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Pavlic M Libiseller K Grubwieser P Schubert H Rabl W 《International journal of legal medicine》2007,121(3):169-174
The benzodiazepine tetrazepam is primarily muscle relaxant with comparably lower central sedating effects and is therefore
commonly prescribed for muscle spasms of different origins. To evaluate tetrazepam metabolism, a study was conducted with
ten healthy volunteers. Blood and urine samples were regularly collected after the intake of 50 mg tetrazepam. Toxicological
analyses revealed that tetrazepam is also metabolized to diazepam and further to nordazepam, which has not yet been reported.
Tetrazepam and diazepam could be detected in urine samples at least 72 h after intake, the diazepam concentration being 33%
(±14% SD), on average, of the tetrazepam concentration. On the basis of three case histories, the importance of the detection
of these newly described metabolites is shown as necessary to prevent false accusations and potential negative legal consequences
for examined persons. 相似文献
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Benzodiazepines have wide-spread used in pharmacotherapy for their anxiolytic, myorelaxant, hypnotic, amnesic and anticonvulsive properties. Despite benzodiazepines are used in clinics over 50 years, they have not been surprisingly tested for capability to induce major drug-metabolizing cytochromes P450. In the current study, we have examined the potency of Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam to induce CYP1A2 and CYP3A4 in primary cultures of human hepatocytes. Benzodiazepines were tested in therapeutic concentrations and in concentrations corresponding to their plasma levels in intoxicated patients. We found weak but significant induction of CYP3A4 mRNA by Midazolam and Medazepam, while other benzodiazepines did not induce CYP3A4 expression. None of the tested compounds induced CYP1A2 mRNA in three independent human hepatocytes cultures. In addition, employing gene reporter assays with transiently transfected hepatocarcinoma cells, we found that tested benzodiazepines did not activate aryl hydrocarbon receptor (AhR), whereas Midazolam and Medazepam slightly activated pregnane X receptor (PXR). Consistently, two-hybrid mammalian assay using hybrid fusion plasmids GAL4-PXR ligand-binding domain (LBD) and VP16-SRC-1-receptor-interacting domain (RID) confirmed PXR activation by Midazolam and Medazepam. In conclusion, Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam can be considered as safe drugs in term of their inability to induce PXR- and AhR-dependent cytochrome P450 enzymes CYP1A2 and CYP3A4. Medazepam and Midazolam slightly activated pregnane X receptor and displayed weak potency to induce CYP3A4 mRNA in human hepatocytes. 相似文献
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