a membrane expansion, reducing the molecular packing and reorganising molecular dipoles. In the present paper we investigated the possibility that those phenomena could be transduced into changes in the curvature of membranes from natural origin. Hence we studied the effect of FNTZ on cellular morphology using human erythrocyte as a natural assay system. Shape changes of erythrocytes were evaluated by light microscopy and expressed as a morphological index (MI). FNTZ induced echinocytosis in a time-dependent manner with MI values significantly higher than those of control (without drug) or DMSO (vehicle) samples. Lidocaine, a local anesthetic known to induce stomatocytosis by incorporating in the inner monolayer, counterbalanced the concentration-dependent FNTZ crenating effects. FNTZ induced protective effects, compared with control and DMSO, against time-dependent hemolysis. Hypotonic-induced hemolysis, was also lowered by FNTZ in a concentration-dependent manner. Both antihemolytic effects suggested a drug-induced membrane expansion allowing a greater increase in cell volume before lysis. In such a complex system like a cell, curvature changes triggered by drug partitioning towards the plasma membrane, might be an indirect effect exerted through modifications of ionic-gradients or by affecting cytoskeleton-membrane linkage. In spite of that, the curvature changes can be interpreted as a mechanism suitable to relieve the tension generated initially by drug incorporation into the bilayer and may be the resultant of the dynamic interactions of many molecular fluxes leading to satisfy the spontaneous membrane curvature.

Cell Size↗
PubMed1998

Benzodiazepine effects on human sleep EEG spectra: a comparison of triazolam and flunitrazepam.

The effects of 0.5 mg triazolam (TRI) and 4 mg flunitrazepam (FNZ) on the sleep electroencephalogram (EEG) were studied in eleven (six for TRI, and five for FNZ) healthy young male subjects. C3 EEG channel data of one baseline night, three drug nights and two withdrawal nights were recorded and their analyzed using a fast Fourier transformation (FFT) method. Changes in the 0.5 Hz to 40 Hz power spectrum showed that: 1) both TRI and FNZ increased higher frequency activity and reduced lower frequency activity on the drug nights; 2) on drug nights, NREM sigma frequency power was more strongly enhanced by TRI than FNZ, while the beta power of both NREM and REM was more strongly enhanced by FNZ than TRI; 3) NREM alpha power increased on the second night of withdrawal from both TRI and FNZ; 4) the power spectra for both NREM and REM sleep returned to baseline levels by the fourth night of withdrawal from either TRI or FNZ. These findings suggest that 0.5 mg TRI and 4 mg FNZ have both common and differing pharmacological effects on the central nervous system. Such differences could be caused by differences in the dose, half-life or systemic distribution of these two drugs.

Adult↗
PubMed1996

Pharmacological characterisation of multiple components in the enhancement by pregnanolone and propofol of [3H]flunitrazepam binding to GABAA receptors.

The enhancement by pregnanolone (5 beta-pregnan-3 alpha-ol-20-one) and propofol (2,6-diisopropylphenol) of [3H]flunitrazepam (FNZ) binding to GABAA receptors in rat whole brain homogenate has been investigated. Two components in the concentration-effect relationship for pregnanolone were distinguished by the sensitivity of one component to antagonism by bicuculline and enhancement by muscimol, and the selective but weak antagonism of the bicuculline-insensitive component by 11-ketoprogesterone (4-pregnen-3,11,20-trione). Unlike pregnanolone, the enhancement by propofol of [3H]FNZ binding appeared to comprise a single component which was insensitive to 11-ketoprogesterone and was only slightly antagonised by bicuculline and slightly enhanced by muscimol. These results provide evidence for distinct GABA-dependent and GABA-independent components of the action of pregnanolone in the enhancement of [3H]FNZ binding, with the GABA-independent component being sensitive to 11-ketoprogesterone. The data also support the suggestion of different binding sites for pregnanolone and propofol.

Anesthetics, Intravenous↗
PubMedDate not supplied

Differential sensitivity to the anxiolytic effects of ethanol and flunitrazepam in PKCgamma null mutant mice.

Tests of ethanol effects in PKCgamma null mutant mice have indicated that PKCgamma plays a role in initial sensitivity to ethanol-induced sedation, hypothermia, and GABA(A) receptor function and impacts neurochemical pathways mediating anxiety. The present study was undertaken to evaluate whether the decreased sensitivity to ethanol previously observed in these mice generalized to the anxiolytic effects of ethanol. PKCgamma null mutant mice and wild-type controls were tested in the elevated-plus maze, the black/white box, and the mirrored chamber after ethanol (0, 1.0, 1.25, 1.5 g/kg) or flunitrazepam (FNZ) (0, 0.015, 0.03, 0.06 mg/kg). Results indicated that although both genotypes exhibited anxiolytic responses to ethanol in the elevated plus-maze, null mutant mice were less sensitive than wild-type control mice; however, in the black/white box, PKCgamma null mutants were more sensitive than controls to the anxiolytic effects of FNZ. Neither ethanol nor FNZ produced anxiolytic responses in the mirrored chamber for either genotype. These results suggest that PKCgamma differentially mediates anxiolytic responses to ethanol and FNZ and that this relationship interacts with each drug's efficacy in reducing anxiety-related behaviors specific to each of the three mazes.

Animals↗
PubMed2001

Flunitrazepam abuse and personality characteristics in male forensic psychiatric patients.

Sixty male non-psychotic forensic psychiatric patients (aged 16-35 years) were studied after they completed their ordinary forensic psychiatric assessment (FPA). The prevalence of flunitrazepam (FZ) abuse was investigated by using both structured and in-depth interviews with the objective of studying the relationship between the abuse and personality traits. The patient's characteristics, DSM-IV disorders, and actual sentences were obtained by studying their files. In order to obtain measures on their personality traits, self-report inventories were administered to the patients. Eighteen out of 60 patients were FZ abusers, but only 4 of them received a diagnosis related to the FZ abuse during the ordinary FPA. In almost all cases, however, indications of the FZ abuse were found in the files. No differences in personality traits were found between the groups. The frequency of previous admissions to an FPA and actual sentences of robbery, weapons offenses, narcotic-related offenses, and other crimes (such as theft) among the FZ abusers deviated significantly from forensic non-FZ abusers. Therefore, the FZ abuse per se might be more responsible for their tendency to commit crimes characterized by danger and thrill-seeking (such as robbery, weapons offences, and theft) than personality. The most important conclusion is that assessment of FZ abuse is needed in forensic psychiatry.

Adult↗
PubMed2001

Flunitrazepam, a 7-nitro-1,4-benzodiazepine that is unable to bind to the indole-benzodiazepine site of human serum albumin.

Benzodiazepine (BDZ) is generally thought to bind to site II of human serum albumin (HSA), also known as the indole-BDZ site, which is located at subdomain III A of the molecule. However, differences in the binding characteristics of BDZ drugs with HSA have been reported. The photolabeling profiles of HSA with [(3)H]flunitrazepam (FNZP) in the presence and absence of diazepam (DZP) were shown to be identical, suggesting that each drug primarily binds to different regions. The results of fluorescent probe displacement experiments showed that FNZP failed to decrease the fluorescence of dansylsarcosine to an extent similar to that of DZP. In the photoinhibition experiment, site I and site II ligands failed to inhibit the photoincorporation of [(3)H]FNZP to HSA. In order to evaluate the photolabeling specificity of FNZP, an attempt was made to photolabel alpha(1)-acid glycoprotein (AGP) which also binds BDZ with similar affinity as HSA. The effect of myristate (MYR) and DZP on the FNZP photolabeling of these two major drug binding plasma proteins was examined. Photoincorporation was inhibited when HSA was photolabeled with [(3)H]FNZP in the presence of MYR but not in the presence of DZP. Conversely, DZP inhibited the photolabeling of [(3)H]FNZP to AGP. These results suggest that FNZP interacts with HSA at regions which are not located in the preformed binding pocket of subdomain III A.

Anti-Anxiety Agents↗
PubMed2003

Flunitrazepam-induced changes in neurophysiological, behavioural, and subjective measures used to assess sedation.

INTRODUCTION: Certain features of event-related potentials (ERPs), electroencephalographic (EEG), and behavioural measures vary with differing states of alertness and/or sedation. PURPOSE: This study was conducted to investigate changes in several measures usually viewed as reflecting states of sedation/sleepiness associated with the use of a range of doses of the hypnotic benzodiazepine (BZD) flunitrazepam (FNZ). METHODS: This was a double blind, independent group design study of the effects of acute oral doses of FNZ in young healthy volunteers. Forty-eight subjects were randomly allocated to one of four groups-FNZ (0.6, 0.8, and 1.0 mg) and placebo (PLAC)-and tested prior to treatment and then in a posttreatment session close to the theoretical peak plasma concentration. ERP latencies and amplitudes were measured at midfrontal (Fz), midcentral (Cz), and midparietal (Pz) using a standard auditory oddball paradigm. EEG changes were assessed at Pz. Behavioural measures included the digit-symbol substitution test (DSST), a cancellation task (CT), and subjective ratings of alertness and attentiveness by the subjects (SUB) and the experimenter (EXP). RESULTS: FNZ led to psychomotor impairments and decreased alertness and attention; these effects were consistent with previous findings. A progressive, dose-related increase in P3 latency occurred in Fz, Cz, and Pz, and there was an increase in N1 (Fz, Cz) and N2 (Fz). N2-P3 amplitude decreased in Fz. EEG power bands beta 1 increased for the two highest doses, but no significant differences were noted in theta, delta, and alpha bands. P3 latencies, experimenter-rated levels of alertness, and DSST scores differentiated all three doses of FNZ from PLAC. CONCLUSION: The most sensitive measures used were P3 latencies of the ERPs (which varied with FNZ dose), DSST, and the experimenter-rated levels of alertness. However, we found no evidence for the assumption that one single phenomenon was reflected in all measures and different mechanisms were probably involved. Further experiments will be needed for more in-depth probing of the finer mechanisms underlying sedation/sleepiness and how they affect behavioural and eletrophysiological measures of the central nervous system (CNS) function.

Adolescent↗
PubMed1996

Simultaneous high-performance liquid chromatographic analysis of flunitrazepam and four metabolites in serum.

A high-performance liquid chromatographic method for the simultaneous determination of flunitrazepam and four metabolites, desmethylflunitrazepam (DMF), 7-aminodesmethylflunitrazepam (7-NH2DMF), 7-aminoflunitrazepam (7-NH2F) and 3-hydroxyflunitrazepam (3-OHF), in serum is described. The method involves a simple extraction from alkalinized plasma (pH 9.5) into diethyl ether-chloroform (80:20, v/v). Prazepam was used as an internal standard for the quantification of the five compounds. Separation was achieved with a 10 microns RSil CN column (300 x 3.9 mn I.D.). The detection wavelength was set at 242 nm. The limits of detection ranged from 2.5 to 5 micrograms/l with a limit of quantification of 10 micrograms/l for all analytes.

Anti-Anxiety Agents↗
PubMed1997

Simple high-performance liquid chromatographic column-switching technique for the on-line immunoaffinity extraction and analysis of flunitrazepam and its main metabolites in urine.

A sensitive, simple and rapid method without sample pretreatment is presented for the simultaneous determination of flunitrazepam and its main metabolites (norflunitrazepam, 7-amino- and 7-acetamidoflunitrazepam) in urine. The single-step procedure is based on a column-switching technique which uses an immobilized antibody in an extraction column following concentration on a precolumn and separation on an analytical column. UV detection was performed at 254 nm. The reusability of the antibody exceeds 88 runs and a complete analysis was performed in less than 40 min. The method shows coefficients of variation below 9.9% and rates of recovery greater than 92% tested at the level of 50 ng/ml urine. The limit of detection was below 2 ng/ml urine for the four compounds.

Anti-Anxiety Agents↗
PubMed1998

Determination of flunitrazepam and its metabolites in blood by high-performance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

A selective assay of flunitrazepam (F) and its metabolites 7-aminoflunitrazepam (7-AF), N-desmethylflunitrazepam (N-DF) and 3-hydroxyflunitrazepam (3-OHF) with liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS, positive ions) is described. The drugs were isolated from serum, blood or urine using a solid-phase extraction procedure previously applied to various drugs of abuse. F-d3 and 7-AF-d3 were used as internal standards. The drugs were separated on ODS column in acetonitrile-50 mM ammonium formate buffer, pH 3.0 (45:55, v/v). After analysis of mass spectra taken in full scan mode, a selected-ion monitoring detection was applied with following ions: m/z 284 (7-AF and F), 287 (7-AF-d3 and F-d3), 314 (F), 300 (N-DF and 3-OHF), 317 (F-d3), 330 (3-OHF). The limits of detection were: 0.2 microg/l for F and 7-AF, 1 microg/l for N-DF and 3-OHF. The method was linear in the range 1-500 microg/l, the recoveries ranged from 92 to 99%. The method was applied for determination of F and metabolites in clinical and forensic samples. LC-APCI-MS seems to be a method of choice for these compounds.

Anti-Anxiety Agents↗
PubMed2003

The importance of a urine sample in persons intoxicated with flunitrazepam--legal issues in a forensic psychiatric case study of a serial murderer.

The sedative-hypnotic benzodiazepine flunitrazepam (FZ) is abused worldwide. The purpose of our study was to investigate violence and anterograde amnesia following intoxication with FZ, and how this was legally evaluated in forensic psychiatric investigations with the objective of drawing some conclusions about the importance of urine sample in a case of a suspected intoxication with FZ. The case was a 23-year-old male university student who, intoxicated with FZ (and possibly with other substances such as diazepam, amphetamines or cannabis), first stabbed an acquaintance and, 2 years later, two friends to death. The police investigation files, including video-typed interviews, the forensic psychiatric files, and also results from the forensic autopsy of the victims, were compared with the information obtained from the case. Only partial recovery from anterograde amnesia was shown during a period of several months. Some important new information is contained in this case report: a forensic analysis of blood sample instead of a urine sample, might lead to confusion during police investigation and forensic psychiatric assessment (FPA) of an FZ abuser, and in consequence wrong legal decisions. FZ, alone or combined with other substances, induces severe violence and is followed by anterograde amnesia. All cases of bizarre, unexpected aggression followed by anterograde amnesia should be assessed for abuse of FZ. A urine sample is needed in case of suspected FZ intoxication. The police need to be more aware of these issues, and they must recognise that they play a crucial role in an assessment procedure. Declaring FZ an illegal drug is strongly recommended.

Adult↗
PubMed1999

Detection of low levels of flunitrazepam and its metabolites in blood and bloodstains.

Detection of low levels of flunitrazepam and its metabolites was developed using solid-phase extraction to isolate the drugs from whole liquid blood and dried bloodstains, with subsequent derivatization with pentafluoropropionic anhydride (PFPA) followed by N-(tert-butyldimethyl-silyl)-N-methyl-trifluoroacetamide (MTBSTFA) with 1% TBDMSCI. Analysis was confirmed by gas chromatography/mass spectroscopy using select ion monitoring (sim) in electron impact mode. The limit of detection of this procedure using 1 ml of blood was determined to be 0.1 microgram/dl.

Anti-Anxiety Agents↗