British Journal of Pharmacology最新文献

{"title":"Troriluzole attenuates opioid intake, reinforcing efficacy, seeking behaviours, physical dependence and antinociceptive tolerance in rats.","authors":"Ewa Galaj, Saadet Inan, Guo-Hua Bi, Sonita Wiah, George Adamson, Allen B Reitz, Zheng-Xiong Xi, Scott M Rawls","doi":"10.1111/bph.70206","DOIUrl":"https://doi.org/10.1111/bph.70206","url":null,"abstract":"<p><strong>Background and purpose: </strong>Riluzole, approved for amyotrophic lateral sclerosis (ALS), has a glutamate-modulating profile favourable for mitigating opioid addiction. It reduces neuronal glutamate release and enhances glutamate reuptake, offering advantages over agents that only increase glutamate reuptake. However, riluzole has pharmacokinetic liabilities that limit repurposing. To overcome these limitations, we designed and prepared the prodrug troriluzole (TRLZ), which retains the mechanistic profile of riluzole but with optimized metabolic and pharmacokinetic properties (e.g., higher oral bioavailability and less pharmacokinetic variability). As dysregulation of glutamate systems during opioid exposure contributes to adverse opioid effects, we tested the hypothesis that TRLZ would inhibit several opioid-derived adverse effects in rats.</p><p><strong>Experimental approach: </strong>In male Long-Evans and Sprague-Dawley rats, effects of TRLZ on oxycodone self-administration were investigated under fixed-ratio and progressive-ratio reinforcement schedules. Effects of TRLZ on food self-administration were also investigated. TRLZ effects on cue-induced reinstatement of oxycodone seeking, and on morphine-induced physical dependence, antinociceptive tolerance and respiratory depression were also investigated. TRLZ was administered intraperitoneally.</p><p><strong>Key results: </strong>TRLZ dose-dependently reduced oxycodone self-administration, reinforcing efficacy and cue-induced reinstatement of oxycodone seeking without affecting inactive lever responding. TRLZ, at high doses, also inhibited food self-administration. TRLZ reduced naloxone-precipitated withdrawal signs in morphine-dependent rats and antinociceptive tolerance during repeated morphine exposure. TRLZ also attenuated morphine-induced respiratory depression.</p><p><strong>Conclusions and implications: </strong>TRLZ, already in clinical trials for cerebellar ataxia, also reduced opioid taking and seeking as well as opioid-derived adverse effects in rats, supporting further study in treating opioid use disorders and pain management.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of prokineticin-2 as potential pharmacodynamic biomarker for overcoming doxorubicin resistance in multicellular breast cancer spheroids.","authors":"Martina Vincenzi, Amin Kremic, Nathalie N Tscheiller, Po-Yen Hsu, Michael W Y Chan, Roberta Lattanzi, Canan G Nebigil","doi":"10.1111/bph.70204","DOIUrl":"https://doi.org/10.1111/bph.70204","url":null,"abstract":"<p><strong>Background and purpose: </strong>Despite advances in immunotherapy, doxorubicin (Dox) chemotherapy is still the irreplaceable first-line therapy for solid tumours such as breast cancer. However, chemotherapy resistance is the major limiting factor, requiring the use of high doses of Dox to achieve the anti-tumour actions, often leading to severe side effects. Unravelling the mechanisms behind chemoresistance and identifying potential biomarkers for mitigating this resistance could enhance current treatment strategies and improve patient outcomes.</p><p><strong>Experimental approach: </strong>We developed human 3D breast cancer spheroids (HBCSs) as a model that closely mimics in vivo tumour structure and microenvironment. Given that hypoxia and elevated levels of the angiogenic cytokine, prokineticin-2 (PK2), are associated with chemoresistance to antiangiogenic therapy, we explored the effect of a hypoxia-inducible factor (HIF-1α) inhibitor on viability defect in HBCSs and the levels of PK2 in the conditioned medium following Dox treatment. We also assessed levels of HIF-1α, active caspase-3, TUNEL and reactive oxygen species (ROS), and CD73 enzymatic activity in HBCSs.</p><p><strong>Key results: </strong>Results showed that HIF-1α inhibitor increased viability defect in the Dox-resistant HBCSs. Interestingly, at higher Dox concentrations, chemoresistance was mitigated independently of HIF-1α and promoted apoptosis and ROS accumulation, which were correlated with PK2 release.</p><p><strong>Conclusions and implications: </strong>Our findings provide the first evidence that PK2 may serve as a predictive pharmacodynamic marker, offering a potential strategy to overcome drug resistance in targeted cancer therapy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnenolone sulfate enables synapse-specific metaplastic gating of heterosynaptic GABAergic plasticity.","authors":"Grzegorz Wiera, Jerzy W Mozrzymas","doi":"10.1111/bph.70194","DOIUrl":"https://doi.org/10.1111/bph.70194","url":null,"abstract":"<p><strong>Background and purpose: </strong>Neurosteroids are well recognized for their modulation of GABAergic signalling, yet their effects on specific inhibitory synapses and on long-term plasticity remain poorly understood. Herein, we investigated how neurosteroids influence synaptic transmission, as well as short- and long-term plasticity at identified excitatory and inhibitory synapses onto CA1 pyramidal neurons.</p><p><strong>Experimental approach: </strong>We combined whole-cell patch-clamp recordings with optogenetic stimulation of parvalbumin-positive and somatostatin-positive interneurons to characterize synaptic responses before and after the application of allopregnanolone or pregnenolone sulfate in slices from male mice.</p><p><strong>Key results: </strong>The two neurosteroids differentially affected inhibitory inputs depending on the presynaptic interneuron type. Specifically, allopregnanolone modulated synaptic responses in a way that is consistent with differences in neurotransmitter transients across studied synapses. In contrast, pregnenolone sulfate selectively altered the balance between excitatory and distinct inhibitory inputs to the same postsynaptic pyramidal neuron. Furthermore, we identified a novel physiological mechanism whereby high-frequency stimulation of excitatory synapses induces heterosynaptic plasticity at inhibitory inputs. This plasticity was expressed in a synapse-specific manner, selectively enhancing inhibition from somatostatin interneurons. Notably, exposure to pregnenolone sulfate revealed a previously hidden capacity for plasticity at parvalbumin synapses.</p><p><strong>Conclusion and implications: </strong>Our findings demonstrate that neurosteroids can selectively shape synaptic integration across distinct inhibitory circuits and metaplastically regulate excitatory-inhibitory co-plasticity in an input-specific manner. By uncovering synapse-specific and intersynaptic mechanisms of neurosteroid action, our study provides new insights into how inhibitory circuit dynamics are fine-tuned to support network stability and learning.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selatogrel: Potential to redefine timely anti-platelet intervention.","authors":"Rudy N Zalzal, Peter P Salem, Ali H Dakroub, Ali H Eid","doi":"10.1111/bph.70203","DOIUrl":"https://doi.org/10.1111/bph.70203","url":null,"abstract":"<p><p>Acute coronary syndrome (ACS) encompasses a number of heart diseases that cause a sudden decrease in coronary perfusion, precipitating cardiomyocyte necrosis or heightened risk thereof. This pathology is a major burden of cardiovascular disease. The etiopathogenesis and clinical manifestation of ACS are predominantly attributable to myocardial hypoperfusion consequent, to coronary vessel occlusion, typically resulting from atherosclerotic plaque rupture and subsequent thrombosis. Dual antiplatelet therapy (DAPT), comprising aspirin and a P2Y₁₂ receptor antagonist, has long been the mainstay of ACS management. Notwithstanding, limitations in the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of conventional DAPT agents persist. Selatogrel (ACT-246475), a novel P2Y₁₂ antagonist currently undergoing Phase III clinical trial, is poised to revolutionise ACS treatment. This highly selective and potent 2-phenylpyrimidine-4-carboxamide analogue is administered subcutaneously. As such, it affords immediate intervention in ACS patients. Importantly, selatogrel has a remarkably rapid onset of action and a favourable safety profile. These advantages render selatogrel a promising candidate for pre-hospital, self-administered ACS treatment, potentially optimising the reduction of total ischaemic time. Having successfully completed several Phase I and Phase II trials, selatogrel is currently undergoing Phase III evaluation to further elucidate its safety and efficacy. Subsequent investigations will serve to support or refine its therapeutic attributes.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol modulates trafficking of galanin receptor subtype 1 but not subtype 2: Insights from live-cell imaging.","authors":"Tianyi Li, Vladana Vukojević, Sho Oasa, Yunfei Bai, Yutao Yang, Hui Li, Yi Tang, Lars Terenius, Tomas Hökfelt, Per Svenningsson, Zhi-Qing David Xu","doi":"10.1111/bph.70192","DOIUrl":"https://doi.org/10.1111/bph.70192","url":null,"abstract":"<p><strong>Background and purpose: </strong>Galanin receptor subtype 1 (GALR1) and subtype 2 (GALR2) are G protein-coupled receptors (GPCRs) that mediate galanin's diverse physiological roles, including neurotransmission and neuronal modulation. Although both receptors share functional similarities, they exhibit distinct differences in signalling pathways. Whilst previous studies have focussed on galanin binding and G-protein selectivity, the role of plasma membrane-specific mechanisms, particularly cholesterol depletion's influence, remains unclear. This study investigates cholesterol's role in regulating trafficking of GALR1 and GALR2 and their function in live cells.</p><p><strong>Experimental approach: </strong>We employed real-time fluorescence techniques-Fluorescence Correlation Spectroscopy (FCS), Fluorescence Cross-Correlation Spectroscopy (FCCS), and Fluorescence Recovery After Photobleaching (FRAP)-to assess receptor-ligand interactions and lateral mobility in PC12 cells expressing EGFP-tagged GALR1 or GALR2.</p><p><strong>Key results: </strong>Both receptors were co-localised, co-trafficked and internalised with galanin, with receptor-peptide complexes dissociating prior to lysosomal degradation. Cholesterol selectively restricted GALR1's lateral diffusion and enhanced galanin binding and complex formation, whereas GALR2 remained unaffected. Interestingly, galanin binding relieved GALR1 from cholesterol-mediated restriction, increasing receptor mobility and suggesting a dynamic, cholesterol-dependent regulatory mechanism.</p><p><strong>Conclusions and implications: </strong>Cholesterol selectively modulates GALR1 trafficking and ligand interactions, whereas GALR2 operates independently of cholesterol, revealing distinct regulatory mechanisms for each receptor subtype. These findings provide new insights into the interplay between membrane composition and receptor function, with potential implications for developing targeted therapies for galanin-related disorders.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of high-intensity interval exercise on metformin pharmacokinetics in healthy men, assessed through a population pharmacokinetic model.","authors":"Stefanos Nikolaidis, Ioannis Kosmidis, Stylianos Papadopoulos, Artemis Lioupi, Marita Gandanidou, Helen Gika, Aristides Dokoumetzidis, Georgios Theodoridis, Vassilis Mougios","doi":"10.1111/bph.70208","DOIUrl":"https://doi.org/10.1111/bph.70208","url":null,"abstract":"<p><strong>Background and purpose: </strong>Metformin and exercise are first-line therapies for prediabetes and type 2 diabetes. However, it is unclear whether the combination of metformin and exercise is synergistic or antagonistic. The aim of this study was to investigate the effect of exercise on metformin pharmacokinetics and help clarify the contradictory outcomes regarding the combination of metformin and exercise.</p><p><strong>Experimental approach: </strong>Nine healthy men completed three 24-h sessions. In all sessions, participants received a single oral dose of 1000 mg metformin. In two of the sessions, they performed a high-intensity interval exercise test, 0.75 h (session A) or 4.65 h (session B), after metformin administration; they performed no exercise in the third session (reference). Venous blood samples were collected pre-dose and at 0.66, 1.4, 2.1, 2.5, 3, 3.5, 4, 4.5, 5.3, 6, 6.5, 7, 8, 10, 12 and 24 h after metformin administration. Non-compartmental pharmacokinetic analysis was performed, and a population pharmacokinetic (PopPK) model was constructed to detect covariates for explaining inter-individual and inter-occasion variability (IOV).</p><p><strong>Key results: </strong>Significant differences were found between sessions for all pharmacokinetic parameters except t_1/2. The PopPK model showed that exercise in session A reduced apparent volume of distribution (V/F) and apparent total plasma clearance (CL/F) by 31% and 25%, respectively; exercise in session B reduced CL/F by 17%.</p><p><strong>Conclusions and implications: </strong>Exercise affected metformin pharmacokinetics, leading to an increase in plasma metformin concentration and becoming a covariate that explains the IOV of metformin pharmacokinetics. Exercise should be performed during a specific time after metformin intake.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.","authors":"Jingyan Zhao, Bing Shang, Sha Xu, Danfeng Zheng, Xiaofang Zhang, Jiawen Lv, Yaqiong Dong, Xiaoda Yang","doi":"10.1111/bph.70191","DOIUrl":"https://doi.org/10.1111/bph.70191","url":null,"abstract":"<p><strong>Background and purpose: </strong>Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.</p><p><strong>Experimental approach: </strong>Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨ_m) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.</p><p><strong>Key results: </strong>Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.</p><p><strong>Conclusions and implications: </strong>Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative metabolomic and transcriptomic analysis of 2D and 3D mesenchymal stem cell cultures for improved therapeutic applications.","authors":"Manju Shrestha, Yun-Seo Kil, Yunju Jo, Simmyung Yook, Ki Hyun Kim, Dongryeol Ryu, Joo-Won Nam, Jee-Heon Jeong","doi":"10.1111/bph.70188","DOIUrl":"https://doi.org/10.1111/bph.70188","url":null,"abstract":"<p><strong>Background and purpose: </strong>Mesenchymal stem cells (MSCs) are used widely in regenerative medicine due to their multipotency and immunomodulatory properties. Compared to conventional two-dimensional (2D) monolayer cultures, three-dimensional (3D) spheroid cultures better mimic the in vivo microenvironment, influencing the metabolic activity and therapeutic efficacy of MSCs. This study aimed to evaluate how 2D and 3D culture conditions affect the behaviour, proliferation, and functional properties of MSCs.</p><p><strong>Experimental approach: </strong>Metabolomic and transcriptomic analyses were conducted on MSCs cultured under 2D and 3D conditions. To assess the metabolic differences, polar metabolites were extracted and analysed using ¹H-NMR spectroscopy. The data was processed with Chenomx and subjected to multivariate statistical analysis. For transcriptomic analysis, RNA sequencing was performed, followed by differential gene expression and gene set enrichment analysis.</p><p><strong>Key results: </strong>The findings reveal that MSCs in 3D spheroids exhibit reduced proliferation, enhanced stemness, and distinct metabolic adaptations, including increased glycolysis and altered nutrient metabolism. Additionally, genes associated with ribosome biogenesis and cell cycle progression were downregulated in 3D MSCs. These changes promote a more quiescent state, favouring its applications on tissue repair and immune modulation.</p><p><strong>Conclusions and implications: </strong>Understanding these metabolic adaptations offers valuable insights for optimising culture conditions, improving MSC-based therapies, and identifying novel therapeutic targets and biomarkers.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New biosensors and transgenic mice for multiplex cGMP imaging.","authors":"Markus Wolters, Martin Thunemann, Barbara Birk, Susanne Feil, Viacheslav O Nikolaev, Moritz Lehners, Robert Feil","doi":"10.1111/bph.70193","DOIUrl":"https://doi.org/10.1111/bph.70193","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cyclic guanosine monophosphate (cGMP) is a versatile second messenger that is important for human (patho-)physiology and pharmacotherapy. Live-cell imaging of cGMP with biosensors allows to elucidate its spatiotemporal dynamics in real time under close-to-native conditions. However, to monitor two separate cGMP pools or cGMP/cAMP crosstalk in the same cell, the respective biosensors must be spectrally compatible.</p><p><strong>Experimental approach: </strong>We describe two new Förster/fluorescence resonance energy transfer (FRET)-based cGMP indicators, membrane-targeted mcGi500 and red-shifted cytosolic red-cGi500, as well as two transgenic mouse lines for global and cell type-specific expression of mcGi500. The performance of the new biosensors was characterised in permeabilised and intact primary vascular smooth muscle cells and compared side-by-side with existing cGMP sensors.</p><p><strong>Key results: </strong>Both mcGi500 and red-cGi500 had a high selectivity for cGMP over cAMP and detected cGMP with about 3 times higher sensitivity than the current 'gold standard', cytosolic cGi500. Red-cGi500 allowed robust detection of cGMP in intact vascular smooth muscle cells. By combining red-cGi500 with the 'green' cAMP sensor Epac1-camps, cGMP and cAMP could be co-imaged in the same cells.</p><p><strong>Conclusions and implications: </strong>Together, our data suggest that red-cGi500 and mcGi500 as well as the mcGi500 transgenic mouse lines are useful tools for advanced cGMP imaging, including multiplex imaging of potential cGMP compartments and crosstalk between cGMP and other signalling molecules.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding fatal toxic effects in checkpoint inhibitor therapy using real-world pharmacovigilance data and machine learning.","authors":"Dongxue Yan, Beibei Lyu, Jie Yu, Siqi Bao, Zicheng Zhang, Meng Zhou, Jie Sun","doi":"10.1111/bph.70195","DOIUrl":"https://doi.org/10.1111/bph.70195","url":null,"abstract":"<p><strong>Background and purpose: </strong>Immune checkpoint inhibitors (ICIs) improve cancer outcomes but are also associated with immune-related adverse events (irAEs), which pose significant challenges for clinical management.</p><p><strong>Experimental approach: </strong>An observational pharmacovigilance analysis on FDA Adverse Event Reporting System was performed to identify ICI-related adverse event (AE) signals. Fatality kinetics simulation and multivariate logistic regression were used to investigate patterns of fatal AEs and multisignal involvement. A machine learning framework, SAFE-ICI, was developed to predict short-term risk and outcomes of fatal irAEs occurring within the first 90 days of ICI therapy.</p><p><strong>Key results: </strong>The analysis identified 358 significant AE signals associated with ICI therapies across 18 organ systems. PD-1/PD-L1 therapies were associated with 54 fatal irAEs, including 23 in non-small cell lung cancer (NSCLC), 5 in melanoma, 6 in renal cell carcinoma (RCC) and 20 in other cancers. Combination therapies were associated with 20 fatal irAEs, including 3 in NSCLC, 6 in melanoma, 7 in RCC and 4 in other cancers, with stable involvement of multiple AE signals. The SAFE-ICI model demonstrated robust performance in predicting fatal irAE risk, successfully stratifying patients into low- and high-risk phenotypes with significantly different survival benefits, in both the discovery and holdout validation cohorts.</p><p><strong>Conclusion and implications: </strong>Our findings highlight the potential of machine learning to improve pharmacovigilance systems and aid clinicians in enhancing patient outcomes during ICI therapy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}