Journal of pharmacological and toxicological methods最新文献

{"title":"Spatial regulation of CD14-like epitope in hematopoietic and ocular tissues of cultured North Atlantic lumpfish (Cyclopterus lumpus) and spotted wolffish (Anarhichas minor) during bacterial infection and temperature variations","authors":"Rebecca R. Kwabiah ,&nbsp;Lauren E. Murphy ,&nbsp;Hélène Paradis ,&nbsp;Rand Al-Badoosh ,&nbsp;Trung Cao ,&nbsp;Vimbai I. Machimbirike ,&nbsp;Hajarooba Gnanagobal ,&nbsp;Ignacio Vasquez ,&nbsp;Aqsa Maqsood ,&nbsp;Kenneth Kao ,&nbsp;Javier Santander ,&nbsp;Robert L. Gendron","doi":"10.1016/j.vascn.2025.108383","DOIUrl":"10.1016/j.vascn.2025.108383","url":null,"abstract":"<div><div>The development of new tools for a better understanding of innate immune mediated responses to tissue damage in emerging model organisms could offer novel approaches to inform toxicology, disease mitigation and/or drug discovery. Innate immunity is one of the first lines of defence in response to tissue damage, with macrophages being key players in these processes. The expression of macrophage protein markers in North Atlantic marine teleost fish has not been extensively studied. Here we used an anti-mammalian-CD14 antibody to explore CD14 epitope expression in hematopoietic and ocular tissues of lumpfish and spotted wolffish. Western blotting indicated that proteins reactive with an anti-mammalian-CD14 antibody with similar molecular weights to mammalian CD14 isoforms exist in both lumpfish and spotted wolffish. Immunohistochemistry (IHC) analysis using this anti-mammalian-CD14 indicated CD14-like reactive epitope expression in head kidney and ocular choroid rete mirabile in both normal healthy lumpfish and in a <em>Vibrio anguillarum</em> marine bacterial pathogenesis paradigm. As infection proceeded in lumpfish, CD14-like expression increased in head kidney and ocular choroid rete mirabile vasculature as revealed by IHC. In addition, we also used a temperature challenge paradigm in spotted wolffish to assess CD14-like reactivity in ocular choroid rete mirabile. A six-week hypothermal condition led to higher levels of CD14-like expression in the wolffish choroid rete mirabile than control temperature or a six-week hyperthermal condition as revealed by IHC. The tissue spatial regulation of CD14 epitope in lumpfish and spotted wolffish we observed herein might serve as a tool in emerging novel model organism-based technologies toward a better understanding of the mechanisms involved in responses to tissue damage.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108383"},"PeriodicalIF":1.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669183","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":"Improved translation of Nav1.5 channel inhibition to in vivo QRS interval prolongation via the hIPSC cardiomyocyte model","authors":"John P. Imredy ,&nbsp;Holly Clouse ,&nbsp;Mei Zhang ,&nbsp;Spencer Dech ,&nbsp;Qiuwei Xu ,&nbsp;Jeremy Ellis ,&nbsp;Shaun Gruver ,&nbsp;Julia C. Hotek ,&nbsp;Christopher P. Regan","doi":"10.1016/j.vascn.2025.108384","DOIUrl":"10.1016/j.vascn.2025.108384","url":null,"abstract":"<div><h3>Introduction</h3><div>Drug risk assessment to ventricular conduction typically involves measuring functional inhibition of the cardiac sodium channel (Na_v1.5) followed by nonclinical in vivo assessment of prolongation of the electrocardiographic QRS interval. The Na_v1.5 IC₅₀ concentration, however, underpredicts the threshold concentrations of in vivo QRS prolongation by 10–20-fold. We here develop and implement a novel human induced pluripotent stem cell derived cardiomyocyte (hIPSC-CM) field potential spike analysis paradigm that facilitates the use of this model for accurate forecasting of QRS prolongation concentration thresholds.</div></div><div><h3>Methods and results</h3><div>Using multi-electrode arrays we record the extracellular field potential spike of hIPSC-CM monolayers. Large variations in the field potential spike amplitudes across the array, however, confound translation of this parameter. To solve this shortcoming we derive a novel time parameter, T_A/Vmax, defined as the quotient of the amplitude (A) and the peak rate of change (V_max) of the of the cardiomyocyte field potential spike. T_A/Vmax normalizes effects on spike amplitude independent of Na_v1.5 inhibition, such as cell density, amplitude drift, and variable attachment of the monolayer to the field potential electrode. Small changes (&lt; 5 %) in T_A/Vmax become statistically significant and directly comparable to threshold QRS interval changes in early in vivo screening models. Characterization of a set of 12 compounds including Class I antiarrhythmics and internal test compounds demonstrates that the T_A/Vmax EC5% more consistently and accurately predicts both clinical and non-clinical QRS prolongation than the Na_v1.5 IC₅₀; accuracy of threshold concentration forecasting improved 16-fold and the correlation coefficient, R, increased from 0.76 to 0.88.</div></div><div><h3>Conclusion</h3><div>Calculation of T_A/Vmax enables use of the hIPSC-CM field potential spike to predict in vivo QRS prolongation. Use of this in vitro model in early screening or mechanistic evaluation of risk to ventricular conduction should facilitate a broader cardiac in vitro electrophysiologic assessment strategy for new molecular entities.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108384"},"PeriodicalIF":1.3,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644485","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":"Metabolomics using high-resolution magic angle spinning nuclear magnetic resonance: Neurotoxicological applications","authors":"Rachel Neita ,&nbsp;Kenna L.R. Hynes ,&nbsp;Grace V. Mercer ,&nbsp;Céline Schneider ,&nbsp;Lindsay S. Cahill","doi":"10.1016/j.vascn.2025.108382","DOIUrl":"10.1016/j.vascn.2025.108382","url":null,"abstract":"<div><div>High-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) is a cutting-edge technology for metabolomics studies that has found application in pharmacology and toxicology. Metabolomics provides insight into how biological systems function, providing a unique chemical fingerprint of the physiological state of an organism. Using the high signal sensitivity and spectral resolution of HRMAS NMR, metabolic screening of intact tissue samples can be performed for complex organs such as the brain. In this study, we present a detailed HRMAS NMR methodology including sample preparation and experimental conditions to ensure data repeatability and reproducibility. We present the results of a neurotoxicology study, involving exposure of adult mice to 50 ppm of a legacy perfluoroalkyl substance, perfluorooctanoic acid (PFOA), through their drinking water for one month (<em>n</em> = 8/group). The PFOA exposed group had a significant increase in the relative concentration of glutamate compared to controls (<em>p</em> &lt; 0.05), illustrating the potential for HRMAS NMR metabolomics to be used to determine the mode of action of neurotoxins and to provide an understanding of the molecular biochemical pathways impacted by toxicant exposure.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108382"},"PeriodicalIF":1.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144628359","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":"Thermal shift assays in drug discovery – Troubleshooting from biochemical to cellular applications","authors":"Danielle Hanke,&nbsp;Jennifer I. Brown,&nbsp;Brent D.G. Page","doi":"10.1016/j.vascn.2025.108380","DOIUrl":"10.1016/j.vascn.2025.108380","url":null,"abstract":"<div><div>Thermal shift assays (TSAs) have become valuable tools within drug discovery and development pipelines. These techniques detect direct physical interactions between small, drug-like molecules and their target proteins in biochemical and cellular settings. While there are several recent articles that outline TSA protocols and highlight their utility in drug discovery projects, this article aims to highlight common issues and solutions for challenges within cutting-edge TSAs. Herein, we have described three commonly used thermal stability assays, differential scanning fluorimetry (DSF), the protein thermal shift assay (PTSA) and the cellular thermal shift assay (CETSA), highlighting specific considerations for their use and implementation. We have also described frequently experienced challenges, including irregular melt curves, challenges with protein detection, and the impacts of buffer and test compounds on TSA performance. Overall, this troubleshooting guide serves to complement established methods and protocols to make TSAs more accessible and of greater use to the scientific community. We believe this will facilitate the use of thermal stability assays in biochemical (cell-free) and biological (cell-based) settings within drug discovery projects and support researchers seeking to develop the next-generation of therapeutic agents.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108380"},"PeriodicalIF":1.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568279","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":"Anticoagulant activity of Eucalyptus essential oils: An in vitro approach and a bioinformatics-based pharmacokinetic-pharmacodynamic analysis","authors":"Jhonatan Felipe dos Santos ,&nbsp;Maria Eduarda Dias Possate ,&nbsp;Maysa Barbosa de Almeida ,&nbsp;Eveline Maria de Melo ,&nbsp;Ricardo Andrade Furtado ,&nbsp;Lays da Silva Moreira Santos ,&nbsp;Isabela Cristina Gomes Honório ,&nbsp;Silvio de Almeida-Junior","doi":"10.1016/j.vascn.2025.108381","DOIUrl":"10.1016/j.vascn.2025.108381","url":null,"abstract":"<div><div>Coagulation disorders pose significant health risks, requiring effective therapies. Natural products emerge as promising anticoagulant agents, standing out in the search for innovative and safe alternatives, integrating <em>in vitro studies</em>, pharmacological analyses and bioinformatics for therapeutic advances. In this context, a study was conducted on the anticoagulant and toxicological activity of three essential oils of <em>Eucalyptus spp.</em>: <em>Eucalyptus citriodora</em>, <em>Eucalyptus globulus</em> and <em>Eucalyptus staigeriana</em>, commercially acquired. The chemical composition was analyzed by gas chromatography coupled to mass spectrometry. The anticoagulant activity was evaluated by <em>in vitro</em> assays of prothrombin time (PT) and activated partial thromboplastin time (aPTT) at concentrations of 0.19 % to 100 %, performed in triplicate. The mechanism of action was investigated by <em>in silico</em> analysis of activated Factor X, and the toxicological potential was evaluated with bioinformatics tools. The major compound identified was citronellal (57.77 %) in <em>E. citriodora</em> essential oil, eucalyptol (77.03 %) in <em>E. globulus</em> oil, and <span>d</span>-limonene (20.89 %) and geranial (10.54 %) in <em>E. staigeriana</em> oil. <em>E. globulus</em> showed greater anticoagulant efficacy, with prolongation of 256 % in aPTT and 147 % in PT, while the other oils showed prolongation of 117 % in PT. The pharmacokinetic parameters showed similarity with commercial anticoagulants, and the ΔG values in the <em>in-silico</em> model for activated Factor X were comparable to those of warfarin. The results confirm the anticoagulant potential of the three essential oils, especially <em>E. globulus</em> oil, which is more indicated for the prospection of new drugs.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108381"},"PeriodicalIF":1.3,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522950","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":"Standardizing high-throughput RNA extraction: Modifying commercial kits for improved purity, yield, and efficiency","authors":"Ruwini D. Rajapaksha,&nbsp;Catherine Brooks,&nbsp;Adriana Rascon,&nbsp;Adam Fadem,&nbsp;Ivy Nguyen,&nbsp;Philip J. Kuehl,&nbsp;John T. Farmer","doi":"10.1016/j.vascn.2025.108379","DOIUrl":"10.1016/j.vascn.2025.108379","url":null,"abstract":"<div><div>High-throughput extraction kits are widely use in clinical and preclinical settings to extract nucleic acids from biological samples due to their scalability, repeatability, and reduced labor. However, achieving high nucleic acid yield and purity while maintaining reliability and reproducibility remains challenging in molecular biology labs, partly due to lack of standardized guidelines for nucleic acid extractions and purification. Variations in extraction kits and extraction chemistries often lead to inconsistence results across experiments.</div><div>To address this variability, we modified manufacturers' extraction protocols by introducing additional chloroform and ethanol extraction steps. These modifications aimed to optimize RNA purity, yield, and extraction efficiency (EE) using Xeno Internal Positive Control (IPC) spiking as a benchmark. We evaluated the performance of three commercially available magnetic-bead-based RNA extraction kits across six naïve non-human primate (NHP) tissue types: brain, heart, kidney, liver, lung, and spleen, using the KingFisher™ Flex automated extraction platform.</div><div>The modified protocols demonstrated significant improvements in RNA purity, yield, and EE across the selected kits. These additional steps enhanced the suitability of extracted RNA for downstream applications, underscoring the importance of considering both kit performance and tissue characteristics in experimental design.</div><div>We further assessed the MagMAX™ <em>mir</em>Vana™ Total RNA Isolation Kit for its ability to remove interfering nucleic acids, such as plasmid DNA and single-stranded DNA (ssDNA), from adeno-associated viral (AAV) vector preparations. Specifically, we invesigated AAV serotype 8 (AAV8) due to its popularity in use for gene and cell therapies. The kit demonstrated high efficiency, removing ≥98 % of non-encapsidated genomes, plasmid DNA, and other impurities, yielding RNA suitable for downstream applications and removing contaminating DNA that would create a false-positive signal and result in over quantification.</div><div>These results emphasize the value of optimized, standardized protocols to improve reproducibility and reliability in RNA extraction workflows, with broad applications in molecular biology, gene therapy, and cell biology research.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108379"},"PeriodicalIF":1.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517504","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 cellular waste to biomarkers; insights into past, present, and future methods to detect immune cell-derived extracellular vesicles using flow cytometry","authors":"Jennifer L. Zagrodnik ,&nbsp;Craig S. Moore","doi":"10.1016/j.vascn.2025.108376","DOIUrl":"10.1016/j.vascn.2025.108376","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) often possess both ubiquitous and unique tetraspanin molecules that can help elucidate their cell-of-origin. Furthermore, the presence and/or absence of specific tetraspanins can be used to phenotype and identify specific subpopulations of EVs. In the context of immune-related disorders (<em>i.e.</em> multiple sclerosis, rheumatoid arthritis, and various cancers), specific immune cell-derived EVs are now being investigated in the context of biomarker exploration, identifying novel disease mechanisms, and monitoring therapeutic responses in patients. Flow cytometry (FCM) is a technique that uses the light scattering properties of cells and/or subcellular particles (<em>e.g.</em> EVs), while combining fluorescent signals that can detect the presence, absence, or abundance of surface and/or intracellular molecules. To date, however, using FCM to accurately quantify EV populations has been challenging due to their relatively small size and weak light scattering and fluorescence properties compared to intact cells. Historically, the application of calibration beads of known sizes, refractory indices, a violet-side scatter, and standardized methodologies have made positive contributions towards the accurate detection and quantification of EVs while also permitting exploration into their biological properties. This review provides a summary and perspective of current FCM methodologies that are used to assess immune cell-derived EVs within biological fluids and cell supernatants. While acknowledging past and current limitations, as well as the recent successes, improvements, and efficiencies of assays used in EV-related research, the field will inevitably continue to advance through the implementation of standards and guidelines to enhance discovery and reproducibility.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108376"},"PeriodicalIF":1.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522949","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":"Toxicology and safety pharmacology investigations on the nervous system: 2024 industry survey","authors":"Simon Authier ,&nbsp;Marcus S. Delatte ,&nbsp;Alison Wakeford ,&nbsp;Wendy Halpern ,&nbsp;Owen McMaster ,&nbsp;Dan Mellon ,&nbsp;Deepa B. Rao ,&nbsp;Martin Traebert ,&nbsp;Jean-Pierre Valentin ,&nbsp;Katie Sokolowski ,&nbsp;Michael K. Pugsley","doi":"10.1016/j.vascn.2025.108378","DOIUrl":"10.1016/j.vascn.2025.108378","url":null,"abstract":"<div><div>The American College of Toxicology (ACT), the Safety Pharmacology Society (SPS) and the Society for Toxicological Pathology (STP) conducted an industry survey in 2024 to assess current industry practices as they relate to neurotoxicity and safety testing of therapeutics. This survey was developed as a follow-up to 2015 survey conducted by the Safety Pharmacology Society (SPS) to identify industry practices as they relate to central, peripheral and autonomic nervous system (‘CNS’) drug safety testing. In the current survey, there were one hundred thirty (130) respondents from Asia (5 %), Europe (32 %) and North America (64 %). Most respondents (54 %) were from pharmaceutical companies of over 1000 employees. Small molecules (89 %), large molecules (73 %), gene therapy (52 %), cell therapy (41 %) and vaccines (38 %) were the types of modalities developed by respondents. Oncology (72 %) and neurology/psychiatry (64 %) were the most frequent therapeutic indications pursued by companies followed by inflammation (56 %), cardiovascular (48 %), rare/orphan (44 %), metabolic (42 %), infectious (35 %) and respiratory (28 %) diseases. Tremors (81 %), emesis (75 %) and salivation (61 %) were more frequently reported than in the 2015 CNS survey while gait/coordination abnormalities (67 %), convulsion (65 %), and peripheral neuropathy (24 %) were unchanged or decreased when compared to the 2015 survey. Most respondents reported using a modified Irwin's test (90 %) added to toxicology studies (80 %) and/or as a standalone study (71 %), a major change from the 2015 survey where most respondents reported using a standalone study. Survey results reflect an industry shift towards the development of new therapies classified as biologics, cell and gene therapies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108378"},"PeriodicalIF":1.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499980","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":"Current practices on the measurement of electrocardiogram and hemodynamic parameters in non–rodent species in regulatory safety assessment studies","authors":"Jean-Pierre Valentin ,&nbsp;Todd Bourcier ,&nbsp;Xuan Chi ,&nbsp;Annie Delaunois ,&nbsp;C. Michael Foley ,&nbsp;Kim A. Henderson ,&nbsp;Pierre Lainee ,&nbsp;Derek J. Leishman ,&nbsp;Dingzhou Li ,&nbsp;Emma Pawluk ,&nbsp;Michael K. Pugsley ,&nbsp;Sridharan Rajamani ,&nbsp;Christopher P. Regan ,&nbsp;Michael G. Rolf ,&nbsp;Rebecca Ross ,&nbsp;Eric I. Rossman ,&nbsp;Stephen D. Tichenor ,&nbsp;Inmaculada C. Villar ,&nbsp;Todd A. Wisialowski ,&nbsp;Jean Wu ,&nbsp;Hugo M. Vargas","doi":"10.1016/j.vascn.2025.107765","DOIUrl":"10.1016/j.vascn.2025.107765","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;Cardiovascular (CV) parameters&lt;sup&gt;1&lt;/sup&gt; such as blood pressure (BP), electrocardiogram (ECG), and heart rate (HR) are recorded in non-rodent non-clinical safety studies to support drug development. However, measurement quality varies depending on the methodology used, including restraint-based or telemetry (implanted or jacketed) techniques. Measurement quality, in this context, refers to the &lt;em&gt;sensitivity and reliability&lt;/em&gt; of CV measurements in affecting baseline values of measured CV parameters and in detecting pharmacological effects. This retrospective multifaceted analysis evaluated the impact of recording methods on baseline CV parameters and their statistical and pharmacological sensitivities in detecting drug-induced CV effects.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Data were collected from three sources: (i) 495 studies from seven pharmaceutical sponsors (2015–2023), (ii) FDA-approved drugs (47 NCEs, 26 NBEs from 2022 to 2023), and (iii) two major CROs (2020−2023). Studies were conducted in dogs, non-human primates (NHP), or minipigs, with treatment durations of up to 52 weeks. Additionally, literature-based and proprietary data were analyzed to assess baseline CV values and methodology sensitivity. A survey was conducted to evaluate statistical analysis practices in these studies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;All 3 datasets showed that the ECG is collected in most repeat dose toxicology studies, but not BP; the findings were largely independent on the modality (i.e., NCE versus NBE) or the indication (i.e., oncology vs. non-oncology). The choice and usage of ECG and BP methods is highly sponsor-dependent, with restraint-based methods for individual sponsors ranging from 0 to 100 %. FDA data showed that telemetry-based methods are predominantly used in short, single dose toxicology/safety pharmacology studies for NCEs. Subsequent studies of longer duration employ predominantly restraint-based snapshot methods. CRO data showed that approximately 30 % of toxicology studies do not include ECGs; however, when an ECG is recorded it is primarily collected in restrained animals using a snapshot approach. BP is infrequently recorded, regardless of methodology, in repeat dose toxicology studies. The de novo analysis and literature-based search showed that baseline BP/HR values were highly variable with consistently higher means under restraint compared to telemetry methods. The root mean square errors for BP/HR were larger under restrained conditions, in both species. Under restrained conditions, the use of fixed formulae for HR-corrected QT resulted in inconsistent QTc values across sponsor and CROs. The survey showed that statistical analysis of ECG/BP data was infrequently performed under restrained conditions in contrast to telemetry-based methods. Proprietary and published case studies showed that drug-induced BP elevation or QTc prolongation observed clinically and in NHP or dog using telemetry ","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107765"},"PeriodicalIF":1.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340716","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":"Characterization of a human wearable ECG device for continuous data collection in freely moving non-rodents","authors":"Christopher P. Regan,&nbsp;Alysia A. Chaves,&nbsp;Theodore Detwiler,&nbsp;Jude Ferraro,&nbsp;Shaun Gruver,&nbsp;Desiree Steve,&nbsp;David Lengel,&nbsp;Julia C. Hotek","doi":"10.1016/j.vascn.2025.108377","DOIUrl":"10.1016/j.vascn.2025.108377","url":null,"abstract":"<div><div>Wearable devices are commonly used in clinical diagnostic medicine/personal health, but their use to collect nonclinical endpoints is limited due species-specific design specifications, data accessibility limitations, and availability of nonclinical telemetry technologies. These create a challenge to adopt and deploy clinical innovation in nonclinical studies. To determine the feasibility of using a human ECG wearable device (WRB) in nonclinical studies, we compared heart rate and ECG intervals between the simultaneously collected ECG from the WRB and implanted telemetry (TEL) device in canine (<em>n</em> = 5) and non-human primate (NHP, <em>n</em> = 4). Continuous ECGs were collected simultaneously from both devices for 24 h prior and 24 h after oral administration of vehicle or Dofetilide (canine <em>n</em> = 5; 0.003, 0.010, 0.030 mg/kg and NHP <em>n</em> = 4; 0.03, 0.06, 0.12 mg/kg). Individual animal 15-min means were reviewed descriptively and via Bland-Altman (BA) analysis to determine bias and limits of agreement (LOA) between devices. Further, Dofetilide dependent QT changes were evaluated using time-matched QT interval comparisons and the results of QTci exposure-response modeling. Data were qualitatively consistent in magnitude and profile between the two measurement platforms. BA demonstrated that bias between devices was &lt;2 ms for HR, PR, and QRS for both species, 2 ms for canine QT, and 6.6 ms for NHP QT, with acceptable LOA for all endpoints. Mean Dofetilide-dependent QT changes over time were not different between devices and calculated Δ∆ QTci EC_+10ms were &lt; 2× between devices within species. Overall, these studies demonstrated the feasibility of using alternative devices and increasing options to collect in-cage ECG to collect nonclinical safety pharmacology and toxicology endpoints.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108377"},"PeriodicalIF":1.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340715","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}