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PubMed1980

I.v. flunitrazepam and i.v. diazepam in conservative dentistry. A cross-over trial.

In a randomized cross-over trial in 82 outpatients aged 15-45 yr undergoing conservative dentistry, a solution of flunitrazepam 0.25 mg ml-1 i.v. (average dose 0.014 mg kg-1) was compared with a solution of diazepam 5 mg ml-1 i.v. (0.29 mg kg-1). Cardiovascular changes, operating conditions and side-effects were similar. Forty minutes after the start of injection, about 85% of all patients could not remember the local anaesthetic injection. Thirty minutes after the end of treatment, only 25% of all patients had recovered. One week later, most patients receiving each drug had only vague memories of their treatment; they had felt more relaxed immediately after the i.v. injection than before. Drowsiness was equally common after flunitrazepam and diazepam. Ataxia was more prolonged with flunitrazepam but arm pain and venous thrombophlebitis were less frequent.

Adolescent↗

PubMed1980

Local reactions after i.v. injections of diazepam, flunitrazepam and isotonic saline.

Local reactions after i.v. injection of diazepam, flunitrazepam and isotonic saline were studied in patients who received extradural analgesia or general anaesthesia. The frequency of thrombophlebitis on the 1st, 3rd and 5th days after the injection of diazepam was 2.1%, 17.0% and 14.9% respectively, after flunitrazepam 10.0%. 10.0% and 14.0%, and after saline 0%, 6.7% and 4.4%. The differences between the groups were not statistically significant (P > 0.05). One month after the injection 15.6% in the diazepam group, 8.5% in the flunitrazepam group and 9.3% in the saline group had pain or tenderness in the arm used for the injection.

Adult↗

PubMed1992

Comparison of the relaxant effects of diazepam, flunitrazepam and midazolam on airway smooth muscle.

The mechanisms by which benzodiazepines produce muscle relaxation and respiratory depression are not known, but they may include actions on peripheral benzodiazepine receptors or central GABA receptors, or a direct action on airway smooth muscle may also be involved. We have compared, therefore, the effects of diazepam, flunitrazepam and midazolam on airway tone by measuring isometric tension of guineapig trachealis muscle. Cumulative concentrations of diazepam, flunitrazepam and midazolam caused concentration-dependent relaxation of resting tone in the tracheal smooth muscle with no significant differences in pD2 values (-log EC50--an index of potency) or intrinsic activities (% of maximum response) for relaxations for the three compounds. Pretreatment with propranolol 10(-6) mol litre-1, flumazenil 10(-7) and 10(-6) mol litre-1 or PK11195 10(-6) mol litre-1 had no effect on diazepam- or midazolam-induced relaxation. Diazepam 3 x 10(-6) mol litre-1 pretreatment shifted the concentration-response curves for acetylcholine, histamine and serotonin (5-HT) to the right by a factor of approximately 2. Flunitrazepam 3 x 10(-6) mol litre-1 pretreatment also shifted the curves for histamine and 5-HT similarly to the right, whereas midazolam pretreatment did not inhibit any agonist-induced contractions. These results suggest that benzodiazepines relax airway smooth muscle, not via neural pathways or central and peripheral benzodiazepine receptors, but by a direct action on airway smooth muscle.

Animals↗

PubMed1993

Metabolic effects of propofol and flunitrazepam given for sedation after aortic surgery.

Sixteen patients who had undergone abdominal aortic surgery were allocated randomly to receive either propofol (total dose 3.2 (SEM 0.3) mg kg-1 h-1) or flunitrazepam (total dose 15 (2) micrograms kg-1 h-1) for 16 h after operation. Metabolic effects of sedation were assessed using a Deltatrac metabolic monitor. Initiation of sedation induced a 25% decrease in VO2 in both groups. The decrease was about 40% at 16 h. VO2 increased within 30 min after discontinuation of propofol and stabilized at values considerably less than the immediate postoperative value. A similar but slower increase was noted with flunitrazepam. While the propofol loading dose reduced the Buffington index and should therefore be avoided, no cardiovascular side effects were noted with the maintenance infusion. Weaning from ventilatory support was achieved within 15 (2) min and 264 (108) min after discontinuation of propofol and flunitrazepam, respectively.

Aortic Aneurysm, Abdominal↗

PubMedDate not supplied

Rapid method for the solid-phase extraction and GC-MS analysis of flunitrazepam and its major metabolites in urine.

Recently, flunitrazepam (Rohypnol) has become an increasingly popular drug of abuse among young adults, who take it for its euphoric effects. In other cases, the drug has been used by rapists for its sedative and hypnotic effects that can induce a catatonialike trance and memory loss in potential victims; as a result, it has been nicknamed the "date-rape drug". For these reasons, the Drug Enforcement Administration recently considered adding the drug (a.k.a. "Roofies") to the same category as heroin and LSD. A selective and sensitive technique has been developed for extracting, detecting, and identifying flunitrazepam and its two major metabolites (7-aminoflunitrazepam and N-desmethylflunitrazepam) in human urine. Using a solid-phase extraction cartridge containing a "mixed-mode" bonded silica gel (Bond Elut Certify), flunitrazepam and its metabolites were selectively isolated from other urine components and quantitated and identified by gas chromatography-tandem mass spectrometry with a benchtop ion mass spectrometer. The extraction method is rapid, reproducible, and precise, and it has a broad linear working range. The overall extraction efficiency was found to be more than 90% for the parent drug as well as the two major metabolites.

Flunitrazepam↗

PubMedDate not supplied

A comparison of sodium hydroxide and sodium sulfide digestion of mouse hair in the recovery of radioactivity following systemic administration of [3H]-nicotine and [3H]-flunitrazepam.

Pigmented (C57BI) and nonpigmented (balb/c) mice, 25 days of age, were treated intraperitoneally with [3H]-nicotine (4 mg/kg, 555 dpm/ng) or [3H]-flunitrazepam (1 mg/kg, 2200 dpm/ng) daily for three days. After 21 days, shaved back hair was digested at 37 degrees C for 24 h with either 1 M sodium hydroxide or 1 M sodium sulfide. With both drugs, sodium sulfide extraction removed the same amount of radioactivity as sodium hydroxide from nonpigmented hair. However, sodium sulfide removed significantly more radioactivity from pigmented hair than did sodium hydroxide. In pigmented hair, sodium sulfide solubilized 35% and 74% of the flunitrazepam- and nicotine-associated radioactivity, respectively. Of this, 12% and 43%, respectively, could be partitioned into ethyl acetate. Microscopic examination of residual pellets after digestion demonstrated a more thorough dissolution of the hair shaft with sodium sulfide with only melanosomes remaining. The results demonstrate the significant interaction of flunitrazepam and nicotine with melanins and the utility of sodium sulfide in increasing drug recovery.

Acetates↗

PubMedDate not supplied

A sensitive immunoassay for flunitrazepam and metabolites.

The objective of this study was to develop an immunoassay that would be capable of detecting flunitrazepam and/or cross-reacting metabolites in urine and comparing the results with those obtained by gas chromatography-mass spectrometry. Doses of Rohypnol varying between 0.5 and 4 mg were given to volunteers, and urine was collected for up to two weeks postingestion. These samples were analyzed by an ELISA that was developed using an antibody raised to flunitrazepam and a drug-enzyme conjugate prepared by attaching 7-aminoflunitrazepam to horseradish peroxidase. Significant levels of flunitrazepam and/or cross-reacting metabolites were detected in urine for up to one week after ingestion. The immunoassay is selective with only diazepam cross-reacting at a level of 1000 microg/L.

Anti-Anxiety Agents↗

PubMed1989

Differential effects of flunitrazepam on human sleep in combination with flumazenil.

The experiments reported here were designed to characterize in detail the spectrum of activity of flunitrazepam in human sleep. The direct and residual effects of flunitrazepam, as well as the antagonism by flumazenil, an antagonist of benzodiazepine receptors, were studied in 28 normal subjects recorded in the sleep laboratory. The five categories of variables--sleep-wake balance, sleep organization, orthodox sleep, phasic events in sleep, and sleep waveforms--were all modified by flunitrazepam. Some of these modifications were observed only on the drug night and were antagonized by flumazenil, whereas others persisted in the placebo postdrug night and were not antagonized by flumazenil. A few variables showed changes intermediate between these two types of reactivity. The results do not fit well with the multiple benzodiazepine receptors theory, but instead support the concept of spare receptors. Along these lines, the study of the reactivity of sleep components to ligands of benzodiazepine receptors can contribute to the better understanding of the neuronal systems involved in their control.

Adult↗

PubMed1977

Relative amnesic actions of diazepam, flunitrazepam and lorazepam in man.

1. Ten postcards were shown to groups of ten to twenty patients over 60, 90 or 270 min after intravenous injection of saline, diazepam (10 and 20 mg), flunitrazepam (1 and 2 mg) and lorazepam (4 mg). 2. Incidence of amnesia was estimated by the patients' ability to recall or recognize these cards and to recall various other incidents in the para-anaesthetic period. 3. The use of a dummy confirmed the reliability of the method of testing for amnesia in man. 4. Flunitrazepam produced a dose-related incidence of amnesia slightly longer than with the equivalent (1 x 10) dose of diazepam. 5. The onset of amnesia was slower with lorazepam (4 mg) but appeared to last for up to four hours. 6. This amnesic action of lorazepam was paralleled by a useful sensitive effect but there was no similar correlation for diazepam and flunitrazepam. 7. With three drugs of different duration of action it should be possible to produce amnesia for any required clinical situation.

Amnesia↗

PubMed1983

Effects of oral and intravenous midazolam, triazolam and flunitrazepam on the sleep-wakefulness cycle of rabbits.

The effect of the new, short-acting benzodiazepine, midazolam as well as that of triazolam and flunitrazepam on the sleep of rabbits was recorded for 6 h. Midazolam at 1 mg kg-1 i.v. augmented both rapid eye movement sleep (REMS) and non-REM sleep (NREMS) only in the first half of the observation period. At 10 mg kg-1 i.v., NREMS was further increased in the first and, to a lesser degree, in the second 3-h period, while REMS was suppressed. Both doses were less effective orally than intravenously. Qualitatively, the effect of triazolam 0.01 and 0.1 mg kg-1 i.v. was very similar to that of the corresponding low and high intravenous doses of midazolam, except that the high dose of triazolam had a prolonged effect on total sleep time. Like midazolam, triazolam was substantially less effective orally than intravenously. Flunitrazepam at 0.1 and 1 mg kg-1 i.v. produced almost the same effects as midazolam and triazolam at the respective low and high intravenous doses, but had a longer duration of action. In contrast to midazolam and triazolam, flunitrazepam was almost as active orally as intravenously.

Administration, Oral↗

PubMed1987

Placental transfer of flunitrazepam following intramuscular administration during labour.

After a single intramuscular dose of flunitrazepam 0.015 mg kg-1 (n = 14) in women 37 to 41 weeks pregnant, the concentrations in the umbilical artery and amniotic fluid were significantly lower than in maternal venous plasma. Although the difference between the maternal venous and umbilical venous plasma concentrations was not significant, the mean fetomaternal ratio was 0.7. The plasma protein binding of flunitrazepam was 80 +/- 4% in the mother and 79 +/- 5% in the umbilical circulation. Both mothers and midwives subjectively estimated intramuscular flunitrazepam as a valuable sedative-anxiolytic agent during the first stage of labour.

Adult↗

PubMed1980

Venous complications after intravenous injection of diazepam, flunitrazepam, thiopentone and etomidate.

The occurrence of phlebitis, thrombosis, and thrombophlebitis after intravenous premedication with diazepam (0.15 mg/kg) dissolved in propylene glycol (Valium) or in polyethylene glycol (Diapam) or flunitrazepam (0.0125 mg/kg), and after intravenous induction of balanced general anaesthesia with thiopentone (4.0 mg/kg) or etomidate (0.3 mg/kg) was studied on the 7th and 14th postoperative days in 115 patients undergoing short-stay varicose vein surgery. Venous complications occurred most frequently after etomidate (43% at 14 days), thiopentone (23% at 14 days), and Valium (21% at 7 days). Diapam caused fewer venous sequelae (9% at 14 days) than Valium (18% at 14 days), but the smallest number of complications were noticed after flunitrazepam (8% at 7 days and none at 14 days). Venous sequelae were more severe and more extended after thiopentone and after etomidate than those after the diazepam preparations. It is concluded that venous complications after flunitrazepam premedication were mild and infrequent and that the incidence of such complications was unacceptably high after etomidate induction.

Adult↗

PubMed1990

Rectal flunitrazepam as premedication in preschool children. A double-blind randomized study.

The efficacy of flunitrazepam (0.04 mg.kg-1) as a premedicant was evaluated in 40 young children of less than 5 years of age in a double-blind, placebo-controlled study. Flunitrazepam was given by the rectal route 15 min prior to an inhalational mask induction with halothane. Sedation score, mask acceptance and induction score were significantly better in premedicated children than in the placebo group. There were no hypoxic episodes, prolonged sedation or other complications in either group. This suggests that flunitrazepam administered rectally in a low dose is an acceptable premedication in young children.

Administration, Rectal↗

PubMed1983

Irreversible binding of [3H]flunitrazepam to different proteins in various brain regions.

Irreversible photolabeling by [3H]flunitrazepam of four proteins with apparent molecular weights 51,000 (P51), 53,000 (P53), 55,000 (P55), and 59,000 (P59) was investigated in various rat brain regions by SDS-polyacrylamide gel electrophoresis, fluorography, and quantitative determination of radioactivity bound to proteins. On maximal labeling of these proteins, only 15-25% of [3H]flunitrazepam reversibly bound to membranes becomes irreversibly attached to proteins. Results presented indicate that for every [3H]flunitrazepam molecule irreversibly bound to membranes, three molecules dissociate from reversible benzodiazepine binding sites. This seems to indicate that these proteins are either closely associated or identical with reversible benzodiazepine binding sites, and supports the hypothesis that four benzodiazepine binding sites are associated with one benzodiazepine receptor. When irreversible labeling profiles of proteins P51, P53, P55, and P59 were compared in different brain regions, it was found that labeling of individual proteins varied independently, supporting previous evidence that these proteins are associated with distinct benzodiazepine receptors.

Animals↗

PubMed1984

Flunitrazepam binding to intact and homogenized astrocytes and neurons in primary cultures.

[3H]Flunitrazepam binds to intact and homogenized mouse astrocytes and neurons in primary cultures. In intact cells, the binding is to a single, high-affinity, saturable population of benzodiazepine binding sites with a KD of 7 nM and Bmax of 6,033 fmol/mg protein in astrocytic cells and a KD of 5 nM and Bmax of 924 fmol/mg protein in neurons. After homogenization, the Bmax values decrease drastically in both cell types, but most in astrocytes. The temperature and time dependency are different for the two cell types, with a faster association and dissociation in astrocytes than in neurons and a greater temperature sensitivity in the astrocytes. Moreover, flunitrazepam binding sites on neuronal and astrocytic cells have different pharmacological profiles. In intact astrocytic cells, Ro 5-4864 (Ki = 4 nM) is the most potent displacing compound, followed by diazepam (Ki = 6 nM) and clonazepam (Ki = 600 nM). In intact neurons, the relative order of potency of these three compounds is different: diazepam (Ki = 7 nM) is the most potent, followed by clonazepam (Ki = 26 nM) and Ro 5-4864, which has little effect. After homogenization the potency of diazepam decreases. We conclude that both neuronal and astrocytic cells possess high-affinity [3H]flunitrazepam binding sites. The pharmacological profile and kinetic characteristics differ between the two cell types and are further altered by homogenization.

Animals↗

PubMed1984

Characterization of Na+-independent GABA and flunitrazepam binding sites in preparations of synaptic membranes and postsynaptic densities isolated from canine cerebral cortex and cerebellum.

The binding of [3H]GABA and [3H]flunitrazepam was performed with synaptic membranes and post-synaptic densities (PSDs) isolated from canine cerebral cortex and cerebellum. Two GABA binding sites were found with cerebral cortex membranes but only one with cerebellar membranes. PSDs isolated from these showed only single binding sites, with cerebellar PSDs exhibiting lower KD values and a larger concentration of sites than did cerebral cortex PSDs. In the case of flunitrazepam, only one binding site was found for all four preparations, with cerebellar PSDs having twice the concentration of sites of cerebral PSDs. Photoaffinity labeling of the flunitrazepam receptor in PSDs resulted in the binding to a 51,000 Mr protein in both cases, with cerebellar PSDs again showing an increased concentration over that found in cerebral cortex PSDs. Based on this work, and on earlier work of ourselves and of others, we conclude that both populations of isolated PSDs contain inhibitory sites, but that the intact PSDs in both preparations are derived from Gray type I, probably excitatory, synapses, and that the inhibitory sites are found in the broken-up material in the PSD fractions which are derived from Gray type II, probably inhibitory, synapses.

Animals↗

PubMed1987

Comparison of tryptic peptides of benzodiazepine binding proteins photolabeled with [3H]flunitrazepam or [3H]Ro 15-4513.

When rat brain membranes were incubated with the benzodiazepine agonist [3H]flunitrazepam or the partial inverse benzodiazepine agonist [3H]Ro 15-4513 in the presence of ultraviolet light one protein (P51) was specifically and irreversibly labeled in cerebellum and at least two proteins (P51 and P55) were labeled in hippocampus. After digestion of the membranes with trypsin, protein P51 was degraded into several peptides. When P51 was photolabeled with [3H]Ro 15-4513, four peptides with apparent molecular weights of 39,000, 29,000, 21,000, and 17,000 were observed. When P51 was labeled with [3H]flunitrazepam, only two peptides with apparent molecular weights of 39,000 and 25,000 were obtained. Protein P55 was only partially degraded by trypsin, and whether it was labeled with [3H]flunitrazepam or [3H]Ro 15-4513 it yielded the same two proteolytic peptides with apparent molecular weights of 42,000 and 45,000. These results support the existence of at least two different benzodiazepine receptor subtypes associated with proteins P51 and P55. The different receptors seem to be differentially protected against treatment with trypsin. In addition, these results indicate that in the benzodiazepine receptor subtype associated with P51 benzodiazepine agonists and partial inverse benzodiazepine agonists irreversibly bind to different parts of the molecule.

Animals↗

PubMed1989

Polychlorinated convulsant insecticides potentiate the protective effect of NaCl against heat inactivation of [3H]flunitrazepam binding sites.

Six polychlorinated convulsant insecticides that potently inhibit t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to rat brain membranes also potentiate the protective effect of NaCl (200 mM) against heat inactivation of [3H]flunitrazepam binding sites on the same membranes. Similar effects were obtained with all "cage" convulsants tested. The rank order of potencies as heat protection potentiators was similar to the rank order of potencies as inhibitors of [35S]TBPS binding (alpha-endosulfan greater than endrin greater than dieldrin greater than toxaphene greater than lindane). alpha-Endosulfan and endrin are more potent in both respects than any previously reported picrotoxin-like (cage) convulsant, but are much less toxic to mammals. The greatly reduced toxicities of alpha-endosulfan and endrin in mammals may reflect partial gamma-aminobutyric acid (GABA)-neutral properties of these compounds. Time courses of heat inactivation of [3H]flunitrazepam binding sites in the presence of 200 mM NaCl plus saturating concentrations of endrin or picrotoxin revealed monophasic components constituting about 88% of the binding sites, suggesting that virtually all [3H]flunitrazepam binding sites are coupled to picrotoxin binding sites in the GABA/benzodiazepine/picrotoxin receptor complex. Protection against heat inactivation constitutes a useful tool for characterizing the various allosterically linked binding sites in neurotransmitter receptor complexes.

Animals↗