Seizure clusters (SCs) are an acute and transient increase in seizure frequency relative to an individual patient's baseline and are associated with an increased risk of injury, morbidity, and potentially mortality if not promptly and adequately treated. Despite their clinical importance, the management of SCs remains highly heterogeneous, primarily due to the absence of a universally accepted definition, which is determined also by the wide variability in seizure semiology and baseline individual burden;, as well as by differences in care settings. Outpatient treatment relies largely on caregivers' ability to recognize SCs and administer rescue medication, whereas inpatient management may also involve invasive routes of administration. We conducted a literature review identifying 32 original articles addressing the treatment of SCs. The analysis focused on definitions, efficacy outcomes, and adverse events across three clinical scenarios: outpatient, Emergency Department (EDs) and Epilepsy Monitoring Units. The results show that in the outpatient setting, the available evidence suggests that diazepam nasal spray (DZP-NS), midazolam nasal spray (MDZ-NS), and oral lorazepam (LZP) solution may demonstrate comparable efficacy and safety. However, comparisons are limited by heterogeneity in studies' designs, patient populations and outcome definitions, as well as by the absence of head-to-head trials. Moreover, geographic differences in drug availability (e.g., USA vs. Europe) limit the development of universally applicable treatment protocols. Consequently, the off-label use of oral benzodiazepines, including clobazam, clonazepam, and lorazepam, remains common when oral therapy is feasible, despite limited evidence. The implementation of a patient-specific Acute Seizure Action Plan (ASAP) incorporating an individualized SC definition is recommended. In contrast, inpatient management shows greater consensus, largely reflecting first-line treatment paradigms for status epilepticus. These include prompt intravenous benzodiazepine administration, followed by the intravenous loading of antiseizure medications such as brivaracetam or lacosamide in cases of seizure recurrence. In ED settings, "empirical" definitions of SCs (i.e., more than three seizures within 24 h) may facilitate timely intervention.

Comparing synaptic mechanisms of iTBS and 10-Hz rTMS corticomotor plasticity

The study examines how chronic resveratrol administration affects behavioral and neurochemical changes caused by Lorazepam (LZP), a classical anti-anxiety medicine associated with neurodegenerative and neurological problems. Forty male rats were placed into four groups: a control group receiving 1% Tween 80, the LZP group receiving 2 mg/kg/day, the Resveratrol group receiving 50 mg/kg/day, and the LZP plus resveratrol group receiving the same doses of LZP and Resveratrol. Oral therapy was given daily for 6 weeks. The animals were euthanized after open field and Y maze behavioral tests. In specific brain regions, neurochemical analyses were performed on GABA, glutamic acid, monoamines (norepinephrine, dopamine, and serotonin) and their metabolites, DNA fragmentation (8-hydroxy-2-deoxyguanosine or 8-HdG), brain-derived neurotrophic factor (BDNF), and Ca-ATPase. Resveratrol therapy improved GABA, glutamic acid, monoamines, and their metabolites in the cerebral cortex, hippocampus, and striatum. Additionally, it reduced DNA fragmentation (8- HdG) and counteracted LZP-induced Ca-ATPase downregulation at a significant level (p < 0.05). Resveratrol also reversed LZP-induced behavioral changes in the Y maze and open field tests. Resveratrol has anxiolytic-like actions like benzodiazepines and neuroprotective capabilities against LZP-induced adverse effects.

Стаття присвячена підготовці здобувачів з публічного управління та адміністрування за другим (магістерськім) рівнем вищої освіти у Житомирському державному університеті імені Івана Франка. У статті розкрито особливість освітньо-професійної програми які полягають в залучені викладачів з досвідом роботи на керівних посадах в органах державної влади та органах місцевого самоврядування, депутатів Верховної Ради України, депутатів місцевих рад, а також провідних експертів з великим досвідом викладацької діяльності в Національній академії державного управління при Президентові України (в часи її функціонування); здійсненні низки практичних заходів щодо використання інноваційних методик навчання та оцінювання студентів спеціальності «Публічне управління та адміністрування»; співпраці з органами влади та органами місцевого самоврядування, що створює можливість для здобувачів проходити виробничу практику в органах державної влади та органах місцевого самоврядування, брати участь у місцевих проєктах, програмах та інших заходах насамперед на рівні Житомирської області. На основі аналізу зазначено, що така освітньо-професійна програма передбачає підготовку фахівців для роботи в органах виконавчої влади і органах місцевого самоврядування, громадських організаціях, здатних забезпечити соціально прийнятний рівень надання адміністративних послуг на засадах відкритості, прозорості, підзвітності, професіоналізму тощо в сучасних умовах та післявоєнний період. Розкрито зміст освітньої програми та чітку структуру, що відповідає предметній області заявленої спеціальності 281 «Публічне управління та адміністрування», а також її спрямування на забезпечення фундаментальної теоретичної і практичної підготовки професіоналів в управлінні та адмініструванні організаціями (установами) публічного сектору. Окреслено можливість формування індивідуальної освітньої траєкторії яка реалізується, зокрема, через вільний вибір видів та форм здобуття освіти, закладів освіти і запропонованих ними освітніх програм, освітніх компонент (далі ОК) та рівня їх складності, методів і засобів навчання.

UGT2B10 is a phase II drug metabolizing enzyme with limited information on its role in the metabolism of drugs, especially in the pediatric hematopoietic stem cell transplantation setting. Previously, we investigated UGT2B10's role through in silico analyses and prioritized acetaminophen (APAP), lorazepam (LOR), mycophenolic acid (MPA), and voriconazole N-oxide (VCZ N-oxide) for invitro investigations. In this report, we present invitro screening of these candidates and of voriconazole (VCZ) to assess their potential to be substrates and/or inhibitors of UGT2B10. Enzyme kinetics experiments included recombinant UGT2B10 and analytical methods based on ultra high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). To determine potential substrates, candidates were incubated at various therapeutically observed concentrations with recombinant UGT2B10 to identify the corresponding glucuronide metabolite. Inhibition capacity was tested using the selective probe cotinine for its glucuronidation to cotinine N-ß-d-glucuronide. IC50 was determined for compounds exhibiting inhibition. Among the tested compounds, LOR (IC50 = 0.01 μM, R2 = 0.9257) and MPA (IC50 = 0.38 mM, R2 = 0.9212) exhibited inhibition potential for UGT2B10. None of the other tested compounds featured inhibition potential and none of the compounds tested exhibited metabolism through UGT2B10. Further exploration on the clinical relevance of this inhibition using modeling strategies, overlapping nature with other UGT isoforms, and screening other molecules for their inhibition potential on UGT2B10 is warranted.

Optimization of the extraction of clonazepam and lorazepam using nano-sponge activated carbon and its determination by high-performance liquid chromatography

Benzodiazepines are frequently encountered in crime scenes, often mixed with adulterants and diluents, complicating their analysis. This study investigates the interactions between two benzodiazepines, lorazepam (LOR) and alprazolam (ALP), with common adulterants/diluents (paracetamol, caffeine, glucose, and lactose) using infrared (IR) spectroscopy and quantum chemical methods. The crystallographic structures of LOR and ALP were optimized using several functionals (B3LYP, B3LYP-D3BJ, B3PW91, CAM-B3LYP, M05-2X, and M06-2X) combined with the 6-311++G(d,p) basis set. M05-2X was the most accurate when comparing experimental and theoretical bond lengths and angles. Vibrational and 13C NMR spectra were calculated to validate the functional’s applicability. The differences between LOR’s experimental and theoretical IR spectra were attributed to intramolecular interactions between LOR monomers, examined through density functional theory (DFT) optimization and quantum theory of atoms in molecules (QTAIM) analysis. Molecular dynamics simulations modeled benzodiazepine–adulterant/diluent systems, predicting the most stable structures, which were further analyzed using QTAIM. The strongest interactions and their effects on IR spectra were identified. Comparisons between experimental and theoretical spectra confirmed spectral changes due to interactions. This study demonstrates the potential of quantum chemical methods in analyzing complex mixtures, elucidating spectral changes, and assessing the structural stability of benzodiazepines in forensic samples.

Anxiolytics cause anxiety in pancreatic cancer

Benzodiazepines are the gold standard for treatment of alcohol withdrawal, yet the selection of a preferred benzodiazepine is limited due to a lack of comparative studies. The primary objective of this study was to compare the efficacy and safety of injectable lorazepam (LZP) and diazepam (DZP) in the treatment of severe alcohol withdrawal syndrome (AWS). Retrospective cohort study of adult patients admitted to an intensive care unit with a primary diagnosis of AWS. Subjects who received at least 12 LZP equivalent units (LEU) of injectable DZP or LZP within 24 hours of initiation of the severe AWS protocol were included. The primary outcome was time with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) scores at goal over the first 24 hours of treatment. A total of 191 patients were included (DZP n = 89, LZP n = 102). Time with CIWA-Ar scores at goal during the first 24 hours was similar between groups (DZP 12 hours [interquartile range, IQR, = 9-15] vs LZP 14 hours [IQR = 10-17]), P = 0.06). At 24 hours, LEU requirement was similar (DZP 40 [IQR = 22-78] vs LZP 32 [IQR = 18-56], P = 0.05). Drug cost at 24 hours was higher in the DZP group ($204.6 [IQR = 112.53-398.97] vs $8 [IQR = 4.5-14], P < 0.01). DZP or LZP are equally efficacious for the treatment of severe AWS. LZP may be preferred due to cost but both medications can be used interchangeably based on availability.

Purpose:This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling.Experimental Design:Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling.Results:LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.Conclusions:We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

Approximately 30% of patients with status epilepticus (SE) become refractory to two or more antiseizure medications (ASMs). There is thus a real need to identify novel targets against which to develop new ASMs for treating this clinical emergency. Among purinergic receptors, the ionotropic ATP–gated P2X7 receptor (P2X7R) has received attention as a potential ASM target. This study evaluated the effect of the selective P2X7R antagonist A740003 on acute seizures in the dentate gyrus (DG) of hippocampal brain slices, where P2X7Rs are highly expressed, with a view to establishing the potential of P2X7R antagonists as a therapy or adjunct with lorazepam (LZP) in refractory SE. Extracellular electrophysiological recordings were made from the DG of male mouse hippocampal slices. Spontaneous seizure-like events (SLEs) were induced by removing extracellular Mg2+ and sequentially adding the K+ channel blocker 4-aminopyridine and the adenosine A1 receptor antagonist 8-cyclopentyltheophylline, during which the early and late application of A740003 and/or lorazepam was evaluated. Our study revealed that, in the absence of changes in mRNA for P2X7Rs or inflammatory markers, P2X7R antagonism did not reduce the frequency of SLEs. However, A740003 in conjunction with LZP delayed the onset of seizures. Furthermore, our results support the need for employing LZP before seizures become refractory during SE as delayed application of LZP increased seizure frequency. These studies reveal possible sites of intervention that could have a positive impact in patients with high risk of suffering SE.

Striatal adenosine A2A receptor involvement in normal and large nest building deer mice: Perspectives on compulsivity and anxiety

Reports related to incidences of drug facilitated crimes (DFCs) have notably increased in recently. In such cases, victims report being assaulted or robbed while under the influence of drugs. Lorazepam (LZ) is frequently used in DFCs as it can easily make victims docile owing to its potent numbing effect. Therefore, a straightforward and green analytical method to analyze LZ in spiked food matrices in connection with criminal acts becomes important. The current study reports a simple, green, and high sample throughput analytical method for determining LZ in food and drink matrices commonly encountered in DFCs, based on recently introduced cellulose paper sorptive extraction (CPSE). For the extraction of LZ from food matrices, pristine cellulose paper (CP, commonly used laboratory filter paper) was used as a sorptive medium. Five pieces of CP (1.5″ × 1.5″ each) were dipped into diluted food matrices (cream biscuits and tea) and stirred on a rotary shaker for 30 min at 200 rpm. The CPs were then dried, and the adsorbed LZ was back-extracted into 2 mL of methanol. The extract was then subjected to GC–MS analysis in selected ion monitoring (SIM) mode. Several parameters, including CP size and number, back-extraction solvent type and volume, sample volume, extraction time and stirring speed, pH, ionic strength, elution time and speed, were thoroughly screened and optimized. Under the optimized conditions, the method was found to be linear in the range of 0.2–10 µg·mL−1 (or µg·g−1) with a coefficient of determination (R2) ranging from 0.996–0.998. The limit of detection and limit of quantification for cream biscuits were 0.054 and 0.18 µg·g−1 whereas they were 0.05 and 0.16 µg·mL−1 for tea samples. For all measurements, the relative standard deviations (%RSD) were always below 10%. Two mL of methanol per sample was used during the entire sample preparation process. The greenness of the proposed procedure was evaluated using Analytical Eco-Scale and GAPI greenness assessment tools. Finally, the CPSE–GC–MS method has been applied for the determination of LZ in forensic food samples which were used in DFCs.

Accumulation and risk prioritization of psychoactive substances in the critically endangered Yangtze finless porpoise.

Introduction: Stereotypical expression in laboratory-housed rodents can be explained by different motivational, coping, and motor dysfunction theories. Here, we aimed to explore the neurocognitive underpinnings of high stereotypical (HS) expression in deer mice (Peromyscus maniculatus bairdii), previously proposed as a model system of compulsive-like behavioral persistence. Specifically, we aimed to establish whether HS behavior is related to an underlying escape-related trigger. Methods: One-hundred and sixteen deer mice were classified as either non-stereotypical (NS) or HS. Mice of each cohort were further subdivided and exposed to either sub-acute (3-day) or chronic (25-day) behavioral restriction (R), and high-dose escitalopram (ESC), lorazepam (LOR), alone and in combination with R (ESC+R and LOR+R, respectively). Mice were reassessed for stereotypical behavior at both time points. Results: Our results indicate that HS behavior is likely not temporally and functionally related to an anxiogenic trigger, i.e., R, but rather that HS is associated with parallel changes in anxiogenic feedback processing. We also show that chronic R alone significantly decreased the time spent in expressing HS behavior in animals of the HS, but not NS phenotype. Discussion: This points to the possibility that HS-expressing mice represent a subgroup of P. maniculatus bairdii in which unique interactions between neurobiology and processes of gradual behavioral organization, may contribute to the expression of the typical behaviors observed in this cohort. Collectively, our findings highlight the value of the deer mouse model system to investigate the potential neurocognitive mechanisms that may underlie the development of persistent phenotypes that can likely not be explained entirely by current theories.

Behavioral changes and neurochemical responses in Chinese rare minnow exposed to four psychoactive substances

Photocatalytic oxidation of pharmaceutical contaminants of emerging concern using sunlight and visible radiation: Mechanism and ecotoxicological evaluation

Clinical Translation of the Fear-Inhibiting Effects of Oxytocin

Alcohol use disorder is a frequent occurrence within the United States, accounting for approximately 18% of the general population. Statistically, 50% of these people experience Alcohol Withdrawal Syndrome (AWS); a clinical diagnosis characterized by autonomic hyperactivity, following abrupt abstinence from heavy alcohol consumption. AWS is a life-threatening disorder that for many years has been treated with tapering doses of benzodiazepines— mostly chlordiazepoxide (CDE) and lorazepam (LOR). This paper seeks to answer the question “Are there better clinical outcomes when treating acute Alcohol Withdrawal Syndrome symptoms with chlordiazepoxide or lorazepam?”. A literature review was conducted to compile and analyze data from Randomized Clinical Trials (RCTs), and peer reviewed journal articles. These sources were carefully critiqued and compared for an overview to support the use of one benzodiazepine therapy over the other in AWS treatment. The revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scale of alcohol withdrawal is the primary measure used to quantify and monitor improvement of AWS and treatment used. CIWA-Ar scalings, dosing regimens (length, doses, number of doses), days to resolution of symptoms, and adverse effects were compared across multiple studies to reach a conclusion. This paper concludes that the use of lorazepam can be more advantageous than traditionally accepted treatments due to its safety profile among patients with liver disease, promising abilities to decrease the time to complete resolution of symptoms, and a potentially easier transfer to sobriety.

In the present study, simultaneous voltammetric determination of noscapine (NOS) and lorazepam (LOR) was studied for the first time. A carbon paste electrode modified with multi-walled carbon nanotubes (MWCNTs) and natural deep eutectic solvent (NANADES) (MWCNTs/NADES/CPE) was used for this purpose. Electrochemical impedance spectroscopy (EIS) was applied for the investigation of the electron transfer rate of [Fe(CN)6]3-/4- as a redox couple probe on the surface of the MWCNTs/NADES/CPE. The modified electrode preserved and combined the properties of the individual modifiers synergistically. A significant enhancement in the peak current responses of NOS and LOR was observed on the modified electrode surface compared to the bare electrode. Under the optimal conditions, the peak current of differential pulse voltammograms was linearly dependent on analyte concentration in the range of 3-1700 µM for NOS and 1-2220 µM for LOR. The limit of detection (LOD) for NOS and LOR was 1.90 µM and 0.69 µM, respectively. Finally, this strategy was also employed for the determination of NOS and LOR in pharmaceutical samples.