- Sorption, plant uptake and metabolism of benzodiazepines. [Journal Article]
- STSci Total Environ 2018 Feb 08; 628-629:18-25
- 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 t...
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 (Kd) or had pH-adjusted log octanol-water partition coefficients (log Dow, 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 Kdvalues 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.
- Fabrication of magnetic zinc adeninate metal-organic frameworks for the extraction of benzodiazepines from urine and wastewater. [Journal Article]
- JSJ Sep Sci 2018 Jan 22
- In this study, an alternative method for synthesizing magnetic cobalt adeninate metal-organic frameworks was developed, and the synthesized materials were examined for their potential application for...
In this study, an alternative method for synthesizing magnetic cobalt adeninate metal-organic frameworks was developed, and the synthesized materials were examined for their potential application for separating and enriching benzodiazepines from complex samples. Benzodiazepines, widely used as hypnotics, muscle relaxants, sedatives, and anxiolytics, are a class of drugs that require being accurately detected and monitored. Results showed that Fe3O4nanoparticles could be well anchored onto the external surface of cobalt adeninate metal-organic frameworks by using amino-silane as a linkage. Their adsorption of benzodiazepines was mainly promoted by intermolecular hydrogen binding, π-π interaction and electrostatic attraction. Their potential application was evaluated by extraction of benzodiazepines in urine and wastewater samples prior to liquid chromatography with mass spectrometry. Under optimum conditions, the calibration curves were linear with a correlation coefficient of ≥ 0.9928 in the concentration range of 10-5000 ng/L for lorazepam and 5-5000 ng/L for estazolam, chlordiazepoxide, alprazolam, midazolam and triazolam. The limits of detection were in the range of 0.71-2.49 ng/L. The percent of extraction recoveries were 80.2-94.5% for urine and 84.1-94.4% for wastewater, respectively. Results suggested that magnetic cobalt adeninate metal-organic frameworks could potentially be a promising material for enriching benzodiazepines from urine and wastewater with high accuracy and precision. This article is protected by copyright. All rights reserved.
- Poly-Drug Use of Prescription Medicine among People with Opioid Use Disorder in China: A Systematic Review and Meta-Analysis. [Journal Article]
- SUSubst Use Misuse 2017 Dec 27; :1-11
- CONCLUSIONS: The results demonstrate that prescription medicine use is widespread among opioid users in China. There needs to be more consideration of poly-drug use, and early interventions and management strategies are needed to prevent poly-drug use among opioid users in China.
- Effect of non-prohibited drugs on the phase II metabolic profile of morphine. An in vitro investigation for doping control purposes. [Journal Article]
- DTDrug Test Anal 2017 Nov 24
- The potential consequences of drug-drug interaction on the strategies adopted by anti-doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro...
The potential consequences of drug-drug interaction on the strategies adopted by anti-doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro the effects of 14 drugs on the principal metabolic pathways of morphine. The selected drugs are among those most commonly used by the athletes, none of them presently included in the World Anti-Doping Agency (WADA) Prohibited List. The non-prohibited drugs included 4 antifungals (fluconazole, itraconazole, ketoconazole, and miconazole), 6 benzodiazepines (alprazolam, bromazepam, clonazepam, lorazepam, lormetazepam, and triazolam), and 4 non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, and nimesulide). The in vitro assays were based on the use of either human liver microsomes or uridine 5'-diphospho-glucuronosyl-transferases. Morphine and its glucuronides were determined by developed liquid chromatography-mass spectrometry procedure after dilution with an aqueous solution containing their deuterated isotopologues as internal standards. Morphine is mainly excreted as phase II metabolites: about 70% of the parent compound is found to be biotransformed by UGT2B7 to morphine-3-glucuronide (6065%) and morphine-6-glucuronide (5-10%). A reduction of the enzymatic activity of the UGT2B7 was recorded in the presence of 9 of the 14 drugs under investigation (ketoconazole, miconazole, itraconazole, diclofenac, ibuprofen, clonazepam, lorazepam, lormetazepam, and triazolam), with a consequent significant reduction of the levels of the glucuronide metabolites. This phenomenon in vivo may affect the rate of the urinary excretion of morphine with the risk of reporting "false negative" results, especially in case of results close to the decision limit value set by WADA.
- Therapy Update for Insomnia in the Elderly. [Review]
- CPConsult Pharm 2017 Oct 01; 32(10):610-622
- CONCLUSIONS: Nonpharmacologic interventions are the first-line therapy for adults with chronic insomnia. Short-term drug therapy may be considered as an alternative or add-on treatment. Hypnotic use is associated with harm and requires close monitoring, especially in older adults.
- LC-MS determination of triazolam and its hydroxy metabolites in mouse dried blood spots: application to transgenic mouse pharmacokinetic studies. [Journal Article]
- BBioanalysis 2017; 9(13):987-1000
- CONCLUSIONS: This validated LC-MS/MS method using DBS extraction was applied to quantitation of TRZ, α-hydroxytriazolam and 4-hydroxytriazolam in a CYP3A4 transgenic mouse oral pharmacokinetic study of TRZ.
- Effects of different doses of triazolam in the middle-of-the-night insomnia: a double-blind, randomized, parallel group study. [Journal Article]
- JNJ Neurol 2017; 264(7):1362-1369
- It has been reported that insomnia characterized by difficulty returning to sleep following a nocturnal awakening, otherwise defined as the middle-of-the-night (MOTN) insomnia, is a common form of in...
It has been reported that insomnia characterized by difficulty returning to sleep following a nocturnal awakening, otherwise defined as the middle-of-the-night (MOTN) insomnia, is a common form of insomnia in adults with growing prevalence by increasing age. The aim of this study is to evaluate the efficacy and safety of different dosages of triazolam in insomnia patients when taken after a MOTN awakening with difficulty returning to sleep. In this double-blind, randomized, parallel group study, 24 patients (mean age 41.00 ± 10.40, 10 female and 14 male) affected by MOTN insomnia were enrolled and randomized into three groups according to different dosages of triazolam: group A (0.0625 mg), group B (0.125 mg), and group C (0.250 mg). A significant increment of total sleep time, sleep efficiency and a reduction of wake after sleep onset, number of awakening and non-REM sleep stage 1 was observed in T1 (triazolam) in comparison to T0 (placebo) by means of polysomnographic recording, irrespective of dosage. After 2 weeks of the treatment, insomnia severity significantly improved in all three groups in comparison to baseline without diurnal residual effects. This study demonstrates that low dose of triazolam objectively and subjectively improves the sleep of patients having MOTN insomnia.
- The effect of triazolam premedication on anxiety, sedation, and amnesia in general anesthesia. [Journal Article]
- KJKorean J Anesthesiol 2017; 70(3):292-298
- CONCLUSIONS: Triazolam 0.25 mg or 0.375 mg reduced the hemodynamic changes associated with anxiety, produced potent amnesia, and improved patient satisfaction. We suggest that triazolam can be used effectively as anesthetic premedication in adults.
- Gender Difference of Hepatic and Intestinal CYP3A4 in CYP3AHumanized Mice Generated by a Human Chromosome-engineering Technique. [Letter]
- DMDrug Metab Lett 2017 Nov 17; 11(1):60-67
- CONCLUSIONS: These findings suggest that the expression and activity levels of CYP3A4 in the liver are higher in females than in males, whereas there is no gender difference in the levels in the intestine of CYP3A-HAC mice.
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- Utility of CYP3A4 and PXR-CAR-CYP3A4/3A7 Transgenic Mouse Models To Assess the Magnitude of CYP3A4 Mediated Drug-Drug Interactions. [Journal Article]
- MPMol Pharm 2017 May 01; 14(5):1754-1759
- Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The...
Species differences in the expression, activity, regulation, and substrate specificity of metabolizing enzymes preclude the use of animal models to predict clinical drug-drug interactions (DDIs). The objective of this work is to determine if the transgenic (Tg) Cyp3a-/-Tg-3A4Hep/Intand Nr1i2/Nr1i3-/--Cyp3a-/-Tg-PXR-CAR-3A4/3A7Hep/Int(PXR-CAR-CYP3A4/3A7) mouse models could be used to predict in vivo DDI of 10 drugs; alprazolam, bosutinib, crizotinib, dasatinib, gefitinib, ibrutinib, regorafenib, sorafenib, triazolam, and vandetinib (as victims); with varying magnitudes of reported CYP3A4 clinical DDI. As an assessment of the effect of CYP3A4 inhibition, these drugs were coadministered to Cyp3a-/-Tg-3A4Hep/Intmice with the CYP3A inhibitor, itraconazole. For crizotinib, regorafenib, sorafenib, and vandetanib, there was no significant increase of AUC observed; with alprazolam, bosutinib, ibrutinib, dasatinib, and triazolam, pretreatment with itraconazole resulted in a 2-, 4-, 17-, 7-, and 15-fold increase in AUC, respectively. With the exception of gefinitib for which the DDI effect was overpredicted (12-fold in Tg-mice vs 2-fold in the clinic), the magnitude of AUC increase observed in this study was consistent (within 2-fold) with the clinical DDI observed following administration with itraconazole/ketoconazole. As an assessment of CYP3A4 induction, following rifampin pretreatment to PXR-CAR-3A4/3A7Hep/Intmice, an 8% decrease in vandetanib mean AUC was observed; 39-52% reduction in AUC were observed for dasatinib, ibrutinib, regorafenib, and sorafenib compared to vehicle treated mice. The greatest effect of rifampin induction was observed with alprazolam, bosutinib, crizotinib, gefitinib, and triazolam where 72-91% decrease in AUC were observed. With the exception of vandetanib for which rifampin induction was under-predicted, the magnitude of induction observed in this study was consistent (within 2-fold) with clinical observations. These data sets suggest that, with two exceptions, these transgenic mice models were able to exclude or capture the magnitude of CYP3A4 clinical inhibition and induction. Data generated in transgenic mice may be used to gain confidence and complement in vitro and in silico methods for assessing DDI potential/liability.