-
Environment International Oct 2021Pharmaceutically active compounds (PhACs) have been shown to accumulate in aquatic and riparian food-webs. Yet, our understanding of how temperature, a key environmental...
Pharmaceutically active compounds (PhACs) have been shown to accumulate in aquatic and riparian food-webs. Yet, our understanding of how temperature, a key environmental factor in nature, affects uptake, biotransformation, and the subsequent accumulation of PhACs in aquatic organisms is limited. In this study, we tested to what extent bioconcentration of an anxiolytic drugs (temazepam and oxazepam) is affected by two temperature regimes (10 and 20 °C) and how the temperature affects the temazepam biotransformation and subsequent accumulation of its metabolite (oxazepam) in aquatic organisms. We used European perch (Perca fluviatilis) and dragonfly larvae (Sympetrum sp.), which represent predator and prey species of high ecological relevance in food chains of boreal and temperate aquatic ecosystems. Experimental organisms were exposed to target pharmaceuticals at a range of concentrations (0.2-6 µg L) to study concentration dependent differences in bioconcentration and biotransformation. We found that the bioconcentration of temazepam in perch was significantly reduced at higher temperatures. Also, temperature had a strong effect on temazepam biotransformation in the fish, with the production and subsequent accumulation of its metabolite (oxazepam) being two-fold higher at 20 °C compared to 10 °C. In contrast, we found no temperature dependency for temazepam bioconcentration in dragonfly larvae and no detectable biotransformation of the parent compound that would result in measurable concentrations of oxazepam in this organism. Our results highlight that while organisms may share the same aquatic ecosystem, their exposure to PhACs may change differently across temperature gradients in the environment.
Topics: Animals; Aquatic Organisms; Biotransformation; Ecosystem; Odonata; Perches; Pharmaceutical Preparations; Temperature; Water; Water Pollutants, Chemical
PubMed: 34139590
DOI: 10.1016/j.envint.2021.106705 -
Emergency Medicine Journal : EMJ Apr 2007Serotonin syndrome is an under-reported and under-recognised condition that occurs on administration of selective serotonin re-uptake inhibitors alone, or in combination...
Serotonin syndrome is an under-reported and under-recognised condition that occurs on administration of selective serotonin re-uptake inhibitors alone, or in combination with other medication known to increase levels of 5-hydroxytryptamine. This case report demonstrates signs and symptoms associated with their overdose and illustrates the importance of recognition of this syndrome to instigate appropriate treatment for the patient.
Topics: Adult; Diphenhydramine; Drug Overdose; Female; Glasgow Coma Scale; Humans; Paroxetine; Serotonin Syndrome; Temazepam
PubMed: 17384366
DOI: 10.1136/emj.2006.040550 -
Environmental Pollution (Barking, Essex... Jun 2021A recent surge in the use and abuse of diverse prescribed psychotic and illicit drugs necessitates the surveillance of drug residues in source water and the associated...
A recent surge in the use and abuse of diverse prescribed psychotic and illicit drugs necessitates the surveillance of drug residues in source water and the associated ecological impacts of chronic exposure to the aquatic organism. Thirty-six psychotic and illicit drug residues were determined in discharged wastewater from two centralized municipal wastewater treatment facilities and two wastewater receiving creeks for seven consecutive days in Kentucky. Zebrafish (Danio rerio) larvae were exposed to the environmental relevant mixtures of all drug residues, all illicit drugs, and all prescribed psychotic drugs. The extracted RNA from fish homogenates was sequenced, and differentially expressed sequences were analyzed for known or predicted nervous system expression, and screened annotated protein-coding genes to the true environmental cocktail mixture. Illicit stimulant (cocaine and one metabolite), opioids (methadone, methadone metabolite, and oxycodone), hallucinogen (MDA), benzodiazepine (oxazepam and temazepam), carbamazepine, and all target selective serotonin reuptake inhibitors including sertraline, fluoxetine, venlafaxine, and citalopram were quantified in 100% of collected samples from both creeks. The high dose cocktail mixture exposure group revealed the largest group of differentially expressed genes: 100 upregulated and 77 downregulated (p ≤ 0.05; q ≤ 0.05). The top 20 differentially expressed sequences in each exposure group comprise 82 unique transcripts corresponding to 74% annotated genes, 7% non-coding sequences, and 19% uncharacterized sequences. Among 61 differentially expressed sequences that corresponded to annotated protein-coding genes, 23 (38%) genes or their homologs are known to be expressed in the nervous system of fish or other organisms. Several of the differentially expressed sequences are associated primarily with the immune system, including several major histocompatibility complex class I and interferon-induced proteins. Interleukin-1 beta (downregulated in this study) abnormalities are considered a risk factor for psychosis. This is the first study to assess the contributions of multiple classes of psychotic and illicit drugs in combination with developmental gene expression.
Topics: Animals; Fluoxetine; Larva; Selective Serotonin Reuptake Inhibitors; Water Pollutants, Chemical; Zebrafish
PubMed: 33689951
DOI: 10.1016/j.envpol.2021.116777 -
Frontiers in Neuroscience 2022Insomnia is a stress-related sleep disorder, may favor a state of allostatic overload impairing brain neuroplasticity, stress immune and endocrine pathways, and may... (Review)
Review
INTRODUCTION
Insomnia is a stress-related sleep disorder, may favor a state of allostatic overload impairing brain neuroplasticity, stress immune and endocrine pathways, and may contribute to mental and physical disorders. In this framework, assessing and targeting insomnia is of importance.
AIM
Since maladaptive neuroplasticity and allostatic overload are hypothesized to be related to GABAergic alterations, compounds targeting GABA may play a key role. Accordingly, the aim of this review was to discuss the effect of GABA receptor agonists, short-medium acting hypnotic benzodiazepines and the so called Z-drugs, at a molecular level.
METHOD
Literature searches were done according to PRISMA guidelines. Several combinations of terms were used such as "hypnotic benzodiazepines" or "brotizolam," or "lormetazepam" or "temazepam" or "triazolam" or "zolpidem" or "zopiclone" or "zaleplon" or "eszopiclone" and "insomnia" and "effects on sleep" and "effect on brain plasticity" and "effect on stress system". Given the complexity and heterogeneity of existing literature, we ended up with a narrative review.
RESULTS
Among short-medium acting compounds, triazolam has been the most studied and may regulate the stress system at central and peripheral levels. Among Z-drugs eszopiclone may regulate the stress system. Some compounds may produce more "physiological" sleep such as brotizolam, triazolam, and eszopiclone and probably may not impair sleep processes and related neural plasticity. In particular, triazolam, eszopiclone, and zaleplon studied in animal models did not alter neuroplasticity.
CONCLUSION
Current models of insomnia may lead us to revise the way in which we use hypnotic compounds in clinical practice. Specifically, compounds should target sleep processes, the stress system, and sustain neural plasticity. In this framework, among the short/medium acting hypnotic benzodiazepines, triazolam has been the most studied compound while among the Z-drugs eszopiclone has demonstrated interesting effects. Both offer potential new insight for treating insomnia.
PubMed: 35968380
DOI: 10.3389/fnins.2022.893015 -
BMC Geriatrics Apr 2021Benzodiazepines (BZDs) and Z-drugs have high potential for developing frequent adverse drug events in older adults (e.g., psychomotor sedation, drug-related dementia,...
The prevalence and prescribing patterns of benzodiazepines and Z-drugs in older nursing home residents in different European countries and Israel: retrospective results from the EU SHELTER study.
BACKGROUND
Benzodiazepines (BZDs) and Z-drugs have high potential for developing frequent adverse drug events in older adults (e.g., psychomotor sedation, drug-related dementia, deliria, drug dependence, etc.). Knowledge of the prevalence and patterns of the use of BZDs/Z-drugs in vulnerable older patients is important in order to prevent and reduce the burden caused by their drug-related complications. Our study focused on international comparisons of the prevalence, country-specific prescribing patterns and risk factors of regular BZD/Z-drug use in nursing home (NH) residents.
METHODS
This cross-sectional study retrospectively analysed data of 4156 NH residents, prospectively assessed in the Services and Health in the Elderly in Long TERm care (SHELTER) project conducted from 2009 to 2014. Residents aged 65+ in 57 NHs in 7 European countries and Israel were assessed by the InterRAI Long-Term Care Facilities instrument. Descriptive statistics and multiple logistic regression models were used to describe the country-specific prevalence, patterns and risk factors of BZD/Z-drug use.
RESULTS
The mean age of the participants was 83.4 ± 9.4 years, 73% were female and 27.7% used BZDs/Z-drugs. The prevalence of BZD/Z-drug use differed significantly across countries, ranging from 44.1% in Israel to 14.5% in Germany. The most frequently prescribed were zopiclone (17.8%), lorazepam (17.1%) and oxazepam (16.3%). Lorazepam, oxazepam and diazepam were used in most of the countries. Brotizolam, temazepam and zolpidem showed highest prevalence in Israel (99.4% of all regular users of this medication in the sample), the Netherlands (72.6%) and France (50.0%), respectively. Residing in Israel was the most significant factor associated with the use of BZDs/Z-drugs or BZDs only (odds ratio [OR] 6.7; 95% confidence interval [CI] 4.8-9.2 and OR 9.7, 95%CI 6.5-14.5, respectively). The use of Z-drugs only was most significantly associated with residing in France (OR 21.0, 95%CI 9.0-48.9).
CONCLUSIONS
Despite global recommendations and warnings, the preference for and extent of use of individual BZDs and Z-drugs in vulnerable NH residents differ significantly across countries. The strong association with country of residence compared to clinical and functional factors denotes that prescribing habits, social, cultural, behavioural, and regulatory factors still play an important role in the current diverse use of these medications.
Topics: Aged; Aged, 80 and over; Benzodiazepines; Cross-Sectional Studies; Europe; Female; France; Germany; Humans; Israel; Male; Netherlands; Nursing Homes; Pharmaceutical Preparations; Prevalence; Retrospective Studies
PubMed: 33902474
DOI: 10.1186/s12877-021-02213-x -
British Journal of Clinical Pharmacology Jan 2003Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained... (Review)
Review
Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.
Topics: Benzodiazepines; Biomarkers; Dose-Response Relationship, Drug; Electroencephalography; Eye Movements; Humans; Motor Skills
PubMed: 12534639
DOI: 10.1046/j.1365-2125.2002.t01-10-01714.x -
Frontiers in Pharmacology 2020Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in...
BACKGROUND
Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in herbal medicine. The aim of this study was to investigate the interactions between imperatorin and diazepam and and to provide evidence-based guidance for the safe clinical use of the drug.
METHODS
In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC values and the type of inhibition. For assessment, six rats were pretreated with 50 mg/kg imperatorin for two weeks, six were administered saline, and a single dose of 10 mg/kg diazepam was administered orally to both groups 30 min after the administration of imperatorin.
RESULTS
Imperatorin inhibited the metabolism of diazepam the competitive mechanism of CYP450. The IC values of imperatorin to nordazepam and temazepam were 1.54 μM and 1.80 μM, respectively. The inhibitory constant values for temazepam and nordazepam were 1.24 μM and 1.29 μM, respectively. Long-term administration of imperatorin significantly increased the AUC, AUC, and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly ( < 0.05). In turn, the AUC, AUC, and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly ( < 0.05).
CONCLUSIONS
This study demonstrates that imperatorin inhibits the metabolism of diazepam both and . These results indicated that more attention should be paid when taking diazepam together with food or herbs containing IMP, although further investigation is still needed.
PubMed: 33041783
DOI: 10.3389/fphar.2020.01079 -
British Journal of Clinical Pharmacology May 1979Effect of diazepam (5 and 10 mg) and temazepam (10, 20 and 30 mg) on the sleep of six healthy middle aged (45-55 years) males was studied using electroencephalography... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Effect of diazepam (5 and 10 mg) and temazepam (10, 20 and 30 mg) on the sleep of six healthy middle aged (45-55 years) males was studied using electroencephalography for sleep measures, and analogue scales for subjective assessments of well being and sleep quality. In placebo studies the sleep of the group was compared with that of young adults (20-29 years). In the older group there was a marked reduction in total sleep time ( < 0.01), an increase in latency to stage 3 sleep ( < 0.01), and an increase in percentage of stage 1 (drowsy) and stage 2 sleep ( < 0.05 and 0.001 respectively). There were no changes in percentage or latency of rapid eye movement sleep. With the middle aged group there was no increase in total sleep time with diazepam and temazepam. Sleep onset latencies were shortened by 5 and 10 mg diazepam ( < 0.05), but there was no change with temazepam. Number of awakenings was reduced by 30 mg temazepam ( < 0.01), and the duration of awakenings was reduced by 5 and 10 mg diazepam ( < 0.05) and by 20 and 30 mg temazepam ( < 0.01). Awake activity was reduced by 5 and 10 mg diazepam ( < 0.001) and by 10 mg ( < 0.05) and 20 and 30 mg ( < 0.001) temazepam. The subjects assessed their sleep as improved with diazepam and with temazepam without residual effects on well-being. Though the effect of diazepam (5-10 mg) and temazepam (10-20 mg) may not be so pronounced as that of other hypnotics, they are likely to be useful over an age range which includes, at least, young adulthood and late middle age. A particular advantage of these drugs is that within these dose ranges they are without residual effects on performance.
Topics: Anti-Anxiety Agents; Diazepam; Humans; Male; Middle Aged; Placebos; Sleep; Sleep Stages; Temazepam; Time Factors
PubMed: 38821
DOI: 10.1111/j.1365-2125.1979.tb00987.x -
Chemosphere Jun 2017Pharmaceuticals as environmental contaminants have received a lot of interest over the past decade but, for several pharmaceuticals, relatively little is known about...
Pharmaceuticals as environmental contaminants have received a lot of interest over the past decade but, for several pharmaceuticals, relatively little is known about their occurrence in European surface waters. Benzodiazepines, a class of pharmaceuticals with anxiolytic properties, have received interest due to their behavioral modifying effect on exposed biota. In this study, our results show the presence of one or more benzodiazepine(s) in 86% of the analyzed surface water samples (n = 138) from 30 rivers, representing seven larger European catchments. Of the 13 benzodiazepines included in the study, we detected 9, which together showed median and mean concentrations (of the results above limit of quantification) of 5.4 and 9.6 ng L, respectively. Four benzodiazepines (oxazepam, temazepam, clobazam, and bromazepam) were the most commonly detected. In particular, oxazepam had the highest frequency of detection (85%) and a maximum concentration of 61 ng L. Temazepam and clobazam were found in 26% (maximum concentration of 39 ng L) and 14% (maximum concentration of 11 ng L) of the samples analyzed, respectively. Finally, bromazepam was found only in Germany and in 16 out of total 138 samples (12%), with a maximum concentration of 320 ng L. This study clearly shows that benzodiazepines are common micro-contaminants of the largest European river systems at ng L levels. Although these concentrations are more than a magnitude lower than those reported to have effective effects on exposed biota, environmental effects cannot be excluded considering the possibility of additive and sub-lethal effects.
Topics: Benzodiazepines; Clobazam; Environmental Monitoring; Europe; Oxazepam; Rivers; Temazepam; Water Pollutants, Chemical
PubMed: 28273540
DOI: 10.1016/j.chemosphere.2017.02.126 -
Blood Oct 2013
Topics: Bone Marrow; Consolidation Chemotherapy; Female; Humans; Induction Chemotherapy; Leukemia, Megakaryoblastic, Acute; Middle Aged; Temazepam
PubMed: 24266031
DOI: 10.1182/blood-2013-05-503581