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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 -
Philosophical Transactions of the Royal... Nov 2014The study of animal behaviour is important for both ecology and ecotoxicology, yet research in these two fields is currently developing independently. Here, we... (Review)
Review
The study of animal behaviour is important for both ecology and ecotoxicology, yet research in these two fields is currently developing independently. Here, we synthesize the available knowledge on drug-induced behavioural alterations in fish, discuss potential ecological consequences and report results from an experiment in which we quantify both uptake and behavioural impact of a psychiatric drug on a predatory fish (Perca fluviatilis) and its invertebrate prey (Coenagrion hastulatum). We show that perch became more active while damselfly behaviour was unaffected, illustrating that behavioural effects of pharmaceuticals can differ between species. Furthermore, we demonstrate that prey consumption can be an important exposure route as on average 46% of the pharmaceutical in ingested prey accumulated in the predator. This suggests that investigations of exposure through bioconcentration, where trophic interactions and subsequent bioaccumulation of exposed individuals are ignored, underestimate exposure. Wildlife may therefore be exposed to higher levels of behaviourally altering pharmaceuticals than predictions based on commonly used exposure assays and pharmaceutical concentrations found in environmental monitoring programmes.
Topics: Animals; Anti-Anxiety Agents; Odonata; Oxazepam; Perches; Predatory Behavior; Water Pollutants, Chemical
PubMed: 25405968
DOI: 10.1098/rstb.2013.0580 -
Frontiers in Microbiology 2021The demand for energy and chemicals is constantly growing, leading to an increase of the amounts of contaminants discharged to the environment. Among these,...
The demand for energy and chemicals is constantly growing, leading to an increase of the amounts of contaminants discharged to the environment. Among these, pharmaceutical molecules are frequently found in treated wastewater that is discharged into superficial waters. Indeed, wastewater treatment plants (WWTPs) are designed to remove organic pollution from urban effluents but are not specific, especially toward contaminants of emerging concern (CECs), which finally reach the natural environment. In this context, it is important to study the fate of micropollutants, especially in a soil aquifer treatment (SAT) context for water from WWTPs, and for the most persistent molecules such as benzodiazepines. In the present study, soils sampled in a reed bed frequently flooded by water from a WWTP were spiked with diazepam and oxazepam in microcosms, and their concentrations were monitored for 97 days. It appeared that the two molecules were completely degraded after 15 days of incubation. Samples were collected during the experiment in order to follow the dynamics of the microbial communities, based on 16S rRNA gene sequencing for Archaea and Bacteria, and ITS2 gene for Fungi. The evolution of diversity and of specific operating taxonomic units (OTUs) highlighted an impact of the addition of benzodiazepines, a rapid resilience of the fungal community and an evolution of the bacterial community. It appeared that OTUs from the genus were more abundant at the beginning of the biodegradation process, for diazepam and oxazepam conditions. Additionally, Tax4Fun tool was applied to 16S rRNA gene sequencing data to infer on the evolution of specific metabolic functions during biodegradation. It finally appeared that the microbial community in soils frequently exposed to water from WWTP, potentially containing CECs such as diazepam and oxazepam, may be adapted to the degradation of persistent contaminants.
PubMed: 34912306
DOI: 10.3389/fmicb.2021.742000 -
NeuropsychobiologyThe anxiolytic activity, the tolerance, and the withdrawal symptoms of buspirone and oxazepam were compared in two groups of 14 and 12 outpatients, respectively,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The anxiolytic activity, the tolerance, and the withdrawal symptoms of buspirone and oxazepam were compared in two groups of 14 and 12 outpatients, respectively, suffering from generalized anxiety in a double-blind study with random allocation of patients. The 6-week active period was preceded and followed by 1 and 2 weeks on placebo, respectively. Clinical assessments were performed before and after the predrug placebo period and every 2 weeks thereafter and included Hamilton anxiety and depression scales and AMDP anxiety subscale. The initial daily dose was 15 mg buspirone or 45 mg oxazepam in 3 intakes and the mean final daily doses were 22.2 and 55.8 mg, respectively. Results showed a slower anxiolytic activity of buspirone compared to oxazepam with less improvement after 2 weeks of treatment. The rebound anxiety following abrupt discontinuation of the drug and the level of side effects did not significantly differ between the two compounds.
Topics: Adult; Anxiety; Buspirone; Double-Blind Method; Female; Humans; Male; Middle Aged; Oxazepam; Psychiatric Status Rating Scales; Substance Withdrawal Syndrome
PubMed: 2134114
DOI: 10.1159/000119464 -
Medicine Feb 2015The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal...
The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression.The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92-1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92-1.04), medazepam (HR, 1.01; 95%CI, 0.84-1.21), nitrazepam (HR, 1.06; 95%CI, 0.98-1.14), oxazepam (HR, 1.05; 95%CI, 0.94-1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09-1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use.Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research.
Topics: Benzodiazepines; Carcinogens; Case-Control Studies; Chlordiazepoxide; Clonazepam; Diazepam; Female; Humans; Logistic Models; Longitudinal Studies; Male; Medazepam; Middle Aged; Nitrazepam; Oxazepam; Proportional Hazards Models
PubMed: 25674736
DOI: 10.1097/MD.0000000000000483 -
Anesthesiology Aug 1973
Review
Topics: Acetates; Anesthetics; Animals; Atropine; Biotransformation; Carbon Tetrachloride; Chloroform; Diazepam; Drug Interactions; Ethers; Fentanyl; Halothane; Humans; Lidocaine; Liver; Lung; Mepivacaine; Methoxyflurane; Oxazepam; Pharmacogenetics
PubMed: 4146380
DOI: 10.1097/00000542-197308000-00004 -
British Journal of Clinical Pharmacology Nov 19901. The effect of severe hypothyroidism on the pharmacokinetics and pharmacodynamics of oxazepam 15 mg given orally (n = 10) and the metabolism of paracetamol 750 mg...
1. The effect of severe hypothyroidism on the pharmacokinetics and pharmacodynamics of oxazepam 15 mg given orally (n = 10) and the metabolism of paracetamol 750 mg given intravenously (n = 8) was investigated before and after treatment with levothyroxine. 2. The median total and unbound clearance of oxazepam increased significantly during the study period from 0.78 ml min-1 kg-1 (0.40-1.25) to 1.22 ml min-1 kg-1 (0.66-1.94) and from 9.3 ml min-1 kg-1 (5.2-14.2) to 15.9 ml min-1 kg-1 (7.8-21.8), respectively (P less than 0.01). 3. The elimination half-life of oxazepam was prolonged by hypothyroidism to a median (range) value of 9.3 h (5.4-21.9) compared with 7.5 h (4.8-10.5) in the euthyroid state (P less than 0.05). 4. Hypothyroidism did not affect the protein binding of oxazepam; median values of the free percentage being 8.2% as compared with 7.7% when euthyroid. 5. The median (range) clearance of paracetamol under hypothyroid conditions was 3.12 ml min-1 kg-1 (1.64-4.40) and 4.70 ml min-1 kg-1 (3.18-5.70) following replacement therapy (P less than 0.01). This increase was associated with a comparable increase in the partial clearance to the glucuronide metabolite: 1.86 ml min-1 kg-1 to 2.70 ml min-1 kg-1. 6. Hypothyroidism was associated with decreased performance in a finger tapping test that was exacerbated by oxazepam. When the patients were euthyroid oxazepam did not produce any effect.
Topics: Acetaminophen; Administration, Oral; Adult; Aged; Female; Humans; Hypothyroidism; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Oxazepam
PubMed: 2271373
DOI: 10.1111/j.1365-2125.1990.tb03844.x -
Pharmaceutics Aug 2021Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not... (Review)
Review
Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug-drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro-in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.
PubMed: 34575401
DOI: 10.3390/pharmaceutics13091325 -
British Journal of Clinical Pharmacology Oct 2008To measure and compare the concentration-time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.
AIMS
To measure and compare the concentration-time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.
METHODS
Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration-time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model.
RESULTS
For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04-0.07) and 0.004 (range 0.002-0.006), respectively. The concentration-time profiles in oral fluid paralleled those in blood.
CONCLUSION
After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.
Topics: Administration, Oral; Adolescent; Adult; Drug Administration Routes; Humans; Hypnotics and Sedatives; Male; Oxazepam; Predictive Value of Tests; Saliva; Serum; Substance Abuse Detection; Treatment Outcome
PubMed: 18662285
DOI: 10.1111/j.1365-2125.2008.03252.x -
British Journal of Clinical Pharmacology Jan 19901. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta-adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol.
Topics: Adult; Drug Interactions; Female; Humans; Labetalol; Male; Oxazepam; Propranolol; Psychomotor Performance; Reaction Time
PubMed: 2297460
DOI: 10.1111/j.1365-2125.1990.tb03599.x