The ageing population, which is often associated with polypharmacy, indicates the need for evolution within the healthcare professions. Future pharmacists must develop new skills and knowledge to meet these challenges, including during their university training. Deprescribing is an essential process for optimising drug intake and reducing the risks associated with polypharmacy, although the term remains little known in France. This study aims to assess the perceptions of pharmacy students regarding deprescribing, and to identify their training needs. A questionnaire based on an American study was distributed. Composed of seven sections, it covered knowledge, confidence, attitudes, the interprofessional role, the required resources, as well as preparedness for deprescribing and sociodemographic data. A total of 407 responses were analysed, along with the qualitative results of two open-ended questions, which were processed using thematic analysis. The results showed that, whereas 66.2% of students felt able to identify potentially inappropriate medicines (PIMs), only 29.6% expressed confidence in their ability to deprescribe these medications. While 97.5% recognised the value of deprescribing PIMs, 88.6% identified numerous obstacles to its implementation. These results highlight the need to adapt pharmacy student training to enhance their skills and confidence in this area.
Climate change poses a significant challenge for global health. The World Health Organization estimates 250 000 additional annual deaths between 2030 and 2050 due to global warming. The healthcare sector is a major contributor to greenhouse gas (GHG) emissions, accounting for approximately 4.4%-5.5% of a country's total carbon footprint, with medicines contributing 5%-10%. This scoping review provides an overview of existing literature on the climate impact of medicines in the hospital sector and identifies knowledge gaps. The review followed PRISMA-ScR guidelines, conducting a comprehensive literature search in PubMed and Embase. Peer-reviewed articles published in the last 20 years, reporting original data on GHG emissions from medicines in the hospital sector were included. Articles were categorized based on therapeutic area, enabling a structured mapping of current areas of evidence. Of the 2986 studies identified, 32 were included. Most focused on emissions from inhaled anaesthetic gases (n = 15), followed by inhaler therapies (n = 6), total healthcare systems (n = 4), ophthalmology (n = 3), surgical procedures (n = 2) and other areas (n = 2). The findings show that research on the climate impact of medicines in the hospital sector remains limited. Knowledge gaps persist across most therapeutic areas, highlighting the need for research to inform climate-friendly strategies and support decision-making.
Due to recently emerging concerns about the nonmedical use of tramadol in Denmark, we hypothesized increasing tramadol detections in medico-legal autopsy cases, with more nonprescribed use and fatal poisonings over time, particularly among young individuals. In 2013-2024, we detected tramadol in 205 decedents. Fourteen (7%) had age ≤ 25 years. Apparently, 82 (40%) had no prescription. Tramadol poisoning caused death in 60 (29%), including 4 (2%) with age ≤ 25. There were 12 accidental poisonings with tramadol alone (age (median [interquartile range]): 52 [46-55] years, tramadol concentration: 3.5 [1.8-5.2] mg/kg, number of detected drugs: 3 [2.5-9]), and 25 accidental poisonings with tramadol and other drugs (age: 43 [32-47] years, tramadol concentration: 0.78 [0.13-1.3] mg/kg, number of detected drugs: 7 [5-10]). Tramadol-positive decedents, decedents without prescription and tramadol poisonings peaked in 2017, with no subsequent increase. Conclusively, data from our area showed no consistent rise in tramadol-positive decedents, nonprescribed use or related poisonings. Accidental tramadol fatalities mostly occurred in middle-aged people and/or were associated with polydrug use. Young decedents were infrequent. However, serious consequences of nonmedical tramadol use other than death, which are not captured in medico-legal autopsy data, can occur. Therefore, preventive measures are still crucial to curb nonmedical tramadol use.
Chronic kidney disease (CKD) remains a significant global health burden despite recent advances in pharmacotherapy, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists. Renal fibrosis, a central pathological hallmark of CKD progression, is mediated by persistent inflammation and macrophage activation, wherein the kallikrein-kinin system-particularly kinin receptors-plays a critical role. Emerging evidence supports the therapeutic potential of dual kinin receptor antagonism, especially targeting B1R, though the precise molecular mechanisms remain incompletely understood, necessitating further investigation. To elucidate the role of kinin receptors in renal injury, male C57BL/6 mice were subjected to folic acid-induced nephropathy and treated with either the B1R antagonist R715 or the B2R antagonist HOE140. Treatments were administered pre- and postfolic acid injection. Renal function was evaluated via serum creatinine, blood urea nitrogen and urine analyses. Renal tissues underwent histopathological assessment and gene expression profiling to assess injury and fibrotic responses. B2R antagonism (HOE140) failed to attenuate acute tubular injury but ameliorated chronic damage by downregulating proinflammatory mediators and upregulating anti-inflammatory markers. In contrast, B1R blockade (R715) exacerbated acute kidney injury yet mitigated chronic fibrosis, improving renal function and reducing profibrotic gene expression. These findings delineate distinct, time-dependent roles of B1R and B2R in modulating macrophage polarization (M1/M2) and fibrogenesis, identifying potential targets for antifibrotic therapies.
Central nervous system tuberculosis (CNS-TB) represents a critical form of extrapulmonary tuberculosis, characterized by high mortality and morbidity. The infection of microglia by Mycobacterium tuberculosis (Mtb) is a crucial factor in the progression of CNS-TB. Ferroptosis plays a significant role in various neurological disorders. However, it remains unclear whether Mtb can induce ferroptosis in microglia and what mechanisms underlie this process. This study demonstrated that Mtb H37Rv infection can induce ferroptosis in microglia, which is characterized by the accumulation of ferrous ions, increased levels of lipid ROS, depletion of glutathione, enhanced lipid peroxidation and reduced expression of Slc7a11 and Gpx4. Additionally, Mtb infection upregulated Sp1 expression, and Sp1 knockdown led to a suppression of ferroptosis induced by Mtb. Mechanistically, we found that Sp1 enhanced the transcription of Mettl14. Subsequently, the N6-methyladenosine modification mediated by Mettl14 stabilized the mRNA of Acsl4, ultimately inducing ferroptosis. Mettl14 also was found to enhance the stability of Sp1 mRNA, establishing a positive regulatory feedback loop. Moreover, knockdown of Acsl4 attenuated Sp1- or Mettl14-mediated ferroptosis in Mtb-infected microglia. Overall, our findings establish a connection between Mtb infection and ferroptosis and delineate a novel mechanism through which H37Rv induces ferroptosis in microglia via the Sp1-Mettl14-Acsl4 axis, offering new insights into the pathogenesis of CNS-TB.
Metformin alleviates oxidized low-density lipoprotein (ox-LDL)-induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox-LDL-induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin-1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin-1 was shown to reverse metformin-mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1-mitophagy pathway, with Caveolin-1 serving as an essential modulator. This NR4A1-mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.
BACKGROUNDS/AIMS:This systematic review aimed to assess associations between genotypes and the risk of experiencing postoperative opioid-related adverse drug events (ORADEs). METHODS:Following PRISMA guidelines and registered with PROSPERO, we searched MEDLINE, Embase and CENTRAL for studies assessing genetic predictors of ORADEs within 24 h postoperatively. Eligible studies included English-written retrospective and prospective cohort studies as well as randomised trials. Risk of bias was assessed using the QUIPS tool. Data were extracted in duplicate, and relative risks with 95% confidence intervals were calculated. Meta-analyses were conducted when ≥ 2 studies assessed the same genetic predictor and ORADE relationship. RESULTS:Of the 119 523 citations, 27 studies (5279 patients) met inclusion criteria. All included studies ranked high risk of bias. Of the 28 investigated predictors, 17 significantly increased or decreased ORADE risk in individual studies. Of the 31 meta-analyses, only two demonstrated significant associations (p < 0.05; COMT rs4680 AA and nausea, and CYP2D6 IM and hyperhidrosis). CONCLUSION:While finding two significant associations, we would expect one to two significant associations at random given the 31 meta-analyses. Findings were limited by heterogeneity, few studies and small sample sizes. The current evidence does not suggest that genotypes should have a central place in the risk stratification of the occurrence of postoperative ORADEs.
OBJECTIVE:While current studies have focused on the incidence of moxifloxacin-associated liver injury, risk factors and clinical characteristics for moxifloxacin-induced liver injury in hospitalized patients remain unexplored. METHODS:We analysed antibiotic-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. A retrospective observational study was further conducted on 1265 hospitalized patients treated with moxifloxacin for infections. Independent risk factors for moxifloxacin-induced DILI were identified via multivariable logistic regression. RESULTS:FAERS data indicated that moxifloxacin-induced liver injury exacerbates clinical outcomes, prolongs hospitalization, and may be life-threatening. Infections were the primary indication for fluoroquinolone use, with gender-specific differences observed in liver injury profiles across quinolones. Retrospective analyses revealed gender as an independent protective factor (p = 0.003). Risk factors included hypoalbuminemia (p = 0.003), hepatic comorbidities (fatty liver, p = 0.013; pre-existing liver injury, p < 0.013), elevated baseline alkaline phosphatase (ALP, p < 0.001) and concomitant use of traditional Chinese medicine or respiratory drugs (p < 0.001). CONCLUSION:Despite widespread clinical use, moxifloxacin's safety profile requires systematic evaluation. Clinicians should monitor liver function and integrate risk stratification, including albumin levels, gender and concomitant medications into prescribing practices. Elucidating DILI mechanisms and high-risk populations may optimize therapeutic decision-making and patient safety.
To address challenges in deprescribing, we investigated the feasibility of an intervention consisting of a clinical medication review (CMR) focused on deprescribing, supported by a training programme for healthcare providers (HCPs) among older patients with hyperpolypharmacy (≥ 10 chronic medications) in primary care. A mixed-methods feasibility study was conducted in six Dutch community pharmacies using Bowen's framework. The intervention comprised HCP training and a five-step deprescribing-focused CMR. Within 6 Bowen domains, 18 outcomes were assessed through (patient) questionnaires, interviews (patients, HCPs), process parameters, and medication dispensing data. Five pharmacists conducted CMRs with 24 patients (median age: 84.5 years). The intervention was well accepted by patients and HCPs. However, barriers emerged regarding implementation and practicality. Consultations lacked complete discussion of patient concerns, and pharmacists reported varying levels of confidence in making deprescribing decisions. Time constraints limited the incorporation of deprescribing into CMRs. On average, 1.3 medications per patient were deprescribed. Within a setting of motivated and CMR-experienced HCPs, adding a focus on deprescribing to CMRs for older patients with hyperpolypharmacy was feasible and well received. Feasibility was supported by high acceptability and deprescribing potential, though barriers in implementation and practicality indicate the need for further evaluation in broader primary care settings.
Many patients report being allergic to opioids and/or have allergy warnings documented in their medical records. However, the reasoning behind these warnings is often unclear and frequently lacks clinical validation. Reported reactions may include skin rashes, itching, severe vomiting, fainting or respiratory arrest occurring during postoperative recovery where opioids were administered. In many cases, there is also uncertainty about which specific opioid was used. An allergy warning to one opioid further raises the question of whether the patient can tolerate other opioids. In this review, we address the exceedingly rare IgE-mediated opioid allergy and cross-reactivity between opioids, along with non-immune-mediated histamine release and other adverse effects of opioids that patients or clinicians may mistake for allergic reactions. We propose a simple risk stratification algorithm for the clinical management of patients labelled as opioid allergic-helping to distinguish who should be referred for allergy evaluation and who can safely be treated with opioids with or without antihistamine pre-treatment.
The accelerating integration of rare earth elements (REEs) in advanced technologies has generated rising concern over human exposure and the attendant toxicological risks. This review presents an up-to-date synthesis of current evidence on REE toxicity across multiple exposure pathways, including inhalation, ingestion and occupational contact, providing an integrative perspective from human clinical data, animal models and in vitro systems. Distinct from traditional reviews, it critically appraises how REE-specific mechanisms, such as oxidative stress, mitochondrial dysfunction and metal ion substitution, produce multiorgan effects with clinical manifestations distinct from those of conventional heavy metals. A key novel finding is the pronounced therapeutic gap. Although chelation is well established for many toxic metals, effective chelation therapy for REE remains largely undeveloped, with current agents like DTPA showing limited efficacy, particularly for gadolinium and cerium, underscoring a major gap in clinical practice. The review highlights vital implications for clinicians, stressing the importance of early exposure recognition, tailored supportive care and the urgent development and validation of REE-specific chelators. Priorities for future research include creating novel chelation strategies and harmonizing international guidance to protect exposed populations. This synthesis aims to equip health professionals, toxicologists and policy-makers with actionable insight, emphasizing the clinical and regulatory urgency of increasing REE exposure and toxicity.
Zhenwu Decoction (ZWD) is a classical formula that has been used for centuries and has the effect of warming yang and promoting diuresis. Clinical research is widely used in urinary, circulatory, nervous, digestive, respiratory and other diseases. ZWD has anti-inflammatory, anti-oxidative stress, anti-fibrosis, immune regulation and other effects. This article elaborates on the components and pharmacokinetics of ZWD, reviews its curative effect and pharmacological action in kidney disease, heart failure, Parkinson's disease and chronic colitis in detail, and summarizes the mechanism of some compounds of ZWD in improving kidney disease. This article provides a reference value for the development and clinical application prospects of ZWD.
Triclosan (TCS) is a widely used antimicrobial agent raising concern about its potential toxicity and adverse effects on fertility. This study investigated the protective efficacy of clomiphene citrate, conventional selenium, nanoselenium and Tribulus terrestris extract (TTE) against TCS-induced toxicity in male rats. Six experimental groups were established: control, TCS-exposed and TCS co-treated with each therapeutic agent. Semen quality; testicular and hepatic biochemical, oxidative and mitochondrial markers; hormone profiles; neurotransmitters; and histopathology were assessed. Specific reproductive (SOX9, inhibin B) and hepatic (Nrf2, NF-κB) markers were quantified to evaluate spermatogenesis, oxidative stress and inflammatory responses. In silico analyses, including molecular docking and molecular dynamics simulations, examined the interactions of TCS with CYP17A1 and GPX4 to elucidate potential mechanisms of enzyme inhibition. The results demonstrated that TCS exposure impaired reproductive and hepatic function, disrupted hormonal balance, induced oxidative stress and tissue damage. Treatments with selenium (conventional and nanoforms) and TTE significantly mitigated these alterations, restoring biochemical and hormonal parameters and improving tissue architecture. Among these, nanoselenium and TTE showed the most pronounced protective effects, emphasizing their comparative efficacy in counteracting TCS-induced toxicity. The findings highlight the potential of nanoselenium and TTE as promising protective agents against TCS-related reproductive and hepatic damage.
BACKGROUND:The involvement and sponsorship of pharmaceutical and medical technology (MedTech) companies in deprescribing and medication optimization activities raise questions about conflicts of interest. We surveyed registrants and attendees of previous International Conferences on Deprescribing to explore views on the acceptability and impact of such involvement and sponsorship. METHODS:We conducted two unlinked, anonymous cross-sectional surveys among all participants of the 2022 and 2024 International Conferences on Deprescribing (376 unique email addresses). The first survey addressed pharmaceutical companies; the second focused on MedTech. Quantitative data were analysed descriptively. Free-text responses were analysed thematically. FINDINGS:The response rate was 33% (n = 116/355) for the pharmaceutical survey and 20% (n = 68/335) for the MedTech survey. Trust in deprescribing information was low for pharmaceutical companies, with 52% reporting distrust (n = 47/91). Trust was somewhat higher for MedTech companies, with 27% expressing distrust (n = 14/52). Forty-eight percent (n = 42/87) said they would be less likely to attend an international deprescribing conference with pharmaceutical sponsorship versus 26% (n = 13/49) for MedTech. Among clinicians and clinician-scientists who completed the survey, 27% (n = 18/67) said pharmaceutical companies, and 27% (n = 10/37) said MedTech companies, somewhat or very much influence their deprescribing decisions. CONCLUSIONS:Despite broad scepticism about private-sector involvement and sponsorship of deprescribing activities, views varied.
Modafinil is approved for excessive daytime sleepiness in narcolepsy, obstructive sleep apnoea (OSA), and shift work sleep disorder (SWSD), but its widespread off-label use raises safety concerns. We evaluated the risk of adverse events (AEs) associated with both labelled and off-label use of modafinil. A systematic search of PubMed, Embase, and Cochrane identified 54 studies that met the inclusion criteria. In labelled uses, narcolepsy patients had significantly elevated risks of diarrhoea (risk ratio [RR]: 2.16, 95% confidence interval [CI]: 1.06-4.41) and nausea compared to those with placebo (RR: 2.44, 95% CI: 1.05-5.72). OSA/hypopnea syndrome patients had higher risks of insomnia (RR: 5.82), anxiety/nervousness (RR: 3.26), and headache (RR: 1.92). SWSD patients had elevated risks of insomnia (RR: 4.09), anxiety/nervousness (RR: 3.85), and nausea (RR: 2.93). Among off-label users, patients with attention deficit hyperactivity disorder had higher risks of insomnia (RR: 4.97) and decreased appetite (RR: 4.21). Patients with major depressive disorder showed higher risks of anxiety/nervousness (RR: 1.95). While modafinil users share common AEs, specific risks vary across patient groups. Our findings on condition-specific AE profiles would support cautious prescribing of modafinil and careful consideration of alternative treatments.
Pulmonary fibrosis (PF) is a chronic and progressive fibrotic disease with limited treatment options, which highlights the urgent need for novel therapeutic strategies. Fibroblast-to-myofibroblast transformation (FMT) and epithelial-mesenchymal transition (EMT) are central mechanisms driving fibrosis progression. This study investigated the therapeutic potential and mechanisms of 7,8-dihydroxyflavone (7,8-DHF), a selective tropomyosin receptor kinase B (TrkB) agonist, in experimental PF models in vitro and in vivo. Human lung fibroblast cells (MRC-5) and mouse lung epithelial cells (MLE-12) were stimulated with transforming growth factor-β1 (TGF-β1). 7,8-DHF suppressed the migration, proliferation and differentiation of TGF-β1-induced MRC-5 cells as well as reduced the protein levels of fibrotic markers including α-smooth muscle actin, connective tissue growth factor, collagen I and fibronectin. Moreover, 7,8-DHF attenuated the migration and EMT of TGF-β1-induced MLE-12 cells. Additionally, 7,8-DHF alleviated bleomycin-induced PF in mice. Mechanistically, 7,8-DHF inhibited the TGF-β1/Smad2/3 signalling pathway in both models. Notably, the anti-fibrotic effects were not reversed by the selective TrkB inhibitor ANA-12, suggesting TrkB-independent action. Instead, 7,8-DHF suppressed Akt activity in MRC-5 and MLE-12 cells. These findings demonstrate that 7,8-DHF alleviates PF by targeting FMT and EMT via TGF-β1/Smad2/3 signalling and Akt inhibition. These results highlight 7,8-DHF as a promising therapeutic candidate for PF.
This study aimed to evaluate the effectiveness of pharmacist-led medication reviews in reducing the anticholinergic burden of hospitalised patients with cardiovascular diseases (CVDs), to identify which anticholinergic medications were most frequently prescribed or discontinued during hospitalisation and to investigate factors associated with an elevated anticholinergic burden via secondary analysis of the INFAR study. An uncontrolled before-and-after design was used, and medication reviews were performed for all patients so that the anticholinergic burden of medications prescribed to older adults during their hospital stay could be examined. The mean age of the 319 patients was 68.9 years (±6.2), and upon hospital admission, 40.4% were classified as having a high anticholinergic burden, decreasing to 22.6% at discharge. Multivariate analysis at admission indicated that polypharmacy (PR = 2.00; 95% CI = 1.47-2.72) and potentially inappropriate medication (PR = 4.47; 95% CI = 2.10-9.53) were independently associated with a higher anticholinergic burden; however, only inappropriate medication was significantly associated with a high burden (PR = 2.39; 95% CI = 1.54-3.71) at discharge. The results indicate that a clinical pharmacist-led medication review may reduce the anticholinergic burden in older adults with CVD, highlighting the importance of such a review in promoting safer prescribing practices during hospitalisation.
