Disease relevance of Narcozep

• In human and rat glioma cell cultures [3H]PK 11195 bound with higher affinity (Kd = 14.01 and 15.76 nM, respectively) than either Ro5-4864 (Ki = 1200 and 84.9 nM, respectively) or flunitrazepam (Ki greater than 10,000 and = 848 nM, respectively) [1].
• Both the GABAmimetic muscimol and the benzodiazepine receptor agonist flunitrazepam were 3-4 times more potent in depressing the spontaneous activity of Purkinje neurons from rabbits with hepatic encephalopathy than from control animals [2].
• Out of 98 patients with a lumbar disc prolapse 50 were premedicated with flunitrazepam orally, 48 with pethidine and triflupromazine intramuscularly [3].
• Respiratory depression following orally administered flunitrazepam for preanesthetic medication in children [4].
• Three cases of convulsive status epilepticus (CSE) following abrupt discontinuation of long-term use of 25 mg of lorazepam in one patient and more than 20 mg of flunitrazepam in two patients are presented; they were non-epileptics and free of other high-risk factors for seizures [5].

Psychiatry related information on Narcozep

• Similar to other benzodiazepines, flunitrazepam produces dose-dependent effects on psychomotor performance and recall [6].
• After the flunitrazepam treatments, the predictions overestimated the actual performance significantly with respect to simple and choice reaction time at the 6-h session after intake [7].
• In contrast, the combined treatment with flunitrazepam and 8-OH-DPAT resulted in a lengthening of the latency of REM sleep significantly greater than that observed with the same dose of each drug alone [8].
• At night, only the highest dose of flunitrazepam (4 mg) induced significant changes in psychomotor sedation, attention, working memory, and prose immediate recall [9].
• Proceedings: Anaesthesia and amnesia with flunitrazepam [10].

High impact information on Narcozep

• In addition, flunitrazepam increased the receptor affinity for its agonist, indicating the presence of functional benzodiazepine binding sites, i.e., gamma-subunits [11].
• We used whole-cell recordings of GABA-elicited CI- currents and flunitrazepam binding experiments in granule cell cultures maintained in low K+ (12.5 mM), cells maintained in low K+ and treated with a single dose of NMDA (10 microM), and cell cultures maintained in depolarizing concentrations of K+ (25 mM) [12].
• Scatchard analysis in both cell lines revealed one class of specific binding sites for [3H] flunitrazepam verified as being MBR by displacement studies with a series of MBR ligands [13].
• Projected in vivo inhibition of CYP3A4-mediated metabolism of flunitrazepam by buprenorphine is 0 [14].
• METHOD: Inhibition of flunitrazepam metabolism by buprenorphine and norbuprenorphine were determined in three human liver microsome preparations carrying the CYP2C19*1/*1 allele [14].

Chemical compound and disease context of Narcozep

• The maximal impairment in simple reaction time following the flunitrazepam treatments occurred earlier relative to the peak plasma concentration of the drug as compared to the diazepam treatments [15].
• Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect [16].
• The association of fluvoxamine with flunitrazepam induced a decrease in REM sleep, equal to the sum of the effects of the two drugs alone [8].
• A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication [17].
• Sleep apneas were not more common or longer after nitrazepam or flunitrazepam, but sleep quality seemed to improve [18].

Biological context of Narcozep

• Pharmacokinetics and tolerance of flunitrazepam in neonates and in infants [19].
• Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration [19].
• CONCLUSION: Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants [19].
• We have compared the kinetics of interaction of this ligand with the benzodiazepine agonist flunitrazepam in the rat cerebellum [20].
• At a concentration of 1 microM or 10 microM, flunitrazepam had no effect on the IC50 values for muscimol or THIP in inhibiting stimulated GABA release [21].

Anatomical context of Narcozep

• In a previous report we described the use of flunitrazepam as a photoaffinity label to monitor the turnover of the gamma-aminobutyric acid/benzodiazepine receptor complex in primary brain and spinal cord cell cultures [Science (Wash. D. C.) 226:857-860 (1984)] [22].
• Fluorography of a sodium dodecyl sulfate-polyacrylamide electrophoresis gel of solubilized hepatic microsomes that had been treated with [3H] flunitrazepam under UV light revealed a band with a monomeric molecular weight between 54,000 and 58,000 [23].
• This postulate was based upon evidence showing changes in binding properties of the BZD receptor following photoaffinity labeling of membranes with flunitrazepam (FLU) [24].
• 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 [25].
• In the present paper it is shown that suriclone possesses a high affinity for flunitrazepam binding sites and that tritiated suriclone binds specifically with high affinity in rat hippocampus (KD = 0.44 +/- 0.03 nM) and rat cerebellum (KD = 0.53 +/- 0.12 nM) [26].

Associations of Narcozep with other chemical compounds

• These observations provide unequivocal evidence that the antagonistic action of flunitrazepam is mediated through its interaction with MBR demonstrating that these drug recognition sites are coupled to steroid biosynthesis activated by tropic hormones [13].
• Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior [27].
• It was observed that affected compounds have a pendant phenyl moiety, analogous to the 5-phenyl group of flunitrazepam, which are proposed to overlap and interact with the same residue or residues in the BZ binding site [28].
• The affinities of four BZD derivatives--nitrazepam, flunitrazepam, diazepam, and chlordiazepoxide--are similar for suriclone and flunitrazepam binding sites [26].
• The determination of the major urinary compounds of eight common benzodiazepines, flunitrazepam, diazepam, midazolam, clonazepam, bromazepam, temazepam, oxazepam, and lorazepam, by micellar electrokinetic capillary chromatography (MECC) is shown to be a simple and attractive approach for confirmation testing of these drugs in human urine [29].

Gene context of Narcozep

• CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam [30].
• We estimate that the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 and 37%, respectively, at therapeutic flunitrazepam concentrations (0.03 microM) [31].
• Bicuculline, a GABAA receptor antagonists, attenuated the inhibition during short IPIs n the ddY mice, while in the El mice, phenobarbital and flunitrazepam, which enhance GABAA receptor function, restored the inhibitory activity comparable to that of the ddY [32].
• Correspondingly, flunitrazepam-non-displaceable binding of [3H]Ro 15-4513 (a benzodiazepine partial inverse agonist), which is a major characteristic of gamma-aminobutyric acid type-A receptors that contain the alpha 6 polypeptide, is also mainly found for cerebellar granule cells of fish and chick [33].
• Ethanol, flunitrazepam, and pentobarbital modulation of GABAA receptors expressed in mammalian cells and Xenopus oocytes [34].

Analytical, diagnostic and therapeutic context of Narcozep

• Flunitrazepam in terminal care [35].
• Urine screening for flunitrazepam: applicability of Emit immunoassay [36].
• Blood samples were collected immediately before and up to 48 hours after drug administration and were assayed by HPLC for flunitrazepam and its metabolites, 7-aminoflunitrazepam, desmethylflunitrazepam, and 3-hydroxyflunitrazepam [37].
• In clinical trials brotizolam 0.125 to 0.5mg improved sleep in insomniacs similarly to nitrazepam 2.5 and 5mg, flunitrazepam 2mg and triazolam 0.25mg, whilst brotizolam 0.5mg was shown to be superior to flurazepam 30mg in some studies [38].
• The time course of radioactivity in the striatum, cerebral cortex and cerebellum in controls and flunitrazepam (1 mg/kg)-treated mice was measured after intravenous injection of [3H]SCH 23390 [39].

References