- Effect of pretreatment regimens of 1-aminobenzotriazole on metabolism and gastric emptying of probe compounds in rat. [Journal Article]
- XXenobiotica 2018 Jun 14; :1-26
- 1. 1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies. 2. The purpose was to evaluate the effect of 2 h ...
1. 1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies. 2. The purpose was to evaluate the effect of 2 h and 16 h pretreatment regimens of ABT on the exposures of triazolam in rat. Another objective was to evaluate the effect of ABT on gastric emptying of acetaminophen. 3. Plasma area under the curve (AUC) of triazolam was increased by 101-fold and 81-fold for the rats pre-treated with ABT at 2 h and 16 h, respectively, compared to control rats. Time to reach maximum concentration was 0.3 h, 4.8 h and 3.7 h in control, 2 h and 16 h pretreatment animals, respectively. In the case of acetaminophen, where Tmax was not delayed, the mean absorption time (MAT) in control, 2 h and 16 h ABT pretreatment groups were 0.3, 4.6 and 2.9 h, respectively, suggesting delayed absorption. This hypothesis was further supported by GastroPlusTM simulation. 4. In summary, extent of triazolam absorption was increased to a similar extent with both 2 h and 16 h ABT pretreatment regimens, suggesting that either of the regimen can be used to increase parent exposures in rat. With ABT pretreatment, delayed absorption of triazolam and acetaminophen was observed, as suggested by delay in Tmax and MAT, respectively.
- Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper. [Journal Article]
- JCJ Clin Sleep Med 2018 May 29
- Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life....
Nightmare disorder affects approximately 4% of adults, occurring in isolation or as part of other disorders such as posttraumatic stress disorder (PTSD), and can significantly impair quality of life. This paper provides the American Academy of Sleep Medicine (AASM) position regarding various treatments of nightmare disorder in adults.
- Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors. [Journal Article]
- ACACS Chem Biol 2018 May 16
- Benzodiazepines are clinically relevant drugs, which bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpola...
Benzodiazepines are clinically relevant drugs, which bind to GABAA neurotransmitter receptors at the α+/γ2- interfaces and thereby enhance GABA induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high affinity site at GABAA receptors is controversially debated in the literature and in silico studies led to discrepant binding mode hypotheses. In the current study computational docking of diazepam into α+/γ2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to α5-containing GABAA receptors (position 3 of the 7-membered diazepine ring), could possibly provide experimental evidence in favor of or against the so far proposed binding modes. Thus, we investigated three pairs of R- and S-isomers of structurally different chemotypes, namely diazepam-, imidazobenzodiazepine- and triazolam-derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in α1β3γ2, α2β3γ2, α3β3γ2 and α5β3γ2-containing GABAA receptors to determine ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities while for the other two chemotypes a discrepancy in binding affinities of the different isomers was observed. Specifically, the R-isomers displayed a loss of binding whereas the S-isomers remained active. These findings are in accordance with our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands rather interact via distinct binding modes than using a common binding mode.
- Segmental Hair Testing of Triazolam to Unmask a Suspected Case of Idiopathic Recurrent Stupor. [Journal Article]
- JCJ Clin Sleep Med 2018 Apr 15; 14(4):697-699
- Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to "endozepine-4" accumulation. This condition has been rece...
Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to "endozepine-4" accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior.
- Sorption, plant uptake and metabolism of benzodiazepines. [Journal Article]
- STSci Total Environ 2018 Jul 01; 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 Kd 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.
- Fabrication of magnetic zinc adeninate metal-organic frameworks for the extraction of benzodiazepines from urine and wastewater. [Journal Article]
- JSJ Sep Sci 2018; 41(8):1864-1870
- 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 accurate detection and monitoring. Results showed that Fe3 O4 nanoparticles 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 interactions 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.
- 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 2018 Jun 07; 53(7):1117-1127
- 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 2018; 10(6):984-994
- 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.
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- 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.