Journal of pharmacological and toxicological methods最新文献

{"title":"Comparison of calcium-sensing dye and multielectrode array methodologies for in vitro seizurogenic risk identification and mitigation","authors":"Catherine E. Garrison,&nbsp;Minxue Huang,&nbsp;Paul Levesque","doi":"10.1016/j.vascn.2026.108444","DOIUrl":"10.1016/j.vascn.2026.108444","url":null,"abstract":"<div><div>Identification and mitigation of seizurogenic risk in drug candidate compounds is of utmost importance in pharmaceutical science, as failure to do so can present serious health risks to patients and delay the development of critical medications. Historically, neurological risk assessment has necessitated the use of animal subjects, which are low-throughput, resource-intensive studies that typically come later during drug discovery. More recently, <em>in vitro</em> multielectrode array (MEA) assays have been developed that have been shown to accurately recapitulate and predict seizurogenicity through measures of network bursting, facilitating higher-throughput evaluation and reducing animal usage. However, these assays still require the use of large numbers of cells (&gt;100,000 cells per well) and specialized plates. The Hamamatsu Functional Drug Screening System (FDSS) uses a Ca²⁺-sensitive dye to detect intracellular calcium fluctuation, and can be used in a standard, 96-well format to detect calcium oscillations in electrically excitable cells, including neurons. In contrast with MEA, the FDSS calcium assay provides much less granular information on spiking activity; however, we show that network parameters that are important proxies of seizure activity are captured in the Ca²⁺ assay. Specifically, the FDSS system can be implemented for quantitative assessment of effects on network bursting in human-derived iPSC glutamatergic neurons. We show a strong correlation in network bursting parameters between traditional MEA approaches and the FDSS Ca²⁺-sensing method for multiple known seizurogenic compounds, including strychnine and picrotoxin, and internal program compounds. This FDSS-based method requires just 20,000 cells per well and can be used in a standard 96-well plate, increasing throughput while reducing the number of cells needed. Furthermore, we demonstrate that both traditional MEA and FDSS-based assays are highly sensitive to the amount of “spent” media present in the assay, with network burst frequency slowing as the amount of pre-conditioned media increases. We thus establish a highly sensitive, iPSC-derived neuronal assay for the assessment of seizurogenic risk for drug-like compounds, and demonstrate the sensitivity of the assay to both test compounds and assay conditions. We anticipate that these methods will enable higher-throughput assessment of neurological risk while also reducing animal usage in drug development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108444"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730678","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":"Modernizing ICH S7A: EFPIA, JPMA, and PhRMA industry perspectives on evolving safety and secondary pharmacology practices","authors":"Jean Pierre Valentin,&nbsp;Katsuyoshi Chiba,&nbsp;Derek J. Leishman,&nbsp;Emma Pawluk,&nbsp;Hugo M. Vargas,&nbsp;Takashi Yoshinaga","doi":"10.1016/j.vascn.2026.108488","DOIUrl":"10.1016/j.vascn.2026.108488","url":null,"abstract":"<div><div>The ICH S7A guideline on safety pharmacology has remained unchanged since its inception in 2000, fulfilling its crucial role in safeguarding clinical trial participants and patients. However, in the meanwhile there has been significant scientific and technological advancements in drug safety science, a paradigm shift in the drug discovery and development process, and a continuously evolving regulatory landscape, that led to the recommendation to revisit, adapt and evolve the ICH S7A guideline (Valentin &amp; Leishman, 2023, 2025). A revision of the guidance would imply opening an ICH process, the first step consists in the development of a ‘concept paper’. In that context, a survey has been developed to determine which elements, if any, of the ICH S7A guideline should be revised. Sixty-five (65) responses were obtained from industry representatives of companies affiliated to EFPIA, JPMA or PhRMA. Overall, there was a large support to revisit most of the pillars originally identified via a ‘revision’ or a ‘Q&amp;As’ ICH procedure. These include revisiting the ‘core battery’ assessment (58 to 68%), the adversity concept (77%), the modality agnosticism of the guideline (89%), the <em>in vitro</em> secondary pharmacology component (85%), the integrated risk assessment principles (75%), and the inclusion of safety pharmacology endpoints in general toxicology studies (72%). However, there were fewer than 50% positive responses to revisiting the timing of the studies with respect to drug development stages and the validation or qualification principles to be applied to novel assays and models (&lt;50% of positive responses). Notably, the majority of respondents viewed the ‘core battery’ studies as valuable, whereas ‘supplemental’ studies were less frequently seen as contributing additional value. Moreover, many indicated that they routinely perform safety pharmacology studies outside of these predefined categories—such as exploratory, mechanistic, or investigative studies. Overall, there was a large agreement between the responses from all territories. The survey results captured which elements of the ICH S7A guideline should be revised to help the development of a formal ICH concept paper.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108488"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730648","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":"Diurnal variations analysis of the cardiovascular parameters in cynomolgus monkeys of stand-alone safety pharmacology studies","authors":"Yangming Chen,&nbsp;Shanshan An,&nbsp;Rui Wu,&nbsp;Leo Pan","doi":"10.1016/j.vascn.2026.108481","DOIUrl":"10.1016/j.vascn.2026.108481","url":null,"abstract":"<div><div>Cynomolgus monkey (<em>Macaca fascicularis</em>) is one of standard non-rodent species for evaluating and determining the effects of test articles on the cardiovascular (CV) system in nonclinical safety pharmacology studies. Telemetry technology is considered the “gold standard” approach for monitoring CV parameters. With the frequent use of cynomolgus monkeys to monitor CV parameters using telemetry technology in stand-alone safety pharmacology studies, the objective of this study was to establish the in-house reference background data for this species and analyze diurnal variations in CV parameters by comparing daytime (07:00–19:00) and nighttime (19:00–07:00) measurements. In the stand-alone safety pharmacology studies, electrocardiograms (ECG), blood pressure and body temperature were recorded from at least 2 h prior each dose to approximately 24 h after dosing using DSI/Ponemah software. The data were collected from 106 cynomolgus monkeys that were previously instrumented with DSI L11-F4 transmitters via surgery. The study results indicated no apparent variations between daytime and nighttime values in systolic blood pressure (SBP, 113 vs. 107 mmHg), diastolic blood pressure (DBP, 78 vs. 74 mmHg), mean arterial pressure (MAP, 90 vs. 85 mmHg), pulse pressure (PP, 36 vs. 34 mmHg), or the PR (82 vs. 87 msec), QRS (35 vs. 36 msec), and RR-corrected QTc (248 vs. 253 msec) intervals. However, diurnal rhythm was observed in heart rate (HR, 159 vs. 125 bpm) and body temperature (BT, 38.1 vs. 37.2 °C), with HR fluctuations consequently influencing QT interval (213 vs. 250 msec) (Comparative approach: daytime values vs. nighttime values). Furthermore, the data comparison between this study and published literature revealed a favorable concordance. (Xiefan Fang, Stephen D. Tichenor, 2023).</div><div>In conclusion, the background data of CV parameters in this study can provide a valuable reference for the cardiovascular evaluation of vivo safety pharmacology studies in cynomolgus monkeys with telemetry technology.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108481"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730649","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":"Cardiotoxic effects of amoxicillin exposure in zebrafish embryos: Functional and molecular","authors":"Azza Naija,&nbsp;Huseyin Yalcin,&nbsp;Dalal Mohamed","doi":"10.1016/j.vascn.2026.108464","DOIUrl":"10.1016/j.vascn.2026.108464","url":null,"abstract":"<div><div>Amoxicillin (AMX), a widely prescribed β-lactam antibiotic, is frequently detected in aquatic ecosystems due to incomplete removal in wastewater treatment plants. While its therapeutic efficacy is well-established, its potential cardiotoxicity in non-target organisms remains underexplored. This study aimed to investigate the effects of AMX exposure on cardiovascular function and gene expression in zebrafish (<em>Danio rerio</em>) embryos—a well-established vertebrate model in toxicological studies.</div><div>Wild-type zebrafish embryos were exposed from 2 to 96 h post-fertilization (hpf) to environmentally relevant (11.99 μg/L), sewage-level (18.68 mg/L), and acute (100 mg/L) AMX concentrations. Mortality rate (MR), deformity rate (DR), body length (BL), and hatching rate (HR) were monitored, and cardiac function was assessed via blood flow (BF), lumen volume (LV), arterial pressure (AP), and pulse interval (PI) in the posterior cardinal vein (PCV) and dorsal aorta (DA). RT-qPCR was used to evaluate gene expression of markers associated with cardiogenesis (gata4, gata5, gata6, tbx5, tbx20), apoptosis (bcl2, casp9), and inflammation (il6).</div><div>Results indicated that AMX exposure accelerated hatching and induced mild but significant morphological deformities, including yolk sac edema and tail flexure. No significant changes were observed in BL. Notably, AMX at 18.68 and 100 mg/L significantly increased BF and LV in both PCV and DA, while AP and PI remained unaffected. Gene expression analysis revealed dose-dependent upregulation of gata4 and tbx5 at higher concentrations, while gata5 and gata6 were upregulated only at the lowest dose. Apoptosis-related genes (bcl2, casp9) and inflammatory marker il6 showed variable expression patterns, indicating a concentration-dependent modulation of cardiac and inflammatory pathways.</div><div>In conclusion, our findings suggest that AMX can exert cardiotoxic effects in zebrafish embryos at environmentally relevant and acute exposure levels. These effects include functional cardiovascular impairments and transcriptional changes in key developmental genes. The study highlights the importance of including cardiovascular endpoints in ecotoxicological assessments of pharmaceuticals and supports the use of zebrafish embryos in safety pharmacology as a predictive model for environmental and human health risks.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108464"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148731192","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 functional analysis-based strategy for early-stage drug safety evaluation","authors":"Zhiying Nie,&nbsp;Yanan Zhao,&nbsp;Cong Huang,&nbsp;Tiejun Bing,&nbsp;Qiang Xia","doi":"10.1016/j.vascn.2026.108459","DOIUrl":"10.1016/j.vascn.2026.108459","url":null,"abstract":"<div><div>Early assessment of candidate drug safety is critical in pharmaceutical development to mitigate post-market withdrawals and reduce potential risks. Approximately 75% of Adverse Drug Reactions (ADRs) are dose-dependent (Type A), often mediated by interactions with unintended off-target proteins. Traditional binding assays have limitations in predicting functional biological effects. To address this challenge, this study aims to investigate how an <em>in vitro</em> secondary pharmacology screening strategy, utilizing a functional assay format, can enable more accurate identification of potential safety liabilities early in drug discovery.</div><div>A high-throughput strategy integrating functional technologies (e.g., FLIPR, HTRF, ADP-Glo) was employed, combining single-point and multi-concentration dose-response screening. Automated instrumentation supported efficient profiling against a panel of 77 safety-related targets using pergolide and antidepressants.</div><div>The screening strategy effectively delineated compound-specific off-target risk profiles. Evaluation of representative antidepressants from different classes—amitriptyline (tricyclic), citalopram (SSRI), and bupropion (NDRI)—using the ICESTP SAFETYPANEL® 77 successfully quantified their off-target interaction risks. Amitriptyline exhibited potent off-target activity against 22 safety-related targets. Citalopram showed interactions with 6 off-targets, whereas bupropion demonstrated the cleanest profile, with activity limited solely to DAT, its intended primary target. These <em>in vitro</em> findings are highly consistent with the established clinical safety profiles of each compound. Furthermore, the functional format enabled discrimination of agonist types, detection of non-linear responses, and reduced false results. Physiological ATP (1 mM) improved predictive accuracy in kinase assays, and automation enhanced throughput.</div><div>This study confirms that a secondary pharmacology screening strategy employing a functional assay format, multi-concentration dose-response curves, and integrated automation provides more comprehensive and predictive data for drug safety assessment. This strategy facilitates the early identification and mitigation of potential safety risks mediated by off-target effects during compound optimization, thereby increasing the overall success rate and cost-effectiveness of new drug development and advancing the discovery of safer and more effective therapeutics.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108459"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730170","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":"Implementation of automated blood sampling in a canine cardiovascular safety pharmacology study to support PK/PD assessment","authors":"Elham Ataei Alizadeh,&nbsp;Georg Rast,&nbsp;Jessica Schiwon,&nbsp;Thomas Trautmann,&nbsp;Chris Cantow,&nbsp;Ferdinand Weinelt,&nbsp;Guido De Meyer,&nbsp;Pieter-Jan Guns,&nbsp;Brian Guth,&nbsp;Michael Markert","doi":"10.1016/j.vascn.2026.108477","DOIUrl":"10.1016/j.vascn.2026.108477","url":null,"abstract":"<div><div>Introduction: Pharmacokinetic (PK) and pharmacodynamic (PD) modeling can elucidate the temporal interplay between drug concentration and physiological effects. Its use in safety pharmacology studies has been hindered, since collecting an adequate number of blood samples from conscious animals poses challenges. This study introduces an automatic blood sampling system into a cardiovascular safety pharmacology study to enable the collection of frequent blood samples from conscious animals to allow for a PK/PD assessment. Method: For this investigation, we employed a telemetry-based approach to obtain cardiovascular data from 4 Beagle dogs. To assess the PK profile of the test compound, an automated blood sampling device was used to facilitate the collection of up to 20 blood samples at predefined time points over the 7-h study period. The cross- over study was conducted using conscious, freely-moving animals, with Moxifloxacin administered as the test compound. Results: Moxifloxacin administered orally in doses of 10 mg/kg, 30 mg/kg and 100 mg/kg reached Cmax of 6340 ± 1087, 15,840 ± 5471 and 29,033 ± 6540 nM, respectively, resulting in a QTc prolongation of 7 ms for 10 mg/ kg, 17 ms for 30 mg/kg and 35 ms for 100 mg/kg. Based on the PK/PD analysis, a 5 ms QTc prolongation occurs with a Moxifloxacin concentration of 6.2 μ M and a 10 ms QTc prolongation occurs with 12 μ M. The feasibility of integrating automated blood samples in a cardiovascular safety pharmacology study using conscious animals has been demonstrated, by collecting enough PK data to support a PK/PD evaluation. Conclusion: The implementation of the automatic blood sampling system provides a significant advancement in safety pharmacology studies, offering a potent instrument for supporting PK/PD modeling.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108477"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730675","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":"Assessment of locomotor activity in rodents using a newly developed automated locomotor activity system","authors":"Isam Sharif,&nbsp;Jessica Man,&nbsp;Stephen Jordan","doi":"10.1016/j.vascn.2026.108437","DOIUrl":"10.1016/j.vascn.2026.108437","url":null,"abstract":"<div><div>In neuropharmacology, safety pharmacology, and neurotoxicity research, evaluating spontaneous locomotor activity is essential for assessing the pharmacological properties and off-target effects of new drugs under development. The aim of this study was to biologically validate the Mobile Activity Rack System (VivaMARS™, Harvard Bioscience/DSI Data Science International™) by evaluating the changes in rats and mice spontaneous locomotor activity in response to amphetamine (neuro-stimulant) and chlorpromazine (neuro-depressant).</div><div>Groups of male CD-1 (ICR) mice and Sprague Dawley® rats (<em>n</em> = 10/group) were administered a single oral gavage dose of vehicle (0.9% <em>w</em>/<em>v</em> saline), amphetamine (10 mg/kg) or chlorpromazine (15 mg/kg). Animals were placed individually inside the VivaMARS system cages/racks to record spontaneous locomotor activity parameters (total ambulation count, distance travelled, total rears) for one-hour sessions; prior to dosing (approximately 24 h prior to dosing), between 45 and 105 min (approximate Tmax) and 23 to 24 h postdose.</div><div>A gradual reduction in the values of each locomotor activity parameter was recorded over the one hour of each recording session across treatment groups in both mice and rats. This was expected due to the anticipated habituation of animals to novel environments.</div><div>Oral administration of amphetamine at 10 mg/kg, resulted in a significant (<em>P</em> &lt; 0.05) increase in all recorded locomotor activity parameters between 45 and 105 min postdose values in both species, when compared to the matched vehicle control group.</div><div>Oral chlorpromazine administration at 15 mg/kg, resulted in a significant (<em>P</em> &lt; 0.05) decrease in all recorded locomotor activity parameters between 45 and 105 min postdose values in both species, when compared to the matched vehicle control group.</div><div>At 24 h postdose, the values of all locomotor parameters in the amphetamine and chlorpromazine treatment groups were comparable to those recorded in the time matched vehicle treatment group for each species. Overall, amphetamine and chlorpromazine produced similar profile effects in both rats and mice.</div><div>The study demonstrates that the VivaMARS™ mobile activity rack system is a sensitive platform for use in quantifying the acute locomotor activity testing in rodents as part of future drug discovery and safety assessments in-house.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108437"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730681","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":"Extending the role of hiPSC-derived cell models in toxicity risk prediction","authors":"Eunho Kim,&nbsp;Ami Kim,&nbsp;Jieun An,&nbsp;Bomi Kim,&nbsp;Subin Kim,&nbsp;Eueun Kim,&nbsp;Jong-Hwan Lee","doi":"10.1016/j.vascn.2026.108502","DOIUrl":"10.1016/j.vascn.2026.108502","url":null,"abstract":"<div><div>Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer powerful platforms for applications such as drug screening, disease modeling, and cell therapy development through its ability to faithfully replicate native behavior of human primary cardiomyocyte. In particular, they support cardiotoxicity risk assessment in alignment with regulatory frameworks such as ICH E14/S7B and HESI/CiPA, addressing key safety endpoints in drug discovery. In this study, 2D and 3D models were used to evaluate drug-induced cardiac responses in a wide variety of settings and conditions.</div><div>2D hiPSC-CMs were differentiated using proprietary protocols. 3D Engineered Heart Tissue (EHT) was generated through protocol provided by Curi Bio. Functional testing was performed using various platforms including Axion Maestro Pro, Nanion FLEXcyte96, and Curi Bio's Mantarray system. Compounds were prepared in recommended solutions, and corresponding negative controls were prepared accordingly.</div><div>Predictive modeling using hiPSC-CMs demonstrated robust stratification of 28 CiPA compounds into high/intermediate and low-risk categories based on FPDcF changes. Application of the FDA's predictive algorithm confirmed statistically significant discrimination between risk groups.</div><div>Cardiotoxicity assessment revealed that most induced ≥70% reduction in cell signal after chronic treatment of 12 diverse anticancer compounds. However, compounds such as Idarubicin (anthracyclines), Erlotinib (TKIs), and Cyclophosphamide (DNA crosslinkers) demonstrated minimal signal attenuation, suggesting class-specific and mechanistic variability in toxicity profiles.</div><div>In both 2D and 3D EHT models, doxorubicin elicited, concentration- and time-dependent reductions in key contractile parameters, including twitch force/amplitude, contraction velocity, and relaxation velocity. While the kinetics and magnitude of responses differed between models, both reliably captured drug-induced dysfunction.</div><div>Overall, our findings highlight the versatility and predictive power of hiPSC-derived cardiomyocyte platforms. Their scalability and physiological relevance support their adoption as key tools for preclinical cardiotoxicity assessment, offering refined alternatives to animal models in the early stages of drug development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108502"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730741","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":"Non-invasive assessment of electromechanical coupling in the study of cardiomyocytes","authors":"Julio Alvarez,&nbsp;Alice Godino,&nbsp;Carolina Scandellaria,&nbsp;Giulia Bruno,&nbsp;Michele Dipalo","doi":"10.1016/j.vascn.2026.108503","DOIUrl":"10.1016/j.vascn.2026.108503","url":null,"abstract":"<div><div>Quantitatively assessing cardiomyocyte contractility, in combination with electrophysiological measures, is crucial for understanding cardiac function, cardiovascular diseases, and pharmacological responses. Drug-induced cardiotoxicity remains a significant concern, contributing to nearly one-third of drug failures in late-stage development and causing approximately 10% of global drug withdrawals. Many compounds affect both ion channel activity and mechanical contraction, highlighting the need for integrated, non-invasive approaches to evaluate electromechanical behavior <em>in vitro</em>.</div><div>This poster presents an innovative approach based on the use of the IntraCell system, developed by Foresee Biosystems, to simultaneously monitor the mechanical contractility at a high frame rate (150 frames per second) and electrical activity of human iPSC-derived cardiomyocytes <em>in vitro</em> by integrating non-invasive optical and electrophysiological techniques. Contractility and displacement dynamics were quantified using Farneback's dense optical flow applied to high-resolution videos acquired through an integrated camera. In parallel, intracellular action potentials (APs) were recorded using a microelectrode array (MEA) system combined with laser-based optoporation technology, which preserves cell integrity and viability. A tailored trigger allowed precise synchronization of mechanical and electrical signals.</div><div>We compared control and dofetilide-treated cells, highlighting drug-induced AP prolongation and its effects on the electromechanical behavior of cardiomyocytes. Specifically, dofetilide treatment led to a slower repolarization phase and delayed relaxation, confirming the platform's ability to detect and correlate pharmacologically induced changes in both electrical and mechanical cardiac function. The system successfully recorded high-quality, intracellular-like action potentials using an entirely non-invasive technique, capturing hallmark features such as early afterdepolarizations (EADs) induced by dofetilide. Moreover, the proposed methodology enabled precise tracking of the time evolution of these signals across contraction-relaxation cycles in both control and treated cells, demonstrating its reliability for dynamic, long-term analysis.</div><div>In conclusion, this methodology enables both acute and long-term monitoring, offering significant potential for drug screening and evaluation of cardiotoxicity. The ability to correlate electrical and mechanical signals offers an innovative perspective on the electromechanical coupling of cardiomyocytes, thereby enhancing the understanding of their physiological and pathological dynamics and filling a critical gap in cardiac research.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108503"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730742","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":"Effect of temperature on human stem cell cardiomyocyte action potential parameters and impact on in vitro to clinical translation","authors":"Kristin L. Rockwell,&nbsp;Todd Wisialowski,&nbsp;Peter Kilfoil","doi":"10.1016/j.vascn.2026.108495","DOIUrl":"10.1016/j.vascn.2026.108495","url":null,"abstract":"<div><div>Previously published work established the correlation between hiPSC-CM APD90 to clinical concentrations of drugs associated with a + 10 ms change in QTc (Kilfoil et al., PMID 34678241). In this prior work, completed at 28 °C, the relationship (expressed in -Log [M] units) between free plasma exposure causing +10 ms QTc (X) and drug concentration causing threshold rate-corrected cAPD90 increase (Y) was described by the linear equation Y = 0.86× - 0.64 (Pearson r² = 0.762). Here, we investigated the effect of temperature on hiPSC-CM action potential parameters and impact on <em>in vitro</em> to clinical translation. 14 compounds were retested at 37 °C to investigate the impact of physiological temperature on this relationship.</div><div>1) Repolarization time (APD90 = 408 ± 20 vs 773 ± 69 ms, <em>p</em> &lt; 0.0001) and spontaneous beat rate (61 ± 5 vs 25 ± 3 beats per min, p &lt; 0.0001) were accelerated at 37 °C compared to 28 °C. When recorded at physiological temperature, these parameters are more physiologically relevant (APD90 200–400 ms, beat rate 50–70 per min). 2) Rate-corrected repolarization was also faster at 37 °C than at 28 °C (cAPD90 = 410 ± 21 vs. 512 ± 25 ms, <em>p</em> &lt; 0.001), reflecting the inability to correct for different heart rates and temperature conditions with one eq. 3) Finally, the cAPD90-QTc relationship at 37 °C is described by the equation Y = 0.98× −0.37 (Pearson r² = 0.8) which is greater than the relationship described by this same subset of compounds at 28 °C (Pearson r² = 0.74).</div><div>These results demonstrate that recording temperature has profound effects on the basal electrophysiological function of these cells, and that the correlation between drug effect on hiPSC-CM repolarization and clinical QTc outcome is enhanced at physiological temperature.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108495"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730743","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}