Journal of pharmacological and toxicological methods最新文献

{"title":"Prediction of toxicity risk and symptom-specific adverse effects using MEA measurements of human iPSC-derived neurons","authors":"Yuto Ishibashi,&nbsp;Nami Nagafuku,&nbsp;Noda Bumpei,&nbsp;Ikuro Suzuki","doi":"10.1016/j.vascn.2026.108445","DOIUrl":"10.1016/j.vascn.2026.108445","url":null,"abstract":"<div><div>In vitro human iPSC-derived neuronal systems are an alternative platform for neurotoxicity testing to animal models and primary cultures. Microelectrode array (MEA), measurement system of the electrophysiological activity, are suitable to evaluate the neurotoxicity of compounds. We have previously reported the electrophysiological responses to known neurotoxicity compounds using MEA in human iPSC-derived neurons. However, the identification of analytical parameters to detecting toxicity of unknown compounds remains an important issue. In this study, we evaluated the toxicity risk of more than 100 compounds. We identify the analytical parameters enabling the separation of responses between neurotoxicity and negative control, and the separation the mechanism of action by using principal component analysis. By comparing the optimized analytical parameters of each testing compound with the standard deviation (SD) of negative control, we can predict general neurotoxicity in relatively quantitatively scale, for example, low risk for lower than SD range, medium risk for 2xSD, and high risk for over 2xSD. The neurotoxicity risk of compounds associated with adverse event reports was detected with a probability of 91.0%, demonstrating that this evaluation method enables highly sensitive and specific prediction of toxicological risks. Additionally, it was shown to specifically detect not only seizure-related risks but also adverse effects such as psychiatric symptoms and headaches. This predictability can help select appropriate concentration levels to avoid toxicity/ adverse effects.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108445"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling atrial fibrillation in vitro: A human iPSC-derived disease platform for therapeutic screening","authors":"Bettina Lickiss,&nbsp;Jan Hunker,&nbsp;Jamie R. Bhagwan,&nbsp;Duncan Borthwick,&nbsp;Steven D. Broadbent,&nbsp;Elena Dragicevic,&nbsp;Sonja Stoelzle-Feix,&nbsp;Peter Linder,&nbsp;Matthias Gossmann","doi":"10.1016/j.vascn.2026.108499","DOIUrl":"10.1016/j.vascn.2026.108499","url":null,"abstract":"<div><div>Atrial fibrillation (AF) is the most common form of cardiac arrhythmia, significantly impacting morbidity and mortality worldwide. Despite its clinical significance, current AF models often rely on animal systems that fail to fully recapitulate human-specific disease mechanisms, limiting their translational potential. This underscores the need for innovative human-based models to better understand AF pathophysiology and screen potential therapeutic agents effectively.</div><div>We developed a novel atrial fibrillation disease model screening assay using commercially available human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs, Axol Biosciences Ltd.). The assay is designed to assess AF-related functional changes in a human-relevant context, with extracellular field potential duration (FPD) as readout parameter. By inducing an AF-like phenotype in vitro, this model enables real-time evaluation of electrophysiological dynamics in human atrial cardiomyocytes, providing a 96well high-throughput platform for drug screening.</div><div>HiPSC-aCMs were pre-cultured in 96well plates for 9 days before electrical tachypacing was applied at 2.5 Hz with the CardioExcyte 96 system for 24 h. After induction of an AF phenotype showing EFP duration shortening, class III antiarrhythmic drugs dofetilide, sotalol and ibutilide were applied at concentrations ranging from 100 pM – 10 μM. Analysis of the cellular responses show a concentration-dependent prolongation of the FPD, reflecting known drug effects of prolonging the cardiac action potential, helping to restore a regular beat rate.</div><div>Our hiPSC-aCM based AF model presents a significant advancement for atrial fibrillation research, offering a physiologically relevant tool for investigating AF mechanisms and evaluating drug efficacy. With its focus on electrophysiology as a functional readout, this assay holds promise for identifying novel therapies with improved translational potential, accelerating the development of effective treatments for AF.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108499"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence of media on toxicity testing using human iPSC-derived cardiomyocytes in monoculture and co-culture models","authors":"Ravi Vaidyanathan,&nbsp;Rebecca Fiene,&nbsp;Michelle Curtis,&nbsp;David Majewski,&nbsp;Alfonso Tedeschi,&nbsp;Simon Hilcove,&nbsp;Blake Anson,&nbsp;Coby Carlson","doi":"10.1016/j.vascn.2026.108498","DOIUrl":"10.1016/j.vascn.2026.108498","url":null,"abstract":"<div><div>The FDA Modernization Act 2.0 underscores the urgent need for non-animal-based new approach methodologies (NAMs) for chemical safety assessment. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are emerging as critical tools in in vitro cardiotoxicity studies, with iPSC-derived cardiac fibroblasts and endothelial cells enabling the development of advanced co-culture and 3D cardiac models. However, serum-free, off-the-shelf media that support both acute and chronic toxicity testing across a broad pharmacological range remain scarce. To address this, we developed a suite of cell culture media and supplements, including iCell Cardiomyocytes Serum-Free Medium (iCSFM), iCell CardioTox Assay Medium (iCTAM), and the iCell Cardiac Co-Culture Supplements. These were specifically designed to maintain cardiomyocyte function, enable flexibility across assay platforms, and support reproducible toxicity testing in 2D (monoculture) and 3D (co-culture) formats. Cardiac function was assessed using multiple platforms: microelectrode array (MEA), voltage-sensitive dye (VSD), and calcium flux assays in 2D monoculture. For toxicity testing, standard viability endpoints were employed using iCSFM and iCTAM to evaluate compounds with known cardiotoxic effects. Seahorse XF (metabolism) and impedance assays (contractility) assessed metabolic and functional toxicity profiles. Compatibility with transduction methods (AAV, BacMam) and hypertrophy induction (ET-1) was also tested. Additionally, functional toxicity was further examined through 3D co-cultures incorporating iPSC-CM, cardiac fibroblasts, and endothelial cells. MEA results demonstrated consistent field potential durations (FPDs), with long-term culture in iCSFM showing slight FPD shortening, while enhancing assay reliability for albumin-binding compounds. A panel of hERG blockers (E-4031, dofetilide, ondansetron) showed dose-dependent effects on cardiac action potential morphology. Metabolic assays revealed decreased maximal respiration with cardiotoxic molecules, while cardiac contractility decreased significantly with chronic idarubicin exposure and increased contraction amplitudes with (<em>S</em>)-BayK-8644. The incorporation of 3D co-culture models showed improved biological relevance, capturing positive inotropic responses and immune response toxicology. These findings underscore the utility of human iPSC-CM for in vitro cardiac function and cardiotoxicity assessment. Our optimized serum-free media formulations enable robust performance in diverse assay platforms, offering a human-relevant approach for pharmacological and toxicological evaluations. These innovations align with regulatory goals to advance NAMs and reduce reliance on animal testing.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108498"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative early tolerability approach for safety assessment of drug candidates","authors":"Fatima-Zahra Khamlichi,&nbsp;Nicolas Pairet,&nbsp;Beatrice Kley,&nbsp;Cindy Janin Jung,&nbsp;Iris Erni,&nbsp;Michael Winter,&nbsp;Stefanie Bauer,&nbsp;Eric Martel,&nbsp;Georg Rast,&nbsp;Heike Schauerte","doi":"10.1016/j.vascn.2026.108451","DOIUrl":"10.1016/j.vascn.2026.108451","url":null,"abstract":"<div><div>During the development of potential new drugs, in-depth pharmacological safety examinations (ICH S7A guideline “core battery”) are crucial to assess potential side effects and the “therapeutic window” of novel test items. However, it remains a challenge to properly preselect the most promising candidate among several auspicious compounds in a project without proceeding with an in-depth profiling using several separated safety studies. Therefore, we aimed to develop and validate an early study combining various readouts assessing multiple organ function within the same study. This will allow data-driven identification of the best candidate not only based on efficacy but also on its safety and tolerability profile. Deprioritized candidates will be excluded from further profiling, enabling to reduce the amount of resources and the number of animals used in pre-clinical research.</div><div>To develop and validate an early tolerability study (ETS) that combines the assessment of multiple organ functions, using a reference compound (clonidine).</div><div>The developed method provides an overview of the effects induced by a compound in multiple organ functions. Repeated oral clonidine administration (SID, for 4 days, at 3 doses) to 24 male rats (4 groups, <em>n</em> = 6) was performed, followed by various physiological (body weight, heart rate, respiratory rate, body temperature, gastro-intestinal function), behavioral (consumption behavior, behavioral score, motor activity), and biochemical (blood and urine analysis) assessment.</div><div>Most of the physiological, behavioral and biochemical findings were consistent with the pharmacological profile of clonidine. We observed a dose-dependent decrease in heart rate and body temperature, as well as changes in behavioral scores, including a decrease in motor activity. We also observed signs consistent with effects on gastrointestinal function, in line with the effects reported for clonidine in rats, and biochemical changes in blood and urine.</div><div>The combined evaluation of multiple organ functions within the same study, on the same group of animals, as depicted here, provides an overview of the adverse effects induced by a compound. Therefore, it can be used early in the safety assessment process of drug development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108451"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Of men, not mice: Strategic implementation of human hearts donated for research in the UK for the mechanistic interrogation of living myocardial slices","authors":"Samuel C. Reitemeier,&nbsp;Danika Hayman,&nbsp;Parisa Keshtkar,&nbsp;Fani Koutentaki,&nbsp;Lorenza Koppers,&nbsp;Fatemeh Kermani,&nbsp;Cesare M. Terracciano","doi":"10.1016/j.vascn.2026.108516","DOIUrl":"10.1016/j.vascn.2026.108516","url":null,"abstract":"<div><div>Mechanistic discoveries mostly rely on animal research or bioengineered human models. However, these platforms often fail to recapitulate human physiology and disease. Here we report a novel approach using adult human hearts, available from the UK NHSBT, explanted exclusively for research and employed to prepare living myocardial slices (LMSs).</div><div>LMSs are ultrathin (300 μm) sections of living cardiac tissue that can be prepared using a vibratome; LMSs maintain the native structure of the heart and can be kept in culture for weeks/months under physiological electro-mechanical conditions. We assessed whether preparing LMSs from donor human hearts is a viable and practical alternative to other research platforms.</div><div>From July 2024 to July 2025, we received 203 donor human heart offers. We accepted and used 39 hearts (20 donated after circulatory death, 19 donated after brain death), an almost ten-fold increase compared with previous years. The donors were 62.5 +/− 14.9 years of age (Mean +/− SD). We only accepted hearts from donors without cardiovascular disease or current infections and were within 6 h transport time (transported in saline solution at 4 °C). LMSs were prepared as described by our group previously (Camelliti et al., 2011; Pitoulis et al., 2020; van der Geest et al., 2025; Watson et al., 2019, 2017).</div><div>We could prepare 30–50 LMSs from a 1 cm3 LV transmural biopsy. LMSs were viable and robust: (force transient amplitude at 2.2 μm sarcomere length: 8.8 +/− 7.2mN/mm2; passive force: 9.4 +/− 6.6mN/mm2 (<em>n</em> = 39)).</div><div>We also tested if it is possible to delay tissue utilisation, to facilitate high throughput, help with the arrival of tissue out-of-hours, and share it with other centres. There was no statistical difference in both force transient amplitude and passive force between fresh LMS and LMS from biopsies stored in cardioplegia for 5 h at 4 °C (active force fresh: 7.8 +/− 4.8mN/mm2; post-cardioplegia: 26.4+/-24mN/mm2; paired <em>t</em>-test: <em>p</em> = 0.272; passive force fresh: 6.1±1.34mN/mm2; cardioplegia: 13.5±5.4mN/mm2; <em>p</em> = 0.132, <em>n</em> = 3 hearts from 8 fresh and 11 post-cardioplegia LMSs).</div><div>Adult donor heart tissue is a viable source of LMSs and can lead to valuable research in mechanisms of disease and treatment, as a valid alternative to animal research or bioengineered models.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108516"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative assessment of contractility and electrophysiology drug-induced effects through human in silico simulations","authors":"Maxx Holmes,&nbsp;Hector Martinez-Navarro,&nbsp;Marcel Mohr,&nbsp;Jean-Marie Chambard,&nbsp;Ambroise Garry,&nbsp;Eva Vermersch,&nbsp;Veronique Ballet,&nbsp;Friedemann Schmidt,&nbsp;Blanca Rodriguez","doi":"10.1016/j.vascn.2026.108521","DOIUrl":"10.1016/j.vascn.2026.108521","url":null,"abstract":"<div><div>Assessing drug-induced changes in contractility and pro-arrhythmic risk is essential in pre-clinical safety pharmacology. While current methods for concurrent assessment of pro-arrhythmic and inotropic cardiotoxicity, like the Langendorff isolated rabbit heart model deliver key insights, they are resource-intensive, relatively low throughput and carry translatability challenges to human physiology. Human-based modelling and simulation may complement traditional methods by providing a cost-effective alternative through accurate, high-throughput drug screening to supplement or replace animal-based models. The objective is to quantitatively evaluate simulations using <em><em>in silico</em></em> human-based models to predict and explain contractility and pro-arrhythmic drug effects, benchmarked against <em>ex vivo</em> Langendorff rabbit data.</div><div>A virtual cohort of (<em>N</em> = 166) of human ventricular myocytes was calibrated to perform a fast, blind assessment of 37 compounds using <em>in vitro</em> IC50 data on the four key channels (hERG, Cav1.2, NaV1.5, Kv4.3). Human physiology was represented <em>in silico</em> by the human electromechanical model ToR-ORd-Land. Simulated active tension, calcium transient and action potential biomarkers were benchmarked against <em>ex vivo</em> rabbit experimental ventricular pressure and QT measurements, commonly used in preclinical assessment. Moreover, a comprehensive sensitivity analysis was performed to identify ionic mechanisms, in addition to the 4 channels, potentially driving drug-induced changes in contractility, and additional experiments and simulations were performed to evaluate their impact.</div><div>86% of compounds show agreement between <em>in silico</em> and <em><em>ex vivo</em></em> using the four-channel data. Simulations identified hNCX1 and late Nav1.5 current inhibition, as additional key mechanisms for contractility. Introducing their measurements increases qualitative agreement to 95% improving both inotropic and electrophysiology matches for several compounds. Close quantitative agreement across contractility and electrophysiology biomarkers (within 25% of <em>ex vivo</em> value) is observed for 76% of compounds. Disagreements correlated with uncertainty in IC50 measurements of hERG and Cav1.2, or in the case for Dobutamine, the need for gain-of-function CaV1.2 data.</div><div>In silico human-based simulations simultaneously predict and explain drug-induced contractile and electrophysiology effects with high accuracy. This approach offers a robust, cost-effective alternative to Langendorff rabbit studies, supporting reduction, refinement and replacement of animal models in pre-clinical safety pharmacology.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108521"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Jacketed telemetry with integrated ECG electrodes: A comparison with traditional implants in beagle dogs","authors":"Rafaat Fares,&nbsp;Anes Bendrimia,&nbsp;Delphine Bouard,&nbsp;Agathe Cambier,&nbsp;Clémence Nadjar,&nbsp;Léandro Fontana,&nbsp;Charles Eynard,&nbsp;Timothé Flenet,&nbsp;Pascal Champeroux","doi":"10.1016/j.vascn.2026.108469","DOIUrl":"10.1016/j.vascn.2026.108469","url":null,"abstract":"<div><div>Jacket telemetry technology enables the collection of both qualitative and quantitative ECG interval data in routine repeat-dose toxicology studies. The ICH M3(R2) guideline Q&amp;As emphasize that integrated safety pharmacology assessments should maintain a level of rigor comparable to stand-alone safety pharmacology studies. However, unlike implanted telemetry, jacket-based ECG electrodes are more prone to displacement or disconnection, especially in socially housed animals such as monkeys and dogs, which can compromise data quality.</div><div>To address these challenges, the Decro jacket—previously validated as a reliable platform for integrating safety pharmacology endpoints in dog toxicology studies—was completely redesigned and upgraded to include integrated 3D ECG electrodes embedded within the jacket. The new design features an adjustable, single-layer soft and stretchable jacket with integrated 3D ECG electrode patches, eliminating the need to shave or trim the animals' fur.</div><div>Our study aimed to evaluate the performance of this new system by comparing its signal quality to that of invasive telemetry in six group-housed Beagle dogs.</div><div>Dogs received vehicle control, quinidine (30 mg/kg), or ivabradine (2 mg/kg) orally according to a Latin square design. To ensure objective comparison, data from both systems were analyzed using a specialized software developed in RPL (RS/1 programming language). Ventricular repolarization was assessed with QT intervals corrected by the probabilistic method and the one-step QTc model. Drug effects on autonomic control were quantified using the High Frequency Autonomic Modulation (HFAM) model known to be highly sensitive to ECG quality signal. Beat-to-beat analysis was fully automated.</div><div>Across four 8-h recording sessions per dog, the jacket showed no damage or adverse interactions, indicating robust design and excellent animal acceptance. High-quality lead II ECG signals were consistently obtained despite intact hair. Mean predose heart rate, PQ, PR, QRS, and QT intervals showed no or minimal differences between jacketed and implanted telemetry. Pharmacological responses to quinidine and ivabradine were reliably detected by both systems, with identical results.</div><div>This upgraded jacket telemetry system overcomes traditional limitations by providing sensitive, high-quality ECG data with improved animal welfare, making it a valuable tool for safety pharmacology assessment in toxicology studies involving conscious dogs.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108469"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JTpeak, a valuable proarrhythmic risk biomarker in telemetered dogs to differentiate pure hERG from multi-ion channel blockers","authors":"Anne-Marie Betat,&nbsp;Eric Delpy,&nbsp;Annie Delaunois,&nbsp;Mathilde Loiseau,&nbsp;Céline Posseme,&nbsp;Anne Maurin,&nbsp;Christophe Drieu La Rochelle,&nbsp;Eric Martel,&nbsp;Jean-Pierre Valentin","doi":"10.1016/j.vascn.2026.108462","DOIUrl":"10.1016/j.vascn.2026.108462","url":null,"abstract":"<div><div>The JTpeak (JTp) interval has been proposed as a complementary, sensitive, and more specific biomarker than the QT interval for assessing proarrhythmic risk. It aims to improve the differentiation between drugs that selectively inhibit hERG channels (associated with high proarrhythmic risk) and those that affect multiple cardiac ion channels (associated with minimal or no risk).</div><div>As previously reported by Darpo et al. in human (<em>J. Clin. Pharmacol.</em>, 2019;60:125–139), the present study aimed to evaluate the effects of five QT-prolonging reference drugs, namely moxifloxacin, dofetilide, dolasetron, ondansetron and quinine, on JTp interval in telemetered conscious dogs (<em>n</em> = 7). PR and QRS intervals were also measured to reflect the effects on other cardiac ion channels. Levocetirizine, a QT-negative control drug, was included for comparison. Each compound was administered orally using a crossover design at two dose levels, with ECG monitoring conducted over a 24-h period post-dosing. Dedicated pharmacokinetic sessions were performed to determine corresponding plasma exposures, and sensitivity parameters were calculated for the new parameter JTp. JTp interval was individually corrected (JTpc) for heart rate variations.</div><div>Compared to vehicle, dofetilide (0.03 and 0.15 mg/kg), moxifloxacin (30 and 100 mg/kg), and ondansetron (10 and 30 mg/kg) produced dose-dependent increases in JTpc interval, consistent with predominant hERG channel blockade. In contrast, dolasetron (6 and 20 mg/kg) and quinine (20 mg/kg) did not affect the JTpc interval. Notably, dolasetron increased both QRS and PR intervals, reflecting its inhibitory effects on sodium and calcium currents. Quinine also showed a slight increase in QRS interval. As expected, levocetirizine (2 and 10 mg/kg) showed no effect on ECG intervals, at any dose or timepoint. Total plasma drug concentrations for each compound increased dose-proportionally.</div><div>In summary, this study demonstrated that drugs with selective hERG-blocking properties specifically prolong the JTp interval. In contrast, drugs with mixed ion channel-blocking activity tend to prolong other ECG intervals, but not the JTp interval. These findings support the relevance of JTp interval assessment as a valuable parameter to complement QT interval measurements in cardiovascular safety pharmacology studies, enhancing the specificity and sensitivity of proarrhythmic risk evaluation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108462"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148731191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining cardiovascular safety: A dual-pathway, mechanistic in silico screen for the detection of trafficking-mediated and “hidden” cardiotoxicity","authors":"Mustafa Al Yagoub","doi":"10.1016/j.vascn.2026.108561","DOIUrl":"10.1016/j.vascn.2026.108561","url":null,"abstract":"<div><h3>Background</h3><div>The Comprehensive in vitro Proarrhythmia Assay (CiPA) shifted cardiovascular safety assessment from binary hERG testing toward mechanistic multichannel integration. A key blind spot remains: many workflows treat ion-channel density (<em>G</em>_max) as static and therefore miss compounds that prolong QT by reducing hERG surface expression rather than by acute pore block.</div></div><div><h3>Methods</h3><div>We present <strong>Biosentry In Silico v1.0</strong>, a dual-pathway in silico screening framework that combines (i) acute multichannel pore block (Hill-based concentration–response) with (ii) a <strong>steady-state trafficking scalar</strong>, implemented as a closed-form equilibrium reduction in functional hERG density at the modeled exposure. Trafficking inputs are handled using explicit evidence states (parameterized, provisional, data-insufficient) within a multi-tier routing workflow; downstream AP outputs use a simplified screening <em>q</em>_Net proxy rather than a regulatory-standard CiPA integral.</div></div><div><h3>Results</h3><div>As a proof-of-concept, a mechanistic ten-compound set spanning balanced blockers, trafficking-dominant agents, and classical proarrhythmic exemplars showed internally consistent behavior: the framework detected strong trafficking-mediated “hidden” liability for Probucol and routed borderline Pentamidine to follow-up, while preserving low-risk labels for established balanced blockers under multichannel integration. On the evaluable CiPA reference subset (<em>n</em> = 21), dual-pathway labeling improved specificity for high-risk detection from 0.923 to 1.000 at fixed recall (0.500), driven by removal of one balanced-blocker false positive rather than increased sensitivity to CiPA High labels.</div></div><div><h3>Conclusions</h3><div>A steady-state trafficking scalar offers a practical proof-of-concept route to incorporate chronic hERG surface-density effects into CiPA-style screening without full protein-lifecycle kinetics. In the present benchmark, the empirical gain is false-positive reduction at unchanged recall; broader detection of trafficking-mediated High-risk labels remains limited by sparse IC_50,traf coverage. This framework is intended for research-stage preclinical screening and assay prioritization, not as a standalone clinical predictor.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108561"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hERG potency data in new drug applications submitted to the U.S. Food and Drug Administration between 2008 and 2024","authors":"Hiba Khalidi,&nbsp;Emily Jo,&nbsp;Mitra Abbasi,&nbsp;Joanne Mahmud,&nbsp;Zofia Bielecka,&nbsp;Christopher E. Pollard,&nbsp;Will S. Redfern","doi":"10.1016/j.vascn.2026.108458","DOIUrl":"10.1016/j.vascn.2026.108458","url":null,"abstract":"<div><div>Since the implementation of ICH S7B by the FDA in 2005, sponsors are required to test human pharmaceuticals at hERG before Phase 1 clinical trials. ICH S7B stipulated that, ‘Ascending concentrations should be tested until a concentration-response curve has been characterized or physicochemical effects become concentration-limiting.’ Thus subsequent New Drug Applications (NDAs) contained hERG potency data. By interrogating the Drugs@FDA database, we have investigated hERG potency in NDAs submitted 2008–2024 inclusive.</div><div>We developed an R-based text-mining pipeline to automate data extraction from machine-readable NDA documents in the Drugs@FDA database, using search terms related to hERG/IKr inhibition. The code screened ~11,000 NDAs and identified 1567 with potentially relevant content. After excluding 1000 non-relevant NDAs (e.g., ophthalmic, topical, diagnostic, and large-molecule drugs &gt;1000 Da), hERG data were expertly curated from the remaining 567 documents (corresponding to 288 drugs) and classified into one of three categories based on the data provided: <strong>(1)</strong> IC₅₀ value (160 drugs); <strong>(2)</strong> percent inhibition at specified concentration (65 drugs); <strong>(3)</strong> no observed block at specified concentration (63 drugs). For category 2 compounds, IC₅₀ values were estimated using the Hill equation (slope = 1) if inhibition was ≥25% (11 drugs); otherwise, compounds were assumed to exhibit no hERG block at the tested concentration (54 drugs). To enable us to use the compounds showing no hERG block, we calculated a ‘worst case’ IC₅₀ by multiplying the quoted test concentration by 100.</div><div>Using only IC₅₀ values from category 1 or those estimated from category 2, no clear temporal trend was apparent. Nor did one emerge by adding ‘worst case’ IC₅₀ values to the dataset. This was the case whether the data were assessed by year or by grouping the data into 2–4 year ‘bins’. No trends emerged when we split the dataset into oncology and non-oncology drugs. Clearly, this analysis is blind to efficacious free drug concentrations and therefore to safety margins. Also, it does not assess the possibility that there may be a trend in hERG potency in INDs that is not reflected in NDAs owing to drug failures in development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108458"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}