Journal of pharmacological and toxicological methods最新文献

{"title":"Independent estimates of the axis of arrhythmia for assessing pro-arrhythmic drugs","authors":"Stewart Heitmann,&nbsp;Jamie I. Vandenberg,&nbsp;Adam P. Hill","doi":"10.1016/j.vascn.2025.107826","DOIUrl":"10.1016/j.vascn.2025.107826","url":null,"abstract":"<div><div>Many classes of drugs can induce potentially lethal cardiac arrhythmias. International safety guidelines (ICH-S7B) therefore recommend that all new drugs be tested for pro-arrhythmic risk prior to conducting human trials. The principal biomarker of drug-induced arrhythmia is prolongation of the ventricular cardiac action potential. Prolongation is known to be caused by drug-block of the hERG channel, hence that channel is of primary interest in safety testing. However, more accurate predictions of pro-arrhythmic risk can be achieved by considering the effect of the drug across multiple ion channels. The axis of arrhythmia is a new metric for predicting the pro-arrhythmic risk directly from a drug's effect on four key ion-currents (ICaL, IKr, INaL, IKs). In a previous study, we derived the axis of arrhythmia from computer simulations of a large population of ventricular cardiomyocytes. There, the axis was defined by the most potent combination of ion-channel blocks that shifted the simulated electrophysiology towards a pro-arrhythmic regime that was characterized by early-afterdepolarizations. In the present study, we derive the axis of arrhythmia using an entirely different method. Here, the axis is derived directly from a dataset of drugs (<em>n</em> = 109) without modeling the action potential. We statistically analyzed the drug potencies for each ion channel to find the linear boundary that optimally segregates the pro-arrhythmic drugs from the benign drugs, according to their clinical risk labels. The orthogonal line to that linear boundary corresponds to the axis of arrhythmia defined in our original study. The agreement between the two methods is remarkable. The axis derived from the simulated cardiomyocytes predicted the pro-arrhythmic risk of n = 109 test drugs with 88.1 %–90.8 % accuracy. In comparison, the axis derived from the drug dataset predicted the pro-arrhythmic risk with 89.9 %—90.8 % accuracy (cross-validated). The difference is negligible. Further analysis revealed that those accuracy rates could be improved to 90.8 %—92.7 % and 89.9 %—91.7 %, respectively, by excluding the IKs current. Such accuracy rates are comparable to the best biophysical model in contemporary computational cardiology. From a theoretical perspective, the independent derivations of the axis of arrhythmia represent convergent findings from complex biophysical models and simple statistical models.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107826"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094729","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":"2025-09-01","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":"2025-09-01","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":"Evaluating a non-invasive telemetry jacket as an alternative to the reference methods for cardio-respiratory safety pharmacological testing in rats","authors":"Fatima-Zahra Khamlichi,&nbsp;Heike Schauerte,&nbsp;Werner Mayer,&nbsp;Leonie-Theresa Hezler,&nbsp;Eric Martel,&nbsp;George Rast,&nbsp;Nicolas Pairet","doi":"10.1016/j.vascn.2025.107767","DOIUrl":"10.1016/j.vascn.2025.107767","url":null,"abstract":"<div><div>The gold standard methods used to assess cardiorespiratory system in rats, whether telemetry implants or whole-body plethysmography (WBP), have their shortcomings. One method requires surgery, while the other involves the isolation of rats. In a 3Rs approach, alternatives such as the use of non-invasive telemetry jackets, allowing simultaneous cardiorespiratory assessment, without hemodynamic parameters evaluation have been considered. No peer-reviewed publication to date has investigated the concordance between cardiorespiratory parameters recorded simultaneously via the jackets and the reference methods, following the administration of a pharmacological compound. Goal: to test and potentially validate the telemetry jackets by comparing data generated using this device with those obtained using gold standard methods at the same time, in the same animal, in an integrative interpretation approach. We compared cardiac (heart rate (HR)) and respiratory (respiratory rate (RR), minute ventilation (MV), tidal volume (TV)) parameters recorded via the invasive (DSI implant), non-invasive (Jacket DECRO) telemetry systems, and via the WBP (Buxco + Notocord HEM), simultaneously in the same male rats (<em>n</em> = 8rats/ pharmacological compound in a cross-over design). The recording lasted 7 h after the per-os administration of vehicle or pharmacological reference compounds tested (Ivabradine or Theophylline) at 3 doses. A generalized linear model was used to assess the effects of the pharmacological compounds. The Bland-Altman method was used to study the agreement between the jackets and the two reference methods. The jackets and reference methods both captured the expected pharmacological effects. For Ivabradine, a significant dose-dependent decrease in HR was observed, while no changes were noted in respiratory variables. Theophylline induced a dose-dependent increase in heart rate and RR. No significant change on TV and MV was noticed with the WBP, whereas a significant increase was shown with the jackets. Bland-Altman analysis revealed an increasing discrepancy in high TV, RR and MV values between the two devices under the experimental conditions of the studies. Jackets can be used as an alternative to implanted telemetry for recording HR without hemodynamic parameters. Although the two respiratory methods detect pharmacological effects, further investigation is needed to determine what is the current state of the respiratory parameters.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107767"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094209","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":"Enhanced cardiotoxicity assessment through propagation pattern analysis using HD-CMOS-MEA in hiPSC-derived cardiomyocytes","authors":"Nami Nagafuku,&nbsp;Naoki Matsuda,&nbsp;Ikuro Suzuki","doi":"10.1016/j.vascn.2025.107810","DOIUrl":"10.1016/j.vascn.2025.107810","url":null,"abstract":"<div><div>Cardiotoxicity is a common reason for drug discontinuation in new drug development. The in vitro microelectrode array (MEA) method using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is expected to be an alternative to animal experiments, but hiPSC-CMs cannot mature sufficiently in two-dimensional culture. In addition, the evaluation method of MEA is mainly based on the field potential duration (FPD) as an index, and the mechanism of action based on conduction velocity and propagation pattern has not been predicted. This research aims to construct an evaluation method focusing on conduction velocity and propagation pattern as indices for MEA. To enable detailed analysis, hiPSC-CMs were measured using a high-density (HD)-CMOS-MEA with 236,880-microelectrodes instead of conventional MEA. Pharmacological tests used compounds and concentrations undetectable by conventional MEA, measuring extracellular potentials for 14 compounds, including negative controls. The HD-CMOS-MEA can record a single cell with dozens of electrodes. Seventeen parameters were established for the propagation pattern, including the number of origins, origin position fluctuation, propagation velocity, and propagation area. A specific increase in origins was detected with isoproterenol, an adrenergic β1 receptor agonist. A decrease in propagation velocity was observed with mexiletine, a Na channel inhibitor. A decrease in propagation area was detected with E4031, a hERG potassium channel inhibitor. Furthermore, differences in conduction velocity and propagation pattern based on the mechanism of action of each compound were revealed, suggesting that cardiotoxicity evaluation using CMOS-MEA may capture differences in channel activity for each concentration of compounds with multiple actions with high sensitivity. Additionally, a decrease in propagation area and propagation velocity was detected 24 h after exposure to 0.1 μM doxorubicin, which exhibits cardiotoxicity when administered chronically. Cardiotoxicity evaluation using CMOS-MEA demonstrated that cardiotoxicity could be detected at lower concentrations and shorter durations of chronic administration compared to conventional cardiotoxicity evaluations. This indicates that cardiotoxicity evaluation using HD-CMOS-MEA may detect cardiotoxicity risks that could not be identified by conventional MEA analysis, based on new parameters. This underscores the potential use of imaging technology in drug discovery and compound toxicity evaluation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107810"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094948","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":"Variability of manual patch clamp data on CaV1.2 and NaV1.5 channels generated using standardized protocols and following ICH S7B Q&A 2.1 best practices – Progress update of a HESI-coordinated multi-laboratory study","authors":"Huimei Yu ,&nbsp;Claudia Alvarez Baron ,&nbsp;Jun Zhao ,&nbsp;Ming Ren ,&nbsp;Shovan Naskar ,&nbsp;Donglin Guo ,&nbsp;Manni Mashaee ,&nbsp;Jose Vicente ,&nbsp;Lars Johannesen ,&nbsp;Jiansong Sheng ,&nbsp;Simon Hebeisen ,&nbsp;James Kramer ,&nbsp;Andrew Bruening-Wright ,&nbsp;Koji Nakano ,&nbsp;Jennifer Pierson ,&nbsp;David Strauss ,&nbsp;Wendy W. Wu","doi":"10.1016/j.vascn.2025.107808","DOIUrl":"10.1016/j.vascn.2025.107808","url":null,"abstract":"<div><div>Concomitant block of Ca_V1.2 and/or Na_V1.5 channels may mitigate Torsade de Pointes risk associated with hERG block. However, Ca_V1.2 channel block may cause bradycardia/hypotension; Na_V1.5 channel block may induce conduction slowing and sudden cardiac death in patients with structural heart diseases. Understanding drug effects on multiple cardiac ion channels can be of value for proarrhythmia risk assessment. Literature shows large degrees of lab-to-lab variability for drug potencies on cardiac ion channels. Ion channel data alignment with drug-induced ECG changes can thus be dataset-dependent. Lab-to-lab differences can arise from different experimental protocols and/or data quality. Thus, ICH S7B Q&amp;A 2.1 was released to provide best practice recommendations for conducting cardiac ion channels assays to support proarrhythmia risk assessment. The goal of this HESI-coordinated, multi-laboratory research effort is to generate block potencies for 28 drugs in low, intermediate, and high proarrhythmia risk categories for hERG, Ca_V1.2, and peak and late Na_V1.5 currents with standardized protocols and best practices. This abstract focuses on the Ca_V1.2 and peak and late Na_V1.5 currents; hERG data are presented in a companion abstract (Alvarez-Baron et al.). Five laboratories conducted manual patch clamp experiments at near physiological temperatures on cell lines over-expressing Ca_V1.2 or Na_V1.5 channels. The research is ongoing, hence drug potencies are not presented. Instead, this abstract presents findings on data variability for each current, estimated using meta-analysis to account for drug-specific (i.e., potencies) and laboratory-specific effects. Systematic data variability was not observed from any laboratory for any current. After removing drug- and laboratory-specific effects, residual data variability was pooled across all drugs/laboratories to estimate overall assay variability. Variability measures for Ca_V1.2 and peak and late Na_V1.5 currents will be shared on the poster. This dataset can be compared with existing clinical data to understand nonclinical-clinical translation. Experiments on these three currents are ~75 % complete. Once complete, outcomes of this study will: 1) inform assay variability and support identification of safety margins for Ca_V1.2 and Na_V1.5 channels; and 2) produce a dataset to develop an in-silico myocyte model that can integrate multi-cardiac ion channel data for proarrhythmia risk prediction.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107808"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094942","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":"Challenges in adapting a conscious dog haemodynamic systems model to an anaesthetised dog protocol","authors":"Joanne Mahmud ,&nbsp;Chris E. Pollard ,&nbsp;Tariq Abdulla ,&nbsp;Barira Islam ,&nbsp;Yevgeniya E. Koshman ,&nbsp;Michael K. Pugsley ,&nbsp;Will S. Redfern","doi":"10.1016/j.vascn.2025.107831","DOIUrl":"10.1016/j.vascn.2025.107831","url":null,"abstract":"<div><div>Previously¹, the cardiovascular-contractility systems model described by Fu et al.² was evaluated and extended using Simcyp™ Designer, a graphical interface platform and physiologically-based pharmacokinetic tool. Model outputs replicated published dog telemetry data¹. In the present study, the model was adapted for use in pentobarbital-anaesthetised beagle dogs, utilizing cardiovascular (CV) and exposure data for atenolol and atropine³. Model adaptations included removal of circadian rhythm, attenuation of baroreflex negative feedback, and development of a pharmacokinetic model in Simcyp™ Designer to accommodate intravenous dose escalation and hysteresis. Model simulations and experimental data for atenolol (0.3, 1, and 3 mg/kg/30 min) showed a decrease in dP/dt_max from 2300 to 1800 mmHg/s and mean arterial pressure (MAP) from 120 to 110 mmHg. The model predicts a decrease in heart rate (HR) from 110 to 85 bpm; however, bradycardia was not observed experimentally. For atropine (0.01, 0.03, 0.1 mg/kg/30 min), model outputs and experimental data displayed an increase in HR (124 to 164 bpm) and dP/dt_max (2650 to 3000 mmHg/s). While experimental MAP data decreased from 130 to 120 mmHg, model outputs predicted an increase from 105 to 130 mmHg. Several challenges were encountered during the development of the anaesthetised systems model. Firstly, the study design for the anaesthetised dog differs markedly from that of conscious dog telemetry. Secondly, the extent to which the baroreceptor reflex is attenuated by the anesthesia is unknown. Furthermore, the Fu et al. model² employs antagonist K_d values to predict haemodynamic effects, rather than <em>in vivo</em> EC₅₀ values. Finally, the decrease in HR predicted by the model following atenolol administration was not observed in anaesthetised dogs, possibly due to low resting cardiac sympathetic tone under the anesthesia. Despite these limitations, the adapted Fu et al.² model has the potential to maximise the use of anaesthetised CV dog data. Specifically: to interpolate CV effects at intermediate dose levels, derive threshold plasma concentrations for detectable CV effects, and predict the CV effects at doses which cannot be tolerated.</div><div>1. Mahmud et al. (2023) SPS Meeting, Brussels, Belgium</div><div>2. Fu et al. (2022) <span><span>https://doi.org/10.1002/psp4.12774</span><svg><path></path></svg></span></div><div>3. Antic et al. (2024) <span><span>https://doi.org/10.1016/j.vascn.2024.107497</span><svg><path></path></svg></span></div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107831"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative comparison of ECG limb lead configurations: Evaluating synonymity of interval measurements using alternative leads under appropriately controlled study conditions","authors":"Courtney Jenkins ,&nbsp;Steve Tichenor","doi":"10.1016/j.vascn.2025.107829","DOIUrl":"10.1016/j.vascn.2025.107829","url":null,"abstract":"<div><div>In Safety Pharmacology studies, electrocardiogram (ECG) waveform recording in a lead II configuration is the established gold standard for ECG lead placement. This approach, with proper surgical techniques, yields high fidelity data suitable for quantitative and qualitative assessment. External lead configurations, using either external telemetry (ET) or manual restraint methods, are widely accepted practices to integrate CV assessments on to general toxicology studies. While both methods can provide reliable data, improper lead placement or unexpected displacement of electrodes can compromise data quality, hindering accurate assessment of waveform morphology and interval measurements. The aim of this project was to investigate advantages of a multi‑lead ECG design, focusing on the feasibility of interchanging external lead configurations to provide concurrent comparison within a single study. This approach allowed for direct comparison of measurements obtained from different external lead configurations. Six non-human primates were equipped with Jacketed ET (JET-3ETA, manufactured by Data Sciences International). Following proper animal acclimation, a 24-h ECG recording period was conducted with ECG leads positioned in standard lead I (lateral vector, coronal plane), II (inferior vector, sagittal plane), and III (inferior vector, frontal plane) orientations. Comparison of lead II to lead III demonstrated minimal differences in ECG interval measurements for HR (0.1 %), PR (0.4 %) QRS (0.6 %), RR (0.1 %), QT (1.7 %) and rate corrected QTc (1.9 %), while differences in lead II to lead I orientations were slightly greater: HR (1.0 %), PR (3.3 %) QRS (0.3 %), RR (0.3 %), QT (3.6 %) and rate corrected QTc (3.0 %). The results demonstrated minimal difference among the different limb leads that were within a range of variation that was biologically inconsequential. This suggests that utilization of an external multi‑lead ECG design on a large animal study can improve data yield or quality by incorporating analysis from other leads if the primary lead (lead II) has waveforms that are of unsuitable quality. The synonymous correlation in measurements from lead II to lead III was expected given their similar orientation within the same electrical plane. This supports the feasibility of interchanging data among these external lead configurations without compromise to data interpretation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107829"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095002","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 retrospective review of the effects of moxifloxacin in dogs at four different test sites","authors":"Kevin Norton ,&nbsp;Michael Scott ,&nbsp;Abdel El Amrani ,&nbsp;Jared Slain ,&nbsp;Nacera Mella ,&nbsp;Steve Denham ,&nbsp;Matt St Peter ,&nbsp;Jill Dalton","doi":"10.1016/j.vascn.2025.107781","DOIUrl":"10.1016/j.vascn.2025.107781","url":null,"abstract":"<div><div>With adoption of the ICH E14/S7B Q&amp;A best practice guidance, non-clinical cardiovascular data sets can be used in place of clinical data to support of a TQT waiver application. However, as part of this guidance each laboratory is required to demonstrate adequate sensitivity of their specific <em>in vivo</em> model using a known positive control agent (e.g., moxifloxacin) or through retrospective review of historical data sets. These requirements raise questions around how often a positive control study should be conducted and how stable the effects of moxifloxacin are across multiple laboratories. In the current review we assessed the effects of moxifloxacin, in dogs, from four test sites. All four laboratories administered moxifloxacin at 10, 30 and 90 mg/kg by oral administration and evaluated cardiovascular parameters for 24 h post administration. The study designs between labs differed slightly, with test sites 1 and 2 utilizing a traditional 4*4 cross-over design in a single housing paradigm, test site 3 utilizing a 4*4 cross-over design with paired housing, and test site 4 utilizing a modified cross-over design with only two dose levels assessed per day. Additionally test site 1, used female animals, with other sites using males. Concentration-QTc modeling was also conducted at two sites with minor site-to-site variances in the blood sample collection methods and timing observed. All sites illustrated comparable dose dependent increases in QTc prolongation. Administration at 90 mg/kg resulted in QTc prolongation of up to 30.5, 35.6 33.2 and 31.2 msec, relative to control, at test sites 1, 2, 3 and 4 respectively. Whilst a review of study specific least significant difference, ranged from 6.4 to 11.1 msec, and residual error ranged from 4.1 to 6.4 msec; with conc-QT modeling, at test site 1 and 4,indicating that concentration ranges of 2867 to 2937 ng/ml would be expected to induce a 10-msec prolongation. These results indicate that when following best practice methodologies, dog CV models are highly consistent, independent of laboratory. This suggests that repeated administration of moxifloxacin across all laboratories is not essential and reliance on historical data sets alone should suffice to confirm model suitability.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107781"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095217","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":"Sensitivity of latin square and ascending dose designs for in vivo QT moxifloxacin positive control to support ICH E14/S7B studies","authors":"Rachael Hardman ,&nbsp;Joyce Obeng ,&nbsp;Jill Nichols ,&nbsp;Karim Melliti","doi":"10.1016/j.vascn.2025.107779","DOIUrl":"10.1016/j.vascn.2025.107779","url":null,"abstract":"<div><div>The Latin square crossover is recommended as best practice for in-vivo QT studies. However, an escalating design may instead be required due to compound long half-life, insufficient toxicity data to inform dose level selection, a need to build up tolerance to the test article to enable safe dosing, or logistics (e.g. avoiding use of multiple simultaneous inhalation dose generation systems thereby reducing risk of contamination). We have performed ICH E14/S7B Q&amp;A compliant in vivo QT validation studies with oral moxifloxacin using both a Latin square and an ascending dose design in primate (<em>n</em> = 4), dog (n = 4 for Latin square and <em>n</em> = 6 for ascending dose design) and minipig (<em>n</em> = 8 for Latin square and <em>n</em> = 5 for ascending dose design). The objective of this work was to compare the sensitivity of the dosing designs and to generate positive moxifloxacin QTc data in support of ICH E14/S7B studies when using an ascending dose design. Increases in QTc at the highest doses for the Latin square and ascending dose designs were + 30 and + 26 msec in primate, +40 and + 34 msec in dog, +86 and + 67 msec in minipig, respectively. Root mean square error (RMSE) values ranged from 5.9 to 10.8 msec for Latin square and 4.1 to 7.3 msec for ascending dose in all species. The smallest statistically detectable difference (SSDD) for the Latin square and ascending dose designs were 10 and 6.6 msec in primate, 10.2 and 5.4 msec in dog, and 11.4 and 10 msec in minipig, respectively. While the SSDD values cannot directly be compared due to the differing N values for dog and minipig, SSDD values were generally low for all species and study designs (6.6–11.4 msec). In conclusion, these data demonstrate that the sensitivity to detect a moxifloxacin-induced increase in QTc was similar with use of either an ascending dose or Latin square design. However, it is important to note that day effect is confounded with treatment effect in an ascending dose design, risking bias in the estimation of a treatment-related effect. Therefore, while sensitivity values were similar between designs, when feasible, Latin square is preferred over ascending dose.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107779"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095211","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}