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PubMed1997

Flunitrazepam excretion patterns using the Abuscreen OnTrak and OnLine immunoassays: comparison with GC-MS.

A study was conducted to compare the performance of the OnLine and OnTrak immunoassays for benzodiazepines with gas chromatographic-mass spectrometric (GC-MS) analysis in detecting flunitrazepam (FNP) and its metabolites in human urine. Urine was collected over a 72-h period from six individuals (four male and two female) who had taken a single oral dose of either 1 or 4 mg of FNP. The OnTrak assay was run at a 100-ng/mL cutoff of nordiazepam (NDP), and the OnLine assay was run with a standard curve from zero to 200 ng/mL of NDP with and without beta-glucuronidase treatment. Each sample was analyzed by GC-MS using FNP, 7-amino-FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP as standards with beta-glucuronidase treatment. The specimens from the 1-mg dose did not yield a positive result by immunoassay over the 72-h collection period. Specimens from the 4-mg dose did yield positive results in both immunoassays. The time of the first positive result ranged from 4 to 12 h, and the time to the last positive result ranged from 18 to 60 h. Treatment of the samples with beta-glucuronidase increased the OnLine values between 20 and 60%, but it did not appreciably increase the detection time. GC-MS analysis showed no detectable levels of FNP, 3-hydroxy-FNP, desmethyl-FNP, 7-amino-3-hydroxy-FNP, and desmethyl-3-hydroxy-FNP. However, all samples collected past time zero showed detectable levels of 7-amino-FNP (> 2 ng/mL) with peak concentrations at 12-36 h. The peak levels of 7-amino-FNP by GC-MS paralleled the peak levels of the immunoassay response. The amount of 7-amino-FNP metabolite quantitated by GC-MS, however, accounted for only 15-20% of the total immunoassay crossreactive FNP metabolites.

Administration, Oral↗
PubMedDate not supplied

Determination of flunitrazepam and its main metabolites in serum and urine by HPLC after mixed-mode solid-phase extraction.

A rapid and sensitive method is presented for the simultaneous determination of flunitrazepam, norflunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam in serum, plasma, and urine. The compounds were extracted by a mixed-mode solid-phase procedure following analysis by high-performance liquid chromatography and ultraviolet detection and using methylclonazepam as the internal standard. The method revealed high recoveries and showed good precision and linearity for all compounds. The limit of detection was at least 1 ng/ml serum (plasma) for all compounds.

Anti-Anxiety Agents↗
PubMedDate not supplied

On-line immunoaffinity extraction and HPLC analysis of flunitrazepam and its main metabolites in serum.

A sensitive, simple, and rapid method for the determination of flunitrazepam and its major metabolites (7-aminoflunitrazepam, 7-acetamidoflunitrazepam, and norflunitrazepam) in serum and plasma is presented. The on-line procedure uses an immobilized, highly reusable antibody against benzodiazepines for selective extraction from serum followed by analysis by high-performance liquid chromatography with ultraviolet detection. This reliable method provides a limit of detection of 1 ng/mL serum, and results are obtained in less than 40 min.

Chromatography, Affinity↗
PubMed2001

3H-nicotine, 3H-flunitrazepam, and 3H-cocaine incorporation into melanin: a model for the examination of drug-melanin interactions.

To explore drug-melanin interactions, we examined the in vitro tyrosinase-mediated formation of melanin from tyrosine in the presence of the 3H-cocaine (3H-COC), 3H-flunitrazepam (3H-FLU), and 3H-nicotine (3H-NIC) at 10-100,000 ng/mL. Polymerization in the presence of 10 or 100 ng/mL of each drug resulted in almost complete drug incorporation into the melanin pellet. Only 12% (3H-NIC) to 28% (3H-FLU) of the pellet-associated radioactivity could be released upon treatment with 6 M HCl. At 1000-100,000 ng/mL, between 20 and 50% of label became melanin-associated. In each case a significant percentage of melanin-associated radioactivity was resistant to treatment with 6 M HCl. Nicotine-associated radioactivity in the polymer was subject to much greater quenching than was 3H-COC or 3H-FLU, suggesting a much tighter association with the melanin. The subsequent demonstration of a covalent adduct of a melanin intermediate and nicotine has demonstrated the utility of this polymerization system as a model for further chemical characterization of drug-melanin interactions.

Cocaine↗
PubMed2002

Improved screen and confirmation test of 7-aminoflunitrazepam in urine specimens for monitoring flunitrazepam (Rohypnol) exposure.

Confirmed and alleged misuses of flunitrazepam (FM2, Rohypnol) have brought about serious interest in the development of an analytical methodology that can be effectively used for preliminary screen and confirmatory test of FM2 (or its metabolites) in urine specimens under high-volume settings. Reported methods do not serve this need well for the following reasons: (1) common benzodiazepine (BZ) immunoassays (IAs) have broad cross-reactivities toward widely prescribed BZs (and their metabolites) and are therefore likely to generate an unacceptable number of false positives and (2) because FM2 is typically used at low doses (1-4 mg), IAs with low cross-reactivities toward FM2 (and its metabolites) are likely to generate false-negative results. In this current study, a familiar and effective two-step IA/gas chromatography-mass spectrometry (GC-MS) approach is successfully developed and applied to clinical specimens. Cross-reacting characteristics of the following BZ IAs toward various BZs (and their metabolites) are evaluated focusing on their effectiveness in serving as the preliminary test reagent in a two-step testing protocol: TDx, Beckman, CEDIA, Roche Cobas Integra, Emit II Plus, and Cozart ELISA. Although other IAs show broad cross-reactivities toward various BZs and their metabolites, diazepam is the only non-FM2 derived compound that exhibits noticeable cross-reactivity toward Cozart ELISA reagent. Cross-reactivity data and data derived from studies conducted on a limited number of clinical specimens demonstrate that, when used to monitor FM2 exposure in a large population group (including those exposed to other BZs), Cozart ELISA has the potential of being as effective as (or better than) those currently used in various workplace drug-testing programs for monitoring respectively targeted drugs. Data derived from this study further suggest that 50 ng/mL apparent 7-aminoflunitrazepam (Cozart ELISA) and 30 ng/mL free 7-aminoflunitrazepam (GC-MS) are potentially effective preliminary test and confirmation test cut-offs. To maximize efficiency, it is further suggested that urine specimens are first diluted by a factor of 5 for the preliminary test in which a 10-ng/mL 7-aminoflunitrazepam standard is used as the assay's cut-off standard.

Anti-Anxiety Agents↗
PubMed1993

Intracerebroventricular injection of naloxone blocks melatonin-dependent brain [3H]flunitrazepam binding.

The pineal hormone melatonin modulates the brain benzodiazepine binding sites and its circadian rhythm. In the present study the effects of intracerebroventricular (i.c.v.) administration of naloxone (10-20 ng), alone or in association with melatonin and/or beta-endorphin, on [3H]flunitrazepam ([3H]FNZ) binding to the rat cerebral cortex of hypophysectomized rats was investigated. Melatonin (10-20 ng), beta-endorphin (10-20 ng), and melatonin + beta-endorphin (10-20 ng of each compound) all increased [3H]FNZ binding to a similar extent and in a dose-related manner. The effects of melatonin (10 ng) on [3H]FNZ binding were prevented by simultaneous injection with the specific opioid antagonist naloxone. Naloxone also blocks, although to a lesser extent, the effects of beta-endorphin and of melatonin + beta-endorphin injections. Moreover, naloxone blocks the hypophysectomy-dependent increase in [3H]FNZ binding. These results implicate the modulation of melatonin-dependent changes on brain benzodiazepine receptors by opioid peptides.

Adrenal Cortex Hormones↗
PubMed1993

Suppressive effect of simultaneous injection of ACTH1-10 and beta-endorphin on brain [3H]flunitrazepam binding.

Seven-day hypophysectomized rats were intracerebroventricularly (i.c.v.) injected with beta-endorphin, ACTH1-10 or beta-endorphin+ACTH1-10 (10-20 ng of each compound) and the [3H]flunitrazepam ([3H])FNZ) binding to the rat cerebral cortex of hypophysectomized rats was assayed one hour later. The i.c.v. injection of ACTH1-10 (10-20 ng) or beta-endorphin (10-20 ng) significantly increased [3H]FNZ binding to a similar extent. The effect of i.c.v. injection of ACTH1-10 on brain binding was blunted by simultaneous beta-endorphin administration at the same doses. The i.c.v. naloxone injection (10-20 ng) did not modify the effect of ACTH1-10 (10 ng) on [3H]FNZ binding, but counteracted, in a dose-related manner, the blocking effect of beta-endorphin on ACTH1-10-dependent brain [3H]FNZ binding. The results suggest the existence of an opioid-melanopeptide integration to control brain benzodiazepine receptors.

Adrenocorticotropic Hormone↗
PubMed1987

Vinpocetine effects on cognitive impairments produced by flunitrazepam.

The effects of pre-treatment with vinpocetine 40 mg, on flunitrazepam-induced impairment of memory, were studied in 8 normal volunteers. Tests of Critical Flicker Fusion Threshold, a Sternberg Memory Scanning Task, along with subjective ratings of drug action were used. Drug effects were found to be modest. Treatment with vinpocetine was associated with improvements in short-term memory processes.

Adult↗
PubMed1985

Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788.

Following a single intravenous dose of 0.1 mg/kg, the pharmacokinetics of Ro 15-1788, a specific benzodiazepine antagonist, have been investigated in 20 healthy male volunteers. In random order injection of Ro 15-1788 has been preceded (5 min) by intravenous dosing with 0.06 mg/kg of lormetazepam (n = 6), 0.03 mg/kg of flunitrazepam (n = 8) or placebo (n = 6). The rapid elimination of the antagonist could be characterized by an elimination half-life between 0.9 to 1.4 h and a total plasma clearance of 727 to 1440 ml/min. These single dose studies indicate that the disposition of Ro 15-1788 was not affected by the acute coadministration of both benzodiazepines.

Adolescent↗
PubMed1977

Diazepam and flunitrazepam as induction agents for cardiac surgical operations.

Diazepam and flunitrazepam were compared in equipotent doses as induction agents for premedicated patients having cardiac surgery. Both drugs caused a significant fall in arterial blood pressure, a rise in Paco2 and a fall in Pao2. There was no significant difference between the two drugs in onset time of anaesthesia, cardiovascular or respiratory depression, or quality of induction. There was also no significant difference from induction with thiopentone in these respects. Diazepam, over a 0.2 to 0.6 mg/kg range of doses showed no difference in toxicity, although induction was clinically smoother with the higher dose.

Anti-Anxiety Agents↗
PubMed1982

The haemodynamic effects of flunitrazepam in anaesthetized patients with valvular or coronary artery lesions.

The Haemodynamic effects of flunitrazepam (FLU) 1.25 mg X m-2 administered intravenously were studied in 18 anaesthetized cardiac patients suffering from isolated mitral (MIT, n = 6), aortic (AOR, n = 6) or coronary (COR, n = 6) lesions. A placebo group of 18 clinically similar patients was used to assess the stability of the cardiovascular parameters under the conditions of the study. Heart rate, systemic arterial pressure, cardiac output and central venous pressure changes were measured 2, 5, 8 and 12 min after FLU or saline injection and compared with reference values collected before the start of the haemodynamic test. In the FLU group, the cardiovascular state of all the patients developed following the same pattern and the greatest differences were observed at 12 min post-injection. These differences, expressed as a percentage of the initial values were (* P less than 0.05; ** P less than 0.001; ns = non-significant): mean systemic arterial pressure: COR, -18% (**);MIT, -13% (*); AOR, -23% (**); heart rate: COR, 0% (ns); MIT, -10% (*); AOR, -12% (*); cardiac output: COR, -15% (**); MIT, -13% (*); AOR, -16% (**); stroke volume: COR, -12%(*);MIT, 0% (ns);AOR,-3%(ns). This shows some differences concerning the SV and heart rate changes in the valvular and COR patients. As compared to the data from the literature, most of the haemodynamic effects of FLU seem relatively independent of the initial level of consciousness.

Adult↗
PubMed1986

Flunitrazepam-fentanyl-induced sedation and analgesia for bone marrow aspiration and needle biopsy in children.

We describe the use of flunitrazepam and fentanyl to produce sedation and analgesia, as an alternative to general anesthesia, for 96 children with malignancies or hematologic diseases, undergoing 122 bone marrow examinations (BME). In 82 cases there was no reaction to the puncture. Most children had complete amnesia and only two remembered some pain. In 10% the sedation and analgesia was considered inadequate and barbiturate was given; seven out of these 12 children were under the age of 3 years. During 117 procedures the children maintained adequate spontaneous ventilation; in five cases the ventilation was assisted. In 13 cases there were minor side-effects including drowsiness and nausea. One child had a short apnea after the procedure.

Adolescent↗
PubMed1988

Antagonism of flunitrazepam-induced sedative effects by flumazenil in patients after surgery under general anaesthesia. A double-blind placebo-controlled investigation of efficacy and safety.

This study aimed to assess the efficacy and safety of flumazenil and a placebo in reversing the residual effects of flunitrazepam used to induce anaesthesia for elective laparoscopy in 49 female patients aged 16 to 52 years. In contrast to the placebo, flumazenil gave reductions in amnesia, sedation score, mood rating for mental sedation and physical sedation, and time taken to complete a psychomotor performance test which lasted throughout the study. There were no significant changes in pulse rate, respiration rate or blood pressure, and no unwanted effects were attributed to flumazenil.

Adolescent↗
PubMed1988

Reversal of flunitrazepam sedation with flumazenil. A randomized clinical trial.

Fifty-nine male patients scheduled for transurethral resection of the prostate under flunitrazepam sedation and spinal analgesia were randomized in a double-blind trial to reversal of sedation with either the benzodiazepine antagonist flumazenil or placebo. Judged by degree of sedation, comprehension and cooperation as well as by estimation of orientation in time and space, flumazenil was superior to placebo (P less than 0.001). The median duration of anterograde amnesia was 16 min after flumazenil and 75 min after placebo (P less than 0.001). Adverse events were more frequent with placebo (P greater than 0.05), while no differences were evident with regard to laboratory data or cardiorespiratory function.

Aged↗
PubMed1988

Suppression of the pressor effect of centrally administered thyrotropin-releasing hormone under halothane, pentobarbital and flunitrazepam anaesthesia.

Intracerebroventricular (i.c.v.) administration of thyrotropin-releasing hormone (TRH) caused an increase in blood pressure (BP) and heart rate (HR) in conscious rats. The pressor effect was greatly diminished by adrenalectomy as well as after pretreatment with phentolamine, an alpha-receptor antagonist or with mecamylamine, a ganglion blocker, suggesting that centrally administered TRH increases BP mainly by stimulating sympathetic activity. Under halothane (0.8%), pentobarbital (33 mg/kg, i.p.) and flunitrazepam (0.8 mg/kg, i.v.) anaesthesia, the pressor effect of TRH was almost completely blocked. The increase in BP induced by peripheral alpha-receptor stimulation with phenylephrine was not affected by the anaesthetics at these doses. Pretreatment with atropine (50 micrograms, i.c.v.) significantly reduced the pressor effect of TRH. Intracerebroventricularly administered haloperidol and bicuculline also partially diminished the increase in BP produced by TRH, while other neurotransmitter blockers such as phentolamine, propranolol and naloxone did not. These results indicate that the anaesthetics at the doses employed interfere with the central neuronal pathway(s), probably cholinergic pathways, through which TRH exerts its pressor effect.

Animals↗
PubMed1993

Anaesthesia for coronary artery bypass grafting: opioid-analgesia combined with either flunitrazepam, propofol or isoflurane.

This is a prospective, open, randomized study comparing three different anaesthetic regimens with respect to haemodynamic stability (cardiac index and pressure measurements), ischaemia (ECG), and loss of awareness (midlatency auditory evoked potentials in 58 patients undergoing coronary artery surgery. Anaesthesia was based on fentanyl 0.01 mg kg-1 bw for induction and 0.8-2.0 mg h-1 in combination with nitrous oxide for maintenance before cardiopulmonary bypass and 0.2-0.6 mg h-1 without nitrous oxide during and after cardiopulmonary bypass. Eighteen patients were anaesthetised with flunitrazepam 0.01 mg kg-1 bw for induction and received thereafter 1-2 mg h-1 for maintenance (group F). In 40 patients anaesthesia was induced with etomidate and maintained with either isoflurane 0.4-1.2 vol% (group I) or propofol 4-10 mg kg-1 bw h-1 (group P). Vasodilators and inotropes were used for haemodynamic control when needed. Haemodynamic variables and ECG were studied at five timepoints (awake; after induction before surgery; after sternotomy; before cardiopulmonary bypass; and 20 min after separation from bypass). During surgical stimulation, vasodilators were needed significantly more frequently in group F, than in groups I and P. Surgery and sternotomy caused an increase in SVI and APs/SV in all groups. Differences between the groups were only found for systemic pressures, which after sternotomy were lowest in group I and before cardiopulmonary bypass were highest in group F. After termination of bypass all groups showed an increase in HR and a decrease in SVI, SVR, and LVSWI compared to the awake state, while CI remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Flunitrazepam in terminal care.

Flunitrazepam is a benzodiazepine of long half-life with sedative, anxiolytic, muscle relaxant and anticonvulsant properties. It has proved effective in controlling terminal agitation, confusion, restlessness, dystonia and fitting in adults and can be given by subcutaneous infusion in combination with other drugs. Its use in children during their terminal illness is described. Good symptom control without excessive sedation was achieved over the 24 h prior to death.

Child↗
PubMed1989

Intravenous flunitrazepam for status epilepticus.

Flunitrazepam (FZP) was administered intravenously, with success, to two patients with status epilepticus. Case 1 was a patient with a tonic-clonic status epilepticus. Intravenous phenytoin had no effect. Case 2 had minor status epilepticus. With the intravenous administration of FZP, diluted 1:10 with distilled water at a dose of 0.03 mg/kg at a slow rate, both patients were relieved of the status epilepticus. Unlike diazepam, FZP neither looks cloudy when diluted with distilled water nor causes angialgia. No disturbances in circulation or respiration occurred. Considering that FZP has a strong anticonvulsant action on status epilepticus, it can be expected to be a useful therapeutic agent for status epilepticus in infants and children.

Child↗