Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Flunitrazepam”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources
PubMed2006

Sweeping technique combined with micellar electrokinetic chromatography for the simultaneous determination of flunitrazepam and its major metabolites.

A sweeping technique, in conjunction with micellar electrokinetic chromatography, for the simultaneous determination of flunitrazepam and its major metabolites, 7-aminoflunitrazepam and N-desmethylflunitrazepam, is described. The optimized conditions for the sweeping and separation were a pH 9.5 buffer, 25mM borate, 50mM cetyltrimethylammonium bromide, 30% MeOH (v/v), and a 151-mm injection length. The calibration functions were all linear with the coefficient of determination (r(2)) exceeding 0.996 for the three target compounds. Using the sweeping procedure, the limits of detection were determined to be 13.4, 5.6, and 12.0ng/mL for flunitrazepam, 7-aminoflunitrazepam, and N-desmethylflunitrazepam, respectively, and the sensitivity enhancement for each compound was within the range of 110-200 fold. The RSDs for the retention time and the peak area were less than 4.10%. The optimized sweeping method was also used to examine a spiked urine sample. We conclude that sweeping with micellar electrokinetic chromatography has considerable potential use in clinical and forensic analyses of flunitrazepam and its metabolites.

Anti-Anxiety Agents↗
PubMed2004

Effects of flunitrazepam on the Lalpha-H(II) phase transition of phosphatidylethanolamine using merocyanine 540 as a fluorescent indicator.

Previous studies of our group demonstrated that flunitrazepam is a lipophilic drug capable of interacting with membranes through a partition equilibrium phenomenon. Its localization at the phospholipid polar head region could explain the decrease in the size of dipalmitoylphosphatidylcholine (dpPC) vesicles, through a mechanism that involves the increment in the relative volume of this region with a subsequent increase in the vesicle's surface curvature. In the present work, we investigated if flunitrazepam can affect the L(alpha)-H(II) phase transition of phosphatidylethanolamine through a similar mechanism. This study was approached by using merocyanine 540, a dye sensitive to the molecular packing of membrane lipids. A detailed analysis of merocyanine absorption and fluorescence emission and excitation spectra was performed. The results indicated that the fluorescence emitted came mainly from the monomeric form of merocyanine and that it resulted a good indicator of this phase transition, as was previously described. Flunitrazepam did not affect significantly the onset of the phase transition but showed a tendency to diminish the dye fluorescence emission intensity, which could involve a lower partition of merocyanine in the vesicles. Moreover, the results suggest that this drug produced a delay in the completeness of the phase transition and a decrement in the cooperativity of this phenomenon.

Dimerization↗
PubMed2004

Development and validation of a gas chromatography-mass spectrometry method for the simultaneous determination of buprenorphine, flunitrazepam and their metabolites in rat plasma: application to the pharmacokinetic study.

Buprenorphine (BUP), a synthetic opioid analgesic, is frequently abused alone, and in association with benzodiazepines. Fatalities involving buprenorphine alone seem very unusual while its association with benzodiazepines, such as flunitrazepam (FNZ), has been reported to result in severe respiratory depression and death. The quantitative relationship between these drugs remain, however, uncertain. Our objective was to develop an analytical method that could be used as a means to study and explore, in animals, the toxicity and pharmacological interaction mechanisms between buprenorphine, flunitrazepam and their active metabolites. A procedure based on gas chromatography-mass spectrometry (GC-MS) is described for the simultaneous analysis of buprenorphine, norbuprenorphine (NBUP), flunitrazepam, N-desmethylflunitrazepam (N-DMFNZ) and 7-aminoflunitrazepam (7-AFNZ) in rat plasma. The method was set up and adapted for the analysis of small plasma samples taken from rats. Plasma samples were extracted by liquid-liquid extraction using Toxi-tubes A. Extracted compounds were derivatized with N,O-bis-(trimethylsilyl)trifluoroacetamide (BSTFA), using trimethylchlorosilane (TMCS) as a catalyst. They were then separated by GC on a crosslinked 5% phenyl-methylpolysiloxane analytical column and determined by a quadrupole mass spectrometer detector operated under selected ion monitoring mode. Excellent linearity was found between 0.125 and 25 ng/microl plasma for BUP, 0.125 and 12.5 ng/microl for NBUP and N-DMFNZ, 0.125 and 5 ng/microl for FNZ, and between 0.025 and 50 ng/microl for 7-AFNZ. The limit of quantification was 0.025 ng/microl plasma for 7-AFNZ and 0.125 ng/microl for the four other compounds. A good reproducibility (intra-assay CV=0.32-11.69%; inter-assay CV=0.63-9.55%) and accuracy (intra-assay error=2.58-12.73%; inter-assay error=0.83-11.07%) were attained. Recoveries were 71, 67 and 81%, for BUP, FNZ and N-DMFNZ, respectively, and 51% for NBUP and 7-AFNZ, with CV ranging from 5.4 to 13.9%, and were concentration-independent. The GC-MS method was successfully applied to the pharmacokinetic study of BUP, NBUP, FNZ, DMFNZ and 7-AFNZ in rats, after administration of BUP and FNZ.

Analgesics, Opioid↗
PubMed1977

Quantitative gas chromatographic analysis of flunitrazepam in human serum with electron-capture detection.

A rapid method for the determination of flunitrazepam and desmethylfflunitrazepam in human serum in the range 10-300 ng/ml is described. Both drugs are isolated from biological material by means of a single extraction, part of the organic phase is evaporated to dryness and the residue is dissolved in a small volume of benzene. Without further purification, the substance is determined gas chromatographically with an electron-capture detector configuration of 63Ni-type. The method permits the quantitative determination of at least 25-300 ng/ml with an overall recovery of flunitrazepam of 99.7 +/- 4.9% and of desmethylflunitrazepam of 98.6 +/- 7.8% from serum. All calculations were carried out by a data system that was programmed for this purpose. The limit of detection for flunitrazepam is of the order of 1 ng/ml in serum. The method is sufficiently sensitive and specific for therapy control purposes. The time needed for an analysis is less than 1 h.

Anti-Anxiety Agents↗
PubMed1996

Identification of domains in human recombinant GABAA receptors that are photoaffinity labelled by [3H]flunitrazepam and [3H]Ro15-4513.

We have used [3H]flunitrazepam and [3H]Ro15-4513 as photoaffinity labelling agents in combination with a chemical cleavage technique to localize the benzodiazepine recognition sites of specific human recombinant alpha 1 beta 1 gamma 2, alpha 1 beta 3 gamma 2 and alpha 6 beta 3 gamma 2 GABAA receptor subtypes. The chemical agent utilized was hydroxylamine, whose substrate is a relatively rare asparagine-glycine amide bond that occurs only in the alpha subunits of the receptors examined in this study. Cleavage products were resolved using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The results of these experiments show that, in the alpha 1 subunit-containing receptors, incorporation of [3H]flunitrazepam occurs within residues 1-103 of the alpha 1 subunit, while incorporation of [3H]Ro15-4513 occurs within the region of the alpha 1 subunit that lies between residue 104 and the C-terminus. Photolabelling of membranes prepared from the alpha 6 beta 3 gamma 2-expressing cell line with [3H]Ro15-4513 resulted in the incorporation of radiolabel into two major protein species of M(r) 56,000 and M(r) 48,000, indicating incorporation into the alpha 6 subunit and possibly also the gamma 2 subunit. Hydroxylamine cleavage of alpha 6-containing receptors labelled with [3H]Ro15-4513 produced a gel profile consistent with the incorporation of the label occurring between residue 125 and the C-terminal. Thus, we have shown that the recognition sites for the agonist [3H]flunitrazepam and the inverse agonist [3H]Ro15-4513 occur within distinct domains of the human GABAA receptor.

Affinity Labels↗
PubMed1984

[Comparison of midazolam and flunitrazepam as premedication administered rectally in infants].

The present study aimed to assess the pharmaco-clinical profile of infants premedicated with rectal midazolam. The results were compared with those of a reference drug, flunitrazepam. Infants undergoing minor surgery were divided into three groups: group A (n = 30), with a mean age of 15.8 +/- 13.2 months and a mean weight of 8.6 +/- 3.3 kg, receiving 0.33 mg X kg-1 flunitrazepam; group B (n = 15), with a mean age of 11.2 +/- 10.7 months and a mean weight of 9.3 +/- 3.1 kg, receiving 0.3 mg X kg-1 midazolam; and group C (n = 30), with a mean age of 15.5 +/- 9.1 months and a mean weight of 10.7 +/- 2.5 kg, receiving 0.4 mg X kg-1 midazolam. An aqueous solution of each drug was administered with atropine sulfate (0.02 mg X kg-1) 20 min prior to induction of anaesthesia. The drug was well tolerated in 84% of cases. Statistically significant haemodynamic changes consisted of: a 9 c X min-1 decrease in heart rate (p less than 0.05) and a 12 mmHg decrease in systolic and diastolic blood pressures (p less than 0.05) in group C; a 6 mmHg decrease in systolic blood pressure (p less than 0.05) in group B. The tranquilizer action was either excellent or good in 93% of groups B and C compared with only 40% in group A (p less than 0.001 in both cases). Somnolence was attained in 60% of group A, 26.6% of group B and 30% of group C. A mask was much better accepted in group C (86.6%) than in group B (66.6%; p less than 0.05) or in group A (36.6%; p less than 0.01). Therefore, midazolam given rectally at 0.4 mg X kg-1 was better than flunitrazepam, because of a greater therapeutic effect for an equivalent rate of side effects.

Age Factors↗
PubMed1985

[Effects of injectable flunitrazepam on hepatic and cardiac output in man].

The effects of intravenous flunitrazepam (0.03 mg X kg-1) on the estimated hepatic plasma output (DPHE), compared with the cardiac output (Q), were studied before its injection and 1 min afterwards. The question asked was whether the decrease in venous return led to a fall in hepatic perfusion. This study was made on patients in neurological coma without any organic lesion. The DPHE was measured by applying Fick's principle, using a continuous infusion of indocyanine green (ICG). The DPHE was given by the amount of ICG perfused in mg X min-1 divided by the arterial concentration of ICG less the concentration of ICG in the hepatic vein (in mg X 1(-1)). Cardiac output was measured by thermodilution. Flunitrazepam did not significantly modify either DPHE or Q; they fell by 5.6% and 3.4% respectively. None of the seven cardiovascular parameters changed during the time of the study. Thus, in unconscious patients with satisfactory haemodynamic conditions prior to the intravenous injection, flunitrazepam did not significantly modify hepatic perfusion.

Adolescent↗
PubMed1987

[Midazolam used for premedication reinforces sleep induced by flunitrazepam].

This single blind study aimed to discover possible effects of intramuscular premedication with midazolam on the sleep induced by intravenous flunitrazepam. 24 male patients, aged 17 to 71 years, who were to undergo surgery to the distal parts of an upper limb under regional anaesthesia, were randomly assigned to two equal groups: in the midazolam group, an intramuscular premedication of 0.12 mg.kg-1 midazolam with 0.5 mg atropine was given, whereas in the control group atropine only was used. In all patients, 1 mg flunitrazepam was given intravenously 45 min after the premedication, before carrying out regional anaesthesia. No other drug was given. In the midazolam group, the time of loss of spontaneous conversation was reduced (p less than 0.05), as well as the time of eye closure (p less than 0.001), and the time for recovery of the capacity to count backwards was increased (p less than 0.001). So, premedication with 0.12 mg.kg-1 midazolam intravenously 45 min before giving 1 mg flunitrazepam reinforced the sleep induced by the latter.

Adult↗
PubMed1989

Relationship between receptor occupancy at 37 degrees C and the anticonvulsant effect of flunitrazepam in rats.

In this investigation an attempt was made to evaluate quantitatively the relationship between benzodiazepine receptor occupancy and the anticonvulsant effect of flunitrazepam in rats. A graded measure of anticonvulsant effect was obtained on the basis of an elevation of pentylenetetrazol (PTZ) threshold concentrations. The concentration-anticonvulsant effect relationship could be described by the Emax model with an EC50 in cerebrospinal fluid of 2.9 +/- 0.8 micrograms/liter and an Emax of 227 +/- 22 mg/liter PTZ (mean +/- SE). In vitro receptor occupancy was determined in a crude brain homogenate at 0 and 37 degrees C, which yielded KD values of 2.2 +/- 0.2 and 26 +/- 2 micrograms/liter, respectively. The results obtained in both experiments were combined by focusing on free flunitrazepam concentrations. This strategy resulted in a nonlinear relationship between receptor occupancy and anticonvulsant effect of flunitrazepam, with 90% of the maximum response achieved at a degree of receptor occupancy of approximately 50% at 37 degrees C.

Animals↗
PubMed1999

Effects of Valeriana officinalis extracts on [3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocampal [3H]GABA release.

Extracts of Valeriana officinalis have been used in folkloric medicine for its sedative, hypnotic, tranquilizer and anticonvulsant effects, and may interact with gamma-aminobutyric acid (GABA) and/or benzodiazepine sites. At low concentrations, valerian extracts enhance [3H]flunitrazepam binding (EC50 4.13 x 10(-10) mg/ml). However, this increased [3H]flunitrazepam binding is replaced by an inhibition at higher concentrations (IC50 of 4.82 x 10(-1) mg/ml). These results are consistent with the presence of at least two different biological activities interacting with [3H]flunitrazepam binding sites. Valerian extracts also potentiate K+ or veratridine-stimulated release of radioactivity from hippocampal slices preloaded with [3H]GABA. Finally, inhibition of synaptosomal [3H]GABA uptake by valerian extracts also displays a biphasic interaction with guvacine. The results confirm that valerian extracts have effects on GABA(A) receptors, but can also interact at other presynaptic components of GABAergic neurons.

Animals↗
PubMed2004

[Flunitrazepam and driving ability].

Major contributions to the investigation of the influence of drugs on driving ability come from experimental studies as apart from epidemiological studies. Regarding experimental studies, the results of a single study are essentially determined by the experimental design. An established assessment of the risk of a drug in regard to driving ability should not be based on either a single study or on synopses, which record only a few studies without detailed information. This article presents an overview of published studies that directly or indirectly deal with the influence of flunitrazepam on driving ability. Benzodiazepines in particular, and amongst these especially flunitrazepam are brought into connection with the impairment of driving ability. This approach emphasises differences regarding the dosages used, the experimental designs and the methods of testing. For reasons of clarity the article on flunitrazepam is subdivided into the topics of acute effects, residual effects, and effects after subchronic application. Different results are reported. A statistical analysis in terms of a meta-analysis was not carried out due to a lack of standardization of the studies.

Anti-Anxiety Agents↗
PubMed1980

Diazepam receptor: specific nuclear binding of [3H]flunitrazepam.

Autoradiographic localization of [3H]flunitrazepam in nuclei of the rat cerebral cortex was further confirmed by biochemical analysis of specific nuclear binding. Highly purified rat cerebral cortex nuclei were shown to bind [3H]flunitrazepam specifically. The Kd(app) for nuclear binding was 28 nM for the nuclei compared with a Kd(app) of 1.1 nM for binding of [3H] flunitrazepam to synaptosomal membrane fractions of the same tissue. Inhibition of the nuclear binding with inosine and hypoxanthine was greater than inhibition of the synaptic membrane fractions. These results lead to to conclude that specific binding may occur at both the synaptic membrane and the nuclear levels and that different endogenous ligands may compete at each site for binding. Furthermore, the possibility exists for translocation and alteration of the bound ligand complex from membrane site to nuclear site.

Animals↗
PubMed1994

The influence of triazolam and flunitrazepam on isokinetic and isometric muscle performance.

The influences of two benzodiazepines (triazolam 0.25 mg and flunitrazepam 2 mg) on isokinetic and isometric muscle performance and on cardiovascular parameters were examined after a standard period of sleep. A randomized and double-blind test procedure was used (n = 15). Triazolam had no significant (p < 0.05) influence on either of the test conditions. Administration of flunitrazepam significantly lowered values for maximal isometric force and for the cardiovascular parameters. It was concluded that triazolam does not influence performance. On the other hand, flunitrazepam does influence a number of strength characteristics and cardiovascular parameters in effort situations.

Adult↗
PubMed1999

Flunitrazepam oxidative metabolism in human liver microsomes: involvement of CYP2C19 and CYP3A4.

The aims were to examine the kinetics of the oxidative metabolism of flunitrazepam in vitro when flunitrazepam was dissolved in dimethylformamide and acetonitrile, and to determine which cytochrome P450 isoform(s) are involved. The kinetics of the formations of 3'-hydroxyflunitrazepam and desmethyl-flunitrazepam were non-linear and best estimated using the Hill equation. Inhibition of their formation was studied using specific chemical inhibitors, expressed enzyme systems and specific antibodies. Ks, Vmax, Clmax and n (slope factor) for the formation of 3'-hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 165-338 and 179 391 microM, 22-81 and 3-10 nmol x mg protein(-1) x h(-1), 6-17 and 0.9-1.9 microl x mg protein(-1) x h(-1), and 2.3-3.6 and 1.6-2.6 respectively when dimethylformamide was the organic solvent. When acetonitrile was the solvent, Ks, Vmax, Clmax and n (slope factor) for the formation of 3'-hydroxyflunitrazepam and desmethylflunitrazepam had ranges of 173-231 and 74-597 microM, 35-198 and 2.7-48 nmol.mg protein(-1) x h(-1), 1347 and 0.7-6.3 microl.mg protein(-1) x h(-1), and 1.5-3.6 and 1.1-2.7 respectively. CYP2C19, CYP3A4 and CYP1A2 mediated the formation of both 3'-hydroxyflunitrazepam and desmethylflunitrazepam. Investigators need carefully to consider the choice of organic solvent to avoid false CYP identification.

Acetonitriles↗
PubMed2006

Flunitrazepam abuse and malicious use in Texas, 1998-2003.

Flunitrazepam is a potent benzodiazepine that is subject to abuse and malicious use. This study describes the patterns of flunitrazepam abuse and malicious use calls received by Texas poison centers during 1998-2003. The distribution of calls by year of call, geographic location of caller, patient gender and age, exposure site, and medical outcome were determined. There was no clear annual trend for abuse calls, but there was a consistent decline in the number of malicious use calls. A significantly higher percentage of abuse calls originated in south and west Texas and of malicious use calls in west Texas. Most abuse patients were males (55%) and adolescents (76%), and most of the exposures occurred in patient's own residence (68%), followed by school (16%). Most of the malicious use patients were females (93%) and adults (74%), and the greatest proportion of the exposures occurred in public areas (47%), followed by the patient's own residence (26%). The highest percentage of both abuse (48%) and malicious use (55%) involved minor effects. However, malicious use calls were significantly less likely to involve no effect (2% vs. 21%) and more likely to involve moderate effects (36% vs. 23%). Reported flunitrazepam abuse and malicious use calls in Texas differed with respect to geographic location of the caller, patient gender and age, exposure site, and medical outcome. Poison centers and health care providers might want to consider these differences when targeting populations for education and prevention efforts.

Adolescent↗
PubMed1979

Comparison of I.M. pethidine, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery.

Pethidine 1 mg kg-1, diazepam 0.25 mg kg-1 and flunitrazepam 0.02 mg kg-1 i.m. wer compared as premedicants in a double-blind study in 145 children undergoing otolaryngological surgery. Both flunitrazepam and pethidine had an anxiolytic effect in the children of less than 5 yr whereas diazepam had little effect. All of the drugs were anxiolytic in the children aged 5 yr and older. Sleep following thiopentone was restless more often in the younger than in the older children. Cardiovascular responses to thiopentone and to tracheal intubation were most obvious following benzodiazepines in children of less than 5 yr. After anaesthesia 10--33% of the older children could not recall pictures shown to them before anaesthesia. Forty-five (+/-SD 13) min after injection, the concentration of diazepam in serum was similar in both age groups; after 90 min it decreased in the younger and increased in the older children. All concentrations of flunitrazepam were significantly greater in the older compared with the younger children.

Adolescent↗
PubMed1979

Comparison of diazepam and flunitrazepam as adjuncts to general anaesthesia in preventing arousal following surgical stimuli.

A comparison has been made between the effects of the administration of flunitrazepam 1 mg i.v. and diazepam 10 mg i.v. in 90 female patients undergoing abdominal surgery. The drugs were given immediately before the skin incision as a booster to the induction agent thiopentone. The response to the incision, the quality of anaesthesia and the need for supplementary medication during maintenance were monitored. A standard post-anaesthesia interview was performed to evaluate the amnesic action and patient acceptability. The skin incision caused only slight increase in arterial pressure and heart rate in both groups. Only six patients of the diazepam group reacted to the incision with defensive movements. The overall quality of anaesthesia was better (P less than 0.05) and the need for supplementary doses of pethidine lower (P less than 0.01) in the flunitrazepam group. Recovery was equally good and the duration of sleep after operation was the same in both groups. The frequency of nausea after operation was low. The post-anaesthesia interview revealed that flunitrazepam possesses a more specific anterograde amnesic action than diazepam. Acceptability of the anaesthesia to the patient was equally good in both groups.

Abdomen↗
PubMed1980

Comparison of oral triclofos, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery.

Triclofos 70 mg kg-1, diazepam 0.25 mg kg-1 and flunitrazepam 0.02 mg kg-1 all in combination with atropine 0.03 mg kg-1 were compared as oral premedicants in 128 children undergoing otolaryngological surgery in a double-blind study. All drugs provided good anxiolysis in children 5 yr and older. In children less than 5 yr, the effects of triclofos were superior to those of diazepam and flunitrazepam. There was a positive correlation between anxiolysis and the ease of induction of anaesthesia. In both age groups, flunitrazepam prevented the fasciculations caused by suxamethonium more effectively than did diazepam or triclofos. The preinduction heart rate after triclofos was greater than after the other drugs and its antisialagogue effect was superior. The mean volume of gastric contents was 0.4 ml kg-1 for all the patients with no statistically significant difference between the groups. The mean pH of gastric contents was 4.5 after triclofos and 2.2 after other drugs. The serum concentration of both benzodiazepines in the older age group was greater than in the younger age group.

Administration, Oral↗