Search Results (9)

In this research, a molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization using oxazepam (OZ) as a template molecule and was subsequently applied as a selective sorbent for the extraction of diazepam (DZP) and its metabolites in urine samples using an SPE cartridge. OZ, temazepam (TZ), nordiazepam (NZ) and DZP were analyzed in the final extracts by high-performance liquid chromatography with diode array detection (HPLC-DAD). The SPE extraction steps were optimized, and the evaluation of an imprinting factor was carried out. The selectivity of the method for OZ versus structurally related benzodiazepines (BZDs), such as bromazepam (BRZ), tetrazepam (TTZ) and halazepam (HZ), was investigated. Under the optimum conditions, the proposed methodology provided good linearity in the range of 10–1500 ng/mL, with limit of detection values between 13.5 and 21.1 ng/mL and recovery levels for DZP and its metabolites from 89.0 to 93.9% (RSD ≤ 8%) at a concentration level of 1000 ng/mL. The proposed method exhibited good selectivity, precision and accuracy and was applied to the analysis of urine samples from a real case of DZP intake. Full article

Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, −0.29; 95% CI, −0.57 to −0.01) and CBT-I (−0.48; −0.68 to −0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (−0.80; −1.25 to −0.36) but not long-term effectiveness (0.19; −0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment. Full article

There has been a significant increase in sodium azide intoxications since the 1980s. Intoxications caused by sodium azide are becoming increasingly prevalent in the Netherlands as a result of its promotion for the purpose of self-euthanasia. The mechanism of toxicity is not completely understood but is dose-dependent. The presented case describes a suicide by sodium azide of a young woman (26 years old) with a history of depression and suicide attempts. The decedent was found in the presence of prescription medicine, including temazepam, domperidone in combination with omeprazole, and the chemical preservative sodium azide. Quantitative toxicology screening of whole blood revealed the presence of 70 µg/L temazepam (toxic range > 1000 µg/L) and 28 mg/L sodium azide (fatal range: 2.6–262 mg/L). Whole blood qualitative analysis revealed the presence of temazepam, temazepam-glucuronide, olanzapine, n-desmethylolanzapine, and acetaminophen. In circles promoting sodium azide, it is recommended to use sodium azide in combination with medications targeting sodium azide’s negative effects, such as analgesics, antiemetics, and anti-anxiety drugs. The medicines recovered at the body’s location, as well as the results of the toxicology screens, were consistent with the recommendations of self-euthanasia using sodium azide. Full article

The fate of pharmaceuticals in the human body, from their absorption to excretion is well studied. However, medication often leaves the patient’s body in an unchanged or metabolised, yet still active, form. Diazepam and its metabolites, ranging up to 100 µg/L, have been detected in surface waters worldwide; therefore, the question of its influence on model aquatic plants, such as duckweed (Lemna minor), needs to be addressed. Lemna was cultivated in a Steinberg medium containing diazepam in three concentrations—0.2, 20, and 2000 µg/L. The activity of superoxide dismutase (SOD) and catalase (CAT), leaf count, mass, and the fluorescence quantum yield of photosynthesis were assessed. The medium was also analysed by LC-MS/MS to determine the concentration of diazepam metabolites. Our results show no negative impact of diazepam on Lemna minor, even in concentrations significantly higher than those that are ecotoxicologically relevant. On the contrary, the influence of diazepam on Lemna suggests growth stimulation and a similarity to the effect diazepam has on the human body. The comparison to the human body may be accurate because γ-Aminobutyric acid-like (GABA-like) receptors responsible for the effect in humans have also been recently described in plants. Therefore, our results can open an interesting scientific area, indicating that GABA receptors and interference with benzodiazepines are evolutionarily much older than previously anticipated. This could help to answer more questions related to the reaction of aquatic organisms to micropollutants such as psychopharmaceuticals. Full article

Insomnia is a common sleep disorder that is closely associated with the occurrence and deterioration of cardiovascular disease, depression and other diseases. The evaluation of pharmacological treatments for insomnia brings significant clinical implications. In this study, a total of 20 patients with mild insomnia and 75 healthy subjects as controls (HC) were included to explore alterations of electroencephalogram (EEG) complexity associated with insomnia and its pharmacological treatment by using multi-scale permutation entropy (MPE). All participants were recorded for two nights of polysomnography (PSG). The patients with mild insomnia received a placebo on the first night (Placebo) and temazepam on the second night (Temazepam), while the HCs had no sleep-related medication intake for either night. EEG recordings from each night were extracted and analyzed using MPE. The results showed that MPE decreased significantly from pre-lights-off to the period during sleep transition and then to the period after sleep onset, and also during the deepening of sleep stage in the HC group. Furthermore, results from the insomnia subjects showed that MPE values were significantly lower for the Temazepam night compared to MPE values for the Placebo night. Moreover, MPE values for the Temazepam night showed no correlation with age or gender. Our results indicated that EEG complexity, measured by MPE, may be utilized as an alternative approach to measure the impact of sleep medication on brain dynamics. Full article

Introduction: Benzodiazepines, including temazepam are described as TSPO antagonists. In fact, TSPO was initially described as a peripheral benzodiazepine receptor (PBR) with a secondary binding site for diazepam. TSPO is a potential imaging target of neuroinflammation because there is an amplification of the expression of this receptor. Objectives: Herein, we developed a novel fluorinated benzodiazepine ligand, [¹⁸F]Fluoroethyltemazepam ([¹⁸F]F-FETEM), for positron emission tomography (PET) imaging of translocator protein (18 kDa). Methods: [¹⁸F]F-FETEM was radiolabelled with an automated synthesizer via a one-pot procedure. We conducted a [¹⁸F]F-aliphatic nucleophilic substitution of a tosylated precursor followed by purification on C18 and Alumina N SPE cartridges. Quality control tests was also carried out. Results: We obtained 2.0–3.0% decay-uncorrected radiochemical activity yield (3.7% decay-corrected) within the whole synthesis time about 33 min. The radiochemical purity of [¹⁸F]F-FETEM was over 90% by TLC analysis. Conclusions: This automated procedure may be used as basis for future production of [¹⁸F]F-FETEM for preclinical PET imaging studies. Full article

The constitutive androstane receptor (CAR) is the essential regulator of genes involved both in xenobiotic and endobiotic metabolism. Diazepam has been shown as a potent stimulator of CAR nuclear translocation and is assumed as an indirect CAR activator not interacting with the CAR cavity. In this study, we sought to determine if diazepam is a ligand directly interacting with the CAR ligand binding domain (LBD) and if it regulates its target genes in a therapeutically relevant concentration. We used different CAR constructs in translocation and luciferase reporter assays, recombinant CAR-LBD in a TR-FRET assay, and target genes induction studied in primary human hepatocytes (PHHs), HepaRG cells, and in CAR humanized mice. We also used in silico docking and CAR-LBD mutants to characterize the interaction of diazepam and its metabolites with the CAR cavity. Diazepam and its metabolites such as nordazepam, temazepam, and oxazepam are activators of CAR+Ala in translocation and two-hybrid assays and fit the CAR cavity in docking experiments. In gene reporter assays with CAR3 and in the TR-FRET assay, only diazepam significantly interacts with CAR-LBD. Diazepam also promotes up-regulation of CYP2B6 in PHHs and in HepaRG cells. However, in humanized CAR mice, diazepam significantly induces neither CYP2B6 nor Cyp2b10 genes nor does it regulate critical genes involved in glucose and lipids metabolism and liver proliferation. Thus, we demonstrate that diazepam interacts with human CAR-LBD as a weak ligand, but it does not significantly affect expression of tested CAR target genes in CAR humanized mice. Full article

Benzodiazepines is a class of medications frequently prescribed to patients with post-traumatic stress disorder. Patients with PTSD have a notable increased risk of suicide compared to the general population. These medications have been theorized to increase suicidality and pose a risk when used in this patient population. Previous research has found little utility of using benzodiazepines in the PTSD population. However, benzodiazepines are still commonly prescribed by some clinicians for their symptomatic benefit. This study aims to identify the comparative efficacy of commonly prescribed benzodiazepines including midazolam, lorazepam, alprazolam, clonazepam, diazepam and temazepam in relation to suicide-related behaviors (SRBs). A total of 38,807 patients who had an ICD9 or ICD10 diagnosis of PTSD from January 2004 to October 2019 were identified through an electronic medical record database. Inclusion criteria include patients that initiated one of the above benzodiazepines after PTSD diagnosis. Exclusion criteria include previous history of benzodiazepine usage or history of SRBs within the last year prior to enrollment. For patients enrolled in this study, other concomitant drugs were not limited. The primary outcome was onset of SRBs with each respective benzodiazepine. SRBs were identified as ideation, attempt, or death from suicide. We emulated clinical trials of head-to-head comparison between two drugs by pooled logistic regression methods with the Firth option adjusting for baseline characteristics and post-baseline confounders. A total of 5753 patients were eligible for this study, with an average follow up of 5.82 months. The overall incidence for SRB was 1.51% (87/5753). Head-to-head comparisons identified that patients who received alprazolam had fewer SRBs compared to clonazepam (p = 0.0351) and lorazepam (p = 0.0373), and patients taking midazolam experienced fewer relative incidences of SRBs when compared to lorazepam (p = 0.0021) and clonazepam (p = 0.0297). After adjusting for the false discovery rate (FDR), midazolam still had fewer SRBs compared to lorazepam (FDR-adjusted p value = 0.0315). Certain benzodiazepines may provide a reduced risk of development of SRBs, suggesting careful consideration when prescribing benzodiazepines to the PTSD population. Full article

The opposing effect of the blood–brain barrier against the delivery of most drugs warrants the need for an efficient brain targeted drug delivery system for the successful management of neurological disorders. Temazepam-loaded nanostructured lipid carriers (NLCs) have shown possibilities for enhancing bioavailability and brain targeting affinity after oral administration. This study aimed to investigate these properties for insomnia treatment. Temazepam-NLCs were prepared by the solvent injection method and optimized using a 4² full factorial design. The optimum formulation (NLC-1) consisted of; Compritol^® 888 ATO (75 mg), oleic acid (25 mg), and Poloxamer^® 407 (0.3 g), with an entrapment efficiency of 75.2 ± 0.1%. The average size, zeta potential, and polydispersity index were determined to be 306.6 ± 49.6 nm, −10.2 ± 0.3 mV, and 0.09 ± 0.10, respectively. Moreover, an in vitro release study showed that the optimized temazepam NLC-1 formulation had a sustained release profile. Scintigraphy images showed evident improvement in brain uptake for the oral ^99mTc-temazepam NLC-1 formulation versus the ^99mTc-temazepam suspension. Pharmacokinetic data revealed a significant increase in the relative bioavailability of ^99mTc-temazepam NLC-1 formulation (292.7%), compared to that of oral ^99mTc-temazepam suspension. Besides, the NLC formulation exhibited a distinct targeting affinity to rat brain. In conclusion, our results indicate that the developed temazepam NLC formulation can be considered as a potential nanocarrier for brain-mediated drug delivery in the out-patient management of insomnia. Full article