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PubMed1998

Gamma-aminobutyric acidA receptor function is desensitised in rat cultured cerebellar granule cells following chronic flunitrazepam treatment.

This study examined gamma-aminobutyric acidA (GABA(A)) receptor function in cultured rat cerebellar granule cells by using microphysiometry following chronic flunitrazepam exposure, and correlated the findings with the alpha1 and beta2/3 subunit protein expression and [3H]muscimol binding after the same treatment paradigm. Flunitrazepam treatment reduced (p < 0.05) the maximal GABA-stimulated increase in extracellular acidification rate (Emax) (16.5 +/- 1.2% and 11.3 +/- 1.0%, 2-day control and treated cells, respectively; 17.4 +/- 1.0% and 9.9 +/- 0.7%, 7-day control and treated cells, respectively; best-fit Emax +/- SEM, n = 7), without affecting the GABA concentration required to elicit 50% of maximal response (EC50) (1.2 +/- 1.7 and 2.3 +/- 1.8 microM, 2-day control and treated cells, respectively; 1.7 +/- 1.5 and 1.5 +/- 1.5 microM, 7-day control and treated cells, respectively; best-fit EC50 +/- SEM, n = 7). Flunitrazepam exposure also abolished the flunitrazepam potentiation of the GABA response, caused a transient reduction of the GABA(A) receptor alpha1 and beta2/3 subunit proteins over the initial 2 days, but did not alter [3H]muscimol binding compared with vehicle-treated cells. The results suggest that changes in GABA(A) receptor subunit protein expression, rather than loss of [3H]muscimol binding sites, underlie the chronic flunitrazepam-mediated desensitisation of GABA(A) receptor function.

Acids↗
PubMed1994

[Topographic changes in cerebral electric activity after premedication with flunitrazepam].

AIM: The effects on cerebral function of premedication with the benzodiazepine flunitrazepam and with morphine were studied on the evening of the preoperative day (2 mg flunitrazepam p.o.) and 90 minutes before induction of anaesthesia (2 mg flunitrazepam plus 15 mg morphine i.m.). DESIGN: The EEG was analysed topographically (17 electrodes) and quantitatively. RESULTS: As a typical effect of benzodiazepines, increases in electrical activity in the frequency band beta-1 of the power spectrum were observed, and could be demonstrated 10 minutes after oral application, mainly in the frontal and central parts of the cortex. Increases in the powerbands delta and theta indicated induction of sleep approximately 15-20 minutes after application and were not looked upon as an effect of the benzodiazepine exclusively. These increases were noticed first in the central, occipital and temporal areas and after 30 minutes in the frontal parts of the cortex. Flunitrazepam plus morphine showed qualitatively similar but quantitatively less pronounced results. Topographical differences were similar to the results of an application of flunitrazepam alone. DISCUSSION: The results demonstrate the importance of a topographical as well as quantitative evaluation in studies on complex interactions of sedative or narcotic drugs and their clinical effects on cerebral function.

Administration, Oral↗
PubMed1996

The major site of photoaffinity labeling of the gamma-aminobutyric acid type A receptor by [3H]flunitrazepam is histidine 102 of the alpha subunit.

The alpha subunit of the gamma-aminobutyric acid type A (GABA(A)) receptor is known to be photoaffinity labeled by the classical benzodiazepine agonist, [3H]flunitrazepam. To identify the specific site for [3H]flunitrazepam photoincorporation in the receptor subunit, we have subjected photoaffinity labeled GABA(A) receptors from bovine cerebral cortex to specific cleavage with cyanogen bromide and purified the resulting photolabeled peptides by immunoprecipitation with an anti-flunitrazepam polyclonal serum. A major photolabeled peptide component from reversed-phase high performance liquid chromatography of the immunopurified peptides was resolved by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The radioactivity profile indicated that the [3H]flunitrazepam photoaffinity label is covalently associated with a 5.4-kDa peptide. This peptide is glycosylated because treatment with the enzyme, peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase, reduced the molecular mass of the peptide to 3.2 kDa. Direct sequencing of the photolabeled peptide by automated Edman degradation showed that the radioactivity is released in the twelfth cycle. Based on the molecular mass of the peptides that can be generated by cyanogen bromide cleavage of the GABA(A) receptor alpha subunit and the potential sites for asparagine-linked glycosylation, the pattern of release of radioactivity during Edman degradation of the photolabeled peptide was mapped to the known amino acid sequence of the receptor subunit. The major site of photoincorporation by [3H]flunitrazepam on the GABA(A) receptor is shown to be alpha subunit residue His102 (numbering based on bovine alpha 1 sequence).

Affinity Labels↗
PubMedDate not supplied

Abuse of flunitrazepam (Rohypnol) and other benzodiazepines in Austin and south Texas.

Flunitrazepam (Rohypnol) is a benzodiazepine sedative-hypnotic that has generated significant media attention in the United States because of its abuse and its association with "date rape." A field investigation was conducted in south Texas to ascertain the nature and consequences of the abuse of flunitrazepam. In semistructured interviews, 66 subjects identified as flunitrazepam users were asked about their use of alcohol and other drugs and their sexual behaviors. Many subjects identified the drugs they had used as "roches" and gave descriptions of tablets of other benzodiazepines that were not consistent with flunitrazepam. Almost all subjects used other drugs, primarily alcohol and marijuana. Adverse consequences included amnesia, discoordination, automobile accidents, sexual assault, and respiratory depression or arrest. A significant proportion of the subjects reported that continued use was unappealing to them. The abuse of sedative-hypnotics in southeast Texas involves several benzodiazepines and is not limited to flunitrazepam.

Adolescent↗
PubMed1993

Effects of midazolam and flunitrazepam on the release of dopamine from rat striatum measured by in vivo microdialysis.

We have studied the effects of midazolam and flunitrazepam on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum in freely moving animals using in vivo microdialysis. I.v. injections of midazolam 0.075 and 0.15 mg kg-1 decreased striatal dopamine concentrations in a dose-dependent manner without affecting the concentrations of DOPAC and HVA. Flunitrazepam 0.015 and 0.03 mg kg-1 also decreased striatal dopamine concentrations in a dose-related manner, but the reductions in DOPAC and HVA were not significant. Flumazenil 6 micrograms kg-1 alone did not affect striatal concentrations of dopamine, DOPAC and HVA, but it prevented the effects of midazolam and flunitrazepam. Flunitrazepam 10 mumol litre-1 also decreased striatal dopamine release when infused through a dialysis probe placed into the striatum, but it failed to affect striatal dopamine release when infused into the ipsilateral substantia nigra. Central administrations of midazolam were effective only when the drug was infused into both sites simultaneously (10 and 100 mumol litre-1) or given by intraventricular injection (0.5 and 1 micrograms). These results suggest that midazolam and flunitrazepam affect striatal dopamine release in a different manner.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Determination of chronic flunitrazepam abuse by hair analysis using GC-MS-NCI.

A 38-year-old male was found comatose at home with an empty package of Rohypnol (2-mg tablets, 10 per package) near the body. Many other drugs, which had recently been stolen from a pharmacy, were also found. The judge in charge of the investigation of the stolen pharmaceuticals asked our laboratory to determine if the subject was a chronic user of flunitrazepam, leading our laboratory to develop a procedure for the detection of this benzodiazepine in human hair. The method involved decontamination of hair samples with dichloromethane, incubation in Sorenson buffer (pH 7.6) in the presence of diazepam-d5 used as internal standard, direct liquid-liquid extraction with diethylether-chloroform (80:20, v/v), derivatization with heptafluorobutyric anhydride and analysis by gas chromatography coupled to mass spectrometry in the negative chemical ionization mode of detection. Flunitrazepam and its major metabolite, 7-amino-flunitrazepam, were both detected. The concentrations determined in the proximal hair segment were 89.5 and 24.0 pg/mg for flunitrazepam and 7-amino-flunitrazepam, respectively.

Adult↗
PubMedDate not supplied

Detection of flunitrazepam and 7-aminoflunitrazepam in oral fluid after controlled administration of rohypnol.

Although administered as a short-acting hypnotic for sleeping disorders, flunitrazepam, often in combination with alcohol or other drugs, was one of the most frequently abused benzodiazepines over the last 10 years. It has been reported in cases of driving under the influence, and its use is associated with marked psychomotor impairment. Studies over the last five years have investigated the use of oral fluid as an alternative matrix to blood and urine, especially when non-intrusive and quick sampling procedures are important (e.g., screening for drugs of abuse at the roadside and screening and confirmatory workplace drug testing). In this study, Rohypnol (flunitrazepam) was administered to four healthy volunteers, and oral fluid samples were collected by spitting into a polypropylene tube at fixed times between 0 and 6 h after the intake of a tablet of 1 mg. A specific and very sensitive method was developed, both for flunitrazepam and for its main metabolite 7-aminoflunitrazepam, based on solid-phase extraction of the oral fluid samples, stored at +4 degrees C, and gas chromatographic-mass spectrometric analyses using negative chemical ionization with methane as the ionization gas. The heptadeuterated parent compound and metabolite were used as internal standards. The respective limits of detection and quantitation were 0.05 microg/L and 0.1 microg/L for flunitrazepam, and 0.1 and 0.15 microg/L for 7-aminoflunitrazepam. The parent drug could only be detected when the analyses were performed within 12-24 h after collection of the oral fluid samples or when 2% of NaF was added to the collection tubes. The stability of flunitrazepam in oral fluid was poor, even at +4 degrees C, when no NaF was added to the sample. In any case, concentrations remained below 1 microg/L. The metabolite was detected in slightly higher concentrations, with or without the presence of NaF, reaching a maximum of 1-3 microg/L within 2-4 h after administration. In all cases the drug was detectable, but at extremely low concentrations, for 6 h after intake of a normal dose of Rohypnol and it will be an analytical challenge to come up with a sufficiently sensitive onsite test for low-dose benzodiazepines in oral fluid.

Administration, Oral↗
PubMed2005

An abuse liability comparison of flunitrazepam and triazolam in sedative drug abusers.

The present double-blind, placebo-controlled study compared the acute effects of oral administration of the benzodiazepine hypnotics flunitrazepam (6 mg/70 kg) and triazolam (1 and 2 mg/70 kg) on measures relevant to abuse liability as well as on psychomotor performance and observer- and participant-rated measures of drug effects in nine sedative drug abusers. Analysis of participant-rated measures collected 24 h after drug administration (next-day; assessing the overall effects of the drug received 24 h earlier) indicated that flunitrazepam, but neither triazolam dose, produced significant increases relative to placebo in next-day ratings of drug liking, the amount of money the drug would be worth on the street, and the amount of money the participant would be willing to pay for the drug on the street. Importantly, these abuse liability differences between flunitrazepam and triazolam were present at a dose of flunitrazepam (6 mg/70 kg) that produced overall drug effects that were comparable to, or significantly less than, those of a high triazolam dose (2 mg/70 kg). Consistent with results of a previous study in our laboratory, these results suggest that flunitrazepam may have a greater abuse liability than triazolam, and that this abuse liability difference emerges on measures taken 24 h after drug administration but not on same-day measures.

Adult↗
PubMed1976

Reduction of psychotomimetic side effects of Ketalar (ketamine) by Rohypnol (flunitrazepam). A randomized, double-blind trial.

A double-blind controlled trial based on 140 women undergoing abortus provocatus was employed to study whether the frequency of side effects after administration of the anaesthetic Ketalar (ketamine) could be reduced by a con-current dose of Rohypnol (flunitrazepam). The control group was given ketamine alone. The dosage of ketamine was 2 mg/kg body weight, supplemented if necessary by 1 mg/kg, in combination with either 2 mg flunitrazepam or placebo. No other anaesthetics were used. On several counts, the combination of ketamine and flunitrazepam was proved to reduce the adverse reactions seen with ketamine alone. Motor restlessness and confusion in the awakening state occurred with significantly less severity and frequency. Amnesia for dreams was significantly more frequent. Memory of dreams was often unpleasant after ketamine alone. The influence on pulse rate was significantly smaller and no significant changes in systolic blood pressure were seen, whereas a significant increase occurred with ketamine alone. Less pronounced fluctuations in diastolic blood pressure occurred with the combination ketamine-flunitrazepam. Respiratory rate increased significantly with both treatments, but respiratory minute volume was lower with the ketamine-flunitrazepam combination.

Abortion, Induced↗
PubMed1983

Drug-alcohol interactions on psychomotor skills: zopiclone and flunitrazepam.

Interaction between alcohol and zopiclone or flunitrazepam as well as the residual effects of both these hypnotics were studied in 20 normal male volunteers who received each 3 of 6 different drug and drink combinations according to a balanced incomplete block design as follows: placebo, zopiclone (7.5 mg), or flunitrazepam (2 mg) was administered double-blind in identical capsules at 23.00 h, and 0.5 g/kg body weight of alcohol or placebo alcohol was given at 08.30 h the following morning. Psychomotor skills of the volunteers were measured before drinking and 30 min, 1.5 h and 2.5 h after it. As compared with placebo, zopiclone had no residual effects, while flunitrazepam had some effects on standing steadiness, tracking, and flicker recognition. Alcohol alone had a non-significant effect on skills, and the combination zopiclone plus alcohol behaved as alcohol alone. Flunitrazepam plus alcohol impaired significantly standing steadiness, tracking, and reactive skills when compared with all other treatments. Time anticipation and hand and foot proprioception were not affected by any treatment. The results suggest that flunitrazepam, unlike zopiclone, has residual effects and interacts with alcohol in the morning following overnight ingestion of the drug.

Adult↗
PubMed1985

Sleep and wake after benzodiazepine hypnotics: a 20-hour EEG comparison of lormetazepam and flunitrazepam.

In an electropharmacokinetic study, the effects of lormetazepam and flunitrazepam were compared by the means of a sleep EEG and waking EEG during the following daytime. At a 1-week interval, 6 normal subjects received at random either 2 mg lormetazepam or 2 mg flunitrazepam in a double-blind, crossover fashion. Sleep EEG was recorded throughout the night; 6-min EEG samples were recorded every hour during 10 hours on the following daytime for spectral analysis. Night sleep after flunitrazepam showed lower Stage IV sleep than after lormetazepam. During daytime, only flunitrazepam induced an increased percentage of beta 2 frequencies, which remained above baseline up to 10 hours after awakening, indicating a prolonged impregnation time. This study permitted comparison of the relative intensity and duration of these two benzodiazepines: lormetazepam appeared to be a short-acting hypnotic while flunitrazepam displayed longer modification of the brain electrical activity.

Adult↗
PubMed2001

Deposition of 7-aminoflunitrazepam and flunitrazepam in hair after a single dose of Rohypnol.

In recent years, there has been a notable increase in the number of reports on drug-facilitated sexual assault. Benzodiazepines are the most common so-called "date-rape" drugs, with flunitrazepam (Rohypnol) being one of the most frequently mentioned. The aim of this study was to determine whether flunitrazepam and its major metabolite 7-aminoflunitrazepam could be detected in hair collected from ten healthy volunteers after receiving a single 2 mg dose of Rohypnol using solid phase extraction and NCI-GC-MS. Such data would be of great importance to law enforcement agencies trying to determine the best time interval for hair collection from a victim of drug-facilitated sexual assault in order to reveal drug use. Ten healthy volunteers (eight women and two men, 21 to 49 years old) participated in the study. The following hair samples were collected from each volunteer: one before flunitrazepam administration, and 1, 3, 5, 14, 21, and 28 days after. In five volunteers, 7-aminoflunitrazepam was detected 24 h after flunitrazepam administration and remained in hair throughout the entire 28-day study period (0.6-8.0 pg/mg). In two cases, 7-aminoflunitrazepam appeared in hair 21 days after drug intake (0.5-2.7 pg/mg), and in two subjects 14 days later (0.5-5.4 pg/mg). In one volunteer, 7-aminoflunitrazepam was detected on day 14 and 21 but concentrations were below the quantitation limit. Flunitrazepam was detected in some samples but all concentrations were below the quantitation limit (0.5-2.3 pg/mg).

Adult↗
PubMed1991

Hormone-stimulated steroidogenesis is coupled to mitochondrial benzodiazepine receptors. Tropic hormone action on steroid biosynthesis is inhibited by flunitrazepam.

The mitochondrial (peripheral-type) benzodiazepine receptor (MBR) is a drug binding site associated with outer mitochondrial membranes which is coupled to intramitochondrial cholesterol transport, the rate-determining step of steroid biosynthesis. To examine the relationship between MBR function and steroid synthesis regulated by polypeptide hormones, the Y-1 adrenocortical and MA-10 Leydig cell lines were used as model systems responsive to adrenocorticotropin and human choriogonadotropin, respectively. Flunitrazepam, a benzodiazepine which binds to MBR with high nanomolar affinity, inhibited the steroidogenic activity of these hormones, or the activation by 1 mM dibutyryl cAMP, in both cell lines by 30-60% with an IC50 of 500-1000 nM. Scatchard analysis in both cell lines revealed one class of specific binding sites for [3H] flunitrazepam verified as being MBR by displacement studies with a series of MBR ligands. The potencies of these ligands to compete against the antagonism of hormone-stimulated steroidogenesis by flunitrazepam correlated significantly with their abilities to compete against [3H]flunitrazepam binding to MBR (r = 0.99). An inhibition in pregnenolone formation was also observed in isolated mitochondrial preparations characterized as a reduction of cholesterol transport to inner mitochondrial membranes. These observations provide unequivocal evidence that the antagonistic action of flunitrazepam is mediated through its interaction with MBR demonstrating that these drug recognition sites are coupled to steroid biosynthesis activated by tropic hormones.

Animals↗
PubMed1986

In vivo [3H]flunitrazepam binding: imaging of receptor regulation.

The use of [3H]flunitrazepam as a ligand to measure alterations in benzodiazepine receptors in vivo in rats was investigated. Animals were injected with [3H]flunitrazepam i.v., arterial samples of [3H]flunitrazepam were obtained and, later, the animals were sacrificed to assay brain binding. [3H]flunitrazepam enters the brain rapidly and binds to benzodiazepine receptors. About two-thirds of this binding is blocked by predosing the animals with 5 mg/kg of clonazepam. The amount of remaining (nonspecific) binding correlates very well (r = 0.88) with the amount of radioactivity found in plasma at the time of death. A series of rats were lesioned unilaterally with kainic acid in the caudate-putamen several months before the infusion of [3H]flunitrazepam. In vivo autoradiography in lesioned rats showed that benzodiazepine binding in globus pallidus and substantia nigra on the side of the lesion was increased significantly as compared to the intact side. The observed changes in benzodiazepine binding were similar to those observed previously in lesioned rats using in vitro techniques. Thus, benzodiazepine receptor regulation can be imaged quantitatively using in vivo binding techniques.

Animals↗
PubMed1979

[Flunitrazepam-pretreatment for prevention of adverse cardiovascular effects following ketamine].

In 18 patients with documented ischaemic heart disease the cardiovascular effects of ketamine (1.5 mg/kg iv) were studied under three different conditions: 1. in awake premedicated patients (n = 6); 2. after the previous administration of flunitrazepam (0.015 mg/kg iv, n = 6) and 3. under conditions of neuroleptanalgesia and muscle relaxation (n = 6). Flunitrazepam prevented or at least attenuated the increases in heart rate (30%), mean arterial pressure (37%), mean pulmonary artery pressure (165%), left ventricular filling pressure (230%), total peripheral resistance (50%), pulmonary vascular resistance (100%) and in the rate-pressure product (66%) which were associated with the use of ketamine as the sole anaesthetic agent. In addition, the flunitrazepam-pretreatment abolished the fall in cardiac index and stroke index which occured in patients given ketamine alone. Flunitrazepam therefore appears to be a promising drug to prevent adverse cardiovascular reactions, when ketamine should be chosen for induction of anaesthesia. Neuroleptanalgesia and muscle relaxation also proved effective in controlling the sympathomimetic actions of ketamine. The response of the mean pulmonary artery pressure and of the ventricular filling pressures to ketamine in this group was even more damped than in the patients pretreated with flunitrazepam alone.

Adult↗
PubMed1981

Comparative haemodynamic and respiratory effects of midazolam and flunitrazepam as induction agents in cardiac surgery.

30 cardiac surgical patients were investigated for comparing the respiratory and haemodynamic repercussions of induction of anaesthesia with either flunitrazepam or 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum). The patients were premedicated with morphine, 0.15 mg/kg i.m., and divided into two groups: one group receiving flunitrazepam 0.03 mg/kg, the other midazolam 0.15 mg/kg injected i.v. over a 15-s period. The induction time and the respiratory depression were similar in both groups. A similar decrease in systolic, diastolic and mean arterial pressures was noted, with maximum decrease of mean arterial pressure of 21% 5 min after injection of flunitrazepam, and of 19% after injection of midazolam. Midazolam produced a significant but transient pulse acceleration of 4% 1 min after the injection, while flunitrazepam produced a moderate decrease of the heart rate. These results indicate that in cardiac surgical patients midazolam produces a moderate respiratory and cardiovascular depression similar to flunitrazepam.

Adult↗
PubMed1982

[Animal experiment studies on the mechanism of action of flunitrazepam (Rohypnol) on the circulation and respiration].

In 29 experiments performed on relaxed cats with artificial respiration, the effects of 0.015; 0.03; 0.06 mg flunitrazepam per kg body weight i.v. with N2O basal anaesthesia and of 0.06 mg flunitrazepam per kg without basal anaesthesia were examined in respect to mean arterial blood pressure, heart rate and the efferent action potentials of the N. sympathicus and the N. phrenicus. In all experiments, a mild and short-term reduction in blood pressure, a slight tachycardia and a very brief inhibition of the sympathetic nerve were observed. Definite actions exercised by flunitrazepam consisted of an inhibition of the respiratory centre which was due to a reduction of the extent and intensity of the inspiratory discharges of the phrenic nerve, although the breathing rate was increased. A comparison of the tests with flunitrazepam alone and in combination with N2O yielded definite differences only in the case of the asphyxia tests. The combination produced a significant inhibition of the vagus centre which was absent when flunitrazepam was used alone.

Adrenergic Fibers↗
PubMed1982

A comparative study of the clinical effects of oral flunitrazepam, medazepam, and placebo.

In a double-blind randomized study 40 patients received 1 mg flunitrazepam, 40 patients received 10 mg medazepam, and 40 patients received placebo p.o. the night before surgery. On the morning of surgery each patient received another identical oral dose of the product or placebo taken the previous night. On the average, the flunitrazepam group slept better, was better sedated, and was less anxious than the medazepam or placebo groups. Similarly, as a reflection of diminished autonomic reactions, the patients receiving flunitrazepam had fewer cardiovascular changes. Flunitrazepam significantly decreased the amounts of thiopentone needed for induction of anesthesia. Medazepam did not. The pronounced sedative, sleep-inducing, and anxiolytic effects of flunitrazepam appear to be of great clinical importance for its use in anesthesiology. Repeated administrations of medazepam seem to be required to produce an evident clinical effect of the drug, possibly via the slow accumulation of metabolites. The main difference between these two benzodiazepine derivatives as regards clinical response therefore seems to be pharmacokinetic in origin.

Adult↗