Journal of pharmacological and toxicological methods最新文献

{"title":"A novel hiPSC-derived neural co-culture assay for seizure liability testing with improved scalability and sensitivity","authors":"Hayato Miyoshi,&nbsp;Eriko Watanabe,&nbsp;Takumi Komikawa,&nbsp;Hirotaka Shirase,&nbsp;Yasushi Shiraishi","doi":"10.1016/j.vascn.2026.108441","DOIUrl":"10.1016/j.vascn.2026.108441","url":null,"abstract":"<div><div>Drug-induced seizures are severe adverse reactions that present significant challenges during drug development. Current methods for assessing seizure liability rely on animal models or in vivo electroencephalogram (EEG) telemetry. While sensitive, these methods have limitations, including low throughput, species-related differences, and ethical concerns, as they conflict with the 3Rs principle (Replacement, Reduction, and Refinement). To address these challenges, we developed a novel in vitro assay using co-cultures of human-induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes to evaluate seizurogenic risks in drug candidates.</div><div>In this study, hiPSC-derived glutamatergic neurons (iCell® Glutaneurons) and astrocytes (iCell® Astrocytes) were cultured and recorded with a multi-electrode array (MEA) system (Maestro Pro). Drug-induced seizure-like hyperactivity was detected by analyzing increases in network burst frequency after drug exposure. We validated the assay using 11 compounds with diverse mechanisms of action, including GABA receptor antagonists, dopamine D2 receptor antagonists, potassium channel blockers, muscarinic M2 receptor agonists, adenosine A1 receptor inhibitors, glutamate receptor antagonists, and negative controls. Results demonstrated high reproducibility across experimental setups and manufacturing batches and corresponded well with clinical findings and previously published data.</div><div>To enhance the throughput and sensitivity of this assay, two novel analytical methods have been developed, in addition to the implementation of 96-well format protocol. Spike Histogram Period (SHP) detection quantified network bursts across wide frequency ranges without the need for manual adjustments, while Irregular Spike Pattern analysis (IrSP) firing pattern analysis detected subtle changes in neural activity between network bursts caused by seizurogenic drugs such as 4-Aminopyridine and Pilocarpine.</div><div>In conclusion, this hiPSC-based MEA assay provides a scalable, sensitive, and ethically responsible approach for assessing seizurogenic risks in drug candidates. By reducing reliance on animal studies and minimizing late-stage seizure risks, it offers a robust tool for advancing safer drug development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108441"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730173","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":"High-resolution in vitro electrophysiological profiling of drug-induced cardiotoxicity using UHD-CMOS-MEA in human iPSC-derived cardiomyocytes","authors":"Naoki Matsuda,&nbsp;Nami Nagafuku,&nbsp;Bumpei Noda,&nbsp;Ikuro Suzuki","doi":"10.1016/j.vascn.2026.108493","DOIUrl":"10.1016/j.vascn.2026.108493","url":null,"abstract":"<div><div>Cardiotoxicity remains a critical hurdle in drug development, with drug-induced QT prolongation and Torsades de Pointes (TdP) frequently resulting in clinical trial termination or post-market withdrawal. Conventional safety assessments—primarily hERG inhibition assays and animal models—offer only a limited view of electrophysiological liability. While the ICH S7B guideline established a foundation for standardized QT risk evaluation, and the CiPA initiative expanded this framework through multi-ion channel, <em>in vitro</em>, and <em>in silico</em> methodologies, challenges persist. These include limited resolution of compound-specific mechanisms involving multiple ion channels, reduced sensitivity at low concentrations, and insufficient evaluation of chronic toxicity. To address these limitations, we developed a field potential imaging (FPI) platform using an ultra-high-density (UHD) CMOS microelectrode array (MEA) comprising 236,880 electrodes. This system enables simultaneous, high-resolution recording of extracellular field potentials from human iPSC-derived cardiomyocyte monolayers, with tens of electrodes capable of monitoring a single cell. This unique spatial resolution allowed us to define novel electrophysiological endpoints: the number and variability of excitation origins, conduction velocity, and propagation area. Using this platform, we profiled the responses of 13 pharmacological compounds across 17 electrophysiological parameters. Distinct mechanistic signatures were observed: isoproterenol (a β₁-adrenergic agonist) increased excitation origin count; mexiletine (a Na⁺ channel blocker) reduced conduction velocity; and E-4031 (a hERG inhibitor) decreased propagation area and induced early afterdepolarizations (EADs). Importantly, 0.1 μM doxorubicin—a chemotherapeutic agent known for chronic cardiotoxicity—induced significant reductions in propagation metrics within 24 h, underscoring the platform's capability to detect chronic toxicity at low doses. Multivariate analysis revealed clear clustering of compounds according to their electrophysiological profiles and mechanisms of action, even in compounds with multi-channel activity. Compared to conventional MEA systems, our UHD-CMOS-MEA platform demonstrated enhanced sensitivity and mechanistic resolution. The integration of novel, spatially resolved electrophysiological endpoints with advanced multivariate analysis defines a next-generation in vitro platform for cardiotoxicity screening. This approach improves sensitivity, supports mechanism-based classification, and enables early detection of both acute and chronic cardiotoxic effects—offering a valuable tool for regulatory toxicology and preclinical cardiac safety evaluation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108493"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730255","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":"Evaluation of mitochondrial toxicity and its application to cardiotoxicity assessment of anticancer drugs using human iPS cells-derived cardiomyocytes","authors":"Tomohiko Taniguchi,&nbsp;Takashi Yoshinaga","doi":"10.1016/j.vascn.2026.108497","DOIUrl":"10.1016/j.vascn.2026.108497","url":null,"abstract":"<div><div>Cardiotoxicity remains a critical concern in drug development, often leading to the discontinuation of promising compounds. While current nonclinical cardiac models allow for the prediction of arrhythmogenic risks, detecting cardiac toxicity including heart failure remains challenging. This issue is particularly pronounced in cancer drugs, where cardiotoxic side effects can significantly impact patient prognosis. Therefore, establishing reliable screening methods for cardiotoxicity at early stages of drug discovery is an urgent need. Given the central role of mitochondria in cardiac energy metabolism, this study investigates mitochondrial dysfunction as a potential indicator of cardiotoxicity. We evaluated the acute effects of several drugs known to induce mitochondrial dysfunction—tamoxifen, amiodarone, flutamide, ketoconazole, nefazodone, and rosiglitazone—on mitochondrial respiration in human iPS cells-derived cardiomyocytes. Oxygen consumption rate (OCR) was used as a quantitative marker of mitochondrial function. Additionally, the long-term exposure effects of anticancer drugs doxorubicin and bortezomib on mitochondrial function were assessed. Acute exposure to tested compounds caused a significant decrease in OCR, indicating impaired mitochondrial function. Doxorubicin and bortezomib suppressed OCR after long-term exposure, and the concentrations at which suppression was observed were equivalent to those reported to decrease cardiac contractility. Mitochondrial dysfunction, as reflected by reduced oxygen consumption, is closely linked to impaired cardiac contractility and the development of heart failure. Our results suggest that OCR-based assays can serve as a valuable tool for early cardiotoxicity screening, particularly for high-risk drug classes such as anticancer agents. Incorporating mitochondrial function assessment into nonclinical safety pharmacology may enhance the predictive power of current evaluation systems.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108497"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730258","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":"Industry perspectives on evolving off-target assessment: Insights from a multicompany IQ DruSafe survey","authors":"Scott Mittelstadt,&nbsp;Berengere Dumotier,&nbsp;Armando Lagrutta,&nbsp;Carrie Larner,&nbsp;Andrew Olaharski,&nbsp;Vicencia Toledo Sales,&nbsp;Friedemann Schmidt,&nbsp;Jean-Pierre Valentin,&nbsp;Doris Zane","doi":"10.1016/j.vascn.2026.108457","DOIUrl":"10.1016/j.vascn.2026.108457","url":null,"abstract":"<div><div>Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become a well-established process and an essential stage in the characterization and development of novel pharmaceuticals. This screening helps ensure candidate molecules possess an acceptable safety profile by detecting interactions with unwanted targets. A recent publication reported that about one-third of the companies surveyed apply a core test of secondary pharmacology targets during drug lead optimization and over 90% of the companies conduct a core <em>in vitro</em> panel before drug candidate selection (Brennan et al., 2024; Schmidt et al., 2025). The paper also highlights that most organizations utilize panels exhibiting a high degree of overlap in the targets assessed, indicating that industry standards for secondary pharmacology screening are becoming increasingly harmonized. Review of data and literature by the IQ DruSafe Secondary Pharmacology Working Group helped to identify 33 additional targets for inclusion in secondary pharmacology profiling, reflecting the industry's drive towards a more comprehensive characterization of off-target risks. With general consensus forming around the composition of a core <em>in vitro</em> screening panel, an industry survey was conducted to identify opportunities to further expand the impact of off-target assessments of new molecules. Sixteen companies responded to a broad range of questions which sought opinions on the potential integration of advanced computational capabilities, improving the evaluation for new or novel drug modalities, and adoption of new technologies for the assessment of off-target toxicology. The survey concluded that the greatest unmet need was an improved understanding of off-target assessments of protein degraders. Additionally, it recommended that panels for specific adverse effects such as convulsions, abuse liability, and neuropathy would be useful. Furthermore, the survey concluded that an industry-wide assessment of <em>in silico</em> capabilities and computational tools would be useful. Lastly, the group acknowledged that a broader discussion to harmonize the way secondary pharmacology results are submitted to regulatory agencies is necessary and beneficial. The effort could reveal innovative approaches that help streamline secondary pharmacology profiling and further strengthen the overall efficiency of drug discovery and development processes.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108457"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730521","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":"A novel method for individual animal correction of the QT interval in the presence of confounding heart rate changes","authors":"Siddhartha Bhatt,&nbsp;Michelina Pinto,&nbsp;Peter Harris,&nbsp;Todd Wisialowski","doi":"10.1016/j.vascn.2026.108471","DOIUrl":"10.1016/j.vascn.2026.108471","url":null,"abstract":"<div><div>The ICH E14/S7B Q&amp;As emphasize importance of robust in vivo cardiovascular studies, in appropriate non-rodent (dog/NHP) species, to perform an integrated risk assessment. It is well established that the QT-interval is inversely correlated with heart rate (HR) and a reliable method is required to determine heart rate corrected QT-interval (QTc-interval) for accurate assessment of QT liability in nonclinical studies. The individual animal correction method using QT/HR relationship (slope) from each animal's vehicle or baseline data is the recommended best practice. However, this method may not perform adequately in the presence of large HR changes. We evaluated the performance of two different individual animal corrections 1) using vehicle slope (QTcVeh) and 2) using treatment specific slope (QTcT) for two compounds. Hydralazine, a direct vasodilator, was included as it caused a large HR increase but does not have a QT-liability (hERG negative). Dofetilide was included as it is a direct hERG blocker without confounding HR changes. Each compound was tested separately in standard crossover paradigm in dogs (<em>N</em> = 4) at doses of 0.1, 1 and 3 mg/kg (Hydralazine) or 0.01, 0.03 and 0.15 mg/kg (Dofetilide). QTcVeh was calculated using the 24-h QT/HR slope from the vehicle treatment. QTcT was calculated using the 24-h QT/HR slope from the treatment phase at each dose level. Hydralazine caused marked decreases in blood pressure (−6 to −39 mmHg) and increases in HR (+18 to +81 bpm), with significant decreases in QT (−13 to −29 msec) at ≥1 mg/kg. QTcVeh was also increased (+9 to +11 msec), whereas QTcT did not show any statistically significant increase demonstrating adequate correction. Dofetilide did not cause any change in HR but did exhibit dose dependent increases in QT (+12 to +27 msec) as well as both QTcVeh (+10 to +27 msec) and QTcT (+10 to +28 msec). These results show that individual animal correction using the ‘standard’ vehicle slope does not perform adequately in the presence of large magnitude HR increases. In such instances, an alternative approach (e.g. using treatment specific slope) should be considered to prevent a false positive for QTc prolongation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108471"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730671","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":"In vitro cell based assays to evaluate EP4 agonist liabilities observed in in vivo studies","authors":"Minxue Huang,&nbsp;Jinqing Li,&nbsp;Julia Li,&nbsp;Laura Armstrong,&nbsp;Paul Levesque","doi":"10.1016/j.vascn.2026.108482","DOIUrl":"10.1016/j.vascn.2026.108482","url":null,"abstract":"<div><div>Prostaglandin E receptor 4 (EP4) agonism promotes both epithelial cell wound healing and has net anti-inflammatory activity, both of which are believed to be critical for the long-term remission of Inflammatory bowel disease (IBD). However, cardiovascular (CV) liabilities, such as tachycardia and hyper/hypotension, and gastrointestinal (GI) liabilities, such as diarrhea, were observed in pre-clinical <em>in vivo</em> studies with EP4 agonists. Here, we will discuss our efforts to develop <em>in vitro</em> cell-based assays to evaluate these liabilities and facilitate program strategy decisions. FCDI Human IPSC-Cardiomyocytes (hIPSC-CMs) have minimal expression of EP4 compared to the human heart, so hIPSC-CMs were transfected with different doses of EP4 plasmid. A dose of 30 ng/well (96-well) generated sufficient EP4 expression without cytotoxicity assessed by cell impedance change. BMS EP4 agonists increased the beat rate and cAMP release in the medium of EP4-transfected hIPSC-CMs in a concentration-dependent manner 8 days after EP4 transfection. These data indicated direct, on-target effects in hIPSC-CMs to increase heart rate. To avoid on-target CV liabilities, a strategy of developing gut-restricted EP4 agonists for IBD with minimal systemic exposure was endorsed. In mouse and NHP telemetry studies, fully systemic EP4 agonists induced a mild, non-dose-dependent decrease in mean arterial blood pressure and increase in heart rate, with heart rate effects generally being more sensitive. Gut-restricted EP4 agonists were identified that had minimal effect on heart rate and blood pressure in mice except at high doses that yielded measurable systemic exposure. The diarrhea liability with EP4 agonists was not resolved with gut-restricted compounds so a short-circuit measurement assay using Ussing chambers and T84 cells (a colon carcinoma epithelial cell line) was developed to understand mechanism. PGE2 and EP4 agonists potently increased cAMP and induced chloride current at concentrations consistent with EP4 target potency when applied to apical membrane of T84 cells. Effects were blocked by EP4 antagonists. These effects demonstrated on-target Cl⁻ secretory diarrheagenic liabilities. <em>The</em> <em>In vitro</em> cardiomyocyte and gut epithelia cell-based assays were used for mechanistic evaluation of target-related tox liabilities and helped in driving strategic decision making.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108482"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730635","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":"Proteins abruptly change function and membrane channels switch between Q10 regions at critical temperatures – The pivotal role of water","authors":"Gerhard M. Artmann,&nbsp;Oliver H. Weiergräber,&nbsp;Samar Damiati,&nbsp;Ipek S. Firat,&nbsp;Aysegül Temiz Artmann","doi":"10.1016/j.vascn.2026.108489","DOIUrl":"10.1016/j.vascn.2026.108489","url":null,"abstract":"<div><div>The role of temperature in the investigation of biological processes, including the effect of pharmaceutical substances, is underestimated. In most experiments, we typically accept temperature accuracy of ±0.5 °C. Often we even lack precise knowledge of the temperature at the measuring point of a cell or membrane patch. However, we know that there are critical temperatures, T_C, at which cellular and protein functions suddenly change or membrane channels switch from one Q10 regime to another. Unfortunately so far we do not have sufficient scientific explanations about the molecular cause of such critical temperatures. However, it is absolutely vital if, for example, we carry out patch clamp measurements that are once below a critical temperature and once above it, because ±0.5 °C temperature accuracy was sufficient for us. We propose the Interfacial Water Quantum-transition model (IWQ model) as a novel paradigm explaining temperature-dependent structural and functional transitions (discontinuities) observed in proteins. The central postulate states that experimentally measured critical temperatures, T_C, are related to physical reference temperatures, T_W, defined by rotational quantum transitions of temporarily free water molecules in the protein-water interface. Applicability of this concept is demonstrated using transitions observed in disparate model systems, viz., hemoglobin, thermosensitive TRP channels or aquaporins. We propose in addition that the same mechanism underlies the definition of body temperatures in homeotherms, the temperature for humans being <em>T</em> = 36.32 °C. The conclusions of the effects reviewed are manifold. With our new understanding, we can explain how body temperatures in different homeothermic species have evolved. It is also clear that many of the cell membrane channels in humans switch their function at body temperature, most precisely at 36.32 °C. It appears clear to us, that this is also the case in other homeothermic species. These species have different body temperatures and, thus, critical switching temperatures that are higher or lower than those of humans. We need to establish whether the critical temperatures of our biological samples are species-specific. If we don't, we risk measuring the same channel in rat cells below their T_c and in humans above our T_c. This would lead to the wrong conclusions.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108489"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730650","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":"From mouse to cynomolgus monkeys toward human: Species differences in endothelial-dependent vasorelaxation in various isolated vascular beds","authors":"Lukas Roubenne,&nbsp;Laura Francese,&nbsp;Elodie Luche,&nbsp;Bruno Le grand,&nbsp;Eric Martel","doi":"10.1016/j.vascn.2026.108517","DOIUrl":"10.1016/j.vascn.2026.108517","url":null,"abstract":"<div><div>Beyond the targeted pharmacodynamic effects, compounds may also affect systemic blood pressure through changes in vascular tone. These effects can be influenced by action on the endothelium. For a better understanding of the mechanisms responsible for changes in blood pressure and enabling a translational interpretation, the <em><em>ex vivo</em></em> assessment of effects on the vascular tone and the endothelial function in isolated arteries of different non-human animal species and humans is of great help. The reactivity of arteries and the endothelium influence can be vascular beds and species dependent making translational interpretation challenging.</div><div>This study aimed to assess the endothelial-dependent responses to acetylcholine (ACH) across various vascular beds from different non-human animal species (rats, mice and monkeys) and healthy human donors.</div><div>Endothelial-dependent vasorelaxation in arteries of rats (Wistar: thoracic aorta, mesenteric), mice (CD1 IGS: thoracic aorta), monkeys (Cynomolgus: abdominal aorta, mesenteric, mammary and subcutaneous) and human (subcutaneous) were evaluated using isolated organ bath (for large arteries, more than 1 mm diameter) or wire myography (for small arteries, 200–400 μm diameter) according to the studied vascular bed. Precontracted (phenylephrine, 1 μM) vascular samples were treated with cumulative concentrations of ACH (1 nM to 10 μM) and key parameters of full concentration-effect relationship (EC50 and Emax) were measured.</div><div>In rats, vasodilation induced by ACH on mesenteric arteries were larger than in the abdominal aorta. Mice aorta were more sensitive to ACH in comparison to the rat aorta. In monkey, ACH-induced relaxation differed among the different vascular beds. The abdominal aorta displayed a slight relaxation and whereas large relaxation were seen in mammary, mesenteric and subcutaneous arteries. Human and monkey subcutaneous arteries exhibited similar ACH vasorelaxation. Overall, ACH-induced relaxation was greater in small than in large arteries, whatever the considered species.</div><div>This study provides preliminary evidence of the variability of endothelium-dependent vasorelaxant responses to ACH across various vascular beds and species which could be used to guide selection of the most relevant vascular bed and species for preclinical investigations. In addition, these results underline necessity of a proper experimental strategy to bridge between studies in non-human and human tissues and enable a translational interpretation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108517"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730717","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":"Enhancing safety and efficacy of pharmacological therapy in HFrEF through computational modelling of myocardial contractility","authors":"Eva Casoni,&nbsp;Francesc Carreras,&nbsp;Mariano Vázquez,&nbsp;Jazmin Aguado-Sierra","doi":"10.1016/j.vascn.2026.108520","DOIUrl":"10.1016/j.vascn.2026.108520","url":null,"abstract":"<div><div>Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and heterogeneous pathophysiology. Computational modelling offers a powerful tool to study cardiac dynamics and evaluate therapeutic strategies across various HF phenotypes. Selective cardiac myosin activators have shown the potential to improve contractility without increasing oxygen consumption or provoking arrhythmias. However, clinical benefits vary significantly among subgroups of patients with heart failure with reduced ejection fraction (HFrEF).</div><div>This study introduces a multiscale computational cardiac model capable of simulating electromechanical behavior in both healthy and failing hearts. The model is used to assess the efficacy and safety of pharmacological interventions under a range of hemodynamic and structural conditions, aiming to support individualized treatment strategies and identify patient subgroups likely to benefit from specific therapies.</div><div>An integrated biventricular hemo-electromechanical model was developed, combining a modified cellular model of myosin activation (incorporating drug-specific kinetics) with a 3D model of myocardial dynamics calibrated using experimental and clinical data. This multiscale framework enables the simulation of systolic duration, sarcomere-level active tension generation, and cardiac output across virtual patients with differing HF severity. Simulations include baseline and drug-modulated conditions, allowing the exploration of differential drug responses and potential adverse effects.</div><div>Initial results demonstrate the model's ability to replicate key features of cardiac performance across a spectrum of HF phenotypes. In simulations with myosin activators, the model predicts increased stroke volume and improved left ventricular ejection fraction (LVEF), particularly in cases of severe HF. Virtual population analysis supports the stratification of patients by treatment responsiveness and safety profile, aligning with observed clinical heterogeneity.</div><div>This computational platform provides a robust and flexible tool for studying cardiac function and pharmacological effects across patient-specific scenarios. It enables the prediction of individualized responses and safety risks, supporting more effective and safer drug selection and dosing strategies. With further validation, this model may aid translational research and guide clinical decision-making in HFrEF management.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108520"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730739","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":"Concentration-QTc modeling provides consistent high QTc sensitivity across species and study designs","authors":"Jaimini Patel,&nbsp;Rachael Hardman,&nbsp;Joyce Obeng,&nbsp;Karim Melliti","doi":"10.1016/j.vascn.2026.108460","DOIUrl":"10.1016/j.vascn.2026.108460","url":null,"abstract":"<div><div>To support an integrated risk assessment for QTc prolongation under the ICH E14/S7B Q&amp;As, the <em>in-vivo</em> QTc assay should follow best practice for demonstrating high drug exposure multiples and sufficient QTc detection sensitivity. Concentration-QTc (C-QTc) modeling can improve study power compared with a traditional by-time analysis and can be used to quantify drug concentration producing a 10 msec effect and any shift between human and pre-clinical species.</div><div>The objective was to compare by-time analysis and C-QTc modeling sensitivity in the 3 large animal species. ICH E14/S7B Q&amp;A compliant <em>in-vivo</em> QTc validation studies were performed with oral moxifloxacin using both a Latin square and an ascending dose design in dog (<em>n</em> = 4 for Latin square and <em>n</em> = 6 for ascending dose design), NHP (n = 4), and minipig (<em>n</em> = 8 for Latin square and <em>n</em> = 5 for ascending dose design). For each study, a separate full PK phase was included.</div><div>For Dog and NHP modeling, basic assumptions were met for the use of a linear mixed effect (LME) model. Least significant difference (LSD) values for LME modeling in dog and NHP for the Latin square design were 3.4–3.5 msec versus 10 msec for the by-time analysis. For the ascending design, LME LSD values were 2.5–2.6 msec for dog and 3.7–4.4 msec for NHP versus respective values of 5.4 msec and 6.6 msec for the by-time analysis. Human multiple of the moxifloxacin critical concentration for dog and NHP was respectively 1.8× and 1.5× for the Latin square and 2.2× and 2.3× for the ascending design. For minipig modeling, basic assumptions for LME were not met, notably due to the high dose effects and a curvilinear C-QTc relationship. An Emax model was used producing LSD values of 3–5 msec versus 10–11 msec for the by-time analysis, and human multiple of 0.5–0.7×. When the high dose was omitted to apply an LME model, LSD values for the Latin square design were 3.9–4.3 msec with a human multiple of 0.5×.</div><div>Moxifloxacin C-QTc modeling provides consistent LSD sensitivity of 3–5 msec for all 3 species and both study designs, meeting requirements for ICH E14/S7B Q&amp;As 5.1 and 6.1.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108460"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148731189","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}