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The Science of the Total Environment Aug 2018In this study, residues of the neuropsychiatric and illicit drugs including stimulants, opioids, hallucinogens, antischizophrenics, sedatives, and antidepressants were...
Contamination profiles, mass loadings, and sewage epidemiology of neuropsychiatric and illicit drugs in wastewater and river waters from a community in the Midwestern United States.
In this study, residues of the neuropsychiatric and illicit drugs including stimulants, opioids, hallucinogens, antischizophrenics, sedatives, and antidepressants were determined in influent and effluent samples from a small wastewater treatment plant, a receiving creek, and river waters in the Four Rivers region of the Midwestern United States. Nineteen neuropsychiatric drugs, eight illicit drugs, and three metabolites of illicit drugs were detected and quantitated in the water samples using HPLC-MS/MS. Residual concentrations of the drugs varied from below the detection limit to sub-μg/L levels. The source of residual cocaine and benzoylecgonine in wastewater is primarily from human consumption of cocaine rather than direct disposal. Wastewater based epidemiology is utilized to estimate the community usage of drugs based on the concentration of drug residues in wastewater, wastewater inflow, and the population served by the centralized wastewater treatment plant. The per-capita consumption rate of methamphetamine (1740 mg/d/1000 people) and amphetamine (970 mg/d/1000 people) found in this study were the highest reported per-capita consumption rates in the USA. Antidepressant venlafaxine found to have the highest environmental emission from the WWTP (333 ± 160 mg/d/1000 people) followed by citalopram (132 ± 60.2 mg/d/1000 people), methamphetamine (111 ± 43.6 mg/d/1000 people), and hydrocodone (108 ± 90.1 mg/d/1000 people). Bee Creek, an immediate receiving water body, is found to be a source of several neuropsychiatric and illicit drugs including methamphetamine, methadone, alprazolam, oxazepam, temazepam, carbamazepine, venlafaxine, citalopram, sertraline, oxycodone, and hydrocodone (p < 0.036) in the Clarks River.
PubMed: 29727969
DOI: 10.1016/j.scitotenv.2018.03.060 -
Epilepsia May 2018Diazepam, administered by the intravenous, oral, or rectal routes, is widely used for the management of acute seizures. Dosage forms for delivery of diazepam by other...
OBJECTIVE
Diazepam, administered by the intravenous, oral, or rectal routes, is widely used for the management of acute seizures. Dosage forms for delivery of diazepam by other routes of administration, including intranasal, intramuscular, and transbuccal, are under investigation. In predicting what dosages are necessary to terminate seizures, the minimal exposure required to confer seizure protection must be known. Here we administered diazepam by continuous intravenous infusion to obtain near-steady-state levels, which allowed an assessment of the minimal levels that elevate seizure threshold.
METHODS
The thresholds for various behavioral seizure signs (myoclonic jerk, clonus, and tonus) were determined with the timed intravenous pentylenetetrazol seizure threshold test in rats. Diazepam was administered to freely moving animals by continuous intravenous infusion via an indwelling jugular vein cannula. Blood samples for assay of plasma levels of diazepam and metabolites were recovered via an indwelling cannula in the contralateral jugular vein.
RESULTS
The pharmacokinetic parameters of diazepam following a single 80-μg/kg intravenous bolus injection were determined using a noncompartmental pharmacokinetic approach. The derived parameters V , CL, t (distribution half-life) and t (terminal half-life) for diazepam were, respectively, 608 mL, 22.1 mL/min, 13.7 minutes, and 76.8 minutes, respectively. Various doses of diazepam were continuously infused without or with an initial loading dose. At the end of the infusions, the thresholds for various behavioral seizure signs were determined. The minimal plasma diazepam concentration associated with threshold elevations was estimated at approximately 70 ng/mL. The active metabolites nordiazepam, oxazepam, and temazepam achieved levels that are expected to make only minor contributions to the threshold elevations.
SIGNIFICANCE
Diazepam elevates seizure threshold at steady-state plasma concentrations lower than previously recognized. The minimally effective plasma concentration provides a reference that may be considered when estimating the diazepam exposure required for acute seizure treatment.
Topics: Animals; Anticonvulsants; Diazepam; Dose-Response Relationship, Drug; Male; Rats; Rats, Sprague-Dawley; Seizures
PubMed: 29682729
DOI: 10.1111/epi.14069 -
Indian Journal of Pharmacology 2017Benzodiazepines (BZD) are widely prescribed to substance users. However, the nonmedical use of prescription BZD often leads to abuse and dependence. Therefore, it is...
BACKGROUND AND AIM
Benzodiazepines (BZD) are widely prescribed to substance users. However, the nonmedical use of prescription BZD often leads to abuse and dependence. Therefore, it is important to detect BZD among substance users seeking treatment. The aim of the present study was to develop an efficient method for testing BZD on dried urine spot (DUS) and evaluating its clinical applicability.
METHODS
This involved optimization of conditions for the detection, recovery, and stability of BZD from dried urine, spotted on filter paper. Enzyme linked immuno-sorbent assay was used for screening whereas confirmation was done by gas chromatography. For clinical applicability, urine samples of BZD users were tested.
RESULTS
The recovery was found to be 99.7% in de-ionized water from 20 μl spotted urine samples. Limit of detection, inter-day and intra-day CV were found to be 100 ng/ml, 4.22% and 3.83%, respectively. BZD were found stable in DUS for 3 weeks at room temperature, and for 3 months at 4°C and -20°C. All the urine samples of benzodiazepine users were found positive by conventional method as well as the DUS method.
CONCLUSION
DUS method proved to be efficient for BZD testing with advantages of ease of collection, transportation, minimal invasiveness and small sample volume. It offers a useful alternative for BZD testing especially in developing countries where logistics of sample collection and transportation could be an important concern.
Topics: Benzodiazepines; Chromatography, Gas; Drug Stability; Enzyme-Linked Immunosorbent Assay; Humans; Limit of Detection; Male; Reproducibility of Results; Specimen Handling; Substance Abuse Detection; Substance-Related Disorders
PubMed: 29674802
DOI: 10.4103/ijp.IJP_578_16 -
Psychopharmacology Apr 2018Screening of drug-induced performance impairment is needed to provide meaningful information for users and prescribers regarding the impact of drugs on driving. The main... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Screening of drug-induced performance impairment is needed to provide meaningful information for users and prescribers regarding the impact of drugs on driving. The main objective was to assess the effects of oxazepam 10 mg (OXA10), oxazepam 30 mg (OXA30), and diazepam 10 mg (DIA10) on standard deviation of lateral position (SDLP) in a highway driving test in actual traffic and to determine the ability of eight neurocognitive tests to detect comparable effects.
METHODS
Twenty-three healthy volunteers participated in a four-way double-blind, placebo-controlled, crossover study. The highway driving test was conducted between 4 and 5 h after drug intake. A range of neurocognitive tests was conducted before and after driving, 2 and 6 h post-treatment, respectively.
RESULTS
Mean SDLP increased by 1.83, 3.03, and 7.57 cm after OXA10, DIA10, and OXA30, respectively. At 2 h post-treatment, all neurocognitive tests, except the useful field of view, showed performance impairment in all active treatments. Effect sizes (ES) were moderate for OXA10, large ES for DIA10, and largest ES for OXA30. Modest correlations were found between changes in SDLP and performance in the attention network test (ANT), the divided attention test (DAT), and the psychomotor vigilance test (PVT).
CONCLUSION
OXA10 caused minor, DIA10 moderate, and OXA30 severe driving impairment. No neurocognitive test was both dose dependently sensitive and able to be associated with driving impairment. No neurocognitive test can replace the on-the-road highway driving test.
Topics: Adult; Attention; Automobile Driving; Cognition; Cross-Over Studies; Diazepam; Double-Blind Method; Female; Healthy Volunteers; Humans; Hypnotics and Sedatives; Male; Mental Status and Dementia Tests; Middle Aged; Oxazepam; Psychomotor Performance; Young Adult
PubMed: 29500585
DOI: 10.1007/s00213-018-4844-5 -
The Science of the Total Environment Jul 2018Reuse of treated wastewater for irrigation of crops is growing in arid and semi-arid regions, whilst increasing amounts of biosolids are being applied to fields to...
Reuse of treated wastewater for irrigation of crops is growing in arid and semi-arid regions, whilst increasing amounts of biosolids are being applied to fields to improve agricultural outputs. Due to incomplete removal in the wastewater treatment processes, pharmaceuticals present in treated wastewater and biosolids can contaminate soil systems. Benzodiazepines are a widely used class of pharmaceuticals that are released following wastewater treatment. Benzodiazepines are represented by a class of compounds with a range of physicochemical properties and this study was therefore designed to evaluate the influence of soil properties on the sorption behaviour and subsequent uptake of seven benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flurazepam, oxazepam, temazepam and triazolam) in two plant species. The sorption and desorption behaviour of benzodiazepines was strongly influenced by soil type and hydrophobicity of the chemical. The partitioning behaviour of these chemicals in soil was a key controller of the uptake and accumulation of benzodiazepines by radish (Raphanus sativus) and silverbeet (Beta vulgaris). Benzodiazepines such as oxazepam that were neutral, had low sorption coefficients (K) or had pH-adjusted log octanol-water partition coefficients (log D, pH6.3) values close to 2 had the greatest extent of uptake. Conversely, benzodiazepines such as flurazepam that had an ionised functional groups and greater K values had comparatively limited accumulation in the selected plant species. Results also revealed active in-plant metabolism of benzodiazepines, potentially analogous to the known metabolic transformation pathway of benzodiazepines in humans. Along with this observed biological transformation of benzodiazepines in exposed plants, previously work has established the widespread presence of the plant signalling molecule γ-amino butyric acid (GABA), which is specifically modulated by benzodiazepines in humans. This highlights the need for further assessment of the potential for biological activity of benzodiazepines following their plant uptake.
Topics: Benzodiazepines; Crops, Agricultural; Humans; Soil; Soil Pollutants; Wastewater
PubMed: 29428856
DOI: 10.1016/j.scitotenv.2018.01.337 -
Journal of Thoracic Disease Nov 2017Aspirin-exacerbated respiratory disease (AERD) affects 15% of severe asthmatics and drug reactions cause 200,000 annual deaths in Europe. A 65-year-old lady presented to...
Aspirin-exacerbated respiratory disease (AERD) affects 15% of severe asthmatics and drug reactions cause 200,000 annual deaths in Europe. A 65-year-old lady presented to emergency for progressive abdominal pain. Her medical history included gallstones, asthma, rhinosinusitis and hypertension. She was regularly medicated with inhaled fluticasone, vilanterol and tiotropium, nasal budesonide, pantoprazole, oxazepam and perindopril. She reported partial asthma control and an exacerbation requiring admission to a respiratory ward 6 weeks before. On examination, there was right upper quadrant tenderness and no other changes. Blood tests were normal, and an ultrasound showed gallbladder stones with normal wall. Intravenous ketorolac led to prompt pain resolution. After 30 minutes she became severely dyspnoeic, with an O saturation of 85% on high flow O. She had no breath sounds on the left lung, and there was no wheezing or prolonged expiration. A chest X-ray showed no pneumothorax and a computed tomography (CT) angiography was performed showing bilateral mucoid impaction and sub-segmental atelectasis. Continuous bronchodilation and systemic steroids led to gradual improving in the following 6 hours. After 9 days of admission on a respiratory ward she was discharged home with no symptoms and normal oxygenation. Importantly, she denied previous allergies to nonsteroidal anti-inflammatory drugs (NSAIDs) and had actually taken diclofenac and nimesulid before with no reactions. This report illustrates both an intravenous NSAID causing severe AERD, and how a chest CT may be instrumental for the diagnosis of life-threatening asthma.
PubMed: 29255644
DOI: 10.21037/jtd.2017.11.36 -
Scientific Reports Dec 2017The bioaccumulation of a broad range of pharmaceuticals and personal care product chemicals (PPCPs) was studied in Cootes Paradise Marsh (CPM), an urban wetland that...
The bioaccumulation of a broad range of pharmaceuticals and personal care product chemicals (PPCPs) was studied in Cootes Paradise Marsh (CPM), an urban wetland that receives tertiary treated municipal waste waters as well as urban storm runoff. We measured PPCPs in caged and wild goldfish, as well as wild carp, and compared observed bioaccumulation factors (BAF) using concentrations in surface waters and fish blood plasma, with modeled BAFs. Thirty-two PPCPs were detected in water from the central CPM site (CPM3) while 64 PPCPs were found at higher concentrations at a site immediately downstream of the effluent outflow (CPM1). Following a 3-week deployment, 15 PPCPs were detected in the plasma of caged goldfish at CPM1, and 14 at CPM3, compared to only 3 in goldfish caged at a reference site. The highest BAF in goldfish were for the antidepressant Σfluoxetine averaging 386 L/kg in caged and 906 L/kg in wild goldfish, respectively. In carp, ΣDiazepam (diazepam and oxazepam) had the highest BAF (927 L/kg). This study identified a broader range of PPCPs in fish and surface waters than previously reported. However, modeled BAFs did not show good agreement with observed whole body or plasma BAFs, demonstrating that more work is needed to better explain bioaccumulation of PPCPs.
Topics: Animals; Cosmetics; Environmental Monitoring; Fishes; Pharmaceutical Preparations; Urban Renewal; Wastewater; Water Pollutants, Chemical; Wetlands
PubMed: 29208974
DOI: 10.1038/s41598-017-15462-x -
Ascertainment of self-reported prescription medication use compared with pharmaceutical claims data.Public Health Research & Practice Oct 2017Evidence on the comparative validity of self-reported medication use in large-scale studies is limited. This study compared self-reported medication use of... (Comparative Study)
Comparative Study
BACKGROUND
Evidence on the comparative validity of self-reported medication use in large-scale studies is limited. This study compared self-reported medication use of prescription-only medications to gold standard pharmaceutical claims (i.e. dispensing) data.
METHODS
We selected a random sample of 500 participants from the 45 and Up Study, a large-scale Australian study, with complete ascertainment of Pharmaceutical Benefits Scheme dispensing records. Self-reported medication use was ascertained by questionnaire requesting data on medications used "for most of the last 4 weeks". In the dispensing data, we determined exposure to specific medications in the same 4-week window as the survey response if we observed a dispensing record ≤90 days before the start of the window. We calculated sensitivity and positive predictive values (PPVs) at the Anatomical Therapeutic Chemical (ATC) classification 3- and 7-digit code levels.
RESULTS
PPVs were ≥75% for 79% of the medications examined at the 3-digit ATC level. The sensitivity/PPV of self-reported versus claims data at the 3-digit level were highest for chronic medications, including cardiovascular medications: 94.4%/96.9%, respectively, for lipid-lowering agents; 92.5%/97.5% for angiotensin agents; 88.8%/93.1% for beta-blockers; and 88.0%/96.9% for calcium-channel blockers. PPVs were ≥65% and sensitivity of self-reported data was 78.9% for psychoanaleptics, 42.1% for analgesics, 26.0% for psycholeptics and 4.8% for antibacterial agents. PPVs for individual medications were ≥75% for 81% of the individual medications examined at the 7-digit level. The sensitivity/PPV for self-reported versus claims data at the 7-digit level varied across individual medications, with highest values being 96.9%/96.9% for warfarin, 94.5%/92.0% for atorvastatin, 94.3%/84.6% for pantoprazole and 93.3%/95.5% for atenolol. The lowest sensitivity of self-reported versus claims data for individual medications was 16.7% for temazepam, 15.2% for perindopril, 11.5% for irbesartan, 11.1% for oxazepam and 3.3% for amoxicillin.
CONCLUSIONS
Self-reported data of the type reported here are useful for identifying exposure to prescription medications, particularly those for chronic use. However, they are likely to be of lesser validity for ascertaining short-term and/or intermittent medication exposure.
Topics: Aged; Aged, 80 and over; Australia; Female; Humans; Male; Medication Adherence; Middle Aged; Pharmacies; Prescription Drugs; Self Report; Surveys and Questionnaires
PubMed: 29114718
DOI: 10.17061/phrp27341702 -
Biochemical Pharmacology Dec 2017Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 2B7 and 2B15 expression by microRNAs (miRNAs) may be an important mechanism underlying...
Identification and validation of the microRNA response elements in the 3'-untranslated region of the UDP glucuronosyltransferase (UGT) 2B7 and 2B15 genes by a functional genomics approach.
Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 2B7 and 2B15 expression by microRNAs (miRNAs) may be an important mechanism underlying inter-individual variability in drug glucuronidation. Furthermore, the UGT2B15 3'-UTR contains a common SNP (rs3100) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT2B7 and UGT2B15 expression through binding to the reference and/or variant 3'-UTRs. Luciferase reporter plasmids containing either the reference or variant 3'-UTRs were screened against a 2,048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Six novel miRNAs (miR-1293, miR-3664-3p, miR-4317, miR-513c-3p, miR-4483, and miR-142-3p) were identified that repressed the reference UGT2B7 3'-UTR, while twelve novel miRNAs (miR-770-5p, miR-103b, miR-3924, miR-376b-3p, miR-455-5p, miR-605, miR-624-3p, miR-4712-5p, miR-3675-3p, miR-6500-5p, miR-548as-3p, and miR-4292) repressed both the reference and rs3100 variant UGT2B15 3'-UTR. Deletion and mutagenesis studies confirmed the binding site location of each miRNA. Although the UGT2B15 rs3100 SNP was located within the miR-376c-3p response element, there was no effect on miRNA binding. miR-142-3p, miR-3664-3p, miR-4317, miR-455-5p, miR-376c-3p, miR-770-5p, miR-3675-3p, miR-331-5p, miR-605, and miR-376b-3p transcript levels were measured by quantitative PCR and correlated with UGT2B7 and UGT2B15 enzyme activities in 27 human liver samples. A significant negative correlation (R = -0.53; p = 0.005) was demonstrated between hepatic miR-455-5p transcript levels and UGT2B15-mediated S-oxazepam glucuronidation activities. Thus, the UGT2B7 and UGT2B15 3'-UTRs contain miRNA response elements for multiple miRNAs that may contribute to variable drug glucuronidation.
Topics: 3' Untranslated Regions; Adult; Aged; Child; Child, Preschool; Female; Gene Expression Regulation, Enzymologic; Genomics; Glucuronosyltransferase; Humans; Liver; Male; MicroRNAs; Middle Aged; Reproducibility of Results; Response Elements; Young Adult
PubMed: 28962835
DOI: 10.1016/j.bcp.2017.09.013 -
Chemosphere Sep 2017Methods were developed to assess uptake and elimination kinetics in Gammarus pulex of nine pharmaceuticals (sulfamethazine, carbamazepine, diazepam, temazepam,...
Methods were developed to assess uptake and elimination kinetics in Gammarus pulex of nine pharmaceuticals (sulfamethazine, carbamazepine, diazepam, temazepam, trimethoprim, warfarin, metoprolol, nifedipine and propranolol) using targeted LC-MS/MS to determine bioconcentration factors (BCFs) using a 96 h toxicokinetic exposure and depuration period. The derived BCFs for these pharmaceuticals did not trigger any regulatory thresholds and ranged from 0 to 73 L kg (sulfamethazine showed no bioconcentration). Metabolism of chemicals can affect accurate BCF determination through parameterisation of the kinetic models. The added selectivity of LC-MS/MS allowed us to develop confirmatory methods to monitor the biotransformation of propranolol, carbamazepine and diazepam in G. pulex. Varying concentrations of the biotransformed products; 4-hydroxypropranolol sulphate, carbamazepine-10,11-epoxide, nordiazepam, oxazepam and temazepam were measured following exposure of the precursor compounds. For diazepam, the biotransformation product nordiazepam was present at higher concentrations than the parent compound at 94 ng g dw. Overall, the results indicate that pharmaceutical accumulation is low in these freshwater amphipods, which can potentially be explained by the rapid biotransformation and excretion.
Topics: Amphipoda; Animals; Biotransformation; Chromatography, Liquid; Fresh Water; Invertebrates; Pharmaceutical Preparations; Tandem Mass Spectrometry; Water Pollutants, Chemical
PubMed: 28554023
DOI: 10.1016/j.chemosphere.2017.05.083