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PubMed2000

Validated method for the therapeutic drug monitoring of flunitrazepam in human serum using liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry with an ion trap detector.

An HPLC-MS-MS method for the quantitative analysis of flunitrazepam in human serum was established. The method features a very simple liquid-liquid extraction, the use of a standard 4-mm HPLC column, isocratic elution using a buffer-free solvent, short retention times in connection with good peak resolution and the sensitivity and selectivity of an ion trap MS-MS detector. The procedure enables unambiguous identification of analytes by their product ion spectra, as well as sensitive quantitation (limit of quantitation for flunitrazepam=0.5 ng/ml). This feature was used for the confirmation of HPLC-UV results for nitrazepam.

Anti-Anxiety Agents↗

PubMed1988

Intravenous injection of flunitrazepam for status epilepticus in children--two case reports.

Two cases of status epilepticus are reported, whose seizures responded well to the injection of flunitrazepam. One patient had generalized tonic clonic seizures and the other had partial seizures. The improvement of their condition was confirmed by both clinical and electroencephalographic examinations. There were no serious side effects observed. Flunitrazepam might have a potential efficacy for the treatment of status epilepticus of both generalized and partial seizures.

Electroencephalography↗

PubMed1983

[Hemodynamic effects of flunitrazepam in cardiac patients during anesthetic induction].

The hemodynamic effects of flunitrazepam were studied in eight coronary patients (group I) and in six patients with compensated cardiac failure (group II) during the induction of anesthesia with droperidol 5 mg and fentanyl 4 micrograms . kg-1. A right sided cardiac catheterization was performed to measure cardiac output by thermodilution. In coronary patients, the hemodynamic parameters were only slightly modified (NS). Cardiac output (-12.7%) and oxygen consumption (-20.4%) decreased; Pvo2 increased from 6.4 +/- 0.1 to 7.3 +/- 0.3 kPa. In patients with cardiac failure, significant cardiovascular changes were not observed. Arterial pressure (-13%), cardiac output (-2.6%), oxygen consumption (-6%) and systemic vascular resistance (-13.4%) decreased; Pvo2 increased from 6.4 +/- 0.5 to 6.8 +/- 0.7 kPa. In both groups, heart rate and pulmonary capillary wedge pressure were unchanged. There was only a significant difference (p less than 0.05) between the decrease in systemic resistance in group II and in the absence of change in systemic resistance in group I. Decrease in oxygen consumption be decrease in oxygen demand could explain the slight decrease in cardiac output. Flunitrazepam was a good hypnotic for the induction of anesthesia in normovolaemic coronary patients and in patients with compensated cardiac failure.

Acid-Base Equilibrium↗

PubMed2003

Effects of zolpidem 10 mg, zopiclone 7.5 mg and flunitrazepam 1 mg on night-time motor activity.

The effects of a single dose of zolpidem (10 mg), zopiclone (7.5 mg) and flunitrazepam (1 mg) on motor activity the following 3 nights were compared to those of a placebo in a double-blind, crossover study. Thirty-three healthy subjects received medication between 10.30 and 11.30 p.m. and were asked to rise between 7.30 and 8.30 a.m. During the night under treatment, flunitrazepam, zopiclone and zolpidem significantly reduced motor activity. Changes in motor activity are quantitatively compatible with the hypothesis of reduced light sleep and wakefulness after sleep onset. During the first or second post-drug night, for zolpidem and zopiclone the opposite effect was observed, i.e. increased activity compared with placebo. These modifications cannot be explained by modified sleep structure. This last result underlines our inadequate understanding of the underlying mechanisms of motor activity during sleep. However, being sensitive and easy to use, actigraphy is an ideal technique to assess the effect of hypnotics on large populations and for long duration studies.

Adult↗

PubMed2003

Comparison of hangover effects among triazolam, flunitrazepam and quazepam in healthy subjects: a preliminary report.

The aim of the present study was to compare the hangover effects of night-time administration of triazolam (0.25 mg), flunitrazepam (1 mg) and quazepam (15 mg) in healthy subjects. Daytime sleepiness and performance level following the night-time administration of the drugs were assessed using Standford Sleepiness Scale (SSS), Sleep Evaluation Questionnaire (SEQ), Multiple Sleep Latency Test (MSLT), actigraphy recordings and Continuous Performance Test (CPT). Fifteen healthy volunteers were given one of the three hypnotics at each drug session, which lasted for 1 week, in a single-blind cross-over fashion. No significant between-drug difference was observed for the psychomotor performance assessed by CPT. Subjective hangover effects assessed by SSS and SEQ in the morning were prominent for flunitrazepam and quazepam relative to triazolam, whereas objective indices such as MSLT or activity counts obtained in actigraphy indicated a marked hangover effect of quazepam compared with the other two compounds restrictively in the afternoon, which were nearly in accordance with their pharmacokinetic profiles.

Activities of Daily Living↗

PubMed1978

Premedication for upper gastrointestinal endoscopy: a comparative study of flunitrazepam, diazepam and neuroleptanalgesia.

Flunitrazepam or diazepam with atropine and a combination of phenoperidine, droperidol and cyclizine (neuroleptanalgesia) were compared as premedication in three groups of 25 patients undergoing routine upper gastrointestinal endoscopy. Drug doses were titrated carefully against response and all three regimes were found to be similar in terms of safety, patient co-operation, relaxation and speed of recovery. Neuroleptanalgesia however produced a statistically significant rise in endtidal pCO2 and systolic blood pressure. The benzodiazepines, and in particular flunitrazepam, produced a significantly greater amnesia for the procedure, patients given these drugs being more willing to undergo repeat endoscopy.

Anti-Anxiety Agents↗

PubMed1977

Flunitrazepam compared with althesin as an induction agent in balanced anaesthesia.

The effects of flunitrazepam and Althesin as anaesthetic induction agents were studied in a double-blind trial in 97 patients undergoing abdominal or gynaecological surgery. There was no difference between the two preparations in respect of the quality of induction. A marked difference in the quality of maintenance of anaesthesia were seen, in favour of flunitrazepam. Recovery was more rapid from Althesin anaesthesia. A low incidence of nausea was observed in both groups.

Adolescent↗

PubMed1978

Effect of age on amnesia and sedation induced by flunitrazepam during local anaesthesia for bronchoscopy.

Bronchoscopy was undertaken in 79 outpatients using local anaesthesia plus an i.v. injection of flunitrazepam 0.01 mg kg-1. The co-operation of the patients and the ease of bronchoscopy were good regardless of the age of the patient. There was an increase in amnesia for the bronchoscopy with increasing age, but the most distinct difference between different age groups was that the amnesic action of flunitrazepam was evident earlier and persisted longer in patients of more than 60 yr. Eye co-ordination and ability to stand steadily and walk on a line returned to normal more slowly in patients more than 60 than in those less than 60 yr, but no differences in recovery were noted between patients less than 40 and those of 40--59 yr, or between those 60--69 and those more than 70 yr.

Adult↗

PubMed1980

Comparison of the subjective effects and plasma concentrations following oral and i.m. administration of flunitrazepam in volunteers.

Flunitrazepam 0.5, 1.0 or 2.0 mg was given by the oral or i.m. routes to groups of volunteers and its effects compared. Plasma concentrations of the drug were estimated by gas-liquid chromatography, in a smaller number of the subjects. The most striking effect was sedation which increased with the dose, 2 mg producing deep sleep although the subjects could still be aroused. The effects of i.m. administration were apparent earlier and sometimes lasted longer than those following oral administration. Dizziness was less marked than sedation, but increased with the dose. There was pain on i.m. injection of flunitrazepam significantly more often than with isotonic saline. Plasma concentrations varied with dose and route and corresponded qualitatively with the subjective effects. The drug was still present in measurable quantities after 24 h even with the smallest dose.

Administration, Oral↗

PubMed1981

Anaesthesia with flunitrazepam and ketamine.

A randomized study of 96 women undergoing hysterectomy was used to compare two anaesthetic techniques: flunitrazepam, ketamine and nitrous oxide in oxygen; and pethidine, thiopentone, nitrous oxide in oxygen and halothane. The techniques exerted small, but significantly different influences on heart rate and arterial pressure. Significantly more patients complained of nausea and vomiting on awakening after inhalation anaesthesia. Amnesia after operation lasted significantly longer after flunitrazepam combined with ketamine and nitrous oxide in oxygen.

Adult↗

PubMed1983

Effects of flunitrazepam on left ventricular performance, coronary haemodynamics and myocardial metabolism in patients with coronary artery disease.

The effects of flunitrazepam 15 micrograms kg-1, on left ventricular (LV) performance, coronary sinus blood flow (CSBF), myocardial oxygen uptake and myocardial lactate balance were studied in nine patients with coronary artery disease undergoing cardiac catheterization. Flunitrazepam produced a decrease in mean aortic pressure (MAP) and in systemic vascular resistance (SVR) with maximal changes from control value observed at 15 min for MAP and at 5 min for SVR. No change in cardiac index was observed. The following changes in variables related to LV performance were observed: (1) a transient increase in heart rate and left ventricular contractility (Vmax); (2) a sustained decrease of left ventricular end-diastolic pressure, maximum at 15 min. Myocardial oxygen consumption was decreased at 15 min but CSBF did not change, whereas total coronary vascular resistance was decreased. Since myocardial lactate extraction was increased and no change in ECG was observed, a coronary steal induced by coronary vasodilatation did not appear to take place.

Carbon Dioxide↗

PubMed1984

Flunitrazepam as an induction agent in children. A clinical and pharmacokinetic study.

Flunitrazepam was studied as an induction agent in paediatric patients. The onset of action was slow and its efficacy uncertain following single doses of 0.03 mg kg-1(n = 4), or 0.04 mg kg-1 (n = 6) i.v. Long-lasting sedative effects were observed following operation. A strong anterograde but not retrograde amnesic effect was obtained, and a possible analgesic sparing property. Flunitrazepam has a faster and more extensive tissue distribution and a more rapid elimination (half-life about 12 h) in children than in adults.

Anesthesia, General↗

PubMed1999

Highly sensitive micro-plate enzyme immunoassay screening and NCI-GC-MS confirmation of flunitrazepam and its major metabolite 7-aminoflunitrazepam in hair.

Flunitrazepam (Rohypnol) is a benzodiazepine used in the treatment of insomnia as a sedative hypnotic and as preanesthetic medication in European countries and Mexico. Although it has no medicinal purpose in the United States, the occurrence of its abuse is increasing. Sexual abuse of both men and women while under the influence of so-called "date-rape" drugs has been the focus of many investigations. Reported date-rape drugs include flunitrazepam (FN), clonazepam, diazepam, oxazepam, gamma-hydroxybutyrate, and many others. FN has been banned in the United States because of its alleged use in such situations. Unfortunately, the detection of FN or its metabolites 7-aminoflunitrazepam (7-AFN) and desmethylflunitrazepam in a single specimen such as urine or blood is difficult in criminal situations because of the likelihood of single-dose ingestion and the length of time since the alleged incident. Hair provides a solution to the second of these problems in that drugs tend to incorporate into hair and remain there for longer periods of time than either urine or blood. There are various techniques for the detection of FN in plasma, blood, and urine, but little work has been done with hair. Hair collection is a virtually noninvasive procedure that can supply information on drug use for several months preceding collection. The objective of this paper was to determine if a commercially available micro-plate enzyme immunoassay system was sufficiently sensitive for the routine screening of 7-AFN in hair by the development of extraction procedures and optimization of the immunoassay kit. Further, this study used the same solid-phase extraction to isolate FN and its major metabolite, 7-AFN, and gas chromatography-mass spectrometry with negative ion chemical ionization for confirmation. Two seven-point standard curves were established ranging from 0.5 pg/mg to 100 pg/mg for 7-AFN and 2.5 pg/mg to 200 pg/mg for FN with respective deuterated internal standards. A replicate analysis of controls was performed to establish inter- and intraday variabilities. Two suicide cases along with one alleged date-rape case and one case of an emergency room patient whose blood screened positive for benzodiazepines were analyzed. All the hair specimens screened positive for benzodiazepines using micro-plate enzyme immunoassay. Two cases, including the date-rape case, were negative for FN and 7-AFN, and two postmortem hair samples were confirmed positive for FN and its metabolite.

Anti-Anxiety Agents↗

PubMed1999

GC-MS determination of flunitrazepam and its major metabolite in whole blood and plasma.

A gas chromatography-mass spectrometry method was developed for the analysis of flunitrazepam (FN) and its major metabolite, 7-amino-flunitrazepam (7-amino-FN), in both plasma and whole blood. The method was based on acid hydrolysis of the samples after dilution with HPLC water followed by extraction and derivatization (heptafluorobutyrate) of the resulting benzophenones. Analysis of plasma and whole blood samples from subjects administered 2-mg doses of FN showed that FN was only detected in whole blood (LOD 5 ng/mL) and not in plasma. However, 7-amino-FN was detected in both plasma and whole blood, although the levels were much higher in plasma. 7-Amino-FN was detected for the entire period of specimen collection (12 h), but FN was only detected in whole blood for 4 h after ingestion with peak levels after 1 h.

Anti-Anxiety Agents↗

PubMedDate not supplied

Serum and urine concentrations of flunitrazepam and metabolites, after a single oral dose, by immunoassay and GC-MS.

A clinical study was conducted to assess the ability of commercially available immunoassays to detect flunitrazepam (FNP) in plasma and urine samples and to compare the results with those obtained by gas chromatography-mass spectrometry (GC-MS). The clinical study consisted of four individuals (two male and two female) who had taken a single 2-mg dose of FNP. Serum was collected over a 48-h period and urine was collected over a 72-h period. The serum and urine samples were analyzed by the COBAS INTEGRA Serum Benzodiazepines assay (SBENZ), the TDx serum and urine Benzodiazepines assay, and GC-MS. The GC-MS procedure was developed for analysis of FNP and metabolites in plasma and urine using an acid hydrolysis step resulting in the formation of specific benzophenones corresponding to FNP and its metabolites. The relative sensitivities of the assays for the detection of FNP and metabolites in serum and urine were GC-MS > SBENZ > TDx. The immunoassay results for serum samples showed peak concentrations of FNP metabolites at 8 h after FNP ingestion for three individuals and at about 1 h for the fourth individual. The GC-MS, SBENZ, and TDx urine immunoassays detected drug above the stated limit of detection (LOD) in 44, 41, and 35 serial FNP urine samples, respectively. FNP metabolites were detected in urine samples with all three assays for up to 72 h after a 2-mg dose. The improved detection rate with the SBENZ assay as compared to the TDx assay is likely explained by its higher cross-reactivity with the major metabolite, 7-amino-flunitrazepam (7-amino-FNP), and its lower LOD.

Administration, Oral↗

PubMed1991

Coronary and left ventricular hemodynamic responses following reversal of flunitrazepam-induced sedation with flumazenil in patients with coronary artery disease.

The effects of reversal of flunitrazepam-induced sedation with flumazenil on coronary hemodynamics, myocardial oxygen consumption (MVO2), and left ventricular (LV) performance were investigated, in a double-blind trial, in 12 patients with stable coronary artery disease undergoing cardiac catheterization. Coronary sinus blood flow was measured by continuous thermodilution. Arterial and coronary sinus blood were analyzed for oxygen and lactate contents. The determinants of LV performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. To reverse flunitrazepam-induced sedation, patients were randomly allocated to receive placebo or flumazenil (by increment, up to 1 mg) at the end of procedure. In the placebo group, no significant hemodynamic changes were observed. In the flumazenil group, heart rate, cardiac index, maximum velocity of shortening, and relaxation time constant were not significantly altered. By contrast, mean aortic pressure and LV end-diastolic pressure (baselines: 90 +/- 5 and 7.3 +/- 4.1 mmHg, respectively) increased (9%, P less than 0.05 and 67%, P less than 0.05, respectively) after flumazenil administration, but these changes represented mainly a return toward presedation values. MVO2 and coronary resistance were not significantly altered, whereas CSBF increased slightly (baseline: 119 +/- 20 ml/min; increase 10%, P less than 0.05). No electrocardiographic evidence of myocardial ischemia was observed during the study. These data show that reversal of benzodiazepine effects with flumazenil is not associated with a major alteration of LV systolic function, relaxation, or coronary hemodynamics in patients with coronary artery disease. Nevertheless, it should be cautiously used when LV end-diastolic pressure is increased at the time of its administration.

Adult↗

PubMed1994

Zopiclone improves sleep quality and daytime well-being in insomniac patients: comparison with triazolam, flunitrazepam and placebo.

In a randomized, double-blind, parallel group study in private practice, zopiclone given for 28 days was compared with flunitrazepam, triazolam and placebo in its effect on quality of sleep and daytime well-being in 1507 patients suffering from insomnia. For quantitative assessment, patients were defined as responders according to either a shortening of sleep latency by at least 15 min, or prolongation of total sleep time by at least 20%, or reduction of the number of nocturnal awakenings to three or less and a fresh feeling in the morning, as well as lack of impairment in daytime well-being as a result of tiredness or anxiety. The responder rate tended to be higher with zopiclone (37.4%) than with flunitrazepam (30%) and triazolam (32.2%) and was significantly greater (p = 0.0017) than with placebo (26.8%). Daytime well-being was particularly responsive to zopiclone and most responsive in severe insomniacs. With the exception of those to triazolam, rates of response were most pronounced in patients with insomnia of a short duration (< or = 1 year) than in those with insomnia of a longer duration (> or = 1 year). Following discontinuation of treatment, all groups showed a moderate reduction in therapeutic effect, but no rebound insomnia occurred.

Azabicyclo Compounds↗

PubMed1994

Systemic absorption and abuse liability of snorted flunitrazepam.

Benzodiazepine hypnotics are widely abused as part of a polydrug misuse culture. This study set out to investigate some pharmacokinetic and pharmacodynamic characteristics of a novel method of abuse, snorting, of flunitrazepam. Twenty healthy volunteers took part: three took 0.5 mg, three took 1 mg, three took 1.5 mg, six took 2 mg and five took placebo. Blood was sampled and ratings of mood, bodily symptoms, strength and liking of drug effect were completed pre- and at 5, 15, 30, 60, 90, 120 and 240 minutes and at 24 hours post-drug. It was found that flunitrazepam could be detected in venous blood 5 minutes after intake. As the dose increased, the peak plasma concentration was higher but also occurred progressively later, the levels reached being comparable to oral or intramuscular administration at 110 minutes. Subjects reported sedation but complained of few side-effects. They liked the drug effects and subjective ratings of strength were correlated with liking and with plasma drug levels.

Administration, Inhalation↗