Temporal and regional associations between fentanyl concentrations in the unregulated drug supply and drug-related mortality in British Columbia, Canada.

Recent advances in toxicology, extraction, and analytical techniques for benzimidazole veterinary drug residues in food.

The pharmacokinetics of tolfenamic acid in Himalayan Griffon vultures. A better understanding for the safety of the drug in old world vultures.

Marine natural product-inspired 2-(3,4,5-trimethoxybenzoyl)quinazolin-4(3H)-one derivative CHNQD-01522: A novel anti-hepatocellular carcinoma agent targeting colchicine binding site of microtubule.

People and communities in Vancouver, British Columbia (BC) have been profoundly impacted by the toxic drug crisis, which has driven a province-wide public health emergency since 2016. In 2023, BC implemented a "Decriminalization Pilot," which temporarily removed criminal sanctions for the possession of small amounts of certain substances. In May 2024, the Decriminalization Pilot was amended to exclude its application in almost any urban outdoor space; a reform colloquially referred to as "Recriminalization." This study sought to address gaps in understanding how law enforcement practices towards people who use criminalized drugs may have changed during the Decriminalization Pilot and subsequent Recriminalization periods. We undertook a community-based, qualitative study. We conducted 21 interviews with people who use criminalized drugs and who interacted with law enforcement in Vancouver between January and May 2025. We employed combined reflexive thematic and interpretative phenomenological analyses. We derived five main themes: 1) confusion over the Decriminalization Pilot; 2) selective enforcement and pervasiveness of policing; 3) police interference with overdose response and other public health interventions; 4) seizures of belongings, including government-supplied resources; and 5) displacement from public space. Our findings illustrate how harmful law enforcement practices that target people who use criminalized drugs, particularly those relying on public spaces for survival, persisted during the evolving drug policy periods. Together, these law enforcement practices along with the lack of understanding regarding the shifting Decriminalization Pilot, may have undermined the potential success of a policy dedicated to decriminalizing drug possession in BC.

High‑dose methotrexate (HD‑MTX) is a cornerstone of pediatric acute lymphoblastic leukaemia (ALL) therapy. However, deviations from protocol-mandated infusion durations need regular monitoring as part of standard quality care. Hence, an observational quality assessment study was planned with a secondary objective to evaluate the acute toxicity in patients who did not receive the infusion within the recommended time period. This study enrolled 42 children (75 cycles) who received HD-MTX (3-5g/m2 over 24h) according to the ICiCLe ALL-14 protocol. The actual infusion duration was recorded, and 48-h MTX levels were measured using an enzyme-multiplied immunoassay technique. Toxicity was graded via CTCAE v5.0. Only 35% of cycles were completed within the targeted 24-h window [Median (IQR): 23.75h (21.25, 25.33)]. Prolonged infusions (> 25h) resulted in significantly higher 48-h MTX levels compared to shortened infusions (median 0.475 vs 0.270µmol/L; p = 0.015). Multivariable analysis identified male sex (OR, 12.24), T-ALL immunophenotype (OR, 8.36), and the infusion duration (OR, 1.50 per hour) as independent predictors of delayed clearance. A 48-h level > 0.315µmol/L predicted development of toxicity (AUC 0.686), though no life-threatening event or mortality was recorded in any cycle. Additionally, MTX levels did not differ significantly across the four HD-MTX cycles that each patient received, and elevated levels in one cycle did not predict delayed clearance in subsequent cycles. Deviations in infusion duration were high and independently drive pharmacokinetic variability and toxicity. Ensuring timely drug delivery is as critical as dose precision.

Beyond HLA: An adaptive nanopore sequencing assay for simultaneous HLA and blood group profiling in transplantation.

Nucleoside analogues are important antiviral and anticancer agents. In this study, we investigated a new class of nucleoside analogues built on a synthetically accessible carbobicyclic scaffold designed as a conformational mimic of ribose. Antiviral screening of our library revealed pan-antiviral activity against a range of viruses, including HCV, HSV, and influenza. Structure-activity relationship (SAR) studies highlighted the critical role of the carbocyclic scaffold. The uracil analogue 2a inhibited influenza A virus replication through direct disruption of the viral polymerase, as confirmed by a minigenome assay and further supported by in silico modeling. Importantly, metabolism studies demonstrated that congested C5'-OH is readily phosphorylated without the need for prodrug formulations. The resulting triphosphate metabolites are not substrates of human DNA/RNA polymerases, a primary mechanism of nucleoside drug toxicity. Supported by comprehensive synthetic schemes, we present a carbobicyclic scaffold with altered architecture as a promising chemotype for developing novel nucleoside therapeutics.

Doxorubicin (Dox) is a widely used anthracycline anticancer drug. However, the clinical application is limited by severe dose-limiting cardiotoxicity and systemic toxicity. To overcome these challenges, recent studies have focused on chemoradiotherapy, reporting that combination nanoparticles with irradiation maximize the therapeutic efficiency. Herein, we developed a radiosensitizing chemotherapeutic agent by conjugating Dox and β-sitosterol (ST-Dox A) to enhance the radiotherapeutic efficacy while minimizing drug dose and toxicity. ST-Dox A self-assembled into 170 nm nanoparticles, which are expected to facilitate passive tumor accumulation via the enhanced permeability and retention (EPR) effect. Moreover, the positively charged nature of ST-Dox A (+22.7 mV) led to improved cytotoxicity and facilitated endosomal escape via the proton sponge effect, compared to the non-charged ST-Dox B. In addition, ST-Dox A showed prolonged intracellular retention, thereby enhancing its availability even at low dosage. In an animal study, a low dose of ST-Dox A (equivalent to 2 mg/kg Dox) combined with a single local irradiation (5 Gy) significantly suppressed tumor growth compared to free Dox or radio combination by increased apoptotic cell death. Consequently, the conjugation of β-sitosterol to Dox would enable passive targeting and sustained exposure of ST-Dox A, offering a promising strategy for a potent radiosensitizer. This approach achieves a significantly enhanced antitumor effect with a low dose of drug and irradiation, minimizing systemic toxicity.

Perinatal brain injury (PBI) is a leading cause of long-term neurological deficits in newborns, yet effective therapies are limited. At the cellular level, PBI involves hypoxic-ischemic stress, neuroinflammation, oxidative damage, excitotoxicity, and disrupted neurovascular and glial development. Traditional animal models and 2D cultures cannot fully capture the spatiotemporal complexity of the developing human brain, highlighting the need for more physiologically relevant systems. Human brain organoids have emerged as advanced three-dimensional models that recapitulate region-specific cytoarchitecture, neuronal and glial differentiation, and early circuit formation. They enable modeling of hypoxic-ischemic and inflammatory insults, allowing for the study of injury-induced changes in neurogenesis, gliogenesis, synaptic development, and cell interactions. Organoids facilitate identification of molecular pathways involved in injury and repair, supporting therapeutic target discovery. Using patient-derived induced pluripotent stem cells, organoids also allow personalized pharmacogenomic studies to assess genotype-dependent drug responses and toxicity. Despite limitations such as variability, lack of vascularization and immune components, and ethical considerations, brain organoids offer a promising platform to bridge developmental neurobiology and translational therapeutics, paving the way for targeted and individualized interventions in PBI.

Accurate drug toxicity prediction is vital for drug discovery, but existing atom-based methods are often computationally inefficient for complex molecules. This limitation creates a need for more efficient yet powerful predictive models. We introduce FGMA, a novel framework designed to address this challenge. FGMA integrates functional groups with molecular fingerprints for a multi-view molecular encoding. The framework extracts key functional groups, treating them as unified entities to reduce computational overhead. These are then combined with MACCS fingerprints using a crossattention mechanism to capture both local chemical motifs and global structural properties. Experimental results demonstrate that FGMA achieves high accuracy and robustness in toxicity prediction tasks. In addition, interpretability analyses successfully identified how specific structural features and functional groups within drug molecules contribute to toxicity outcomes. Our findings validate that combining functional groups with fingerprints is an effective strategy that balances computational efficiency and representational power. The model's interpretability offers valuable, actionable insights into structure-toxicity relationships, aiding in the design of safer compounds. FGMA offers an effective, efficient, and interpretable tool for drug toxicity analysis. It stands to accelerate the drug discovery pipeline by enabling faster and more insightful safety assessments of potential drug candidates.

Renal dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) often results from common causes like drug toxicity, infection, or transplant-associated thrombotic microangiopathy (TA-TMA). However, renal graft-versus-host disease (GVHD) may be ignored. We discuss a 49-year-old man who experienced worsening kidney function despite being in hematologic remission and having negative results for infections and autoimmune diseases. A renal biopsy showed chronic tubulointerstitial injury consistent with renal GVHD, along with existing TMA. Treatment with eculizumab did not lead to improvement, likely indicating significant chronic damage. This case highlights the need to maintain clinical suspicion and to perform timely renal biopsies in cases of unexplained kidney dysfunction after transplant.

Leishmania spp., the causative agents of leishmaniasis, pose significant global health threats, with visceral leishmaniasis being the most severe and fatal form. The increasing drug resistance in the treatment of leishmaniasis emphasizes the urgent need for novel therapeutic approaches. One promising strategy involves targeting essential cellular mechanisms such as nutrient acquisition, particularly iron, which is critical for energy metabolism and signal transduction. Leishmania spp. cannot synthesize heme de novo and rely on host-derived iron and heme for survival and pathogenicity. Gallium [Ga(III)] is an iron [Fe(III)]-mimetic molecule that has emerged as a promising antimicrobial agent, offering a novel approach to combat infections, mainly by replacing Fe(III) in redox enzymes thereby disrupting essential metabolic pathways and impairing microbial viability. In this study, the antiparasitic activity of Ga (III)-protoporphyrin IX (GaPPIX) was tested against Leishmania major and Leishmania infantum, both in promastigotes and intracellular amastigotes. Our results demonstrate that GaPPIX inhibits the viability of both species, specifically targeting the enzymatic activity of cytochrome c oxidase, with a higher sensitivity observed in L. major. The inhibitory effect is reversed by hemin, suggesting specificity for Leishmania heme-dependent cellular processes and a possible cytostatic action. Moreover, we found that GaPPIX can effectively synergize with miltefosine. This feature, coupled with its minimal toxicity toward human cells, makes GaPPIX a good candidate to be potentially developed as a novel anti-Leismania agent.IMPORTANCEThis study is significant as it addresses a critical challenge in leishmaniasis management, namely, the increasing incidence of drug resistance and toxicity, compounded by the scarcity of effective therapeutic options. We demonstrate that GaPPIX, a heme-mimetic compound, exhibits potent antiparasitic activity against both Leishmania major and Leishmania infantum, while displaying minimal cytotoxicity toward human cells, underscoring its potential as a safe and targeted therapeutic candidate. Importantly, the ability of GaPPIX to synergize with the first-line drug miltefosine highlights its translational relevance in combination therapies, which are essential for overcoming resistance and improving treatment efficacy. Collectively, these findings advance GaPPIX as a promising approach for the development of innovative therapeutics against a neglected but globally significant disease.

Primary hepatocyte cultures serve as an ex vivo model of liver physiology. This study aims to employ poly(vinyl alcohol) (PVA) nanofiber membranes (NMs) to establish a three-dimensional (3D) culture system that supports the long-term functionality of primary hepatocytes. Primary hepatocytes were monocultured on a PVA NM or indirectly cocultured with NIH3T3 fibroblasts on a distinct polycaprolactone (PCL) NM layer. Monocultured and cocultured hepatocytes maintained prolonged survival without supplemental growth factors. Cocultured hepatocytes formed larger aggregates composed of cell clusters attached to untreated nanofibers than monocultured cells. However, most primary hepatocytes cultured on NaOH-treated PVA NM and Arg-Gly-Asp (RGD) peptide-blended PVA (RGD-PVA) NM, under monoculture and coculture conditions, formed non-aggregated cells in a single-cell layer. In a bioinert assay, unstimulated dendritic cells were activated on untreated but not NaOH-treated PVA NM. CYP3A4 activity was higher in cocultured cells on RGD-PVA NM with fibroblasts than in monocultured cells on PVA and RGD-PVA NM. Functional hepatocyte cultures were successfully maintained in a 3D single-cell layer on RGD-PVA NM, along with fibroblasts in a layer-by-layer coculture, for a prolonged period. The prolonged culture of hepatocytes in a 3D single-cell layer may facilitate further drug discovery, toxicity studies, and translational liver research.

Nightclubs, often perceived as safe spaces for entertainment, can nevertheless harbour hidden dangers. Despite their popularity among young adults, the prevalence and characteristics of fatalities associated with nightclub attendance remain unknown. This research aimed to characterise the nature and frequency of nightclub-related deaths in the UK. We conducted a retrospective observational study using media reports and coroner verification to identify and characterise nightclub-related deaths in the UK between 2009 and 2024. Nightclub-related deaths encompassed those found deceased inside the venue and those who died within a few hours of attendance, typically on the same night. Articles were screened by hand, and included articles underwent standardised data extraction. Data were corroborated by searching open-source legal proceedings and communicating with the responsible coroner. There were 89 deaths associated with 75 nightclubs, with a median victim age of 22 years (range 16-54 years) and a rate of 5.9 per annum. Trauma-related injuries 45/89 (51%) and drug-related toxicity 36/89 (40%) were the primary causes. Blunt head injuries 19/45, mostly related to altercations 13/19, and penetrating trauma from knife injuries 17/45 accounted for most trauma deaths. MDMA was named as a cause in almost all drug-related deaths, 34/36 (94%), occurring at a rate of 2.4 per annum. Of the 89 victims, seven were under 18-years-old. Only 25/75 (33%) of the nightclubs with a fatal incident remained open under the same name. Using open-source media and coroners, this study identified nearly six deaths per year associated with UK nightclubs. Victims are predominantly young adults, with trauma and drug toxicity the leading causes. These findings underscore the need for targeted interventions, including enhanced safety measures and harm reduction strategies, to prevent future tragedies.

Baicalin (Bn), a bioactive compound derived from natural plants, has significant pharmaceutical value and is used in the treatment of diseases such as influenza. However, excessive baicalin administration may lead to increased drug toxicity, immune system disturbances, reduced therapeutic efficacy, and allergic reactions. The synergistic combination of a bimetallic MOF and carbon nanotubes (CNTs) yields a pronounced enhancement in the electrochemical signal toward the analyte. In this study, a simple and low-cost one-pot method was proposed to fabricate ZnNi-MOF@MWCNT nanocomposites, which were used to develop an electrochemical sensor for the detection of Bn. Under optimized conditions, the sensor demonstrated a wide linear detection range of 5 × 10-9 to 6 × 10-7 M for Bn, with a limit of detection (LOD) of 1.12 × 10-9 M and a sensitivity of 130 A M-1. The sensor exhibited excellent stability, reproducibility, and resistance to interference from various substances. Additionally, the sensor showed satisfactory stability and recovery rates when applied to a real sample of goat serum. The proposed sensor material can be synthesized at room temperature, offering a new approach for the green synthesis of MOF-derived materials in pharmaceutical analysis.

Substance Use and Toxicity Deaths in Pregnancy.

Cancer is one of the diseases with high incidence and mortality rates. As a result, many studies have led to the development of therapeutic agents such as immune checkpoint inhibitors. However, the research on cancer treatment is still essential because of problems including drug resistance, genetic variation among patients, and drug toxicity. To address these problems, several candidate chemicals, including phytochemicals, have been studied for cancer treatment. Phytochemicals exhibit a variety of biochemical and physiological functions in the body and have been studied as having lower toxicity than synthetic chemicals. These properties have led to research into their potential as anti-cancer agents as well as their therapeutic applications for a variety of other diseases. The structural diversity of phytochemicals leads to considerable variations in their mechanisms of action. Therefore, it is important to understand the mechanism of action of each phytochemical when studying phytochemicals. Tangeretin (TAN) is mainly extracted from citrus fruits and is characterized by the presence of a methyl group. The presence of a methyl group in TAN is thought to enhance its intracellular uptake and confer greater resistance to degradation compared with other phytochemicals. Previous studies on the use of TAN in cancer treatment have mainly focused on its ability to induce oxidative stress as the primary anti-cancer mechanism. In addition, some studies suggest that TAN also exerts various other anti-cancer effects, such as upregulating tumor suppressor proteins, inducing apoptosis, and reducing the proportion of cancer stem cells (CSCs). This review highlights the anti-cancer effects of TAN in different cancers and aims to provide data to support future research.

TcGAPDH peptidic inhibitors derived from dinoponeratoxin M-PONTX-Dq4e with trypanocidal effect.

Biopolymer of zein/agarose hydrogels for efficient co-delivery of 5-fluorouracil/curcumin in human colorectal carcinoma treatment.