Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107820
Ranor C.B. Basa , Randall S. Ingermanson , Filiberto Catalan-Perez , Ricardo Serrano , Ariel Wang , Alyson Smith , Jeffrey M. Hilton , Patrick M. McDonough , Cherie Handley , Lilian Harrison , Ameena Pascua , Mark Mercola , Jeffrey H. Price
Human-induced pluripotent stem cell (hiPSC) models are more species-relevant than animal models and are amenable to high-throughput scalability. Previously, our Kinetic Image Cytometry (KIC) proarrhythmia assay examining calcium kinetics in hiPSC-cardiomyocytes (CMs) had a clinical accuracy of ~90 % (Pfeiffer, et al., 2016); when augmented with deep learning, accuracy increased to 95 % (Serrano, et al., 2023). Expanding upon this work, we screened 31 compounds with known clinical effects (effector classes: sarcoplasmic reticulum/calcium release, plasma membrane/ion channel, mitochondrial/myosin, and negative controls) in a 7-point concentration-response format—bracketing clinical exposures—using a panel of patient-derived hiPSC-CMs. We loaded hiPSC-CMs with Cal-520 (a green-channel calcium indicator), BeRST-1 (a far red-channel membrane voltage dye), TMRM (a mitochondrial membrane potential dye), and Hoechst (for nuclei), then exposed them to test compounds acutely. We then acquired interleaved calcium and voltage movies at 60 Hz (30 Hz/channel) as well as single images of TMRM and Hoechst. Vala's image analysis software, CyteSeer, was used to simultaneously measure calcium/action potential (AP) kinetics on—and to derive contraction metrics from—those movies. Furthermore, we mathematically characterized and classified calcium/AP waveforms to quantify compound-induced cardiotoxic effects. Additionally, we assessed mitochondrial health (using TMRM fluorescence) as well as acute cytotoxicity (using nucleus morphology) in the same experiment. By multiplexing these readouts on a single-cell level, we were able to correctly classify 30/31 (96.8 %) compounds on the basis of earliest-observed adverse effects (if any) by primary effector class at clinically-relevant test concentrations. While the data were more complex than initially expected (e.g., due to pleiotropic clinical effects and/or multiple efficacy−/toxicity-related targets), this multiplexed approach has the potential to elucidate mechanistic classes or targets quickly; and some of the more unexpected results from our screen highlight the need for de-risking early in drug development using relatively inexpensive and highly scalable hiPSC models. A larger study is currently underway to examine a library of 300+ compounds in order to comprehensively validate and refine our multiplexed assay.
{"title":"Assessing the cardiotoxicity of 31 compounds using a multiplexed kinetic image cytometry (KIC)-based assay: Harnessing the predictive power of human iPSC-cardiomyocytes for early drug development","authors":"Ranor C.B. Basa , Randall S. Ingermanson , Filiberto Catalan-Perez , Ricardo Serrano , Ariel Wang , Alyson Smith , Jeffrey M. Hilton , Patrick M. McDonough , Cherie Handley , Lilian Harrison , Ameena Pascua , Mark Mercola , Jeffrey H. Price","doi":"10.1016/j.vascn.2025.107820","DOIUrl":"10.1016/j.vascn.2025.107820","url":null,"abstract":"<div><div>Human-induced pluripotent stem cell (hiPSC) models are more species-relevant than animal models and are amenable to high-throughput scalability. Previously, our Kinetic Image Cytometry (KIC) proarrhythmia assay examining calcium kinetics in hiPSC-cardiomyocytes (CMs) had a clinical accuracy of ~90 % (Pfeiffer, <em>et al.</em>, 2016); when augmented with deep learning, accuracy increased to 95 % (Serrano, <em>et al.</em>, 2023). Expanding upon this work, we screened 31 compounds with known clinical effects (effector classes: sarcoplasmic reticulum/calcium release, plasma membrane/ion channel, mitochondrial/myosin, and negative controls) in a 7-point concentration-response format—bracketing clinical exposures—using a panel of patient-derived hiPSC-CMs. We loaded hiPSC-CMs with Cal-520 (a green-channel calcium indicator), BeRST-1 (a far red-channel membrane voltage dye), TMRM (a mitochondrial membrane potential dye), and Hoechst (for nuclei), then exposed them to test compounds acutely. We then acquired interleaved calcium and voltage movies at 60 Hz (30 Hz/channel) as well as single images of TMRM and Hoechst. Vala's image analysis software, CyteSeer, was used to simultaneously measure calcium/action potential (AP) kinetics on—and to derive contraction metrics from—those movies. Furthermore, we mathematically characterized and classified calcium/AP waveforms to quantify compound-induced cardiotoxic effects. Additionally, we assessed mitochondrial health (using TMRM fluorescence) as well as acute cytotoxicity (using nucleus morphology) in the same experiment. By multiplexing these readouts on a single-cell level, we were able to correctly classify 30/31 (96.8 %) compounds on the basis of earliest-observed adverse effects (if any) by primary effector class at clinically-relevant test concentrations. While the data were more complex than initially expected (<em>e.g.</em>, due to pleiotropic clinical effects and/or multiple efficacy−/toxicity-related targets), this multiplexed approach has the potential to elucidate mechanistic classes or targets quickly; and some of the more unexpected results from our screen highlight the need for de-risking early in drug development using relatively inexpensive and highly scalable hiPSC models. A larger study is currently underway to examine a library of 300+ compounds in order to comprehensively validate and refine our multiplexed assay.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107820"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094615","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107821
Ahmed Khedher , Patricia Davidson , Pauline Thiebaud , Stijn Robben , Cyril Cerveau , Jamie Bhagwan , Mael Le Berre , Rita S.R. RIbeiro
Cardiac adverse events are among the top reasons for discontinuing drugs in early clinical phase studies, where drugs with cardiotoxic liabilities are responsible for one third of regulatory failures. These alarming statistics highlight the widespread occurrence and significant financial burden of ineffective drugs that proceed from preclinical animal studies. Despite advancements in cardiac bioengineering, challenges remain regarding physiological relevance, cost, and throughput. To address these challenges, an innovative 3D cardiac model, the SmartHeart (SH), was developed. This model facilitates the self-assembly and maturation of ring-shaped cardiac tissues and allows for precise in-situ measurements of various parameters (e.g. contraction stress, strain, beating metrics, membrane action potential and calcium signaling). The technology is based on standard 96-well plates coated with a structured hydrogel, which features an array of conical-shaped microwells, each surrounding a central pillar. Within less than 48 h after cell seeding, the tissues (composed of iPSC-derived ventricular cardiomyocytes (Axol) and fibroblasts) demonstrated rhythmic contractions. The contractility stress and strain as well as the beating rate of the tissues were quantified by monitoring the variation of the central pillar's area with known stiffness (12 kPa) with time. After 14 days, the tissues presented morphological signs of maturation and were exposed to several classical drugs. The presence of isoproterenol caused a positive inotropic and chronotropic response. A negative inotropic response was induced by nifedipine and the tissues became quiescent when exposed to high doses of mexiletine, which is consistent with its known pharmacological effects as a sodium channel blocker. The hydrogel's optical transparency allows compatibility with high-resolution image-based techniques. This includes the use of voltage-sensitive fluorescent dyes, such as FluoVolt that showed an intensity spike just before the tissue contraction. Likewise, cellular spatial organization and intracellular morphology, e.g. cardiomyocyte cytoskeletal fiber elongation and striation, showing signs of maturation, could be visualized using immunofluorescence. In conclusion, the SmartHeart 3D-cardiac model provides an advanced solution to the ongoing challenges in drug discovery by enabling precise, real-time monitoring of cardiac tissue function and maturation. This innovative platform offers robust and relevant readouts for high-throughput and high-content screening, significantly enhancing the assessment of drug efficacy and safety.
{"title":"SmartHeart: An innovative high throughput assay to generate and assess cardiac micro tissues from hiPSCs answering to the current challenges of drug discovery","authors":"Ahmed Khedher , Patricia Davidson , Pauline Thiebaud , Stijn Robben , Cyril Cerveau , Jamie Bhagwan , Mael Le Berre , Rita S.R. RIbeiro","doi":"10.1016/j.vascn.2025.107821","DOIUrl":"10.1016/j.vascn.2025.107821","url":null,"abstract":"<div><div>Cardiac adverse events are among the top reasons for discontinuing drugs in early clinical phase studies, where drugs with cardiotoxic liabilities are responsible for one third of regulatory failures. These alarming statistics highlight the widespread occurrence and significant financial burden of ineffective drugs that proceed from preclinical animal studies. Despite advancements in cardiac bioengineering, challenges remain regarding physiological relevance, cost, and throughput. To address these challenges, an innovative 3D cardiac model, the SmartHeart (SH), was developed. This model facilitates the self-assembly and maturation of ring-shaped cardiac tissues and allows for precise in-situ measurements of various parameters (e.g. contraction stress, strain, beating metrics, membrane action potential and calcium signaling). The technology is based on standard 96-well plates coated with a structured hydrogel, which features an array of conical-shaped microwells, each surrounding a central pillar. Within less than 48 h after cell seeding, the tissues (composed of iPSC-derived ventricular cardiomyocytes (Axol) and fibroblasts) demonstrated rhythmic contractions. The contractility stress and strain as well as the beating rate of the tissues were quantified by monitoring the variation of the central pillar's area with known stiffness (12 kPa) with time. After 14 days, the tissues presented morphological signs of maturation and were exposed to several classical drugs. The presence of isoproterenol caused a positive inotropic and chronotropic response. A negative inotropic response was induced by nifedipine and the tissues became quiescent when exposed to high doses of mexiletine, which is consistent with its known pharmacological effects as a sodium channel blocker. The hydrogel's optical transparency allows compatibility with high-resolution image-based techniques. This includes the use of voltage-sensitive fluorescent dyes, such as FluoVolt that showed an intensity spike just before the tissue contraction. Likewise, cellular spatial organization and intracellular morphology, e.g. cardiomyocyte cytoskeletal fiber elongation and striation, showing signs of maturation, could be visualized using immunofluorescence. In conclusion, the SmartHeart 3D-cardiac model provides an advanced solution to the ongoing challenges in drug discovery by enabling precise, real-time monitoring of cardiac tissue function and maturation. This innovative platform offers robust and relevant readouts for high-throughput and high-content screening, significantly enhancing the assessment of drug efficacy and safety.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107821"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094719","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107812
Jin Chang
Physiological relevance and accuracy in cardiac safety pharmacology studies is of the utmost importance, as supported by the recent changes in ICH guidelines and the CiPA committee's efforts. Although most of the studies focused on hERG-affecting molecules and the arrhythmic risk related to Action Potential elongation, iPSC-derived cardiomyocytes have the potential to be a more thorough assay with more physiological relevance. In this study, we demonstrate how laser optoporation technology opens transient nanopores within the cell's membrane and allows for Action Potential (AP) recordings from cardiac cells and compare the results to traditional MEA-based Field Potential Measurements. In particular, we show how the response to a potassium channel blocker (dofetilide) is comparable when looking at the APD90(>30 % increase) but that the APD30 is shortened (>10 % decrease) which we would not be able to measure with traditional MEA. The response to an Ica blocker (Nifedipine) reveals how the drug affects the depolarization currents, which can not be measured with traditional MEA. In addition, Beta-adrenergic (isoproterenol) receptor response demonstrated how the AP-amplitude remains unchanged while the contractility is increased (>30 %). We also show how the technology is non-invasive and label-free, allowing for reliable and stable measurements over 3 weeks, and how the results are comparable to previous validated data. With these results, we suggest further exploration of this technique in its use in safety pharmacology to predict cardiotoxic effects, potentially serving as an upgrade on previous technology which was limited to Field Potential Duration elongation effects.
{"title":"Evaluation of laser optoporation-induced action-potential-like measurements on iPSC-cardiomyocytes and the assessment of drug-induced effects on APD and contractility","authors":"Jin Chang","doi":"10.1016/j.vascn.2025.107812","DOIUrl":"10.1016/j.vascn.2025.107812","url":null,"abstract":"<div><div>Physiological relevance and accuracy in cardiac safety pharmacology studies is of the utmost importance, as supported by the recent changes in ICH guidelines and the CiPA committee's efforts. Although most of the studies focused on hERG-affecting molecules and the arrhythmic risk related to Action Potential elongation, iPSC-derived cardiomyocytes have the potential to be a more thorough assay with more physiological relevance. In this study, we demonstrate how laser optoporation technology opens transient nanopores within the cell's membrane and allows for Action Potential (AP) recordings from cardiac cells and compare the results to traditional MEA-based Field Potential Measurements. In particular, we show how the response to a potassium channel blocker (dofetilide) is comparable when looking at the APD90(>30 % increase) but that the APD30 is shortened (>10 % decrease) which we would not be able to measure with traditional MEA. The response to an Ica blocker (Nifedipine) reveals how the drug affects the depolarization currents, which can not be measured with traditional MEA. In addition, Beta-adrenergic (isoproterenol) receptor response demonstrated how the AP-amplitude remains unchanged while the contractility is increased (>30 %). We also show how the technology is non-invasive and label-free, allowing for reliable and stable measurements over 3 weeks, and how the results are comparable to previous validated data. With these results, we suggest further exploration of this technique in its use in safety pharmacology to predict cardiotoxic effects, potentially serving as an upgrade on previous technology which was limited to Field Potential Duration elongation effects.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107812"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094842","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107816
Luca Del Core , Marcel Mohr , Jean-Marie Chambard , Véronique Ballet , Ambroise Garry , Friedemann Schmidt , Gary R. Mirams
Mathematical action potential (AP) models describe the changes in the membrane voltage due to a complex interplay between ionic currents, and their interactions with drug compounds. These models can guide preclinical risk assessments for drug-induced cardiac arrhythmia and extract more information from animal-based experiments. The rabbit Purkinje fiber has been used in preclinical studies, as it includes the major currents present in human ventricular myocytes. A recently proposed mathematical AP model of the rabbit Purkinje fiber, combined with ion channel screening data, predicted drug effects on AP changes, with an agreement of up to 80 % (Mohr et al., 2022). To explain the 20 % mismatch, we first improve the original AP model by re-calibrating its parameters to fit control AP traces. Subsequently we test our inference method in terms of uncertainty quantification of the control parameters. Finally, we compare the calibrated model and the original model in terms of prediction of AP %-changes induced by reference drug compounds with well-studied channel block properties and low measurement error (sd < 10). Preliminary results indicate that after calibrating the ionic conductances, the correlation between observed and predicted %-change in APD50 (APD90) increased from −0.1 (0.04) to 0.43 (0.34). We are currently working on fitting model predictions to experimental AP changes in the presence of a new set of compounds, to infer the block of various ion channels, in terms of 50 % inhibitory concentration (IC50). The aim is to perform an experimental test for any computationally inferred IC50s which have not been measured, particularly for those drug compounds whose action potential changes are not explained by the existing ion channel screening data.
{"title":"Inferring ion channel block from rabbit Purkinje fiber action potential recordings","authors":"Luca Del Core , Marcel Mohr , Jean-Marie Chambard , Véronique Ballet , Ambroise Garry , Friedemann Schmidt , Gary R. Mirams","doi":"10.1016/j.vascn.2025.107816","DOIUrl":"10.1016/j.vascn.2025.107816","url":null,"abstract":"<div><div>Mathematical action potential (AP) models describe the changes in the membrane voltage due to a complex interplay between ionic currents, and their interactions with drug compounds. These models can guide preclinical risk assessments for drug-induced cardiac arrhythmia and extract more information from animal-based experiments. The rabbit Purkinje fiber has been used in preclinical studies, as it includes the major currents present in human ventricular myocytes. A recently proposed mathematical AP model of the rabbit Purkinje fiber, combined with ion channel screening data, predicted drug effects on AP changes, with an agreement of up to 80 % (Mohr et al., 2022). To explain the 20 % mismatch, we first improve the original AP model by re-calibrating its parameters to fit control AP traces. Subsequently we test our inference method in terms of uncertainty quantification of the control parameters. Finally, we compare the calibrated model and the original model in terms of prediction of AP %-changes induced by reference drug compounds with well-studied channel block properties and low measurement error (sd < 10). Preliminary results indicate that after calibrating the ionic conductances, the correlation between observed and predicted %-change in APD50 (APD90) increased from −0.1 (0.04) to 0.43 (0.34). We are currently working on fitting model predictions to experimental AP changes in the presence of a new set of compounds, to infer the block of various ion channels, in terms of 50 % inhibitory concentration (IC50). The aim is to perform an experimental test for any computationally inferred IC50s which have not been measured, particularly for those drug compounds whose action potential changes are not explained by the existing ion channel screening data.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107816"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094846","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107818
Niall MacQuaide , Taylor Watters , Shahrum G. Ghasemi , Lewis Hamilton , Mark Bryant , Godfrey L. Smith
The acute effects of drugs (~1 h) on the electrical activity, particularly those related to hERG block have been extensively studied in iPSC-derived cardiomyocytes (iPSC -CMs). However, long-term (>12 h) drug exposure can also lead to slowly developing actions on hERG channels that result in QT prolongation, the most common are drugs that inhibit hERG trafficking to the surface membrane and cause an acquired long QT phenotype. The aim of the study is to assess the ability of iPSC-CM based assays to study the action of drugs known to inhibit hERG trafficking over a longer period using serum-free solutions. The following functional cellular parameters were measured over 72 h at 24 h intervals: (i) action potential duration (ii) contractile kinetics (iii) iPSC -CM monolayer integrity (iv) plasmalemma integrity (iv) membrane hERG expression. We used iCell2 (FujiFilm-CDI) iPSC -CMs, which we plated on a 96well plate and incubated in a serum free media. We performed automated image and signal analysis using a proprietary analysis platform (CellOPTIQ®- Clyde Biosciences). We tested 6 concentrations of Pentamidine and Arsenic Trioxide (ATO) which are both known to affect hERG trafficking and assessed chronic toxicity, electrophysiological, metabolic dysfunction. Pentamidine showed obvious prolongation of APD90 in the clinical range (1-3 μM) after 72 h and after 24 h at higher concentration (3-10 μM). ATO induced APD prolongation at 1-3 μM but shortening at 10 μM indicating mixed ion channel trafficking or metabolic effects. Western blot analysis of the membrane fraction showed significant downregulation of hERG expression of cells exposed to 48 h of 1 μM pentamidine. This work demonstrates the utility of chronic studies of IPSC-CMs to study the medium-long term actions of drugs on the hERG activity. The associated biochemical assays can confirm the extent to which reduction of hERG expression in the plasmalemmal membrane is responsible for the action.
{"title":"Correlation electrical repolarization and membrane hERG abundance in iPSC cardiomyocytes induced by chronic drugs actions on channel trafficking","authors":"Niall MacQuaide , Taylor Watters , Shahrum G. Ghasemi , Lewis Hamilton , Mark Bryant , Godfrey L. Smith","doi":"10.1016/j.vascn.2025.107818","DOIUrl":"10.1016/j.vascn.2025.107818","url":null,"abstract":"<div><div>The acute effects of drugs (~1 h) on the electrical activity, particularly those related to hERG block have been extensively studied in iPSC-derived cardiomyocytes (iPSC -CMs). However, long-term (>12 h) drug exposure can also lead to slowly developing actions on hERG channels that result in QT prolongation, the most common are drugs that inhibit hERG trafficking to the surface membrane and cause an acquired long QT phenotype. The aim of the study is to assess the ability of iPSC-CM based assays to study the action of drugs known to inhibit hERG trafficking over a longer period using serum-free solutions. The following functional cellular parameters were measured over 72 h at 24 h intervals: (i) action potential duration (ii) contractile kinetics (iii) iPSC -CM monolayer integrity (iv) plasmalemma integrity (iv) membrane hERG expression. We used iCell2 (FujiFilm-CDI) iPSC -CMs, which we plated on a 96well plate and incubated in a serum free media. We performed automated image and signal analysis using a proprietary analysis platform (CellOPTIQ®- Clyde Biosciences). We tested 6 concentrations of Pentamidine and Arsenic Trioxide (ATO) which are both known to affect hERG trafficking and assessed chronic toxicity, electrophysiological, metabolic dysfunction. Pentamidine showed obvious prolongation of APD90 in the clinical range (1-3 μM) after 72 h and after 24 h at higher concentration (3-10 μM). ATO induced APD prolongation at 1-3 μM but shortening at 10 μM indicating mixed ion channel trafficking or metabolic effects. Western blot analysis of the membrane fraction showed significant downregulation of hERG expression of cells exposed to 48 h of 1 μM pentamidine. This work demonstrates the utility of chronic studies of IPSC-CMs to study the medium-long term actions of drugs on the hERG activity. The associated biochemical assays can confirm the extent to which reduction of hERG expression in the plasmalemmal membrane is responsible for the action.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107818"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094848","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107793
David J. Heal , Jane Gosden , Sharon L. Smith
Intravenous self-administration (IVSA) evaluates whether a CNS drug-candidate produces rewarding effects that could cause psychological dependence in patients and lead to its diversion for abuse. The model was originally developed to investigate powerful reinforcers like opiates and stimulants. For that reason, IVSA is not well adapted to detect the abuse potential of a new generation of drugs with moderate/low abuse potential. Using experience gained from conducting IVSA experiments with many types of drugs of abuse and novel drug-candidates, we offer insights on obtaining translationally predictive results from IVSA experiments, and technical refinements to increase the sensitivity and granularity of the findings. All experiments were conducted in mildly food-restricted, male, Sprague-Dawley rats with implanted with intravenous catheters. Standard IVSA tests were conducted on low fixed ratio (FR) schedules (FR3 or FR5), not FR10 as recommended in CDER/FDA guidance (CDER/FDA, 2017). As a technical refinement, the relative reinforcing effect was assessed by break-point determination on a progressive ratio (PR) schedule of reinforcement. All break-points were determined across a range of reinforcing drug doses to ensure the maximum reinforcing effect was identified. Moderate reinforcers, MDMA (entactogen), butorphanol (κ-agonist/μ-partial agonist), and (−)pentazocine (κ-agonist/μ-antagonist) produced break-points between 25 and 33 lever-presses/infusion. Weak reinforcers, WIN55,212 (CB1/CB2 agonist), diazepam, midazolam and methohexital (all GABA-A receptor positive allosteric modulators [PAMs]) produced mean break-points of 17–22 lever-presses/infusion. In contrast, powerful reinforcers like the opioids, eg heroin, remifentanil, oxycodone, and stimulants, eg cocaine, methylphenidate, supported mean break-points ranging between 41 and 98 lever‑presses/infusion. The break-point for saline (non-reinforcing control) was 10.4 ± 0.8 lever-presses/infusion. The results were used to design and conduct successful IVSA evaluations on cannabidiol (CBD), ulotaront and samidorphan on a FR3 schedule, difelikefalin, dasotraline, centanafadine, and soticlestat on a FR5 schedule, and PR/break-point determinations on samidorphan and naloxone. CNS drug development is in an era where new entactogens, psychedelics and drugs with novel mechanisms are undergoing clinical evaluation. Refinements to IVSA testing that we advocate have proven value based on experiments with known substances of abuse and novel drug-candidates.
{"title":"Intravenous self-administration – Valid experimental designs to evaluate the abuse potential of psychedelics, entactogens and drugs with novel mechanisms","authors":"David J. Heal , Jane Gosden , Sharon L. Smith","doi":"10.1016/j.vascn.2025.107793","DOIUrl":"10.1016/j.vascn.2025.107793","url":null,"abstract":"<div><div>Intravenous self-administration (IVSA) evaluates whether a CNS drug-candidate produces rewarding effects that could cause psychological dependence in patients and lead to its diversion for abuse. The model was originally developed to investigate powerful reinforcers like opiates and stimulants. For that reason, IVSA is not well adapted to detect the abuse potential of a new generation of drugs with moderate/low abuse potential. Using experience gained from conducting IVSA experiments with many types of drugs of abuse and novel drug-candidates, we offer insights on obtaining translationally predictive results from IVSA experiments, and technical refinements to increase the sensitivity and granularity of the findings. All experiments were conducted in mildly food-restricted, male, Sprague-Dawley rats with implanted with intravenous catheters. Standard IVSA tests were conducted on low fixed ratio (FR) schedules (FR3 or FR5), not FR10 as recommended in CDER/FDA guidance (CDER/FDA, 2017). As a technical refinement, the relative reinforcing effect was assessed by break-point determination on a progressive ratio (PR) schedule of reinforcement. All break-points were determined across a range of reinforcing drug doses to ensure the maximum reinforcing effect was identified. Moderate reinforcers, MDMA (entactogen), butorphanol (κ-agonist/μ-partial agonist), and (−)pentazocine (κ-agonist/μ-antagonist) produced break-points between 25 and 33 lever-presses/infusion. Weak reinforcers, WIN55,212 (CB1/CB2 agonist), diazepam, midazolam and methohexital (all GABA-A receptor positive allosteric modulators [PAMs]) produced mean break-points of 17–22 lever-presses/infusion. In contrast, powerful reinforcers like the opioids, eg heroin, remifentanil, oxycodone, and stimulants, eg cocaine, methylphenidate, supported mean break-points ranging between 41 and 98 lever‑presses/infusion. The break-point for saline (non-reinforcing control) was 10.4 ± 0.8 lever-presses/infusion. The results were used to design and conduct successful IVSA evaluations on cannabidiol (CBD), ulotaront and samidorphan on a FR3 schedule, difelikefalin, dasotraline, centanafadine, and soticlestat on a FR5 schedule, and PR/break-point determinations on samidorphan and naloxone. CNS drug development is in an era where new entactogens, psychedelics and drugs with novel mechanisms are undergoing clinical evaluation. Refinements to IVSA testing that we advocate have proven value based on experiments with known substances of abuse and novel drug-candidates.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107793"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095193","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}
The E14/S7B Q&A guidelines introduce the concept of “double negative” (negative hERG and negative in vivo QTc) non-clinical data which can be used along with negative Phase 1 clinical QTc data to substitute for a clinical Thorough QT study in specific cases (Q&As 5.1 and 6.1). The non-clinical data are to be generated using “best practice” designs in order to support data quality and consistency across the industry. For the in vivo QT assay, best practice recommendations require characterization of individual study sensitivity, verification of independence QTc from heart rate, demonstration of test facility sensitivity and pharmacological translation to human using a positive control. We have previously validated E14/S7B Q&A compliant in vivo QT assays in dog and non-human primate. The objective of this work was to perform the validation in the minipig as the third non-rodent species commonly used for cardiovascular safety assessment. A positive control telemetry study was performed with moxifloxacin (30, 120, 300 mg/kg) using a double Latin square crossover study design (n = 8), followed by an ascending dose design (n = 5). A single PK sample was drawn during the telemetry phase, and a separate full PK phase was included at all dose levels for PK/PD assessment to determine translation to human. Moxifloxacin-induced increases in QTc were observed, with a maximal increase at the highest dose of 86 and 67 msec for the double cross-over and ascending dose designs, respectively. Smallest statistically detectable differences (SSDD) for QTc were 11 msec for the double cross-over and 10 msec for the ascending dose design. Based on the free plasma exposures and magnitude of the QTc effects from the crossover data, a 10 msec effect was observed at 0.77× of the free moxifloxacin concentration known to produce a 10 msec QTc effect in human. In conclusion, we have validated an E14/S7B Q&A compliant in vivo QT assay in the minipig for both cross-over and ascending dose designs and shown good translation to human, completing the Labcorp™ offering for in-vivo E14/S7B Q&A compliant studies.
{"title":"Validation of in vivo QT ICH E14/S7B Q&A guidance in minipig","authors":"Rachael Hardman , Joyce Obeng , Jill Nichols , Karim Melliti","doi":"10.1016/j.vascn.2025.107778","DOIUrl":"10.1016/j.vascn.2025.107778","url":null,"abstract":"<div><div>The E14/S7B Q&A guidelines introduce the concept of “double negative” (negative hERG and negative in vivo QTc) non-clinical data which can be used along with negative Phase 1 clinical QTc data to substitute for a clinical Thorough QT study in specific cases (Q&As 5.1 and 6.1). The non-clinical data are to be generated using “best practice” designs in order to support data quality and consistency across the industry. For the in vivo QT assay, best practice recommendations require characterization of individual study sensitivity, verification of independence QTc from heart rate, demonstration of test facility sensitivity and pharmacological translation to human using a positive control. We have previously validated E14/S7B Q&A compliant in vivo QT assays in dog and non-human primate. The objective of this work was to perform the validation in the minipig as the third non-rodent species commonly used for cardiovascular safety assessment. A positive control telemetry study was performed with moxifloxacin (30, 120, 300 mg/kg) using a double Latin square crossover study design (<em>n</em> = 8), followed by an ascending dose design (<em>n</em> = 5). A single PK sample was drawn during the telemetry phase, and a separate full PK phase was included at all dose levels for PK/PD assessment to determine translation to human. Moxifloxacin-induced increases in QTc were observed, with a maximal increase at the highest dose of 86 and 67 msec for the double cross-over and ascending dose designs, respectively. Smallest statistically detectable differences (SSDD) for QTc were 11 msec for the double cross-over and 10 msec for the ascending dose design. Based on the free plasma exposures and magnitude of the QTc effects from the crossover data, a 10 msec effect was observed at 0.77× of the free moxifloxacin concentration known to produce a 10 msec QTc effect in human. In conclusion, we have validated an E14/S7B Q&A compliant in vivo QT assay in the minipig for both cross-over and ascending dose designs and shown good translation to human, completing the Labcorp™ offering for in-vivo E14/S7B Q&A compliant studies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107778"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095349","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}
Pub Date : 2025-09-01Epub Date: 2025-09-19DOI: 10.1016/j.vascn.2025.107777
Kamila J. Sadko , Derek J. Leishman , Hannah Garver , Gregory Fink , Marc B. Bailie , Adam Lauver
Released in 2022, the FDA's draft guidance “Assessment of Pressor Effects of Drugs”, proposes that a dedicated clinical study for chronic use drugs should be powered to rule out a potential systolic arterial blood pressure (BP) increase of 3 mmHg over 24 h. Given the resource commitment of clinical studies, sensitive nonclinical prediction of potentially meaningful BP increases would be valuable. This study aimed to determine the utility of long-term rat studies for detecting acute and chronic blood pressure changes. We hypothesized that studies using rats have adequate stability and variability to detect BP changes ≥3 mmHg over several weeks. Available data from a historic rodent assessment of 80 days duration (N = 9) in vehicle treated Sprague Dawley rats was used. The data were assessed for minimal detectable differences (MDDs), least significant differences (LSDs), and changes from baseline for all BP measures in light and dark 12 h, days, and weeks. Day 15 was used as the reference day and Day 43 as the comparison for day-to-day and light and dark changes from baseline to simulate a 4-week study with a week-long baseline assessment. In week comparison, week 2 was compared to week 5. A one-way t-test was conducted against an assumed mean difference of 0 to evaluate for significance. Study average difference from baseline for the dark cycle were 1.80 ± 1.42 (mean ± standard deviation), 1.99 ± 1.34, and 1.86 ± 1.25 mmHg for diastolic (Dia), systolic (Sys), and mean arterial pressure (MAP), respectively. Light cycle differences were 0.54 ± 1.23, −0.04 ± 1.101, and 0.143 ± 0.91 mmHg for Dia, Sys, and MAP . Day-to-day differences of 1.21 ± 1.29, 0.89 ± 1.12, and 0.931 ± 1.01 mmHg for Dia, Sys, and MAP were seen. Week-to-week differences were − 2.55 ± 1.47 mmHg for Sys, 2.30 ± 1.29 mmHg for MAP, and 1.87 ± 1.22 mmHg for Dia. Results were not significantly different from 0. Overall, rats demonstrated small insignificant changes from baseline in their blood pressure measures across a longitudinal study. The low variability observed was sufficient to encourage further evaluation of the minimal detectable differences which is currently underway.
{"title":"Are current rat studies sensitive to detect blood pressure changes per the new FDA draft clinical blood pressure guidance?","authors":"Kamila J. Sadko , Derek J. Leishman , Hannah Garver , Gregory Fink , Marc B. Bailie , Adam Lauver","doi":"10.1016/j.vascn.2025.107777","DOIUrl":"10.1016/j.vascn.2025.107777","url":null,"abstract":"<div><div>Released in 2022, the FDA's draft guidance “Assessment of Pressor Effects of Drugs”, proposes that a dedicated clinical study for chronic use drugs should be powered to rule out a potential systolic arterial blood pressure (BP) increase of 3 mmHg over 24 h. Given the resource commitment of clinical studies, sensitive nonclinical prediction of potentially meaningful BP increases would be valuable. This study aimed to determine the utility of long-term rat studies for detecting acute and chronic blood pressure changes. We hypothesized that studies using rats have adequate stability and variability to detect BP changes ≥3 mmHg over several weeks. Available data from a historic rodent assessment of 80 days duration (<em>N</em> = 9) in vehicle treated Sprague Dawley rats was used. The data were assessed for minimal detectable differences (MDDs), least significant differences (LSDs), and changes from baseline for all BP measures in light and dark 12 h, days, and weeks. Day 15 was used as the reference day and Day 43 as the comparison for day-to-day and light and dark changes from baseline to simulate a 4-week study with a week-long baseline assessment. In week comparison, week 2 was compared to week 5. A one-way <em>t</em>-test was conducted against an assumed mean difference of 0 to evaluate for significance. Study average difference from baseline for the dark cycle were 1.80 ± 1.42 (mean ± standard deviation), 1.99 ± 1.34, and 1.86 ± 1.25 mmHg for diastolic (Dia), systolic (Sys), and mean arterial pressure (MAP), respectively. Light cycle differences were 0.54 ± 1.23, −0.04 ± 1.101, and 0.143 ± 0.91 mmHg for Dia, Sys, and MAP . Day-to-day differences of 1.21 ± 1.29, 0.89 ± 1.12, and 0.931 ± 1.01 mmHg for Dia, Sys, and MAP were seen. Week-to-week differences were − 2.55 ± 1.47 mmHg for Sys, 2.30 ± 1.29 mmHg for MAP, and 1.87 ± 1.22 mmHg for Dia. Results were not significantly different from 0. Overall, rats demonstrated small insignificant changes from baseline in their blood pressure measures across a longitudinal study. The low variability observed was sufficient to encourage further evaluation of the minimal detectable differences which is currently underway.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107777"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095344","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}
Pub Date : 2025-09-01Epub Date: 2025-06-19DOI: 10.1016/j.vascn.2025.107765
Jean-Pierre Valentin , Todd Bourcier , Xuan Chi , Annie Delaunois , C. Michael Foley , Kim A. Henderson , Pierre Lainee , Derek J. Leishman , Dingzhou Li , Emma Pawluk , Michael K. Pugsley , Sridharan Rajamani , Christopher P. Regan , Michael G. Rolf , Rebecca Ross , Eric I. Rossman , Stephen D. Tichenor , Inmaculada C. Villar , Todd A. Wisialowski , Jean Wu , Hugo M. Vargas
<div><h3>Introduction</h3><div>Cardiovascular (CV) parameters<sup>1</sup> 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 <em>sensitivity and reliability</em> 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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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
{"title":"Current practices on the measurement of electrocardiogram and hemodynamic parameters in non–rodent species in regulatory safety assessment studies","authors":"Jean-Pierre Valentin , Todd Bourcier , Xuan Chi , Annie Delaunois , C. Michael Foley , Kim A. Henderson , Pierre Lainee , Derek J. Leishman , Dingzhou Li , Emma Pawluk , Michael K. Pugsley , Sridharan Rajamani , Christopher P. Regan , Michael G. Rolf , Rebecca Ross , Eric I. Rossman , Stephen D. Tichenor , Inmaculada C. Villar , Todd A. Wisialowski , Jean Wu , Hugo M. Vargas","doi":"10.1016/j.vascn.2025.107765","DOIUrl":"10.1016/j.vascn.2025.107765","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular (CV) parameters<sup>1</sup> 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 <em>sensitivity and reliability</em> 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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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":"2025-09-01","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}
Pub Date : 2025-09-01Epub Date: 2025-08-20DOI: 10.1016/j.vascn.2025.108391
Michael K. Pugsley , Brett R. Winters , Stephen D. Tichenor , Simon Authier , Yevgeniya E. Koshman , Krystle G. Correll , Michael J. Curtis
This editorial prefaces the annual themed issue on those methods with application to safety pharmacology (SP) in the Journal of Pharmacological and Toxicological Methods (JPTM). Highlighted content is derived from the 2024 Safety Pharmacology Society (SPS) meeting held in San Diego, CA, USA. The meeting showcased 122 posters, many of which are reproduced as abstracts published in JPTM. The manuscripts predominantly reflect updates to core battery safety evaluation and data analysis methods and include areas of novel investigation within SP. The results from several surveys including an updated salary survey by the SPS, current industry practices on neurotoxicity by the ACT, SPS and STP and results on the need to revisit the ICH S7A guidance on safety and secondary pharmacology by EFPIA, JPMA, and PhRMA provide timely updates. Other manuscripts include in vitro assessment methods for sodium channel block using MEA arrays, and a comparison of the in vitro effects of positive control drugs on the hERG channel current using different testing procedures. In vivo cardiovascular manuscripts include an overview of surgical telemetry implantation methods, utility of automated blood sampling methods in SP studies, evaluation of the performance characteristics for common QTc data collection methods, and an evaluation of a clinically used wearable ECG device for use in SP studies. There is also an overview of the impact of respiratory SP and a comprehensive review and comparison of current practices regarding methodological approaches used to acquire CV data in repeat-dose non-rodent toxicology studies. The 21 years of consecutive themed issues on SP methods attends to the importance of methods evaluation and the contribution of SP to the process of methods evaluation.
{"title":"Safety Pharmacology: Achieving a quarter century milestone as a scientific discipline","authors":"Michael K. Pugsley , Brett R. Winters , Stephen D. Tichenor , Simon Authier , Yevgeniya E. Koshman , Krystle G. Correll , Michael J. Curtis","doi":"10.1016/j.vascn.2025.108391","DOIUrl":"10.1016/j.vascn.2025.108391","url":null,"abstract":"<div><div>This editorial prefaces the annual themed issue on those methods with application to safety pharmacology (SP) in the <em>Journal of Pharmacological and Toxicological Methods</em> (JPTM). Highlighted content is derived from the 2024 Safety Pharmacology Society (SPS) meeting held in San Diego, CA, USA. The meeting showcased 122 posters, many of which are reproduced as abstracts published in JPTM. The manuscripts predominantly reflect updates to core battery safety evaluation and data analysis methods and include areas of novel investigation within SP. The results from several surveys including an updated salary survey by the SPS, current industry practices on neurotoxicity by the ACT, SPS and STP and results on the need to revisit the ICH S7A guidance on safety and secondary pharmacology by EFPIA, JPMA, and PhRMA provide timely updates. Other manuscripts include in vitro assessment methods for sodium channel block using MEA arrays, and a comparison of the in vitro effects of positive control drugs on the hERG channel current using different testing procedures. In vivo cardiovascular manuscripts include an overview of surgical telemetry implantation methods, utility of automated blood sampling methods in SP studies, evaluation of the performance characteristics for common QTc data collection methods, and an evaluation of a clinically used wearable ECG device for use in SP studies. There is also an overview of the impact of respiratory SP and a comprehensive review and comparison of current practices regarding methodological approaches used to acquire CV data in repeat-dose non-rodent toxicology studies. The 21 years of consecutive themed issues on SP methods attends to the importance of methods evaluation and the contribution of SP to the process of methods evaluation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108391"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890531","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}
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