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Journal of Addiction MedicinePatients suffering from substance use disorder, including for instance benzodiazepines, may have comorbidity with attention deficit hyperactivity disorder (ADHD)....
Patients suffering from substance use disorder, including for instance benzodiazepines, may have comorbidity with attention deficit hyperactivity disorder (ADHD). Centrally acting stimulants play an important role in the treatment of ADHD. Before such treatment can be initiated, withdrawal of benzodiazepines may be necessary. Urine testing is the preferred method for monitoring adherence in benzodiazepine withdrawal, but there is a lack of studies reporting detection time. Here, we report a case of a 30-year-old woman with substance use disorder and ADHD who had detectable metabolites of diazepam 79 days after withdrawal. To our knowledge, no cases with detection time equivalent to this have previously been published. This case report serves as an example that clinicians may need to consider interindividual pharmacokinetic characteristics when interpreting the results of urine drug tests, and that a positive urine test may still be consistent with abstinence from a certain drug. In the current case, a high body mass index and a genetic polymorphism gave a reasonable explanation for the prolonged detection of diazepam metabolites.
Topics: Adult; Benzodiazepines; Diazepam; Female; Humans; Oxazepam; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 34954745
DOI: 10.1097/ADM.0000000000000944 -
The Science of the Total Environment Mar 2022Uptake of contaminants is linked to their toxicity and is usually estimated through their lipophilicity (logK). Here, we review current literature regarding... (Review)
Review
Uptake of contaminants is linked to their toxicity and is usually estimated through their lipophilicity (logK). Here, we review current literature regarding bioconcentration, i.e. uptake of contaminants from the external environment only, and the effects of exposure to neuroactive pharmaceuticals in fish. We aim to determine if lipophilicity is a suitable predictor of bioconcentration of these compounds in fish, to identify major drivers of bioconcentration and explore the link between bioconcentration potential and toxicity, focusing on survival, growth, condition, behaviour and reproduction endpoints. Additionally, we compare concentrations known to elicit significant effects in fish with current environmental concentrations, identifying exposure risk in ecosystems. The majority of studies have focused on antidepressants, mainly fluoxetine, and encompasses mostly freshwater species. Few studies determined pharmaceuticals bioconcentration, and even a smaller portion combined bioconcentration with other toxicity endpoints. Results show that lipophilicity isn't a good predictor of neuroactive pharmaceuticals' bioconcentration in fish, which in turn is highly influenced by experimental parameters, including abiotic conditions, species and life-stage. The need for increased standardization of experimental settings is key towards improving accuracy of environmental risk assessments and application in future regulatory schemes. Still, increased fish lethality was linked to increased bioconcentration, yet no other correlations were observed when considering effects on growth, condition, behaviour or reproduction, likely as a result of insufficient and variable data. In the context of current environmental concentrations, several neuroactive pharmaceuticals were found to be potentially threatening, while data on occurrence is lacking for some compounds, particularly in brackish/marine systems. Specifically, nine compounds (fluoxetine, citalopram, sertraline, amitriptyline, venlafaxine, clozapine, carbamazepine, metamfetamine and oxazepam) were found at concentrations either above or critically close to minimum response concentrations, thus likely to affect fish in freshwater and brackish or marine environments, which supports further exploration in risk management strategies and monitoring programs in aquatic environments.
Topics: Animals; Bioaccumulation; Ecosystem; Pharmaceutical Preparations; Research Design; Water Pollutants, Chemical
PubMed: 34953825
DOI: 10.1016/j.scitotenv.2021.152543 -
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 -
Journal of AOAC International Apr 2022Anesthetics and sedatives are frequently used to prevent abrasions caused by stress and to facilitate fish management. However, drug residues may persist and cause...
BACKGROUND
Anesthetics and sedatives are frequently used to prevent abrasions caused by stress and to facilitate fish management. However, drug residues may persist and cause changes in fish conditions and induce side effects. In addition, drugs that are not permitted for use in edible fish are sometimes potentially used in fish. The drugs can also be found in wastewater and are likely to be detected in fish.
OBJECTIVE
The purpose of this study was to establish a quantitative analytical method for 10 anesthetic and sedative (azaperone, chlorpromazine, diazepam, estazolam, haloperidol, nitrazepam, nordiazepam, oxazepam, perphenazine, and temazepam) residues in fish sold in Korean markets.
METHOD
Shrimp, flounder, and eel samples were selected as matrices. Acetonitrile (ACN) containing 0.1% formic acid was selected as an extraction solvent for shrimp and 100% ACN for flounder and eel. The QuEChERS method with C18 and primary secondary amine (PSA) was used as the extraction procedure, and the analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
RESULTS
Limit of quantitation, recovery, accuracy, and precision were validated, and satisfactory results were obtained for the drugs. All results applied to the real samples were negative.
CONCLUSIONS
An optimal validation method was studied. Since the results for all samples were negative, it is considered that additional studies are needed by increasing the number of drugs.
HIGHLIGHTS
The most effective QuEChERS pretreatment method and conditions of LC-MS/MS for the analysis of anesthetics and sedatives in fish were established.
Topics: Anesthetics; Animals; Chromatography, Liquid; Drug Residues; Fishes; Hypnotics and Sedatives; Limit of Detection; Tandem Mass Spectrometry
PubMed: 34894253
DOI: 10.1093/jaoacint/qsab155 -
Forensic Science International Jan 2022This study reports the prevalence and concentrations of sedative-hypnotic drugs as exemplified by benzodiazepines (BZD) and zolpidem (Z-hypnotic) in blood samples from...
BACKGROUND & OBJECTIVES
This study reports the prevalence and concentrations of sedative-hypnotic drugs as exemplified by benzodiazepines (BZD) and zolpidem (Z-hypnotic) in blood samples from drivers involved in road traffic accidents (RTA) in the Padova region of Italy. Another aim of the study was to estimate the prevalence of these drugs with concentrations in blood above the therapeutic intervals and above specific per se limits.
METHODS
A total of 4066 blood samples collected from drivers involved in RTA were analysed for the presence of alcohol, drugs of abuse and medicinal drugs with sedative-hypnotic properties. Prevalence of drivers positive for BZDs and zolpidem were reported according to the reporting limit of our laboratory (1 ng/mL) in a sort of zero tolerance approach and compared with the prevalence according to analytical cut-offs used in the "European Union's research project on Driving Under the Influence of Drugs, Alcohol and Medicines" (DRUID). The impairment-based, per se limits adopted in Norway and in England and Wales and the values used to define "therapeutic ranges" in blood and in plasma/serum were also applied to the case study.
RESULTS
175 blood samples were positive for sedative-hypnotics above 1 ng/mL, with the following prevalence: diazepam 44%, nordazepam 41.8%, lorazepam 32.6%, zolpidem 28%, oxazepam 25.6%, alprazolam 16%, delorazepam 11,6%, lormetazepam 11,6%, temazepam 11.6%, clonazepam 11.6%, triazolam 6.9%, N-desalkylflurazepam 4.6%, bromazepam 2.3%. When applying DRUID analytical cut-offs, the prevalence of BZDs and zolpidem sharply decreases. Applying the impairing cut-offs used in Norway, 56% of positive samples were above the limits equivalent to a BAC of 0.2 g/L, 39% above the limits corresponding to 0.5 g/L, and 23% above the cut-off corresponding to 1.2 g/L. Only 1% of the drivers had drug concentrations above the per se concentration limits adopted in England and Wales [26]. When comparing blood levels with therapeutic ranges in plasma, bromazepam, lormetazepam and delorazepam were often found above the highest limits. The adjustment of the concentrations with the plasma-to-blood ratios causes a significant increase of cases above the therapeutic ranges in plasma.
CONCLUSIONS
Sedative-hypnotic drugs are medicinal substances frequently identified in drivers involved in RTA, commonly in concentrations associated with driving impairment. Besides the concentrations of drugs in blood, several factors have to be considered to conclude that a driver was impaired. The frequent association with alcohol, cocaine and other BZDs, confirms the abuse potential of these medications.
Topics: Accidents, Traffic; Bromazepam; Driving Under the Influence; Ethanol; Hypnotics and Sedatives; Pharmaceutical Preparations; Prevalence; Substance Abuse Detection; Zolpidem
PubMed: 34814082
DOI: 10.1016/j.forsciint.2021.111097 -
Case Reports in Psychiatry 2021Benzodiazepine (BZD) misuse is a worldwide problem that healthcare professionals encounter in daily practice. High-dose BZD withdrawal is usually a long process that may...
Benzodiazepine (BZD) misuse is a worldwide problem that healthcare professionals encounter in daily practice. High-dose BZD withdrawal is usually a long process that may require referral to an inpatient rehabilitation unit. Relapses after withdrawal are common. BZD withdrawal can cause complications including seizures, suicidal behavior, anxiety, and depression. Guidelines describe tapering protocols for modest doses; however, protocols for exceptionally high-dose BZD withdrawal are not well described. Herein, we describe a BZD tapering protocol for a patient with daily use of high-dose (1800 mg) oxazepam (OXP). The BZD tapering was administered in an inpatient psychiatric hospital, and the outcome was evaluated monthly after discharge for three months. This report describes a unique case of high-dose OXP withdrawal and also outlines an optional protocol to apply when clinicians encounter these unusual cases.
PubMed: 34777889
DOI: 10.1155/2021/2140723 -
Molecules (Basel, Switzerland) Oct 2021Partially and exhaustively methylated β-cyclodextrins [(2-methyl)-β-CD (MCD), heptakis-(2,6-di--methyl)-β-CD (DIMEB), and heptakis-(2,3,6-tri--methyl)-β-CD (TRIMEB)]...
Partially and exhaustively methylated β-cyclodextrins [(2-methyl)-β-CD (MCD), heptakis-(2,6-di--methyl)-β-CD (DIMEB), and heptakis-(2,3,6-tri--methyl)-β-CD (TRIMEB)] have been compared in the hydrolysis and enantiodiscrimination of benzodiazepine derivative ()- or ()-oxazepam hemisuccinate (OXEMIS), using nuclear magnetic resonance (NMR) spectroscopy as an investigation tool. After 6 h, MCD induced an 11% hydrolysis of OXEMIS, remarkably lower in comparison with underivatized β-CD (48%), whereas no hydrolysis was detected in the presence of DIMEB or TRIMEB after 24 h. DIMEB showed greater ability to differentiate OXEMIS enantiomers in comparison to TRIMEB, by contrast MCD did not produce any splitting of racemic OXEMIS resonances. Both enantiomers of OXEMIS underwent deep inclusion of their phenyl pendant into cyclodextrins cavities from their wider rims, but tighter complexes were formed by DIMEB with respect to TRIMEB.
Topics: Hydrolysis; Magnetic Resonance Spectroscopy; Methylation; Models, Molecular; Molecular Structure; Oxazepam; beta-Cyclodextrins
PubMed: 34770758
DOI: 10.3390/molecules26216347 -
The Science of the Total Environment Feb 2022Over a period of 12 months, the fate of three hormones, 12 antibiotics and 30 pharmaceutically active substances (PhACs) was investigated during open-air storage...
Over a period of 12 months, the fate of three hormones, 12 antibiotics and 30 pharmaceutically active substances (PhACs) was investigated during open-air storage without and with composting of anaerobically digested and dewatered sewage sludge. The effect of oxidation conditions during storage on degradation of hormones and PhACs in the sludge biomass was also examined. Under summer and winter conditions in Uppsala County, Sweden, two field-scale sludge windrows were constructed: open-air storage of sewage sludge windrow without composting (NO-COM)) and open-air storage windrow with composting (COM). NO-COM achieved effective removal of ∑Hormones (85%) and ∑Antibiotics (95%), but lower removal of ∑PhACs (34%), during the study year. The top layers of the sludge pile had significantly lower concentrations of ∑PhACs (3100-5100 ng/g ash) than deeper layers (8000-11,000 ng/g ash). After one year of composting, the degradation in the COM windrow resulted in concentrations of ∑Hormones (
oxazepam (0.0805 day). In conclusion, composting of sludge was effective in degrading the target hormones, antibiotics, and PhACs. Topics: Composting; Pharmaceutical Preparations; Sewage; Soil; Sweden
PubMed: 34740644
DOI: 10.1016/j.scitotenv.2021.151271 -
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 -
Ecological Applications : a Publication... Dec 2021The social environment (i.e., the suite of social interactions that occur among individuals that can result in variation in social ranks) is a commonly overlooked aspect...
The social environment (i.e., the suite of social interactions that occur among individuals that can result in variation in social ranks) is a commonly overlooked aspect of biology when scientists evaluate the effects of chemical contaminants. The social environment, however, represents the arena in which individual-level performance shapes group- or population-level outcomes and may therefore mediate many of the ultimate consequences of chemicals for wildlife. Here, we evaluated the role that the social environment plays in determining the consequences of pollutant exposure. We exposed groups of juvenile brown trout (Salmo trutta) to an emerging pharmaceutical pollutant that is commonly detected in freshwaters (the benzodiazepine, oxazepam) and allowed them to form dominance hierarchies. Exposure affected dominant and subordinate fish differently, causing fish to become less aggressive at high doses and subordinate fish to become more competitively successful at low doses. These perturbations had further consequences for growth, fin damage, and survival. Exposure also modulated physiological stress in the hierarchy, and social status itself affected how much oxazepam was absorbed in tissues, potentially creating a dynamic feedback loop that further influences the asymmetric effects of exposure on differing social statuses. Many effects followed a "U-shaped" dose-response curve, highlighting the importance of nonlinear, low-dose effects. Altogether, we show that social structure in animal groups can interact with and modulate the effects of an environmental contaminant. We underscore the need to account for an organism's natural ecological context, including their social environment, in future experiments and environmental risk assessments to predict the effects of chemical contaminants on wildlife.
Topics: Animals; Environmental Pollutants; Social Environment; Social Status; Stress, Physiological; Trout
PubMed: 34549857
DOI: 10.1002/eap.2454