Journal of pharmacological and toxicological methods最新文献

{"title":"Enhancing efficiency in cynomolgus monkey cardiovascular assessment through non-invasive blood pressure measurement","authors":"Sunwoo Choi,&nbsp;Won-Tae Kim,&nbsp;Yang-Im Cho,&nbsp;Jung-Ho Noh,&nbsp;Seung-Ju Cho,&nbsp;Yang-Ji Cha,&nbsp;Sukmo Kang","doi":"10.1016/j.vascn.2026.108463","DOIUrl":"10.1016/j.vascn.2026.108463","url":null,"abstract":"<div><div>Invasive blood pressure (IBP) measurement is considered the gold standard for assessing blood pressure as a cardiovascular parameter in nonclinical primate studies due to its high accuracy and ability to provide continuous data. However, IBP requires surgical implantation by skilled personnel and the use of specialized equipment, making it costly and logistically demanding, particularly when integrated into toxicology studies. To address these challenges, this study aimed to evaluate the feasibility and reliability of cuff-based non-invasive blood pressure (NIBP) measurement as an alternative in cynomolgus monkeys, and evaluate its comparability to the conventional IBP method for cardiovascular screening. The overall goal was to explore a more cost-effective and ethically favorable approach to cardiovascular safety pharmacology. In this study, cynomolgus monkeys were surgically implanted with wireless transmitters to collect continuous IBP data. Concurrently, NIBP was measured by applying a cuff on the monkey's upper arm, and a jacket was used to prevent the animal from manipulating the cuff, enabling repeated measurements in conscious conditions. SDNN was calculated from ECG data to compare stress responses between IBP and NIBP. Results indicated that, although NIBP lacked continuous monitoring capabilities, the overall trends in systolic, diastolic, and mean blood pressure changes were largely consistent between the two methods. As the animals underwent sufficient training and acclimatisation to the jacket, the success rate of NIBP data acquisition improved steadily, enhancing the method's practical utility. While absolute NIBP values differed somewhat from those of IBP, the cuff-based method proved sufficiently robust for early-phase cardiovascular assessment in primates, suggesting its potential utility, particularly when IBP is reserved for definitive analysis. In conclusion, cuff-based NIBP measurement represents a viable and less resource-intensive alternative for preliminary cardiovascular monitoring in cynomolgus monkeys. This non-invasive approach not only reduces the cost and complexity of studies, but also contributes to refinement by minimizing animal distress, enabling repeated measurements without anesthesia, and enhancing overall welfare. These improvements align directly with the 3Rs principles in safety pharmacology research.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108463"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148731194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The multi-channel cell force analyzer CFAref for quantifying bi-axially, drug induced forces in cell monolayers and co-cultures","authors":"Till P. Creutz,&nbsp;Karya Uysal,&nbsp;Ipek S. Firat,&nbsp;Tomo Šarić,&nbsp;Gerhard M. Artmann,&nbsp;Aysegül Temiz Artmann","doi":"10.1016/j.vascn.2026.108491","DOIUrl":"10.1016/j.vascn.2026.108491","url":null,"abstract":"<div><div>The routine analysis of intrinsic and drug-induced tensile forces in cultured cell layers based on CellDrum technology is a promising tool for reliable toxicological biomechanical studies. If the number of contractile cells is known, the cell tension data is available in mN/mm² and the data measured in different laboratories can be compared. This study details validation experiments on the function, sensitivity, and accuracy of the technology using human aortic smooth muscle cells (SMCs) and murine cardiomyocytes. The CellDrum technology uses 3.4-4 μm thin quality controlled, pretested 16 mm in diameter PDMS membranes attached to a cylindrical applicator. Cell layers are cultivated in 500 μL culture medium atop the membrane causing its downward bending. Intrinsic and drug-induced stresses within the cell layer cause the membrane to rise or fall. The tensile stress is calculated from this deflection. Cell cultivation was performed according to published protocols; cell visualization was realized using confocal imaging and fluorescence staining. To assess cell counts, the images were processed in ImageJ software. The reproducibility of the mechanical membrane tension without cells (500 μL cell culture volume) was less than 1% variation. Prevailing and induced forces of smooth muscle cell monolayers were found to be accurate within 2–7%. Important for reproducible and acceptable measurements was that the membrane deflection at the pole was only about 1 mm at 16 mm membrane diameter allowing uniform cell growth on the entire membrane. If the membrane diameter was i.e. 8 mm, the cells would sediment at the pole of a membrane hemisphere and form a clump. We present a) the CellDrum technology principle; b) signal-to-noise ratio data, c) evaluation experiments with SMC monolayers and murine cardiomyocytes, and d) time course data if possible of test cell layers. For murine cardiomyocytes we demonstrate the Frank-Starling effect quantitatively. The CellDrum technology is well suited for routine mechanical cell tension measurements and is recommended for pharmacological and toxicological studies. It could largely replace the use of organ rings from animal vessels. The fact that even the Frank-Starkling effect can be measured makes the future replacement of the Langendorff heart very likely.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108491"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148731187","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":"Utilizing in vitro assays to assess drug-induced central nervous system liabilities","authors":"Louisa A.K. Zolkiewski,&nbsp;Kimberley L. Rockley,&nbsp;Karen Jones,&nbsp;Katie Newman,&nbsp;Hannah Jennings,&nbsp;Magali-Anne Maizieres,&nbsp;Ruth Roberts,&nbsp;Michael Morton","doi":"10.1016/j.vascn.2026.108442","DOIUrl":"10.1016/j.vascn.2026.108442","url":null,"abstract":"<div><div>Central nervous system (CNS) liabilities (e.g. seizures) remain a significant cause of drug development attrition, yet they are typically not identified until late-stage <em>in vivo</em> toxicology studies where adverse findings can result in costly delays or project termination. Further, ~25% of clinical trial failures are due to safety concerns that were undetected in earlier <em>in vivo</em> studies. This emphasises the urgent need for predictive, human-relevant <em>in vitro</em> assays that can be implemented earlier in the drug development process to assess CNS safety risks. The cardiovascular safety field has benefitted from early-stage screening using human ion channel assays and human induced pluripotent stem cell (hiPSC)-cardiomyocytes. Similarly, we developed two complementary <em>in vitro</em> CNS safety assays: 1) an ion channel panel evaluated via automated electrophysiology, and 2) an hiPSC-neuronal model analyzed using microelectrode array (MEA) to measure electrical activity in response to known seizurogenic compounds. In addition to seizure risk, sedation is a common adverse finding in preclinical studies. To address this, we aimed to validate our <em>in vitro</em> CNS assay for predicting sedative compound effects. GABAergic signalling plays a crucial role in the sleep-wake cycle, with GABA_A receptor activation resulting in sedation. We tested 14 sedative compounds (targeting both GABA and non-GABA pathways) and 5 non-sedative controls in the hiPSC-neuronal model. MEA analysis showed that GABA_A agonists (muscimol, etomidate, ethanol) and certain ion channel antagonists (valbenazine, dextromethorphan, primidone) reduced neural firing and burst activity, indicating sedative effects. Negative control compounds produced no significant changes. Of the 19 known compounds screened, 85% were accurately classified. Automated patch-clamp electrophysiology further confirmed these findings by testing compound interactions with GABA_A and other CNS ion channels. These results support the use of our <em>in vitro</em> CNS models for detecting sedative and seizurogenic effects, thus enhancing translational relevance. These platforms offer valuable human-based tools for early hazard identification and prioritisation of drug candidates, as well as interpreting CNS-related findings from <em>in vivo</em> studies thus complying with the principles of 3Rs to minimise and replace the use of animals in scientific testing. Ongoing work is focused on expanding this model to evaluate additional sedation-related ion channels.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108442"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730171","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-throughput impedance-based assessment of cytotoxicity and senescence in cancer immunotherapy models","authors":"Ronald Knox,&nbsp;Martin Ziller,&nbsp;Michael Dudek,&nbsp;Barbara Schoerg,&nbsp;Giovanna de Filippi,&nbsp;Marta Lemme,&nbsp;Elena Dragicevic,&nbsp;Michael George,&nbsp;Niels Fertig,&nbsp;Sonja Stoelzle-Feix","doi":"10.1016/j.vascn.2026.108448","DOIUrl":"10.1016/j.vascn.2026.108448","url":null,"abstract":"<div><div>Immunotherapy has become a transformative approach in cancer treatment, complementing traditional therapies. Key to its success is the ability to assess T cells that selectively eliminate cancer cells and to monitor the functional performance of engineered immune cells such as CAR T cells. This study evaluates the AtlaZ, a high-throughput impedance-based platform, for real-time, label-free monitoring of immune-mediated cytotoxicity and senescence-induced growth arrest across solid tumor and liquid tumor cell models. We utilized the AtlaZ system (Nanion Technologies), based on Electrical Impedance Spectroscopy (EIS), which enables monitoring of cell behavior across six 96-well plates. The platform operates over a frequency range of 0.1 kHz to 100 kHz, distinguishing between changes in proliferation, cytotoxicity, adhesion, and barrier integrity. We evaluated cytolytic activity in epithelial A549 lung adenocarcinoma cells, K562 leukemia cells, and SKOV-3 ovarian carcinoma cells. CAR T cell responses targeting the EGFR receptor were studied, along with prototypic immune cell-mediated cytolysis using CD8+ T cells and Natural Killer (NK) lymphocyte cells. Additionally, we investigated senescence-related growth arrest in murine RT2 β-cc and human HCT116 cells using established senescence-inducing protocols. Time-resolved impedance analysis captured progressive cytolysis of adherent A549 cells co-cultured with cytotoxic T lymphocytes, showing 37–59% killing over 27 h depending on effector-to-target ratios. In tethered suspension K562 leukemia cells, antibody-mediated cell adhesion enabled robust signal detection similar to adherent cells. Upon addition of CD8+ T cells and NK cells, impedance signals rapidly declined, indicating cytolysis. Full cytolysis was achieved in 7.8 h with CD8+ T cells and 4.6 h with NK cells. Importantly, for liquid tumor cell models, tethering reagents were selective for target cells, avoiding signal interference from effectors. In senescence studies, impedance monitoring successfully captured a transition from proliferative to growth-arrested states in both murine and human cancer cells, reflected by stable, plateaued impedance profiles over time. The AtlaZ system enables dynamic, label-free analysis of cytotoxicity and senescence across various liquid (suspension) or solid (adherent) cell models. Its ability to detect early cellular responses and differentiate between growth inhibition and cell death makes it a powerful tool for preclinical immunotherapy development and toxicological research.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108448"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730175","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":"Comparable study of whole cell patch clamp recording for hERG channel under physiological temperature using high-throughput automated patch clamp system QPatch II and Qube","authors":"Kazuya Tsurudome,&nbsp;Hironori Ohshiro,&nbsp;Taku Izumi","doi":"10.1016/j.vascn.2026.108501","DOIUrl":"10.1016/j.vascn.2026.108501","url":null,"abstract":"<div><div>The activity of cardiac ion channels is crucial for generating action potentials with proper timing and duration. Drug-induced dysfunction of these channels can lead to adverse cardiac events such as QT prolongation, ventricular arrhythmias, and sudden death. These effects remain a major cause of drug withdrawal or failure to gain regulatory approval. To improve drug safety assessment, the Comprehensive in vitro Proarrhythmia Assay (CiPA) was developed, emphasizing the need to evaluate drug effects on ion channels under physiological temperature. We evaluated the inhibitory effects of a compound on hERG channels at physiological temperature (35 °C) using whole-cell patch clamp experiments with automated systems QPatch II and Qube. Temperature conditions during measurement were set to either 25 °C or 35 °C. After establishing whole-cell configuration, the CiPA voltage protocol was applied at 5-s intervals to measure hERG channel currents. Following vehicle application to record control currents, the compound was applied to assess inhibitory effects on the hERG channel. Previous studies using QPatch Compact showed that hERG channel behavior changes significantly when recordings are performed at 35 °C compared to 25 °C. Similar trends were observed with QPatch II and Qube, including reduced time constants to reach steady-state current, increased tail current amplitudes, and faster tail current rise times. We also investigated temperature-dependent drug effects using erythromycin. At room temperature, hERG current inhibition at 1000 μM was around 50–60%, whereas at 35 °C, the IC50 was significantly lower (60–90 μM), and nearly complete inhibition was seen at 1000 μM. This confirmed erythromycin's greater potency at physiological temperature. Tests with multiple compounds under both temperature conditions yielded results consistent with existing literature and previous QPatch Compact studies. These findings support the robustness of QPatch II and Qube in detecting temperature-dependent effects aligned with outcomes from manual patch clamp systems. Our results emphasize the importance of recording at physiological temperature to obtain accurate pharmacological data, supporting automated patch clamp systems in CiPA-compliant safety assessments. This enhances the predictive power and reliability of preclinical cardiotoxicity screening.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108501"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730261","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":"Vision-based AI for automated analysis of primate behaviors","authors":"Yevgeniya E. Koshman,&nbsp;Wei Liang,&nbsp;Surekha S. Akella,&nbsp;Andy H. Vo,&nbsp;Christian W. Grant,&nbsp;James Jasiek,&nbsp;Lexie A. Smith,&nbsp;Shuai Niu,&nbsp;Vivian Zhao,&nbsp;Suzanne E. Ybarra,&nbsp;Terry R. Van Vleet","doi":"10.1016/j.vascn.2026.108449","DOIUrl":"10.1016/j.vascn.2026.108449","url":null,"abstract":"<div><div>Atopic dermatitis is a chronic inflammatory skin disorder characterized by systemic inflammation, compromised skin barrier function, and persistent pruritus (itch). Interleukin (IL)-31 and its receptor, IL-31 receptor A (IL-31RA), are pivotal in driving pruritic responses and have been demonstrated to trigger itching in animal models, including mice, dogs, and monkeys. Traditional methods for quantifying scratching behavior induced by IL-31 typically involve manual and blinded scoring from video recordings over extended durations, which can be labor-intensive, prone to variability, and subjective.</div><div>Our group has developed and validated an artificial intelligence model that combines computer vision techniques—specifically optical flow movement detection—with machine learning methods. This model automates the measurement of scratching behavior in a cynomolgus monkey inducible itch model, reducing manual labor by more than 80%. It achieves a classification accuracy of 95% and an area under the curve (AUC) of 0.92 when evaluated against expert-labeled holdout datasets. By objectively quantifying itch duration, this approach provides reliable phenotyping data, streamlines behavioral assessments in preclinical studies, and is readily adaptable to analyze other behaviors across different animal models.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108449"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730513","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 respiratory parameters, toxicokinetic data, and arterial blood gas parameters during 8-hour continuous fentanyl infusion to male rats","authors":"Adrion R. Stanford,&nbsp;Gregory Sondag,&nbsp;Tom Miller,&nbsp;Jeanette Mathews,&nbsp;Joseph Pergolizzi,&nbsp;George Dungan,&nbsp;Robert Raffa,&nbsp;Kevin Norton","doi":"10.1016/j.vascn.2026.108456","DOIUrl":"10.1016/j.vascn.2026.108456","url":null,"abstract":"<div><div>Fentanyl is a well-known opioid that is used intravenously for anesthesia (paired with a sedative-hypnotic and a muscle relaxant) and as an analgesic; Fentanyl has been shown to be up to 100 times more potent than opioids such as morphine, heroin, or oxycodone, which are known to cause respiratory depression. The purpose of this study was to develop a concentration-effect curve observing minute volume, respiratory rate, and tidal volume of fentanyl over time and to determine any physiological effects of fentanyl through arterial blood gas parameters using three studies sponsored by Enalare Therapeutics, Inc. at Charles River Laboratories, Ashland, Ohio. All data for this project was compiled using three intravenous infusion studies measuring respiratory parameters, toxicokinetic data, and arterial blood gas parameters, respectively. The first study utilized sixteen rats infused with a loading and continuous dose of fentanyl and saline over an eight-hour period. Respiratory rate, tidal volume, and minute volume were measured. The second study focused on the toxicokinetics of fentanyl, infusing rats with a loading and continuous dose of fentanyl and vehicle over an eight-hour period. The third study infused rats with a loading and continuous dose of fentanyl and vehicle over a five-hour period while exploring arterial blood gas parameters. The dose resulted in increases in all respiratory parameters (with an initial drop at 1.5 h and increased through 5 h post start of infusion) as fentanyl concentration increased over time and also resulted in a decrease of pH, an increase in PCO2, and an increase in bicarbonate (HCO3) over time. All animals experienced a modest and consistent respiratory acidosis and respiratory depression by 1.25 h post start of infusion and abated from 1.25 to 5 h post start of infusion. The animals were assessed to have experienced chest wall rigidity or “wooden chest syndrome” due to ineffective ventilation observed with increased respiratory rate while maintaining a stable tidal volume. These data highlight that it is feasible and beneficial to add arterial blood gas analysis to respiratory studies to assess a test material's risk profile on respiratory function.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108456"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730520","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":"Drug interaction with UDP-glucuronosyltransferase (UGT) enzymes is a predictor of drug-induced liver injury","authors":"Danielle Thomas,&nbsp;Amy Nielsen,&nbsp;Olivier Barberan,&nbsp;Minjun Chen","doi":"10.1016/j.vascn.2026.108483","DOIUrl":"10.1016/j.vascn.2026.108483","url":null,"abstract":"<div><div>Drug induced liver injury (DILI) can have severe negative outcomes on patient survival of hepatotoxic adverse drug reactions (ADRs), attrition of new drug programs, and post-market withdrawal of approved drugs. Cytochrome P450 (CYP) enzyme metabolism has been associated with increased dose-dependent DILI risk. Additionally, studies have indicated other metabolizing enzymes, like UDP-Glucuronosyltransferase (UGT) enzymes, can induce DILI via the toxicity of reactive metabolites. Although metabolism of some noncytochrome P450 (non-CYP) enzymes have been associated with DILI induction, their relationship with DILI development has not been systematically characterized.</div><div>The in-vitro drug-enzyme interactions of 317 drugs with 42 non-CYP enzymes acting as substrates, inducers, and/or inhibitors were retrieved from historical regulatory documents using PharmaPendium. Bioactivity data was obtained from Reaxys. PharmaPendium is a translational tool that makes regulatory grade documents from the EMA and FDA fully text searchable for pharmacokinetic, metabolism, efficacy, and drug safety data. Reaxys contains chemistry data and bioactivity data from journal articles and patents. The drugs selected for the data set and their DILI concern classification were obtained by the Liver Toxicity Knowledge Base (LTKB) data set developed by the US Food and Drug Administration (FDA)’s National Center for Toxicological Research (NCTR). The relationship between DILI concern (high versus low) and drug-enzyme interactions with non-CYP enzymes were examined binomially. Multivariate linear regression was used to assess associations between DILI concern and enzymatic relationship.</div><div>Examining the in vitro drug-enzyme interactions for potential DILI concern revealed that non-CYP enzymes are highly associated. Specifically, 31 drugs in the 317 drug data set interacted with enzymes in the UGT1 family with 21 of 31 (67%) having high DILI concern. Analysis also showed that a drug that acts as a dual UGT substrate-inhibitor is associated with high DILI concern as compared to a drug that is a pure UGT substrate.</div><div>Drug interactions with UGT enzymes may independently predict DILI, and their combined use with the rule-of-two model further improves overall predictive performance. These findings could expand the currently available tools for assessing the potential for DILI in humans which can improve translational assessment and drug development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108483"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730636","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":"Least significant differences for QT and QTc intervals in regulatory toxicology studies using jacketed external telemetry in canines and non-human primates","authors":"Abdel-Ilah El Amrani,&nbsp;Jill Dalton,&nbsp;Stephen Tichenor,&nbsp;Courtney Jenkins,&nbsp;Jennifer Shaffer,&nbsp;Kevin Norton","doi":"10.1016/j.vascn.2026.108468","DOIUrl":"10.1016/j.vascn.2026.108468","url":null,"abstract":"<div><div>We previously showed that the Least Significant Differences (LSDs) for uncorrected interval (QT) and corrected QT for changes in heart rate (QTc) in parallel design studies using jacketed external telemetry (JET) are comparable to cross-over design studies using implanted canine telemetry studies. Therefore, the threshold for detecting statistically significant increases in QT/QTc in JET studies is close to that observed in cross-over studies. In the present study, LSD values were calculated using large cohorts of canines (Beagles) and non-human primates (NHPs, Cynomolgus) JET investigations (15 and 28 studies, respectively) from 5 testing facility sites. Animal data was collected on IACUC/AEC approved protocols (Institutional Animal Care and Use Committee/Animal Ethics Committees). Each investigation involved 4 groups of 3 to 6 animals/sex/group dosed in parallel designs with oral or intravenous routes of administration. ECG parameters were continuously recorded by JET over 20 to 24 h postdose, and the QT interval was corrected using the Miyazaki or Holzgrefe formulae. When combined and uncombined sexes were considered, median LSD values for QT and QTc were 10.8 ± 5.3 and 6.2 ± 2.9 msec, respectively for canines (15 studies) and 15.3 ± 7.2 and 11.0 ± 5.3 msec, respectively for NHPs (28 studies). When combined sexes only were considered, median LSD values for QT and QTc were 10.8 ± 5.3 and 6.2 ± 2.9 msec, respectively for canines (11 studies) and 14.8 ± 7.5 and 10.1 ± 4.9 msec, respectively for NHPs (23 studies). When uncombined sexes only were considered, median LSD values for QT and QTc were 10.2 ± 3.9 and 6.9 ± 2.6 msec, respectively for canines (4 studies) and 16.2 ± 8.0 and 17.8 ± 8.2 msec, respectively for NHPs (<em>n</em> = 5 studies). LSD values for QT and QTc for combined sexes were lower than those for uncombined sexes in NHPs but not in canines. This investigation shows that jacketed ECG can be adequate to support an integrative risk assessment of QT prolongation in the jacket-telemetered canines and NHPs dosed according to a parallel design and point out the necessity of combining males and females in the estimation of LSD values in parallel group design in NHPs, whenever possible.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108468"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730670","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":"Statistical power analysis of standard cardiovascular safety pharmacology studies in telemetry implanted dogs and nonhuman primates","authors":"Shanshan An,&nbsp;Min Li,&nbsp;Miao He","doi":"10.1016/j.vascn.2026.108478","DOIUrl":"10.1016/j.vascn.2026.108478","url":null,"abstract":"<div><div>Cardiovascular safety assessment serves as a critical gatekeeper for novel therapeutics entering first-in-human (FIH) trials, with QT/QTc interval prolongation risk being paramount—drug-induced ventricular repolarization delay may trigger fatal arrhythmias. The recent ICH E14/S7B Q&amp;As enable the incorporation of high-quality nonclinical QTc data into integrated risk assessments to support Thorough QT (TQT) study waivers, contingent upon meeting rigorous validation criteria. Robust understanding of statistical sensitivity underpins confidence in study results, yet systematic power analysis of standard CV studies remains limited.</div><div>To address this gap, we conducted a retrospective analysis of cardiovascular telemetry studies in standard cynomolgus monkeys (<em>n</em> = 132) and beagle dog (<em>n</em> = 140), separately, to determine the statistical power of these experimental models. Studies typically utilized a 4 × 4 (dog) or 4 × 4 (NHP) in Latin-Square manner paradigm. Data were collected for approximately 24 h, and derived results from the predose and each 1‑hour period for statistical analysis using a linear ANOVA model.</div><div>The minimum detectable differences (MDD) with 80% statistical power were calculated for standard parameters (e.g. heart rate (HR), ECG intervals etc). MDDs for dogs, using a <em>N</em> = 4 and 8 crossover design, were: QRS-interval (3.3 msec in males and 3.1 msec in females), PR-interval (7.6 msec in males and 7.7 msec in females) and QTc-interval (10.1 msec in males and 10.3 in females). MDDs for NHP, using a <em>N</em> = 4 and 8 crossover design, were: QRS-interval (2.8 msec in males and 2.8 msec in females), PR-interval (5.8 msec in males and 7.5 msec in females), and QTc-interval (10.5 msec in males and 9.7 in females). Additionally, we also report reference intervals of root mean square error (RMSE) and he 2.5th and 97.5th percentile of the RMSE as a measure of variability in the studies.</div><div>Overall, our results indicate that the nonrodent CV model is a sensitive tool to detect CV risk in early safety studies. Furthermore, the results also demonstrate assay sensitivity of functional endpoints, and support use of data in the contest of IACH E14/S7B Q&amp;As.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"140 ","pages":"Article 108478"},"PeriodicalIF":2.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148730674","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}