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Anaesthesia Jan 1995The clinical pharmacodynamics of temazepam were investigated in patients who received spinal anaesthesia. Total plasma and cerebrospinal fluid temazepam concentrations...
The clinical pharmacodynamics of temazepam were investigated in patients who received spinal anaesthesia. Total plasma and cerebrospinal fluid temazepam concentrations were measured and correlated with the clinical effects. Sedation was measured by three separate methods. None, including an aggregated score of all three measures, was correlated closely with either the plasma or the cerebrospinal fluid levels (p = 0.86 and 0.12 respectively). Anxiety was measured before and after premedication. The two scores were correlated but the change in anxiety after premedication did not correlate with either the plasma or the cerebrospinal fluid concentrations (p = 0.11 and 0.45 respectively). Short-term memory was measured before and after premedication. The decline in short-term memory ability was moderately well correlated with both the plasma and the cerebrospinal fluid levels (p = 0.0005 and 0.013 respectively). With temazepam, the variation in sedative and anxiolytic effects between subjects is explained not by differences in pharmacokinetics but rather by differences in the pharmacodynamic response. Because sedative and anxiolytic effects are poorly correlated, but the amnesic effect is well correlated with temazepam concentrations, different sites of action for these effects are suggested.
Topics: Aged; Aged, 80 and over; Anesthesia, Spinal; Anxiety; Conscious Sedation; Dose-Response Relationship, Drug; Humans; Male; Memory, Short-Term; Middle Aged; Premedication; Temazepam
PubMed: 7702140
DOI: 10.1111/j.1365-2044.1995.tb04503.x -
Pharmaceutics May 2020The opposing effect of the blood-brain barrier against the delivery of most drugs warrants the need for an efficient brain targeted drug delivery system for the...
The opposing effect of the blood-brain barrier against the delivery of most drugs warrants the need for an efficient brain targeted drug delivery system for the successful management of neurological disorders. Temazepam-loaded nanostructured lipid carriers (NLCs) have shown possibilities for enhancing bioavailability and brain targeting affinity after oral administration. This study aimed to investigate these properties for insomnia treatment. Temazepam-NLCs were prepared by the solvent injection method and optimized using a 4 full factorial design. The optimum formulation (NLC-1) consisted of; Compritol 888 ATO (75 mg), oleic acid (25 mg), and Poloxamer 407 (0.3 g), with an entrapment efficiency of 75.2 ± 0.1%. The average size, zeta potential, and polydispersity index were determined to be 306.6 ± 49.6 nm, -10.2 ± 0.3 mV, and 0.09 ± 0.10, respectively. Moreover, an in vitro release study showed that the optimized temazepam NLC-1 formulation had a sustained release profile. Scintigraphy images showed evident improvement in brain uptake for the oral Tc-temazepam NLC-1 formulation versus the Tc-temazepam suspension. Pharmacokinetic data revealed a significant increase in the relative bioavailability of Tc-temazepam NLC-1 formulation (292.7%), compared to that of oral Tc-temazepam suspension. Besides, the NLC formulation exhibited a distinct targeting affinity to rat brain. In conclusion, our results indicate that the developed temazepam NLC formulation can be considered as a potential nanocarrier for brain-mediated drug delivery in the out-patient management of insomnia.
PubMed: 32422903
DOI: 10.3390/pharmaceutics12050451 -
BMC Geriatrics Jun 2018Studies on persistence of benzodiazepine agonist (BZDA) withdrawal in older outpatients are few, and few studies on long-term persistence over years have yet been... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Studies on persistence of benzodiazepine agonist (BZDA) withdrawal in older outpatients are few, and few studies on long-term persistence over years have yet been published. To describe the persistence of temazepam, zolpidem, and zopiclone (BZDA) withdrawal among older outpatients at 3 years from the beginning of withdrawal, as well as any changes in use of other medications.
METHODS
92 outpatients (≥55 years) with primary insomnia, long-term BZDA use as hypnotics (mean duration of BZDA use 9.9 ± 6.2 years), and willingness to withdraw from BZDAs each received either melatonin or a placebo nightly for one month. During this period, BZDAs were meant to be gradually withdrawn. Sleep hygiene counselling and psychosocial support were provided. Three years later, use of BZDAs and other medications was determined by interview and confirmed from medical records.
RESULTS
Of the original 92 outpatients, 83 (90%) participated in the 3-year survey (mean follow-up 3.3 ± 0.2 years). The number of BZDA-free participants decreased from 34 (37%) at 6 months to 26 (28%; intention-to-treat) at 3 years, that of irregular BZDA users decreased from 44 (48%) at 6 months to 27 (29%) at 3 years, while that of regular users increased from 11 (12%) at 6 months to 30 (33%) at 3 years (P = 0.001). Those who were regular BZDA users at 3 years had at baseline (before withdrawal) higher BMI (P = 0.001) than did other participants. At 3 years, the total number of medications remained unchanged for non-users (P = 0.432), but increased for the irregular (P = 0.011) and regular users (P = 0.026) compared to baseline. At 3 years, compared to baseline, use of antidepressants, dopamine agonists, melatonin, and NSAIDs/paracetamol was significantly more common in the whole cohort, but their use did not differ between the BZDA-user subgroups. Randomization to melatonin or placebo during BZDA withdrawal was unrelated to BZDA-withdrawal result.
CONCLUSIONS
At 3 years after withdrawal, the number of BZDA-free participants had decreased, but still one-third of the subjects remained BZDA-free, and one-third had reduced their use. Successful BZDA withdrawal did not lead to any increase in total number of medications; use of symptomatic medications in the whole cohort, however, did increase.
Topics: Aged; Azabicyclo Compounds; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypnotics and Sedatives; Male; Outpatients; Piperazines; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Substance Withdrawal Syndrome; Temazepam; Time Factors; Zolpidem
PubMed: 29907085
DOI: 10.1186/s12877-018-0829-9 -
Cells Nov 2020The constitutive androstane receptor (CAR) is the essential regulator of genes involved both in xenobiotic and endobiotic metabolism. Diazepam has been shown as a potent...
The constitutive androstane receptor (CAR) is the essential regulator of genes involved both in xenobiotic and endobiotic metabolism. Diazepam has been shown as a potent stimulator of CAR nuclear translocation and is assumed as an indirect CAR activator not interacting with the CAR cavity. In this study, we sought to determine if diazepam is a ligand directly interacting with the CAR ligand binding domain (LBD) and if it regulates its target genes in a therapeutically relevant concentration. We used different CAR constructs in translocation and luciferase reporter assays, recombinant CAR-LBD in a TR-FRET assay, and target genes induction studied in primary human hepatocytes (PHHs), HepaRG cells, and in CAR humanized mice. We also used in silico docking and CAR-LBD mutants to characterize the interaction of diazepam and its metabolites with the CAR cavity. Diazepam and its metabolites such as nordazepam, temazepam, and oxazepam are activators of CAR+Ala in translocation and two-hybrid assays and fit the CAR cavity in docking experiments. In gene reporter assays with CAR3 and in the TR-FRET assay, only diazepam significantly interacts with CAR-LBD. Diazepam also promotes up-regulation of CYP2B6 in PHHs and in HepaRG cells. However, in humanized CAR mice, diazepam significantly induces neither nor genes nor does it regulate critical genes involved in glucose and lipids metabolism and liver proliferation. Thus, we demonstrate that diazepam interacts with human CAR-LBD as a weak ligand, but it does not significantly affect expression of tested CAR target genes in CAR humanized mice.
Topics: Adult; Animals; Cell Line; Cell Proliferation; Constitutive Androstane Receptor; Diazepam; Female; Genes, Reporter; Hepatocytes; Humans; Ligands; Liver; Male; Mice; Middle Aged; Protein Domains; Protein Transport; Receptors, Cytoplasmic and Nuclear
PubMed: 33255185
DOI: 10.3390/cells9122532 -
Journal of Analytical Toxicology Jul 2023Postmortem whole blood samples can differ greatly in quality where hyperlipemia is a frequent variable that can influence the results of analytical methods. The aim of...
Postmortem whole blood samples can differ greatly in quality where hyperlipemia is a frequent variable that can influence the results of analytical methods. The aim of this study was to investigate the influence of lipemia on postmortem analysis as well as demonstrate the usage of Intralipid in comparison to pooled postmortem lipids as matrix additives for meaningful evaluation and validation of hyperlipidemic postmortem samples. Hyperlipidemic blood samples were simulated by adding different concentrations of Intralipid or pooled authentic postmortem lipids to bovine whole blood. The hyperlipidemic blood samples were spiked with 14 benzodiazepines and five sedative and antianxiety drugs (alprazolam, clonazepam, 7-aminoclonazepam, diazepam, flunitrazepam, 7-aminoflunitrazepam, hydroxyzine, lorazepam, midazolam, nitrazepam, 7-aminonitrazepam, nordazepam, oxazepam, propiomazine, dihydropropiomazine, temazepam, triazolam, zolpidem and zopiclone). Samples were prepared with liquid-liquid extraction followed by ultra-high performance liquid chromatography-mass spectrometry. The effects of lipemia on the recovery of analytes and internal standards (ISs) were evaluated to determine the effect of, and any differences between, the two additives. Lipemia was found to cause major interference when quantifying the analytes. For most analytes, the ISs could compensate for analyte losses. However, the most hydrophilic analytes (7-amino metabolites), together with the most lipophilic analytes (propiomazine and dihydropropiomazine), were greatly affected by lipemia (<50% recovery), and the IS could not compensate for analyte losses. In general, lower analyte recoveries were observed for samples with Intralipid as a lipemic additive in comparison to those containing pooled postmortem lipids. Both Intralipid and pooled postmortem lipids showed marked effects on the analytical results. Intralipid gave a good indication of the effects of lipemia and could be a useful tool for making a meaningful evaluation of hyperlipidemic postmortem samples during the method development and validation.
Topics: Animals; Cattle; Tandem Mass Spectrometry; Benzodiazepines; Phospholipids; Hyperlipidemias
PubMed: 37130054
DOI: 10.1093/jat/bkad025 -
The Analyst Feb 2024Pharmaceutical polymers and excipients represent interesting but often overlooked chemical classes in clinical exposure and bioanalytical research. These chemicals may...
High-abundance peaks and peak clusters associate with pharmaceutical polymers and excipients in urinary untargeted clinical metabolomics data: exploration of their origin and possible impact on label-free quantification.
Pharmaceutical polymers and excipients represent interesting but often overlooked chemical classes in clinical exposure and bioanalytical research. These chemicals may cause hypersensitivity reactions, they can be useful to confirm exposure to pharmaceuticals, and they may pose bioanalytical challenges, including ion suppression in liquid chromatography-mass spectrometry (LC-MS-)based workflows. In this work, we assessed these chemicals in light of a rather surprising finding presented in two previously published studies, namely that usage of cyclosporine A, an immunosuppressive drug which is known to be cleared through excretion in the bile, explained the largest amount of variance in principal component analysis of urinary LC-SWATH/MS small-molecule profiling data. Specifically, we examined the freely-accessible 24-hour urine metabolomics data of 570 kidney transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT03272841). These data unveiled thousands of high-abundance polymer peaks in some samples, which were associated with the use of the macrogol (, polyethylene glycol) 3350 oral laxative agent. In addition, we found multiple clusters of high-abundance peaks which were linked to the exposure to two pharmaceutical excipients, namely short-chain polyethylene glycol (molecular weight <1000 Da) and polyethoxylated castor oil (also known as Kolliphor® EL or Cremophor® EL). Respectively, these excipients are used in temazepam capsules and cyclosporine A capsules, and the latter provides a plausible explanation for the rather surprising finding that instigated our work. Moreover, such explanation and our findings in general put emphasis on taking into consideration these and other pharmaceutical polymers and excipients when exploring, processing, and interpreting clinical small-molecule profiling data.
Topics: Humans; Excipients; Cyclosporine; Polymers; Cohort Studies; Polyethylene Glycols; Metabolomics
PubMed: 38251754
DOI: 10.1039/d3an01874a -
Healthcare (Basel, Switzerland) Aug 2023Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have... (Review)
Review
Effectiveness of Exercise, Cognitive Behavioral Therapy, and Pharmacotherapy on Improving Sleep in Adults with Chronic Insomnia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, -0.29; 95% CI, -0.57 to -0.01) and CBT-I (-0.48; -0.68 to -0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (-0.80; -1.25 to -0.36) but not long-term effectiveness (0.19; -0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment.
PubMed: 37570447
DOI: 10.3390/healthcare11152207 -
Diazepam and its metabolites in the mothers' and newborns' hair as a biomarker of prenatal exposure.Journal of Physiology and Pharmacology... Aug 2013Pregnant women are exposed to benzodiazepines for therapeutic purposes during gestation. The goal of this study was to evaluate prenatal exposure to benzodiazepines....
UNLABELLED
Pregnant women are exposed to benzodiazepines for therapeutic purposes during gestation. The goal of this study was to evaluate prenatal exposure to benzodiazepines. Time of exposure during course of pregnancy is a significant aspect of fetal exposure to drugs. Benzodiazepine concentration assay in hair of mothers and newborns exposed prenatally to these drugs was performed in the studies. Development, validation and evaluation of benzodiazepine determination method in mothers and their newborns enables assessment of health risks for the child and implementation of adequate therapeutic procedures. We used A LC-ESI-MS/MS method that allowed determination of diazepam (the main benzodiazepine used by pregnant women was diazepam) and its metabolites (nordazepam, oxazepam) in hair of mothers and newborns. LOQ 10 pg/mg of hair was used in the study.
RESULTS
concentration of nordazepam was higher than parent drug (diazepam) and higher in newborns' hair when compared to mothers'. The mean concentrations of diazepam in mothers' hair were 31.6±36.0 and 34.1±42.4 pg/mg in the second and third trimester of pregnancy respectively. The mean concentration of diazepam in newborns' hair was higher and reached levels of 53.3±36.5 pg/mg. The mean concentration of nordazepam in the mothers' hair corresponding to the second and third trimester was 52.9±48.1 and 89.9±122.8 pg/mg, respectively. Nordazepam in the newborns' hair was detected at the mean level of 108.1±144.2 pg/mg. It was concluded that diazepam and nordazepam are permanently incorporated into the hair structure. Presence of diazepam and its metabolites in newborn's hair confirms that these benzodiazepines permeate placental barrier. Segmental analysis of mothers' hair enabled the assessment of drug administration time. Diazepam and its metabolites determined in hair of newborns may serve as biomarkers of prenatal exposure to these drugs. The performed LC-MS/MS analysis was accurate enough to determine even low concentrations of benzodiazepines, at the level of few pg/mg of hair. Levels of diazepam detected in hair of newborns were higher than levels determined in mothers. This may confirm the fact, that fetus's ability to metabolize diazepam is scarce. Nordazepam was found in higher concentrations in hair of newborns than in hair of mothers, which may suggest that it is cumulated in child's organism. Other metabolites of diazepam--oxazepam and temazepam--were detected in very few cases, in low concentrations.
Topics: Biomarkers; Chromatography, Liquid; Diazepam; Female; Hair; Humans; Infant, Newborn; Maternal-Fetal Exchange; Mothers; Nordazepam; Pregnancy; Pregnancy Trimesters; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 24101397
DOI: No ID Found -
European Neuropsychopharmacology : the... Oct 2015Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally...
Benzodiazepines are commonly used medications that alter sleep spindles during non-rapid eye movement (NREM) sleep, however the topographic changes to these functionally significant waveforms have yet to be fully elucidated. This study utilized high-density electroencephalography (hdEEG) to investigate topographic changes in sleep spindles and spindle-range activity caused by temazepam during NREM sleep in 18 healthy adults. After an accommodation night, sleep for all participants was recorded on two separate nights after taking either placebo or oral temazepam 15 mg. Sleep was monitored using 256-channel hdEEG. Spectral analysis and spindle waveform detection of sleep EEG data were performed for each participant night. Global and topographic data were subsequently compared between temazepam and placebo conditions. Temazepam was associated with significant increases in spectral power from 10.33 to 13.83 Hz. Within this frequency band, temazepam broadly increased sleep spindle duration, and topographically increased spindle amplitude and density in frontal and central-posterior regions, respectively. Higher frequency sleep spindles demonstrated increased spindle amplitude and a paradoxical decrease in spindle density in frontal and centroparietal regions. Further analysis demonstrated temazepam both slowed the average frequency of spindle waveforms and increased the relative proportion of spindles at peak frequencies in frontal and centroparietal regions. These findings suggest that benzodiazepines have diverse effects on sleep spindles that vary by frequency and cortical topography. Further research that explores the relationships between topographic and frequency-dependent changes in pharmacologically-induced sleep spindles and the functional effects of these waveforms is indicated.
Topics: Administration, Oral; Adolescent; Adult; Brain; Electroencephalography; Female; Humans; Hypnotics and Sedatives; Male; Polysomnography; Sleep Stages; Temazepam; Young Adult
PubMed: 26195197
DOI: 10.1016/j.euroneuro.2015.06.005 -
JAMA Network Open Oct 2020The proportion of patients who develop long-term benzodiazepine use remains controversial, as do the length of time before long-term use develops and the factors... (Comparative Study)
Comparative Study
IMPORTANCE
The proportion of patients who develop long-term benzodiazepine use remains controversial, as do the length of time before long-term use develops and the factors associated with long-term use.
OBJECTIVE
To investigate the incidence of long-term benzodiazepine and related drug (BZDR) use and factors associated with the development of long-term use implementing a follow-up design with new BZDR users.
DESIGN, SETTING, AND PARTICIPANTS
This population-based cohort study used a nationwide cohort of 129 732 new BZDR users in Finland. New users of BZDRs aged 18 years or older were identified from the prescription register maintained by the Social Insurance Institution of Finland as individuals who initiated BZDR use during 2006 and had not used BZDRs from 2004 to 2005. The follow-up continued until death, long-term hospitalization, a gap of 2 years in BZDR use, or December 31, 2015. The population was analyzed according to age at treatment initiation, categorized into younger (<65 years) and older (≥65 years) subcohorts. Analyses were conducted from May 2019 to February 2020.
EXPOSURES
Use of BZDRs, modeled from register-based data using the PRE2DUP (from prescriptions to drug use periods) method.
MAIN OUTCOMES AND MEASURES
Long-term BZDR use, defined as continuous use of 180 days or longer, and factors associated with long-term vs short-term use, compared using Cox proportional hazards models.
RESULTS
Among the 129 732 incident BZDR users, the mean (SD) age was 52.6 (17.7) years, and 78 017 (60.1%) individuals were women. During the follow-up period, 51 099 BZDR users (39.4%) became long-term users. Long-term treatment was more common in the older subcohort (19 103 individuals [54.5%]) than the younger subcohort (31 996 individuals [33.8%]). At 6 months, 28 586 individuals (22.0%) had become long-term users: 11 805 (33.7%) in the older subcohort and 16 781 (17.7%) in the younger subcohort. The largest proportions of initiators who became long-term users were those persons who initiated treatment with nitrazepam (76.4%; 95% CI, 73.6%-79.1%), temazepam (63.9%; 95% CI, 62.9%-65.0%), lorazepam (62.4%; 95% CI, 59.7%-65.1%), or clonazepam (57.5%; 95% CI, 55.9%-59.2%). Factors associated with the development of long-term use included male sex, older age, receipt of social benefits, psychiatric comorbidities, and substance abuse.
CONCLUSIONS AND RELEVANCE
The findings of this population-based cohort study conducted in Finland suggest that the incidence of subsequent long-term BZDR use in individuals who initiate use of BZDRs is high, especially among older persons, and that the specific BZDR used initially is associated with the development of long-term BZDR use and should be carefully considered when prescribing BZDRs. The observed factors that appear to be associated with development of long-term BZDR use also should be considered in clinical decision-making when starting and monitoring BZDR treatment.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Benzodiazepines; Cohort Studies; Female; Finland; Humans; Incidence; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Substance-Related Disorders; Time Factors; Young Adult
PubMed: 33119104
DOI: 10.1001/jamanetworkopen.2020.19029