Search Results (335)

The overdose crisis in North America is increasingly driven by illicitly manufactured fentanyl and other high-potency synthetic opioids, which are associated with severe and unpredictable opioid-induced respiratory depression (OIRD). Current pharmacologic strategies to prevent fatal overdose have largely emphasized downstream rescue through opioid antagonism (e.g., naloxone), leaving limited attention to upstream pharmacologic modification of respiratory risk. In this Opinion article, we argue that buprenorphine should be reframed not only as a treatment for opioid use disorder (OUD), but also as a pharmacologic modifier of OIRD risk in fentanyl-dominant drug markets. Drawing on its partial μ opioid receptor agonism, ceiling effect on respiratory depression, and exceptionally high receptor affinity, we describe how buprenorphine can displace full agonists while limiting respiratory suppression. We further situate this pharmacology within emerging population-level observations from North American fentanyl contexts, suggesting reduced overdose mortality among individuals receiving opioid agonist therapy, particularly buprenorphine. In fentanyl-dominant drug markets, reframing buprenorphine as a modifier of respiratory risk has direct implications for clinical messaging about overdose protection, medication selection for individuals with ongoing illicit opioid use, and policy approaches aimed at reducing opioid-related mortality. Full article

The COVID-19 pandemic introduced unprecedented societal disruptions that may have altered patterns of acute substance-related harm. Despite extensive research on overdose mortality, there remains limited real-time, population-level evidence based on Emergency Medical Services (EMS) data. This study provides a national, multi-year characterization of temporal trends in alcohol- and drug-related overdose incidents in Israel across thirteen defined pandemic phases. A total of 18,348 overdose cases recorded between 1 January 2019 and 31 December 2022 were analyzed. Descriptive statistics were calculated, event frequencies were normalized by period length, and loglinear Poisson models were applied to compare occurrences across periods. Cluster analysis was used to explore joint age- and gender-related patterns. Alcohol-related overdoses demonstrated marked fluctuations across pandemic phases, whereas drug-related overdoses showed comparatively moderate variation and a gradual increase over time. Age- and gender-specific heterogeneity was observed across periods. As an observational study based on EMS records, causal inference cannot be established. These findings provide population-level surveillance evidence of dynamic overdose patterns during prolonged societal disruption and highlight the importance of integrating EMS-based monitoring into public health preparedness strategies. Full article

Background: Drug use settings are critical determinants of overdose risk and other drug-related harms. Although sex differences in drug use patterns are well documented, less is known about sex differences in the types of locations where people use drugs. This study examined sex differences in drug use settings among people who use opioids. Methods: Data were from the baseline survey of the OASIS project, a community-based study conducted in Baltimore, Maryland (N = 869), focusing on 9 specific types of locations where participants reported drug use in the past 30 days: their own residence, someone else’s residence, street, alley, park, abandoned building, public restroom, car, and other locations. Bivariate and multivariable logistic regression models examined associations between sex and drug use settings, adjusting for age, race, education, homelessness, and frequency of drug use. Results: The sample included 346 women and 523 men. In adjusted models, women had significantly lower odds than men of using drugs on the street (aOR = 0.49, 95% CI 0.35–0.70), in alleys (aOR = 0.50, 95% CI 0.35–0.69), parks (aOR = 0.57, 95% CI 0.42–0.78), abandoned buildings (aOR = 0.53, 95% CI 0.38–0.75), cars (aOR = 0.55, 95% CI 0.41–0.73), and other locations (aOR = 0.59, 95% CI 0.37–0.94). Sex was not significantly associated with drug use at one’s own residence or someone else’s residence. Conclusions: Women who use opioids were significantly less likely than men to use drugs in public and semi-public settings, which may reflect gendered patterns of stigma, interpersonal violence, and safety concerns. Harm reduction programs should focus on making current drug use settings safer and developing additional safer settings with an emphasis on addressing barriers for women to access harm reduction services, including women-centered overdose prevention centers and household-based overdose response training. Full article

Background and Objectives: Appropriate antimicrobial dosing according to kidney function is essential to ensure therapeutic efficacy while minimizing toxicity and antimicrobial resistance. Despite established dosing guidelines and electronic prescribing systems, errors in renal dose adjustment of antimicrobials, particularly in the setting of acute kidney injury, remain common among hospitalized patients. Materials and Methods: A point-prevalence study was conducted on 31 October 2024 at a tertiary-care hospital in Greece to evaluate the appropriateness of antimicrobial dosing in relation to renal function. Patient characteristics, renal parameters, and antimicrobial prescriptions were extracted from electronic medical records. Glomerular filtration rate (GFR) was estimated using the MDRD formula. Comparative analyses were performed between correctly and incorrectly dosed cases, and between overdosing and underdosing episodes. Results: A total of 235 hospitalized patients were evaluated (mean age 64.8 ± 18.6 years; 43.4% female). Overall, 15.7% (37/235) received at least one antimicrobial dose inappropriate for their renal function. Among 37 patients where dosing errors were identified, overdosing was noted in 23 (62.2%), underdosing in 16 (43.2%), adding up to 39 prescriptions, while in 2 patients (5.4%), both mistakes were noted in different prescribed antimicrobials. Drug-specific error rates varied considerably: ceftazidime and cefuroxime showed the highest rates of inappropriate dosing (40% each), followed by colistin (33.3%) and acyclovir (33.3%). Piperacillin/tazobactam, the most frequently prescribed agent (n = 50), had a 14% error rate, mainly due to underdosing (10%). Patients with dosing errors were significantly older (71.5 vs. 64.1 years, p = 0.0220) and had worse renal function, including higher serum creatinine (1.68 vs. 1.19 mg/dL, p = 0.0174), lower GFR (58.5 vs. 75.9 mL/min/1.73 m², p = 0.0009), and more frequent dialysis (13.5% vs. 4.3%, p = 0.0422). They also received a higher median number of antimicrobials (2 vs. 1, p = 0.0185). Conclusions: Inappropriate antimicrobial dosing based on kidney function remains common in hospitalized patients, particularly among older individuals and those with impaired renal function or polypharmacy. Targeted antimicrobial stewardship strategies focusing on renal dose adjustment and agents that are more frequently dosed inappropriately, such as colistin, acyclovir, cefuroxime, and ceftazidime, as well as agents that are frequently prescribed despite a relatively lower rate of inappropriate dose, such as piperacillin/tazobactam, are needed to enhance prescribing safety and optimize therapeutic outcomes. Full article

Paracetamol (PAR) overdose is a major cause of drug-induced liver injury and is also associated with renal toxicity, both involving mitochondrial dysfunction and oxidative stress. This study investigated the dose- and organ-specific effects of the mitochondria-targeted antioxidant MitoTempo (MT) on PAR-induced hepatorenal toxicity in mice. Male C57BL/6J mice received a single toxic dose of PAR (600 mg/kg), either alone or combined with MT (20 or 40 mg/kg). Twenty-four hours after treatment, serum markers of liver and kidney injury were measured, and mitochondrial function was assessed in both organs. PAR administration caused severe liver injury and moderate renal dysfunction, accompanied by increased mitochondrial oxidative stress, glutathione imbalance, mitochondrial permeability transition pore opening, and disruption of electron transport chain (ETC) integrity. MT co-treatment attenuated several PAR-induced mitochondrial alterations in a dose- and tissue-dependent manner; however, MT did not consistently confer protection and, in some settings, exacerbated oxidative stress and bioenergetic dysfunction, particularly in the kidney. Notably, recovery of ETC protein levels by MT was not consistently associated with restoration of enzymatic activity. Overall, these findings demonstrate that MT exerts dual, dose- and organ-specific effects on PAR-induced mitochondrial dysfunction, highlighting that mitochondria-targeted antioxidants are not universally protective. Full article

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Liver disease encompasses a wide range of conditions, each requiring tailored therapeutic approaches. This review describes and critically discusses treatments with robust evidence for improving liver health. Ursodeoxycholic acid (UDCA) is a drug approved by the Food and Drug Administration of the USA to treat primary biliary cholangitis (PBC). In addition, UDCA has been demonstrated to protect against metabolic dysfunction-associated steatohepatitis, fibrosis, and drug-induced liver injury (DILI). The mechanism of action of UDCA has been attributed not only to decreasing the effects of toxic bile acids but also to protecting mitochondrial integrity and function, as well as to antioxidant, anti-inflammatory, and anti-apoptotic activities. UDCA can scavenge reactive oxygen species (ROS) and activate the nuclear factor-E2-related factor-2 (Nrf2) pathway, thereby exerting antioxidant activity. The anti-inflammatory activity of UDCA is associated with its ability to inhibit the nuclear factor-κB pathway. Pirfenidone is a well-recognized antifibrotic drug for the treatment of idiopathic pulmonary fibrosis; its effects on liver fibrosis have also been demonstrated. Pirfenidone exerts anti-inflammatory effects by attenuating the nucleotide-binding oligomerization domain-like receptor 3 inflammasome signaling pathway. The antioxidant actions of pirfenidone are associated with its ability to upregulate the Nrf2 pathway. Both the anti-inflammatory and antioxidant properties of pirfenidone act together to attenuate lung and liver fibrosis, decreasing transforming growth factor-β levels, inhibiting profibrogenic hepatic stellate cell activation, and increasing extracellular matrix degradation. Methyltransferases utilize S-adenosyl-L-methionine (SAM) as a methyl donor for most transmethylation reactions in the body. SAM increases reduced glutathione (GSH) levels, exerting important antioxidant effects. Evidence indicates that SAM prevents fibrosis and attenuates hepatocellular carcinoma development, improving patient survival. N-acetylcysteine (NAC) is a precursor to L-cysteine and GSH and is used in clinical settings to treat cancer, nephropathy, heart disease, pulmonary fibrosis, polycystic ovary syndrome, and influenza. Regarding the liver, NAC is the most accepted treatment for DILI, especially after paracetamol overdose. Owing to its antioxidant and anti-inflammatory actions, NAC has been successfully used to treat chronic liver injuries, including hepatosteatosis and fibrosis. Therefore, ursodeoxycholic acid, pirfenidone, S-adenosyl-L-methionine, and N-acetylcysteine could represent therapeutic strategies for the treatment of liver pathologies. Full article

Background: The issue of beta blocker poisoning has received little attention, despite the widespread use of these compounds in cardiac and neuropsychiatric care. Safety profiles differ, and some beta blockers appear in poisonings far beyond what their usage rates imply. This study characterizes beta blocker intoxication patterns in Belgium, focusing on propranolol, by integrating national prescription data, poisoning reports, and adverse drug reaction records. Methods: Belgian prescription data, poison centre reports, and European ADR databases were analysed to identify intoxication patterns and demographic or clinical characteristics associated with these events. Results: Poisoning data revealed propranolol as markedly overrepresented compared to prescription rates and was the primary beta blocker implicated in self-harm-related overdoses. These cases occurred mainly in women, younger individuals, and patients with psychiatric or cardiovascular comorbidities. Co-exposures with benzodiazepines, antidepressants, and other psychoactive agents were frequent, and propranolol was linked to more complex intoxication patterns than other beta blockers. Conclusions: Propranolol shows a distinct toxicological profile and is disproportionately involved in intoxications, especially in vulnerable groups and in combination with psychoactive drugs. These findings highlight the need for greater awareness, targeted prevention, and careful monitoring. Full article

Opioid-related iatrogenic harms, including opioid use disorder, overdose, and opioid-induced respiratory depression, constitute a major patient safety challenge. Although clinicians document key safety signals in unstructured clinical narratives, many of these indicators are not readily captured by conventional surveillance approaches that rely on structured administrative data. This clinically focused narrative review synthesizes 47 empirical studies published between 2009 and 2025 that applied artificial intelligence (AI) methods to identify opioid-related harms from clinical text and to address the resulting ascertainment gap. Across studies, administrative coding systems, including ICD-10, often under-ascertain opioid-related events, whereas text-based AI can identify additional cases and contextual details often documented primarily in narrative records, such as fluctuating mental status, suspected drug causality, and responses to naloxone. Methodologically, the literature has progressed from interpretable rule-based lexicons to machine learning and deep learning models and, more recently, to transformer-based approaches, including large language models (LLMs) for classification and schema-driven extraction. Rule-based systems established the feasibility of transparent surveillance and frequently recovered clinically documented cases missed by billing codes. Subsequent supervised and deep learning approaches expanded scalability and, in a smaller subset of studies, were integrated into electronic health record workflows with operational metrics reported. More recent transformer- and LLM-based studies emphasize richer extraction schemas and benchmark development, including characterization of overdose context and intentionality and identification of potential prodromal neurocognitive signals, although external validation, calibration, and prospective outcome evaluation remain inconsistently reported. Given that the evidence base is predominantly retrospective and that clinical workflow studies remain comparatively few, a pragmatic near-term clinical role is to provide detection-to-triage decision support rather than autonomous diagnosis, in which systems surface candidate cases with reviewable evidence for clinician adjudication. Future progress will require greater standardization of phenotype definitions, routine equity auditing and subgroup reporting, stronger external validation and calibration at operational thresholds, and a shift from retrospective discrimination metrics toward prospective assessments of the clinical workflow impact, clinical utility, and patient-centered outcomes. Full article

Background: Rapid Sequence Induction (RSI) is a widely used method for emergency airway management in critically ill and clinically unstable patients. Beyond the risks inherent to the procedure itself, RSI is almost exclusively performed in emergency settings where patients present with severe physiological derangement and a high risk of aspiration. In postmortem examinations, forensic toxicology results may be influenced by the patient’s clinical condition, the sampling site, the postmortem interval (PMI), and postmortem drug redistribution (PMR). This review aims to evaluate the existing literature regarding PMR of drugs commonly used during RSI. Methods: PubMed/MEDLINE, Embase and the Cochrane Library were searched for studies on PMR of drugs used in intravenous (IV) RSI (up to November 2025). Human and animal studies, patient populations comparable to critically ill individuals requiring RSI, and forensic case reports of exclusively IV drug administration were included. Studies on recreational use, overdose and non-IV administration were excluded. Results: Data on the PMR of IV-administered RSI drugs remain limited. Most available studies involve Intensive Care Unit (ICU) patients or individuals who underwent RSI in emergency settings. Fentanyl and midazolam appear to demonstrate notable PMR. Several factors influencing postmortem drug concentrations were identified. Although these findings are consistent with the existing literature, the small number of studies and the heterogeneity of data preclude definitive conclusions. Conclusions: Critical patient condition, including frailty due to advanced age, hemodynamic instability (particularly in ICU patients), hypoalbuminemia, body mass index (BMI), and injury and/or trauma, as well as the interval between IV drug administration and death, appear to affect postmortem concentrations of drugs used during RSI. The potential for PMR of certain agents, such as fentanyl and midazolam, adds further complexity. Given the scarcity of consolidated evidence and until further research provides more robust data, postmortem drug levels should not be interpreted as directly reflective of antemortem concentrations. Full article

The overdose mortality landscape has shifted from predominantly opioid exposures to a polysubstance epidemic increasingly driven by illicit fentanyl and fentanyl analogs combined with other centrally active agents. Among the co-intoxicants, veterinary α₂-adrenoceptor (α₂AR) agonists such as xylazine have emerged as clinically confounding adulterants. Recent reports from forensic toxicology, medical examiners, and border/interdiction agencies indicate that medetomidine, a veterinary sedative racemate with the highly selective α₂AR agonist enantiomer dexmedetomidine, is increasingly being detected together with fentanyl and its analogs in seized materials and postmortem assays. Prior reviews have covered these aspects. The current review synthesizes current evidence and clinical experience relevant to fentanyl + medetomidine co-exposure-induced respiratory depression—a primary cause of death. We focus on convergent µ-opioid receptor (MOR) and α₂AR signaling within key physiological substrates, including respiratory rhythm-generating networks, ascending arousal pathways, chemosensory reflex control of ventilation, and autonomic cardiovascular regulation, integrating mechanistic pharmacology, respiratory and cardiovascular toxicology, emergency-room treatment, and emerging public-health implications. Available evidence supports a model in which combined MOR and α₂AR activation produces additive-to-synergistic suppression of ventilation and consciousness, attenuation of hypoxic ventilatory drive and CO₂ responsiveness, with marked sympatholysis manifested as bradycardia and hypotension, all of which can persist beyond presumptive opioid reversal with a MOR antagonist. We discuss the implications for prehospital and emergency care. In sum, the increasing detection of medetomidine in the illicit fentanyl supply represents an emerging and potentially high-risk co-exposure pattern that may be only partially naloxone-responsive. Lastly, we highlight potential future pharmacologic countermeasures for polysubstance overdose, such as the BK-channel antagonist ENA-001, which may address naloxone-insensitive ventilatory suppression in opioid-dominant polysubstance overdose. Full article

Social factors profoundly shape the bereavement process for individuals who have lost someone to a drug-related death. In this study, we integrate qualitative (n = 19), quantitative (n = 5), and mixed-methods (n = 2) results from a large research project on drug-related bereavement and utilise Bronfenbrenner and Morris’s bioecological model as an analytical framework. The results of the project demonstrate that bereavement following a drug-related death is deeply rooted in social context, and they highlight that the process of grieving a drug-related death requires the navigation of complex personal, familial, and societal challenges. Sociocultural understandings of addiction and societal stigma must be addressed to create a more supportive environment for bereaved individuals. A more cohesive and responsive support system can be developed by understanding and acting at all levels of Bronfenbrenner and Morris’s model, encompassing individual competencies, organisational structures, broader social environments, and systemic policies. Focusing on a family and compassionate community approach, our research promotes an inclusive and empathetic societal response to these multifaceted losses. Furthermore, the importance of enhanced professional competencies, interdisciplinary collaboration, and the implementation of organisational change is emphasised in order to meet the needs of those affected by a drug-related death. Ultimately, social work can play a pivotal role in this context. Full article

Acetaminophen (APAP) overdose is a major global cause of drug-induced liver injury (DILI), and the rising incidence of APAP-induced hepatotoxicity has raised substantial concern in the medical community, highlighting an urgent need for effective therapeutic approaches. Coptidis Rhizoma alkaloids (CRAs) have shown hepatoprotective effects in multiple hepatic disease models. This study aimed to investigate the therapeutic efficacy and the underlying mechanisms of CRA in acetaminophen (APAP)-induced acute liver injury. After identifying 18 alkaloid components in CRA, we employed an integrated strategy of untargeted metabolomics and network pharmacological analysis to investigate the underlying mechanisms. The potential mechanisms were subsequently validated through histopathological examination and molecular biology assays. Our results showed that CRA exerted dose-dependent protection against APAP-induced liver injury in vitro and in vivo. This protective effect was mediated by enhanced hepatic glutathione (GSH) biosynthesis via increased intracellular cysteine (Cys) availability. In the mouse model, hepatic Cys and GSH levels were increased by 2.2-fold and 1.8-fold, respectively, relative to the model group, which consequently attenuated oxidative stress damage. Furthermore, CRA suppressed APAP-induced activation of ERK and NF-κB, reducing the phosphorylation levels by 39.2% and 38.0%, respectively. Accordingly, it also downregulated the subsequent expression of inflammatory mediators in the TNF signaling pathway. These findings provide crucial mechanistic insights into the hepatoprotective role of CRA against APAP-induced toxicity, establishing a valuable foundation for developing novel therapeutic or preventive strategies for APAP-induced liver injury. Full article

Background and Objectives: The relationship between psychiatric disorders and systemic inflammation remains incompletely understood. Increasing evidence suggests that inflammatory processes may play a role in the biological mechanisms underlying suicidal behavior. This study aimed to investigate the association between classical inflammatory markers and hemogram-derived inflammatory indices in patients who attempted suicide by oral drug overdose. Materials and Methods: This retrospective observational comparative study included 343 patients hospitalized following a suicide attempt by oral medication overdose and 421 age- and sex-matched healthy individuals. Serum C-reactive protein (CRP), albumin levels, complete blood count parameters, and derived inflammatory indices, including the CRP-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), systemic immune–inflammation index (SIII), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), were analyzed. Results: Patients with suicide attempts had significantly higher CRP, leukocyte, neutrophil, and monocyte levels compared to the comparison group. CAR, NLR, SIII, and MLR values were also significantly elevated, whereas PLR did not differ between groups. ROC analysis demonstrated that CAR showed the highest discriminative ability for suicide attempt, with high sensitivity and specificity. Conclusions: Hemogram-derived inflammatory indices, particularly CAR, were significantly associated with suicide attempts. These easily accessible and low-cost biomarkers may provide additional biological insight into suicide risk assessment. Further prospective studies are needed to confirm these findings. Full article

Background: Intranasal drug delivery is a preferred route for emergency administration of naloxone in opioid overdose due to its rapid onset of action and ease of use. However, limited knowledge exists on the delivery efficiency and safety of nasal sprays in neonates, particularly in life-threatening situations such as coma states where breathing is compromised. This study presents a physiology-based simulation of spray deposition and runoff loss in a 10-day-old infant nose model. Methods: Spray characteristics, including droplet size distribution, exiting velocity, and plume angle, were measured and implemented in ANSYS Fluent droplet tracking model. Naloxone film thickness was measured on ex vivo porcine nasal mucosa at varying angles and used in the Eulerian Wall-Film model. Simulations were conducted in a 10-day-old nose geometry across multiple doses (0.25, 0.50, 1.0, and 2.0 mL) in supine and 45° inclined postures to quantify regional deposition, liquid film translocation, and pharyngeal runoff. Results: While a 0.25 mL spray was fully retained in the nasal passages, higher doses exceeded the mucosal holding capacity and caused significant runoff. Runoff into the pharynx was 18.5% and 10.1% for the spray volume of 0.50 mL in the 45° back tilt and supine positions, respectively. The 1.0 mL spray caused 55.1% and 53.5% runoff in the 45° back tilt and supine positions, while the 2.0 mL spray caused 77.5% and 76.8% runoff in the 45° back tilt and supine positions, respectively. Conclusions: These findings highlight the critical influence of spray volume on drug delivery outcomes in neonates and provide quantitative guidance for optimizing intranasal naloxone administration in emergency pediatric care. Full article