Journal of pharmacological and toxicological methods最新文献

{"title":"Characterization of vasoactive agents in a canine safety pharmacology PKPD model: A HESI initiative","authors":"Yevgeniya E. Koshman ,&nbsp;C. Michael Foley ,&nbsp;Jennifer Pierson ,&nbsp;Siddhartha Bhatt ,&nbsp;Todd Wisialowski ,&nbsp;Hugo A. Vargas ,&nbsp;Peter Hoffmann ,&nbsp;Kevin Norton ,&nbsp;Eric I. Rossman ,&nbsp;Mark A. Osinski ,&nbsp;Kelly Ashcroft-Hawley ,&nbsp;Michael K. Pugsley","doi":"10.1016/j.vascn.2025.107790","DOIUrl":"10.1016/j.vascn.2025.107790","url":null,"abstract":"<div><div>Increases in arterial blood pressure (BP) contribute to adverse cardiovascular (CV) outcomes in patients; preclinical effects of a drug on BP are routinely evaluated during the safety pharmacology assessments as outlined in the ICH S7A guidance. A Health and Environmental Sciences Institute (HESI) Consortium initiated a multi-site study with the objective to assess the ability of the standard conscious telemetry instrumented CV dog model to detect drug-induced changes in BP and evaluate translation to human data. The goal of these studies is also to determine the reproducibility and consistency of BP assessment when measured across different laboratories using the same study protocol and recording methodology to detect drug-induced changes in hemodynamics using drugs known to clinically elevate and reduce BP. Animals were chronically instrumented with a BP catheter and ECG electrodes for telemetric collection of hemodynamic and ECG endpoints, respectively. Study endpoints include systolic, diastolic, and mean BP, heart rate, electrocardiogram (ECG), body temperature, and locomotor activity. Drugs evaluated include midodrine (alpha-1 agonist), nifedipine (calcium channel blocker), hydralazine (direct-acting smooth muscle relaxant), prazosin (alpha-1 blocker) and milrinone (phosphodiesterase-3 inhibitor). Drugs were selected based on known pharmacological mechanisms of action, primary cardiovascular effects as well as availability of clinical effect and exposure data. Drugs were evaluated in beagle dogs using a double (8 × 4) Latin square design and administered orally at 3 doses selected to match clinical exposure data with a vehicle control. A full pharmacokinetic profile for each drug was conducted in dogs at doses selected using automated blood sampling (ABS). Initial analysis shows that all 5 positive control drugs show consistent hemodynamic profiles (e.g., BP elevation or reduction) in the dog as seen in humans. These data sets with additional testing at multiple sites will be amenable to further statistical analysis, super-interval analysis and follow-up study endpoint evaluation such as pressure waveform analysis. The results from this chronically instrumented conscious dog model will provide essential information about accuracy and consistency in blood pressure measurement across multiple sites and translation of preclinical BP data to clinical outcomes.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107790"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095183","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":"Investigating convulsion triggers in canine toxicity study for preclinical compound: A case study","authors":"Chisato Kaneko,&nbsp;Keisuke Itagaki,&nbsp;Kensho Kanehisa,&nbsp;Ryuichi Komatsu,&nbsp;Masaki Honda,&nbsp;Jumpei Kiyokawa,&nbsp;Sho Akai,&nbsp;Hiromi Suzuki","doi":"10.1016/j.vascn.2025.107791","DOIUrl":"10.1016/j.vascn.2025.107791","url":null,"abstract":"<div><div>Convulsions are a serious side effect of pharmaceuticals, and it is crucial to assess the convulsion risk of new drug candidates before clinical trials to ensure the creation of safe drugs. In a repeated toxicity study in dogs, our preclinical compound (CH-X) induced convulsions which were not observed in rats. The convulsions were considered to be induced by off-target effects because target information indicated the low possibility of on-target toxicity. Upon checking the metabolites in each animal species, metabolites (M1 and M2) that are produced more in dogs than in rats were found. The following evaluations were conducted to elucidate the mechanism of the convulsions observed in dogs. 1) Off target panel assay: Several off targets were detected, and among them, monoamine transporters (MAT) were identified as potential targets. The compounds inhibited the function of dopamine transporter in a concentration dependent manner. As for other MAT, the compounds showed different inhibitory profile. 2) In vitro microelectrode array (MEA) assay using human iPS-derived neurons: CH-X, M1 and M2 affected the electrophysiological parameters of neural activity. Total spikes and synchronous burst firings were decreased by the compounds. As a result of PCA analysis, CH-X, M1 and M2 caused changes similar to those of monoamine transporter inhibitors. 3) Metabolic enzyme inhibition study in dogs: Convulsions in dogs occurred even under the condition that systemic exposure of M1 and M2 was suppressed by metabolic enzyme inhibitor, indicating that the metabolites may not be the major cause of the convulsion. The series of mechanistic investigation approach demonstrated in this study provided valuable insights into the mechanisms of drug-induced convulsions.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107791"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095187","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":"Spontaneous incidence of convulsions, tremors, salivation and ataxia in control animals: A multi-site retrospective analysis comparing non-human primates, dogs, minipigs, rabbits, rats and mice","authors":"Simon Authier,&nbsp;Raquel Lorenzo,&nbsp;Mylene Pouliot,&nbsp;Kim Bujold","doi":"10.1016/j.vascn.2025.107799","DOIUrl":"10.1016/j.vascn.2025.107799","url":null,"abstract":"<div><div>The background incidence of common neurological clinical signs was evaluated in commonly used laboratory animal species. Salivation, tremors and ataxia can be considered as premonitory clinical signs to seizures but can also be observed in normal healthy animals in the absence of seizures. We characterized and compared the incidence of spontaneous convulsions, tremors, salivation and uncoordination/ataxia in control non-human primates, dogs, minipigs, rabbits, rats and mice from drug safety testing studies. A retrospective analysis was conducted with data from GLP facilities in North America and Europe including non-human primates (<em>n</em> = 8805), dogs (<em>n</em> = 24,553), minipigs (<em>n</em> = 2359), rabbits (<em>n</em> = 21,476), rats (<em>n</em> = 312,261) and mice (<em>n</em> = 131,272). Data from telemetered and jacketed animals were included. For rats and mice, the incidence of spontaneous convulsions was lowest at less than 6 weeks of age, was stable from 6 to 26 weeks of age and then increased progressively for older animals reaching 0.66 % in rats and 0.60 % in mice above 38 weeks. When comparing species, the incidence of spontaneous convulsion was lowest in minipigs (0 %) followed by mice (0.03 %), rats (0.06 %), rabbits (0.07 %), dogs (0.11 %) and non-human primates (0.17 %). Uncoordination/ataxia was observed in all species with increasing incidence in mice (0.04 %), minipigs (0.21 %), rats (0.23 %), rabbits (0.32), non-human primates (0.79 %) and dogs (1.00 %). As expected, dogs presented the highest incidence of salivation followed by non-human primates and minipigs. Spontaneous salivation was minimal in mice, rats and rabbits. Spontaneous tremors were observed in 1.6 % of dogs and non-human primates and reached 1 % in minipigs. The incidence of tremors in mice, rats and rabbits was negligible. The data summarized provides a robust characterization of spontaneous neurological clinical signs across multiple research facilities which can help during interpretation of safety pharmacology studies involving neurological assessments.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107799"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a human wearable ECG device for continuous in-cage data collection in non-rodents","authors":"Julia C. Hotek,&nbsp;Alysia A. Chaves,&nbsp;Theodore Detwiler,&nbsp;Jude Ferraro,&nbsp;Shaun Gruver,&nbsp;Desiree Steve,&nbsp;David Lengel,&nbsp;Min Deng,&nbsp;Christopher P. Regan","doi":"10.1016/j.vascn.2025.107828","DOIUrl":"10.1016/j.vascn.2025.107828","url":null,"abstract":"<div><div>Wearables are commonly used in clinical diagnostic medicine and personal health tracking. However, their use to collect nonclinical endpoints is limited due design specification differences for human vs animal data (i.e. data format limitations, low sampling rates) and availability of nonclinical telemetry technologies both of which create a general “barrier to entry” to adopt and take advantage of clinical innovation in nonclinical studies. To determine the feasibility of using a human ECG wearable device (WRB) in nonclinical studies, we compared heart rate (HR) and ECG intervals between the wearable and implanted telemetry in canine and non-human primate (NHP). For this, <em>n</em> = 5 canine and <em>n</em> = 4 NHP, previously implanted with Stellar (STL) telemetry implants, were jacket-acclimated and then continuous ECGs (500 Hz) were collected 24 h prior and 24 h after oral administration of vehicle or dofetilide (canine: 0.003, 0.010, 0.030 mg/kg; NHP: 0.03, 0.06, 0.12 mg/kg) simultaneously from both devices. Data were extracted as 15-min means and reviewed qualitatively, by a Bland-Altman analysis (BA) to determine bias and 95 % limits of agreement (LOA) between measures, and by comparing the dofetilide-dependent average vehicle-adjusted QTci prolongation (DoubleDelta) from 1 to 3 h postdose. Generally, the 15 min averages over the 48 h period/dose levels were qualitatively consistent in magnitude and profile between the two measurement platforms. BA demonstrated that the measurements between the 2 devices were similar with bias (LOA) as follows: canine: HR +1 bpm (+8,-6); PR +0.4 ms (+9,-8); QRS +1 ms (+4,-2); QT +2 ms (+14,-11) and NHP: HR 0 bpm (+4,-4); PR +0.4 ms (+14,-13); QRS +2 ms (+8,-5); QT +7 ms (+29,-15). Dofetilide-dependent DoubleDelta QTci prolongation was similar between measurement platforms (STL vs. WRB): NHP: 0.03 mg/kg: +6 ms vs +7 ms, 0.06 mg/kg: +23 ms vs +20 ms, 0.12 mg/kg: +35 ms vs +41 ms; and canine: 0.003 mg/kg: +1 ms vs +3 ms, 0.010 mg/kg: +5 ms vs +6 ms, 0.030 mg/kg: +17 ms vs +17 ms. Overall, these studies demonstrate the feasibility of using alternative devices to collect in-cage ECG and provide initial data to investigate the broader potential of re-purposing clinical wearable devices to collect nonclinical safety pharmacology and toxicology endpoints.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107828"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094998","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":"Spectrum of effects detected in the rat functional observational battery following administration of non-CNS targeted and CNS targeted compounds","authors":"Shanshan An Master ,&nbsp;Rui Wu Master ,&nbsp;Sue McPherson Master","doi":"10.1016/j.vascn.2025.107798","DOIUrl":"10.1016/j.vascn.2025.107798","url":null,"abstract":"<div><div>The Functional Observational Battery (FOB) is an established systematic evaluation of nervous system function in the rat, comprising more than 30 parameters across autonomic, neuromuscular, sensorimotor and behavioral domains. Assessment of CNS function using behavioral assays is largely dependent on multiple subjective endpoints, and the experience in test facility. To establish reference background data, and assess the sensitivity and specificity of the FOB test, we collected the FOB results from 360 studies performed in the past three years that were targeted for CNS and non-CNS disorders. Examination was performed with the technician blind to the animal's treatment. Approximately 11 % compounds tested had an effect in the FOB test, including 4 % CNS compounds, 3 % non-CNS indication compound, 1 % antidiabetic compounds, and 3 % others. These effects occurred with higher incidence at CNS indication compound were forelimb grip strength (1.9 %), hindlimb foot splay (1.9 %), low arousal (2.2 %), abnormal gait pattern (1.9 %), firm or flaccid body tone (2.2 %), firm or flaccid extensor response (1.7 %), uncoordinated landing in air righting reflex and abnormal palpebral closure (0.8 %). The most common effects noted for both CNS indication and non-CNS indication compound were changes in rectal temperature (7.8 % of studies), hindlimb grip strength (2.2 % of studies), locomotor activity (2.8 % of studies), rearing frequency (3.6 % of studies), abnormal posture (1.4 % of studies). Remaining FOB parameters were affected by 2 % CNS compounds and 2 % non-CNS indication compound. The parameters such as gait pattern, arousal, body tone, extensor response, forelimb grip strength and hindlimb foot splay are good indicators of CNS adverse events with higher incidence. The Functional Observational Battery (FOB) test is sensitivity for CNS targeted compounds, and can provide reference for potential pharmacological mechanisms and follow-up neurotoxicity studies. Individual parameters such as rearing frequency, locomotor activity, and hindlimb grip strength, rectal temperature had both high incidences in CNS and non-CNS incidences, and are not specific indicators of possible CNS adverse events. The FOB test as part of the safety pharmacology core battery is valuable for the assessment for non-CNS targeted compounds.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107798"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095107","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 neurobehavioral evaluation of subcutaneously administered amphetamine, WIN55,212–2, 2,5-dimethoxy-4-Iodoamphetamine, and morphine in mice","authors":"Lawrence M. Carey,&nbsp;Jonelle May,&nbsp;David Holdsworth,&nbsp;Zachary Zimmerman,&nbsp;Jill Dalton","doi":"10.1016/j.vascn.2025.107796","DOIUrl":"10.1016/j.vascn.2025.107796","url":null,"abstract":"<div><div>The neurobehavioral effects of certain classes of CNS active compounds (e.g., stimulants, depressants, neuroleptics) have been well characterized in rats. However, relatively less is known about the neurobehavioral effects of other types of CNS active compounds (e.g., cannabinoid receptor and serotonin 2A [5-HT2A] receptor agonists), and even less in mice. Given the increasing interest in development of therapeutics acting upon these targets, characterizing the neurobehavioral effects of these agents is warranted. The objective of this study was to evaluate the potential acute neurobehavioral effects of amphetamine, the cannabinoid CB1/CB2 agonist WIN55,212–2, the 5-HT_2A receptor agonist 2,5-dimethoxy-4-Iodoamphetamine (DOI), and morphine in mice. Amphetamine (10 mg/kg), WIN55–212-2 (10 mg/kg), DOI (10 mg/kg) and morphine (20 mg/kg) were administered via subcutaneous injection to male CD-1 mice (<em>n</em> = 8/group). Neurobehavioral evaluations including assessments of activity, autonomic, excitability, neuromuscular, physiological, and sensorimotor function were conducted in home cage and open field prior to dosing and at 30 min and 24 h postdose. Effects of amphetamine included high arousal, induction of stereotypy, unkempt appearance, piloerection, alterations in pupil response, salivation, hyperthermia, tremors, and increases in rearing counts, handling reactivity, difficulty of removal, body tone, and respiratory rate. Effects of WIN55,212–2 included low arousal, changes in posture/body carriage, analgesia, impairments in gait/mobility, alterations in pupil response, and decreases in rearing, startle response, handling reactivity, body tone, and respiratory rate. Effects of DOI included induction of stereotypy, alterations in pupil response, ptosis/palpebral closure, and decreases in startle response and body tone. Effects of morphine included changes in posture/body carriage, induction of stereotypy, alterations in pupil response, impairments in gait/mobility, hypothermia, analgesia, and decreases in arousal/alertness, rearing counts, difficulty of removal, and handling reactivity. In conclusion, amphetamine, WIN55,212–2, DOI, and morphine produced various neurobehavioral effects consistent with the known, prototypical effects of these drugs in other species, thereby demonstrating the utility of mice as a suitable model to detect drug-induced neurobehavioral changes via divergent mechanisms of action.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107796"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095103","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":"Siddhartha R. Bhatt,&nbsp;Dingzhou Li,&nbsp;Alexandra Franz,&nbsp;Michelina Pinto,&nbsp;Corey Petrella,&nbsp;Peter Harris,&nbsp;Todd Wisialowski","doi":"10.1016/j.vascn.2025.107786","DOIUrl":"10.1016/j.vascn.2025.107786","url":null,"abstract":"<div><div>Pivotal cardiovascular (CV) safety pharmacology studies using telemetered non-rodent (dog and nonhuman primate (NHP)) models provide key data that enable development of novel therapeutics. Statistical power calculations demonstrate the sensitivity of an experimental model as well as provide rationale for study design including sample size selection. The power of a statistical test is the probability of detecting a signal (e.g. a CV effect) when there truly is a signal. Robust understanding of statistical sensitivity also underpins the confidence in study results, yet systematic power analysis of standard CV studies is currently lacking. We analyzed pooled data from CV telemetry studies in standard cynomolgus monkeys (<em>n</em> = 21) and beagle dog (<em>n</em> = 27), separately, to determine the statistical power of these experimental models. Studies typically utilized a 4 × 4 (dog) or 8 × 4 (NHP) vehicle +3 dose level crossover paradigm. Data were collected for approximately 24 h, and derived results were binned into time intervals for statistical analysis using a linear ANOVA model. The minimum detectable differences (MDD) with 80 % statistical power were calculated for standard parameters (e.g. blood pressure (BP), heart rate (HR), ECG intervals etc). MDDs for dogs, using a <em>N</em> = 4 crossover design, were: BP (5–7 mmHg), HR (10 bpm), QT-interval (9 msec), and QTc-interval (6 msec). MDDs for NHP, using a <em>N</em> = 8 crossover design, were: BP (4–5 mmHg), HR (11 bpm), QT-interval (13 msec), and QTc-interval (9 msec). Additionally, we also report MDDs for alternate groups sizes (e.g. <em>N</em> = 4, 8 and 12) as well as reference intervals of root mean square error (RMSE) as a measure of variability in the studies. Using the 2.5th and 97.5th percentiles of the RMSE, we also report the lower and upper bounds of the MDDs for each parameter. 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 (e.g. QTc MDD &lt;10 msec) and support use of data in the context of ICH E14/S7B Q&amp;As. Lastly, these results will enable informed selection of appropriate models and study designs for CV studies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107786"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095283","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":"Association between gastrointestinal effects in rodent toxicity studies and decreased locomotor activity in rodent safety pharmacology studies","authors":"Sana Gupta ,&nbsp;Todd Wisialowski ,&nbsp;Jamie K. DaSilva","doi":"10.1016/j.vascn.2025.107797","DOIUrl":"10.1016/j.vascn.2025.107797","url":null,"abstract":"<div><div>Safety pharmacology (SP) evaluations are required for small molecule drug candidates (ICH-S7A) to identify effects on the cardiovascular, central nervous (CNS), and respiratory systems. Gastrointestinal (GI) effects are common in drug development, manifesting preclinically as emesis (large animals), nonspecific clinical observations, and/or histopathological abnormalities in GI tissues (toxicology studies). Decreases in locomotor activity (LA) are a common finding in rodent CNS SP studies; however, it is often not possible to differentiate primary CNS effects from secondary GI effects, particularly given that rodents are non-emetic. The relationships between GI-related clinical signs and GI pathology in rodent toxicity studies and decreased quantitative LA in rodent SP studies was quantified via contingency tables using Chi-Squared tests. A binary logistic regression was computed to describe the log odds of a decrease in LA when certain GI predictors are present. Data evaluated across similar dose levels for each compound (<em>n</em> = 65) showed a correlation between the presence of GI clinical signs and GI pathology (X^2 = 5.454, <em>p</em>-value = 0.01952. Sensitivity = 50 %, Specificity = 76.23 %), as well as the presence of GI clinical signs and decreased LA (X^2 = 23.265, <em>p</em>-value = 1.411e-06. Sensitivity = 45.45 %, Specificity = 83.06 %). Although the GI pathology and decreased LA correlation was not significant, the specificity for this association was high at 94.54 %, indicating that the there is a strong correlation between negative LA and negative pathology findings (X^2 = 0.50847, p-value = 0.4758. Sensitivity = 7.79 %, Specificity = 94.54 %). A final regression model (reduced to the lowest Akaike Information Criterion [AIC]) identified food consumption and distended abdomen as predictors. Food consumption was a significant predictor of decreased LA (<em>p</em> = 2.16e-05), suggesting that compounds that impact food consumption could also impact animal behavior, including activity levels. The final regression model has an AUC of 0.621 (95 % CI: 0.5533–0.6797); while not exceptionally strong, it is slightly better than random at distinguishing occurrences of decreased LA. When present, the potential contribution of GI effects to decreased LA in SP assessments should be considered in addition to direct effects on the CNS.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107797"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095106","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":"Benefits of early in vitro screening for seizure liability in problem solving and decision making","authors":"Kimberly L. Rockley,&nbsp;Ruth A. Roberts,&nbsp;Michael J. Morton","doi":"10.1016/j.vascn.2025.107845","DOIUrl":"10.1016/j.vascn.2025.107845","url":null,"abstract":"<div><div>Seizure liability remains a significant cause of attrition throughout drug development both in pre-clinical and clinical studies. This emphasizes the need for improved methodologies to detect seizure liability prior to in vivo toxicology studies, ideally with reduced reliance on animals and better translation to humans. Much like the Comprehensive in vitro Proarrhythmia Assay (CiPA) which is now widely accepted for early assessment of cardiovascular safety, we have developed an approach utilizing hiPSC-neuronal cell microelectrode array (MEA) and ion channel screening for early seizure prediction. In our MEA assay, seizurogenic compounds were identified correctly with high predictivity, and correlations were observed between the in vitro and clinical exposures of many therapies known to cause seizure. We have used these assays in the early phase of nonclinical testing, and successfully de-risked and prioritized a chemical series. For example, after testing a number of compounds, one was identified with low seizure risk compared to the others in the series – this compound had distinct structural features. In another study of compounds undergoing nonclinical testing, exposures that caused no CNS signs or convulsions in rats, aligned with the results of the MEA study. Conversely, where convulsions were reported in rats, seizurogenic responses were present in the MEA study at comparable concentrations. Since these studies use human derived cells, they can be used to determine the human relevance of seizures observed in nonclinical studies. For example, nonclinical testing of a compound caused convulsions only in dogs. Testing a range of metabolites in the MEA assay revealed only the dog-specific metabolite caused seizurogenic phenotype. In addition, screening this metabolite against a panel of ion channel targets revealed a hit, providing mechanistic insight and also the opportunity to redesign the compound to eliminate the liability. Collectively, these studies demonstrate the utility of this approach for early seizure prediction to provide mechanistic information, early de-risking, and support optimal drug design using human in vitro models.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107845"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095263","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":"Rodent models of anxiety and compulsion: When multiple endpoints add value","authors":"Justyna Glazar,&nbsp;Iain Porter,&nbsp;Victoria Ascough,&nbsp;Sharon Rowton","doi":"10.1016/j.vascn.2025.107842","DOIUrl":"10.1016/j.vascn.2025.107842","url":null,"abstract":"<div><div>Anxiety disorders are the most diagnosed mental illnesses and exist independently or as comorbidity with conditions such as autism spectrum disorder, major depressive disorder, and/or substance use disorder. The acute treatment of moderate to severe anxiety includes medications, such as benzodiazepines, whereas for long-term treatment and compulsive disorders, selective serotonin reuptake inhibitors (SSRIs) are often prescribed. The objective of this investigation was to demonstrate the advantages of conducting a battery of behavioral tests to characterize the anxiolytic, anxiogenic, and/or anti-compulsive properties of drugs. Animal anxiety models are based on the natural tendency of rodents to avoid a potentially dangerous situation (e.g., open, brightly lit, or novel environments). Animal models of compulsive-like behavior are based on natural, repetitive behaviors exhibited by rodents (e.g., digging). Within this investigation, assessments were conducted using the elevated plus maze (EPM), staircase, light/dark box, Nestlet shredding, and marble burying tests in male C57BL/6 J mice. Investigations were conducted following intraperitoneal administration of 10 mg/kg paroxetine, fluoxetine, or atropine; 6 mg/kg diazepam; 0.1 mg/kg WIN55,212–2; or 4 mg/kg yohimbine; these doses did not adversely affect locomotor activity. Results show how, by evaluating multiple endpoints, results can be interpreted in terms of compulsion, anxiety, and in some instances, impulsivity with a greater degree of confidence. For example, atropine decreased marble burying by 63 %, Nestlet shredding by 94 %, and time in the light zone by 63 % compared with controls, demonstrating that effects on marble burying and Nestlet shredding were not due to anti-compulsive effects or anxiolysis. These preliminary investigations support the requirement for conducting testing for multiple endpoints when characterizing the potential anxiety or compulsive effect of a novel drug. Multiple endpoints can be considered within the same animals and may be considered for inclusion within toxicology studies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107842"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095380","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}