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PubMed2003

Normal coupling of brain benzodiazepine and neurosteroid modulatory sites on the GABA-A receptor complex in human hepatic encephalopathy.

To assess the possible implication of the allosteric coupling of different modulatory sites at the GABA-A receptor complex in hepatic encephalopathy (HE), we investigated in autopsied frontal cortex of six cirrhotic patients and six appropriately-matched controls, the modulatory effects of the benzodiazepine site agonist flunitrazepam on the binding of [3H]muscimol and the effect of the neurosteroid site agonist allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) on the binding of [3H]muscimol and [3H]flunitrazepam. There were no significant differences in either the magnitude E(max): 11.5+/-1.1% (controls) versus 10.2+/-2.2% (HE patients) or the efficacy EC(50): 20.2+/-5.5 nM (controls) versus 17.7+/-6.2 nM (HE patients) of flunitrazepam modulation of [3H]muscimol binding. Allopregnanolone also showed modulation of both sites to a comparable extent in brain tissue from cirrhotic patients and controls E(max): [3H]muscimol, 15.1+/-2.8% (controls) versus 13.8+/-1.9% (HE patients); [3H]flunitrazepam, 17.9+/-2.3% (controls) versus 19.1+/-2.3% (HE patients), EC(50): [3H]muscimol, 386.5+/-25.8 nM (controls) versus 373.8+/-13.1 nM (HE patients); [3H]flunitrazepam, 49.8+/-22.9 nM (controls) versus 55.5+/-14.0 nM (HE patients). These findings demonstrate unequivocally that the GABA-A sites and their benzodiazepine and neurosteroid modulatory sites manifest normal allosteric coupling in brain in human HE. Therefore, if increased "GABAergic tone" is implicated in the pathophysiology of HE, this must be the consequence of increased brain concentrations of endogenous benzodiazepine and/or neurosteroid ligands for components of the GABA-A receptor complex rather than alterations of the receptor proteins themselves.

Adult↗
PubMed1980

Molecular heterogeneity of benzodiazepine receptors.

Benzodiazepines exhibit reversible, stereospecific high affinity binding to mammalian brain membranes, and the respective binding sites for 3H-flunitrazepam represent pharmacologically and clinically relevant receptors for benzodiazepines. Recently it has been demonstrated that reversibly bound 3H-flunitrazepam becomes irreversibly attached to a specific membrane protein with apparent molecular weight of 50,000 when incubations are performed in the presence of UV light. Irreversible binding of 3H-flunitrazepam to this protein had pharmacological properties similar to reversible benzodiazepine receptor binding, indicating that 3H-flunitrazepam is a photoaffinity label for the benzodiazepine receptor. Using irreversible binding of 3H-flunitrazepam and subsequent electrophoretic separation of the labelled proteins in SDS-gels followed by fluorography, we found that in hippocampus and several other brain regions at least two different types of benzodiazepine receptors exist. Each seems to be associated with a gamma-aminobutyric acid (GABA) receptor.

Animals↗
PubMed1980

Comparison of three benzodiazepines for oral premedication in minor gynaecological surgery.

Diazepam 10 and 20 mg, lorazepam 2.5 and 5.0 mg, flunitrazepam 1 and 2 mg, and a placebo, were compared in a randomized double-blind controlled trial as oral premedication for 210 patients undergoing minor gynaecological surgery. Flunitrazepam 1 mg and lorazepam 2.5 mg were superior to placebo (P less than 0.001 and P less than 0.05 respectively) in relieving patient anxiety when assessed by a trained observer 60 min after premedication. Flunitrazepam 1 mg also produced more drowsiness (P less than 0.01) than the placebo. Comparisons of other low-dose benzodiazepine groups with the placebo, and of the large dose with the small dose of each drug revealed no significant changes in anxiolysis or drowsiness. Dizziness and prolonged drowsiness were not apparent with low-dose flunitrazepam. The data suggests that flunitrazepam 1 mg offers advantages over placebo, diazepam 10 mg and lorazepam 2.5 mg for routine oral premedication in minor gynaecological surgery.

Adolescent↗
PubMed1999

Benzodiazepines in Miami-Dade County, Florida driving under the influence (DUI) cases (1995-1998) with emphasis on Rohypnol: GC-MS confirmation, patterns of use, psychomotor impairment, and results of Florida legislation.

Benzodiazepines are central nervous system depressant drugs often detected in biological samples from driving under the influence (DUI) offenders. They are associated with marked psychomotor impairment and represent up to 20% of all Miami-Dade County, Florida DUI urine samples analyzed in our laboratory annually. Flunitrazepam emerged in the mid-1990s as an illegal drug in the U.S. that was predominantly abused recreationally and associated with sexual assaults. Immunoassays for benzodiazepines do not discriminate between different benzodiazepines, and certain metabolites, such as 7-aminoflunitrazepam, react poorly with immunoassay reagents. A simple and sensitive method for the detection and quantitation of major benzodiazepines and metabolites by gas chromatography with mass selective detection is presented. This method was used to confirm benzodiazepines in general and flunitrazepam in particular. Data collected over a three-and-a-half-year period are summarized. Whereas flunitrazepam was present in up to 10% of DUI cases in 1995 and 1996 and had fast become the most frequently encountered benzodiazepine in Miami-Dade County DUI-related urine samples, a dramatic drop in case numbers followed the legal reclassification of the drug as a Schedule I substance in Florida in February 1997. Flunitrazepam was often used alone or in combination with cannabis and cocaine. A recent rise in clonazepam cases coincides with the decrease in flunitrazepam confirmation and may indicate a new trend in the abuse of benzodiazepines in South Florida.

Benzodiazepines↗
PubMed1993

The influence of the gamma 2L subunit on the modulation of responses to GABAA receptor activation.

1. Whole-cell patch clamp recordings were made from L-cells transfected with 2 combinations of subunits of the GABAA receptor. Log concentration-response curves were constructed to gamma-aminobutyric acid (GABA) on alpha 1,beta 1,gamma 2L containing cells and compared to those from alpha 1,beta 1 containing cells. The effects of flunitrazepam, pentobarbitone and alphaxalone on the concentration-response relationships were also examined. 2. From the log concentration-response curves, GABA had a mean (+/- s.e. mean) pEC50 = 5.2 +/- 0.09 and slope factor = 1.7 +/- 0.02 on alpha 1,beta 1,gamma 2L cells which were significantly different from the values obtained from alpha 1,beta 1 cells where the pEC50 = 5.6 +/- 0.02 and the slope = 1.5 +/- 0.02. 3. Flunitrazepam produced a parallel leftward shift of GABA concentration-response curves on alpha 1,beta 1,gamma 2L cells. The EC50 for flunitrazepam = 6.3 +/- 2.7 nM. No increase in the maxima of the GABA concentration-response curves was found in the presence of flunitrazepam. Flunitrazepam did not potentiate responses from alpha 1,beta 1 cells. 4. The log concentration-response curves from both populations of cells were shifted to the left by equal amounts by pentobarbitone. A significant increase in the maximal response to GABA was also produced by pentobarbitone. This occurred at lower concentrations of pentobarbitone on alpha 1,beta 1 cells. 5. Alphaxalone produced leftward shifts of GABA log concentration-response curves of similar magnitudes in both populations of cells. Significant increases in the maxima were found at 100 nM in alpha 1, beta 1 cells but not up to 1 microM in alpha 1,beta 1,gamma 2L cells.6. These results provide further evidence of the modulatory role of the gamma 2L subunit of the GABAA receptor containing alpha 1 and beta 2 subunits. As well as influencing the apparent affinity of GABA and conferring benzodiazepine modulation, it also appeared to regulate the increase in maximal response produced in the presence of barbiturates and steroids. This latter effect may imply that barbiturates and steroids increase the channel open-state probability in the presence of GABA and that this effect is diminished by the presence of the gamma 2L subunit.

Anesthetics↗
PubMed2000

Characterization of the interaction of zopiclone with gamma-aminobutyric acid type A receptors.

Zopiclone is a cyclopyrrolone that is used clinically as a hypnotic. Although this drug is known to interact with neuronal gamma-aminobutyric acid type A receptors, its binding site(s) within the receptor oligomer has been reported to be distinct from that of the classical benzodiazepines. After photoaffinity labeling with flunitrazepam, receptors in rat cerebellar membranes showed differentially reduced affinity for flunitrazepam and zopiclone by 50- and 3-fold, respectively. Because histidine 101 of the alpha-subunit is a major site of photolabeling, we have made specific substitutions of this residue and studied the consequences on the binding properties of zopiclone and diazepam using recombinant alpha1beta2gamma2-receptors transiently expressed in tsA201 cells. Both compounds showed similar binding profiles with receptors containing mutated alpha-subunits, suggesting a similar interaction with the residue at position 101. At alpha1beta2gamma3-receptors, flunitrazepam affinity was dramatically decreased by approximately 36-fold, whereas the affinity for zopiclone was decreased only 3-fold, suggesting a differential contribution of the gamma-subunit to the binding pocket. Additionally, we used electrophysiological techniques to examine the contribution of the gamma-subunit isoform in the receptor oligomer to ligand recognition using recombinant receptors expressed in Xenopus oocytes. Both compounds are agonists at alpha1beta2gamma2- and alpha1beta2gamma3-receptors, with flunitrazepam being more potent but less efficacious. In summary, these data suggest that histidine 101 of the alpha1-subunit plays a similar role in ligand recognition for zopiclone, diazepam, and flunitrazepam.

Amino Acid Substitution↗
PubMed1984

Effects of zopiclone and benzodiazepine hypnotics on search in short-term memory.

The effects of zopiclone 7.5 mg in comparison to flunitrazepam 1 mg, triazolam 0.25 mg and lormetazepam 1 mg on stages of information processing in a memory-scanning task were investigated in 10 normal volunteers using a double-blind placebo-controlled cross-over design. Overall reaction times for the test were significantly increased 1 h following treatment with zopiclone, flunitrazepam and triazolam and in the morning following nighttime medication with flunitrazepam. The effects of zopiclone, flunitrazepam and triazolam were found to be located in the serial comparison and response-selection organization stages of the reaction process although both flunitrazepam and triazolam caused additional impairment of stimulus encoding.

Adult↗
PubMed1992

Distribution of benzodiazepine binding sites in the brain of the male Japanese quail and its correlation to a hormonal control: quantitative autoradiography study.

Quantitative receptor autoradiography was used to study the neuroanatomical distribution and effects of gonadal hormones on [3H] flunitrazepam binding in the male Japanese quail brain. In gonadally intact quail brains, [3H] flunitrazepam displayed a heterogeneous distribution, with elevated levels in the posterior brain regions such as the stratum griseum et fibrosum superficiale and stratum griseum centrale of the optic tectum. Lower values were observed in the anteriorly located brain sites such as the nucleus septalis (lateralis et medialis), the cortex dorsolateralis and the nucleus lateralis hypothalami. Castration affected [3H] flunitrazepam binding levels in brain areas known to contain gonadal steroid receptors as well as in some areas which were devoid of gonadal steroid receptors. Castration in fact, elevated [3H] flunitrazepam binding in the nucleus preopticus anterior and reduced binding levels in archistriatum dorsalis et ventralis and in the nucleus intercollicularis; all of these areas are known to have gonadal steroid receptors. In two regions which do not contain such receptors, namely the hyperstriatum ventrale and the cerebellum pars granularis, castration increased [3H] flunitrazepam binding. In order to determine whether the gonadal steroid effect is due to changes either in the number of binding sites (Bmax) and or affinity binding state (KD), saturation binding studies were carried out in some of the areas described above in brains of quail which were castrated or castrated and given replacement therapy with testosterone or estradiol for 2 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

A double-dissociation of behavioural and event-related potential effects of two benzodiazepines with similar potencies.

This study was designed to explore the role of benzodiazepine affinity to benzodiazepine binding site on acute psychomotor, subjective and memory effects, as well as auditory Event Related Potential (ERP) latencies, in healthy volunteers. Two benzodiazepines with similar affinity to benzodiazepine binding sites, or potency, were compared: the atypical compound lorazepam (2.0 mg), which has been reported to impair priming, and a standard benzodiazepine, flunitrazepam (0.6 mg, 0.8 mg, 1.0 mg). The study followed a placebo-controlled, double-blind, parallel-group design. Sixty subjects completed a test battery before treatment and at theoretical peak plasma concentration of drugs. Lorazepam and 1.0 mg of flunitrazepam led to comparable alterations on psychomotor, subjective and auditory episodic memory measures. A double-dissociation was found for lorazepam and the equipotent dose of flunitrazepam (1.0 mg): lorazepam was more deleterious than flunitrazepam in time taken to identify fragmented shapes. Lorazepam also impaired direct and indirect stem-completion in comparison to placebo, but this effect was abolished when time to identify shapes was used as a covariate. By contrast, 1.0 mg of flunitrazepam prolonged auditory ERP latencies to a greater extent than lorazepam. High affinity to the benzodiazepine binding sites does not seem to explain the consistent lorazepam-induced impairment of indirect stem-completion. Differences in impairment profile between the benzodiazepines employed may relate to the modality (visual or not) of the tasks used.

Adolescent↗
PubMed2004

Potentiated modulation of pregnolone on GABAA receptors in behaviorally stressed borderline-hypertensive rats.

The modulatory effects of behavioral stress on [(3)H]flunitrazepam, an agonist for the central-type benzodiazepine receptor binding to the GABA(A)-benzodiazepine receptor complex, in borderline hypertensive rats (BHR) were examined. In repeatedly immobilized (for 2 weeks, for 2 h/d) BHR, enhancement of [(3)H]flunitrazepam binding to the receptor was observed to be potentiated. The percent enhancement of [(3)H]flunitrazepam binding in BHR was higher than that in normotensive control Wistar-Kyoto rats. Pregnanolone, a neuroactive steroid that has been reported to be a putative endogenous modulator in the stress response, concentration dependently enhanced [(3)H]flunitrazepam binding to the receptor. Enhancement of [(3)H]flunitrazepam binding was observed to be potentiated by the same immobilized stress, and the EC(50) values of pregnanolone in BHR was significantly lower than those in controls and E(max) values were higher. From the above results, it can be concluded that neural modulation to behavioral stress, especially in GABAergic neurotransmission, is exaggerated in BHR. We propose strain-specific differences of stress reactivity as an important pathogenetic factor in psychosomatic disorders including stress-induced hypertension. This is supported by reports showing exaggerated cardiovascular and symathoadrenal responses to stress in BHR.

Animals↗
PubMed1994

Effects of Kamikihito, a traditional Chinese medicine, on neurotransmitter receptor binding in the aged rat brain determined by in vitro autoradiography (2): changes in GABAA and benzodiazepine receptor binding.

We investigated the effects of the long-term administration of Kamikihito (KKT) on the specific binding of [3H]muscimol and [3H]flunitrazepam in the brains of young and aged rats using in vitro quantitative autoradiography. Specific [3H]muscimol binding in aged rats was decreased in all brain regions examined compared with that in young rats, whereas [3H]flunitrazepam binding did not change in any of the brain regions. Scatchard analysis revealed that the maximal number of [3H]muscimol binding sites in the cortex and thalamus was significantly decreased in aged rats compared with young rats, while its affinity remained unchanged. Long-term administration of KKT in young rats had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast, the same treatment in aged rats produced a significant increase in [3H]flunitrazepam binding to the cortex, caudate/putamen and accumbens, and it tended to decrease the [3H]muscimol binding. These results suggest that the selective reduction of specific [3H]muscimol binding in the brain may be responsible, at least in part, for anxiety-related behavior in aged rats. Furthermore, it appears that the significant increase in specific [3H]flunitrazepam binding produced in the brains of aged rats by the long-term administration of KKT may be responsible for the anxiolytic effects of this agent.

Aging↗
PubMed1995

Effects of intravenous anesthetics on function and metabolism in the reperfused working rat heart.

We investigated the comparative effects of ketamine, flunitrazepam, diazepam and midazolam on function and metabolism in reperfused rat hearts. Seventy-two hearts were rapidly excised and perfused with buffer as a Neely's working model. Whole heart ischemia was induced for 15 min followed by reperfusion for 20 min. Four intravenous anesthetics in 2 different concentrations (10 and 50 times of therapeutic concentrations) were administered during reperfusion. The data were compared to a control group in which intravenous anesthetics were not used. At the end of reperfusion, myocardial metabolites were measured by liquid chromatography. Cardiac outputs in the both groups given lower and higher doses of ketamine and flunitrazepam and in the groups given the higher dose of diazepam and midazolam were significantly lower than that in the control group [at the end of reperfusion: control: 60.4; ketamine: 48.8 (lower) and 14.6 (higher); flunitrazepam: 50.2 (lower) and 50.6 (higher); diazepam: 62.6 (lower) and 42.5 (higher); midazolam: 59.5 (lower) and 51.2 (higher), ml/min]. The levels of ATP in all higher concentration anesthetic groups were significantly lower than those in the control group (control: 23.7, ketamine: 17.8, flunitrazepam: 17.8, diazepam: 17.7, midazolam: 17.7, mumol/g). These results suggest that ketamine and flunitrazepam moderately depress cardiac function more than diazepam and midazolam when they are given during reperfusion.

Anesthetics↗
PubMed1999

[Rohypnol should be classified as a narcotic].

Flunitrazepam, widely known by its trade names (e.g. Rohypnol), may cause severe violence, especially in combination with alcohol. Flunitrazepam abusers become cold-blooded, ruthless and violent, and do not remember their violence. Reputedly it is supplied to professional hit-men and enforcers by their bosses to promote ruthless efficacy. One case report describes how a young man, intoxicated with flunitrazepam and involved in causing serious knife and gunshot wounds and taking hostages, felt so invincible that he openly challenged the police, threatening them with an assault rifle, but was himself shot. Flunitrazepam may exert pharmacological effects on GABA-ergic systems, thus lowering serotonin levels. The impulsive execution of violent crimes and suicide attempts in which a violent method (hanging, shooting, self-stabbing) has been used are associated with the presence of low serotonin levels. It is therefore recommended that flunitrazepam should be classified as a controlled substance in Sweden as it is elsewhere.

Adult↗
PubMed1990

Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: presence of independent binding site for ethyl beta-carboline-3-carboxylate.

Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited [3H]flunitrazepam binding to benzodiazepine receptor, but not [3H]muscimol binding to GABAA receptor as well as t-[3H]butylbicycloorthobenzoate [( 3H] TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively [3H] flunitrazepam binding. On the other hand, the binding of beta-[3H]CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated [3H]muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-[3H]CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for [3H]flunitrazepam, [3H]muscimol and [3H]TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested.

Animals↗
PubMed1990

[Premedication with triazolam].

The suitability of triazolam for oral premedication was evaluated in comparison to flunitrazepam. 65 consenting female patients scheduled for gynaecological surgery took part in the trial, were randomly allocated in two groups and were given 0.5 mg triazolam or 2 mg of flunitrazepam as oral premedication 90 min preoperatively. No difference was found in the anxiolytic potency (possible difference d = 0.65 standard deviation, less than 3 points on the anxiety score). Both drugs significantly reduced anxiety (alpha less than 0.01). Anxiolysis depended on the initial anxiety; the higher the initial anxiety score, the better the anxiolytic effect. Triazolam was found to have an antidepressant effect (alpha less than 0.05) and asthenic affects decreased (n.s.). Flunitrazepam had a tendency to increase depression (n.s.) and asthenic effects increased (alpha less than 0.05). No differences were found in the degree of sedation and in the amnestic effect. Systolic pressure remained unchanged in both groups, whereas values of diastolic pressure increased to the same extent in both groups. While heart rate increased after triazolam, it decreased after flunitrazepam. Both groups had comparable initial heart rates. Possible mechanisms to explain this discordance of heart rate-changes are discussed. Triazolam is comparable to flunitrazepam as an oral premedicant and is a suitable drug for short surgical procedures if rapid postoperative recovery is required.

Adult↗
PubMed1988

Benzodiazepine interactions with GABAA receptors on chick ciliary ganglion neurons.

gamma-Aminobutyric acidA (GABAA) receptors on chick ciliary ganglion neurons can be modulated by benzodiazepines and identified by radiolabeled benzodiazepine binding. Enhancement of submaximal GABA responses by benzodiazepines was demonstrated using a multibarrel pipette to construct complete benzodiazepine dose-response curves for single cells in culture. EC50 values of 22 +/- 5 nM, 1.1 +/- 0.3 microM, and 4.6 +/- 0.5 microM were obtained for flunitrazepam, clonazepam, and chlordiazepoxide, respectively. Chlordiazepoxide shifted the GABA dose-response curve to lower GABA concentrations without increasing the maximal response to GABA, demonstrating that benzodiazepines enhance the GABA response by increasing the receptor affinity for GABA. The imidazodiazepine Ro15-1788 potentiated the GABA response with an EC50 of 250 +/- 70 nM, and Ro5-4864 (chlorodiazepam) partially blocked the GABA response both in the presence and absence of chlordiazepoxide. Scatchard analysis of data from binding studies with [3H]flunitrazepam to ganglion membrane homogenates was consistent with the presence of a single class of high affinity sites with a KD of 34 +/- 6 nM and a Bmax of 145 +/- 26 fmol/mg of protein. Several lines of evidence indicated that the sites were associated with GABAA receptors. The KD of [3H]flunitrazepam binding was similar to the EC50 for flunitrazepam modulation of the GABA response. The level of [3H]flunitrazepam binding was enhanced approximately 50% over control levels by GABA. The binding was decreased both by clonazepam and by Ro5-4864 at concentrations similar to those required for the compounds to modulate the GABA response. These studies demonstrate that ciliary ganglion GABAA receptors are similar in major respects to GABAA receptors in the central nervous system but may differ in minor pharmacological properties.

Animals↗
PubMed1986

Biochemical studies with the new thienotriazolo-diazepine brotizolam.

Brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) is a newly developed thienotriazolo-diazepine with distinct hypnotic effects. It was biochemically characterized by performing various receptor binding studies, uptake and release studies in vitro and determining homovanillic acid brain concentrations in vivo. Using [3H]-flunitrazepam as a radioligand, brotizolam showed an extremely high affinity for specific benzodiazepine binding sites in the rat brain, demonstrated by an IC50 value of 1.0 nmol/l. Using both [3H]-flunitrazepam and [3H]-brotizolam as radioligands, a strong correlation between the IC50 values of brotizolam and various benzodiazepines could be shown. [3H]-Flunitrazepam as well as [3H]-brotizolam bound with similar affinities to cerebellar and hippocampal synaptosomal membranes. In contrast to [3H]-flunitrazepam binding, however, [3H]-brotizolam had twice the number of specific binding sites in the hippocampus. According to the maximum binding of [3H]-flunitrazepam, the inhibition curve of brotizolam also increased in the presence of 10(-4) mol/l gamma-aminobutyric acid and decreased remarkably in the presence of 10(-4) mol/l bicuculline. Using [3H]-muscimol as a ligand, a modulating effect of brotizolam could be shown by increasing the low affinity with no change in the number of binding sites. From various further receptor binding studies, as well as from in vitro uptake and release studies of [3H]-noradrenaline, [3H]-serotonin and [3H]-dopamine, no indication was found of another biochemical effect of brotizolam. There was also no change in the homovanillic acid concentration in the rat brain striata in vivo after brotizolam treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

A useful tool for predicting the clinical effects of hypnotics in humans: averaged photopalpebral reflex.

The averaged photopalpebral reflex (PPR) is an index which objectively assesses the arousal level of humans. The dose-response curve of flunitrazepam, a benzodiazepine derivative, was investigated by using PPR in the present study. Ten healthy male university students were given flunitrazepam 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and placebo in a double-blind, crossover design. PPR and subjective assessment were recorded before and after drug administration. P1 and P2 latencies of PPR were prolonged by flunitrazepam 0.5 mg, 1.0 mg and 1.5 mg in a dose-dependent manner. The prolongation of latencies by flunitrazepam 2.0 mg was weaker than that by 1.5 mg, but was more potent than that by 1.0 mg. In self-assessments, sleepiness, muscle weakness and vagueness of thought were observed after drug ingestion. Sleepiness was correlated with the prolongation of the PPR latencies. These results suggest that PPR could be a useful tool for psychopharmacological investigations in normal humans, that flunitrazepam might be a clinically potent hypnotic drug, and that its peak effect occurs 2-3 h after administration.

Adult↗