Temazepam Research Articles

Selective Extraction of Diazepam and Its Metabolites from Urine Samples by a Molecularly Imprinted Solid-Phase Extraction (MISPE) Method.

In this research, a molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization using oxazepam (OZ) as a template molecule and was subsequently applied as a selective sorbent for the extraction of diazepam (DZP) and its metabolites in urine samples using an SPE cartridge. OZ, temazepam (TZ), nordiazepam (NZ) and DZP were analyzed in the final extracts by high-performance liquid chromatography with diode array detection (HPLC-DAD). The SPE extraction steps were optimized, and the evaluation of an imprinting factor was carried out. The selectivity of the method for OZ versus structurally related benzodiazepines (BZDs), such as bromazepam (BRZ), tetrazepam (TTZ) and halazepam (HZ), was investigated. Under the optimum conditions, the proposed methodology provided good linearity in the range of 10-1500 ng/mL, with limit of detection values between 13.5 and 21.1 ng/mL and recovery levels for DZP and its metabolites from 89.0 to 93.9% (RSD ≤ 8%) at a concentration level of 1000 ng/mL. The proposed method exhibited good selectivity, precision and accuracy and was applied to the analysis of urine samples from a real case of DZP intake.

Investigation of Diazepam Sequential Metabolism with Hepatocytes via a Microfluidic Device

Objectives and hypothesisThe purpose of this study is to investigate the sequential metabolism of diazepam (DZP) in a dynamic system. In rat liver, DZP can be metabolized into primary metabolite temazepam (TZP), nordiazepam (NDP), p‐hydroxydiazepam (PHD), and secondary metabolite oxazepam (OXP) and temazepam glucuronide (T‐G). It is reported that a lag time of DZP metabolite formation can be observed in rat liver single‐pass perfusion and PK study. We are using a microfluidic device to represent liver sinusoid and to investigate the contribution of metabolism and drug transport in the disposition of diazepam and its metabolite along the sinusoid. Ordinary differential equation (well‐stirred model) and partial differential equation (PDE) models are being developed to characterize the disposition of DZP and its metabolites. We hypothesize that characterization of sequential metabolism in a dynamic system compared to a static system (microsomal incubation or static hepatocyte incubation) can provide a more accurate prediction of in vivo sequential metabolism.MethodsThe perfusion study was conducted with rat hepatocytes. Rat hepatocytes were seeded in collagen I coated microscopy slides to form a monolayer, followed by three‐day enzyme induction. An ibidi® μ‐sticky slide was mounted on the microscopy slide to create a microfluidic device. Hepatocyte culture medium containing 5 μM DZP was perfused through the device and subsequently perfused by DZP‐free culture medium. The concentration of diazepam and its metabolites in the perfusate was measured by LC/MS/MS. Mathematical modeling was applied to predict the concentration‐time (C‐t) profile of the perfusion study via Mathematica version 12.3 (software). The model parameters include metabolic intrinsic clearance (CLint,met) and passive diffusion clearance (CLdiff), partitioning into membranes, hepatocyte volume, and device volume. Other relevant model parameters were collected by literature search.ResultsAt 10 μL/min flow rate, three primary metabolites all show similar lag time (pre device dead volume plus device volume) to that of DZP. OXP shows a longer lag time compared to T‐G. The lag time of T‐G is similar to that of primary metabolites. However, a significant decline of TZP and NDP formation at a steady‐state is observed, but not PHD. One possible rationale is constant enzyme loss for CYP3A (responsible for TZP, NDP formation), but not CYP2D (responsible for PHD formation). For the DZP‐free perfusion phase, a similar lag time was observed for DZP and its metabolites. A well‐stirred model and a PDE model to characterize the dimension and spatial information are being optimized.ConclusionsGenerally, this microfluidic device can characterize the sequential metabolism of diazepam. The C‐t profiles of DZP and its metabolites are similar to that of the liver single‐pass perfusion study. Due to the existence of transporters, the lag time of T‐G is similar to that of primary metabolites. As a future study, the distribution of DZP and its metabolites along the device will be measured by MALDI imaging. The information of spatial distribution is expected to further help optimize and validate the mathematical models.

New requirements for temazepam

New requirements for temazepam

Temazepam withdrawal

Temazepam withdrawal

Temazepam withdrawal

Temazepam withdrawal

Catatonia Associated with Temazepam Withdrawal

Catatonia Associated with Temazepam Withdrawal

Zopiclone, but not temazepam, appears to impair driving in the elderly the morning after administration,

Zopiclone, but not temazepam, appears to impair driving in the elderly the morning after administration,

Withdrawal of temazepam gelcaps

Withdrawal of temazepam gelcaps

Simple and sensitive liquid chromatography/tandem mass spectrometry method for the determination of diazepam and its major metabolites in rat cerebrospinal fluid.

Diazepam (DZP) is one of the most commonly prescribed drugs for treating status epilepticus (SE). A simple, sensitive and selective LC/MS/MS method with a wide linear calibration range was developed to quantify DZP and its major metabolites, N-desmethyldiazepam (DMDZP), temazepam (TZP), and oxazepam (OZP), in rat cerebrospinal fluid (CSF). The method was used to simultaneously determine the concentrations of all analytes in a small sample volume (as little as 25 microL) of rat CSF. The lower limits of quantification (LLOQ) of the method are 0.04 ng/mL for DZP and 0.1 ng/mL for its metabolites. The calibration range is 0.04-200 ng/mL for DZP and 0.1-200 ng/ml for the metabolites. All intra- and inter-assay coefficients of variation (%CV) and mean percent errors of the method are less than 12%. This method successfully addresses the need to determine low therapeutic drug concentrations in small physiological samples, namely rat CSF. Moreover, it can be used to investigate the distribution of the drug and its metabolites among blood plasma, brain tissue, and CSF in pharmacokinetic and pharmacodynamic studies in a variety of laboratory animals. With respect to animal experiments involving assays in CSF, this method addresses two of the three criteria of Russell and Bruch (Principles of Humane Experimental Techniques, 1959, Methuen and Co., London) for minimizing animal use, namely refinement and reduction.

Effects of Diazepam and Its Metabolites on Nocturnal Melatonin Secretion in the Rat Pineal and Harderian Glands. A Comparative In Vivo and In Vitro Study

We investigated the effects of diazepam (DZP) and its three metabolites: nordiazepam (NZP), oxazepam (OZP), and temazepam (TZP) on pineal gland nocturnal melatonin secretion. We looked at the effects of benzodiazepines on pineal gland melatonin secretion both in vitro (using organ perifusion) and in vivo in male Wistar rats sacrificed in the middle of the dark phase. We also examined the effects of these benzodiazepines on in vivo melatonin secretion in the Harderian glands. Neither DZP (10−5–10−6 M) nor its metabolites (10−4–10−5 M) affected melatonin secretion by perifused rat pineal glands in vitro. In contrast, a 10−4 M suprapharmacological concentration of DZP increased melatonin secretion of perifused pineal glands by 70%. In vivo, a single acute subcutaneous administration of DZP (3 mg/kg body weight) significantly affected pineal melatonin synthesis and plasma melatonin levels, while administration of the metabolites under the same conditions did not. DZP reduced pineal melatonin content (−40%), N-acetyltransferase activity (−70%), and plasma melatonin levels (−40%), but had no affects on pineal hydroxyindole-O-methyltransferase activity. Neither DZP nor its metabolites affected Harderian gland melatonin content. Our results indicate that the in vivo inhibitory effect of DZP on melatonin synthesis is not due to the metabolism of DZP. The results also show that the control of melatonin production in the Harderian glands differs from that observed in the pineal gland.

Drug release from an ensemble of swellable crosslinked polymer particles

This paper presents a new model suitable to describe the drug release from drug delivery systems constituted by an ensemble of drug loaded crosslinked polymer particles. The model accounts for the main factors affecting the drug release such as the particle size distribution, the physical state and the concentration profile of the drug inside the polymeric particles, the viscoelastic properties of the polymer–penetrant system and the dissolution–diffusion properties of the loaded drug. In order to check the validity of the model, release experiments were performed by using crosslinked polyvinyl-pyrrolidone (PVP) particles and two different model drugs, MAP (medroxyprogesterone acetate) and TEM (Temazepam). MAP and TEM were chosen because of their completely different dissolution behaviours in water. In particular, TEM undergoes a phase transition to the crystalline state upon dissolution when it is loaded in the polymeric network in the amorphous state. The comparison with the experimental results confirms that the most important factors determining the drug release kinetics can be properly accounted for.

Assessing nighttime vigilance through a three-letter cancellation task (3-LCT): effects of daytime sleep with temazepam or placebo

Nocturnal sleepiness is a common complaint suffered by night-shift workers, especially in conditions of an abrupt shift of the wake–sleep cycle. Alertness management strategies can minimize the adverse effects of sleep loss and circadian rhythm desynchronization and promote optimal vigilance in operational settings. Within these strategies, one possibility is to use short periods of “prophylactic sleep” (before long periods of work), which can be facilitated by hypnotics. Vigilance can be evaluated by means of several tests which, sometimes, imply procedures and devices not easily employable in operational settings. In such conditions pencil and paper tests of vigilance can be very useful in the assessment of attentional performance degradation due to sleep loss and/or inversion of the sleep–wake cycle. In this study we evaluated the sensitivity of a three-Letter Cancellation Task (3-LCT) in revealing nighttime variations of vigilance in a laboratory simulation of acute night shift, after a diurnal sleep with placebo (PLC) or temazepam (TMZ). Nocturnal levels of vigilance were also assessed using the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT). All tests were administered four times at 2-h intervals during nighttime after a daytime sleep. Results show that the 3-LCT is sensitive to variations of vigilance occurring during a laboratory simulation of acute night shift. We also found some effects of TMZ, which in the first nocturnal session caused a slowing down of visuoattentive performance. Nocturnal variations of vigilance detected through the 3-LCT were similar to those revealed by means of MSLT, while the ability to maintain wakefulness was substantially spared during the night.

Cognitive behavior therapy, temazepam, or both improved short-term outcomes for older adults with persistent insomnia

Source Citation Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia. A randomized controlled trial. JAMA. 1999 Mar 17:281:991-9.

Racemization and stereoselective alcoholysis of temazepam

Enantiomers of temazepam (TMZ), an anxiolytic drug in clinical use, were resolved and stabilized by the use of aprotic solvents in chiral stationary phase high-performance liquid chromatography (CSP-HPLC). The enantiomers were used to study racemization and heteronucleophilic substitution (alcoholysis) reactions in anhydrous acidic methanol and ethanol. Kinetics of spontaneous racemization and stereoselective conversions to 3-O-methyltemazepam (MeTMZ) and 3-O-ethyltemazepam (EtTMZ) were determined by circular dichroism (CD) spectropolarimetry and CSP-HPLC. The rates of conversion of rac-TMZ to rac-MeTMZ (or rac-EtTMZ) were determined by ultraviolet-visible spectrophotometry. The results indicated that, for example, both N4-protonated and unprotonated forms of (S)-TMZ underwent spontaneous racemization and its 3S-hydroxyl group was highly stereoselectively substituted at C3 position by the ethoxy group of ethanol to form EtTMZ enriched in (S)-EtTMZ. Similar stereoselective reactions occurred for TMZ enantiomers in acidic methanol. Chirality 11:179–186, 1999. Published 1999 Wiley-Liss, Inc.

Rapid and simple chromatographic method for the determination of diazepam and its major metabolites in human plasma and urine

A simple, rapid, sensitive and selective HPLC method has been developed for the analysis of diazepam (DZP) and its major metabolites, N-desmethyldiazepam (DMDZP), temazepam (TZP) and oxazepam (OZP), in plasma and urine, using clonazepam (CZP) as the internal standard and chloroform as the extracting solvent, with a 10 ng/ml limit of quantitation for the four assayed drugs, and an average (±S.D.) recovery of 87.7±6.46%, 92.9±5.31%, 91.4±4.01% and 91.7±2.68% for DZP, DMDZP, TZP and OZP, respectively (from plasma), and 89.6±2.26%, 90±4.24%, 87.45±0.64% and 94.50±0.71% for DZP, DMDZP, TZP and OZP, respectively (from urine). The method has also proved to be selective and reproducible.

Company appeals to retain temazepam capsules

Company appeals to retain temazepam capsules

Company appeals to retain temazepam capsules

Company appeals to retain temazepam capsules

Effects of temazepam (TZ) on the pharmacokinetics (PK) and pharmacodynamics (PD) of remifentanil (REMI) in surgical patients: A population (POP) approach.

Effects of temazepam (TZ) on the pharmacokinetics (PK) and pharmacodynamics (PD) of remifentanil (REMI) in surgical patients: A population (POP) approach.

Gel-filled temazepam capsule ban proposed

Gel-filled temazepam capsule ban proposed

Concentration-dependent metabolism of diazepam in mouse liver.

Previous mouse liver studies with diazepam (DZ), N-desmethyldiazepam (NZ), and temazepam (TZ) confirmed that under first-order conditions, DZ formed NZ and TZ in parallel. Oxazepam (OZ) was generated via NZ and not TZ despite that preformed NZ and TZ were both capable of forming OZ. In the present studies, the concentration-dependent sequential metabolism of DZ was studied in perfused mouse livers and microsomes, with the aim of distinguishing the relative importance of NZ and TZ as precursors of OZ. In microsomal studies, the Kms and Vmaxs, corrected for binding to microsomal proteins, were 34 microM and 3.6 nmole/min per mg and 239 microM and 18 nmole/min per mg, respectively, for N-demethylation and C3-hydroxylation of DZ. The Kms and Vmaxs for N-demethylation and C3-hydroxylation of TZ and NZ, respectively, to form OZ, were 58 microM and 2.5 nmole/min per mg and 311 microM and 2 nmole/min per mg, respectively. The constants suggest that at low DZ concentrations, NZ formation predominates and is a major source of OZ, whereas at higher DZ concentrations, TZ is the important source of OZ. In livers perfused with DZ at input concentrations of 13 to 35 microM, the extraction ratio of DZ (E[DZ]) decreased from 0.83 to 0.60. NZ was the major metabolite formed although its appearance was less than proportionate with increasing DZ input concentration. By contrast, the formation of TZ increased disproportionately with increasing DZ concentration, whereas that for OZ decreased and paralleled the behavior of NZ. Computer simulations based on a tubular flow model and the in vitro enzymatic parameters provided a poor in vitro-organ correlation. The E[DZ], appearance rates of the metabolites, and the extraction ratio of formed NZ (E[NZ, DZ]) were poorly predicted; TZ was incorrectly identified as the major precursor of OZ. Simulations with optimized parameters improved the correlations and identified NZ as the major contributor of OZ. Saturation of DZ N-demethylation at higher DZ concentrations increased the role of TZ in the formation of OZ. The poor aqueous solubility (limiting the concentration range of substrates used in vitro), avid tissue binding and the coupling of enzymatic reactions in liver, favoring sequential metabolism, are possible explanations for the poor in vitro-organ correlation. This work emphasizes the complexity of the hepatic intracellular milieu for drug metabolism and the need for additional modeling efforts to adequately describe metabolite kinetics.