Journal of pharmacological and toxicological methods最新文献

{"title":"Enhanced detection sensitivity in nonclinical cardiovascular telemetry studies: Impact of a characterized facility","authors":"Ty Speece,&nbsp;Zac Hawkins","doi":"10.1016/j.vascn.2025.107789","DOIUrl":"10.1016/j.vascn.2025.107789","url":null,"abstract":"<div><div>In the context of a cardiovascular telemetry study, test facility characterization refers to the comprehensive assessment and description of the laboratory environment, equipment, procedures, and other relevant factors that could influence the outcomes and interpretation of the study. The goal is to ensure the integrity, reproducibility, and validity of telemetry data collected from implanted animals. Model verification, particularly regarding sensitivity analysis, is fundamental for ensuring the validity of these studies. In this investigation, we assessed the influence of transitioning to a purpose-built telemetry facility on model sensitivity, focusing on dofetilide-induced QT prolongation. Beagle dogs previously implanted with Data Sciences International ™ implants were relocated into a new facility, purpose built for telemetry studies. Following ICH E14/S7B guidelines, animals were administered dofetilide to induce QT prolongation. Sensitivity analysis, including the minimum detectable difference (MDD) and least significant difference (LSD) for the corrected QT interval (QTcI), was performed at both the previous facility and the newly established purpose-built facility. During baseline data collection, persistent signal dropout was observed in all animals resulting in data loss of ~20 % of total data collected. Troubleshooting steps included internal hardware and software diagnostics, battery assessment, and environmental assessments. The Received Signal Strength Indicator (RSSI) feature within the telemetry software was leveraged to pinpoint the source of interference. Data analysis revealed a consistent source of interference with an average strength of 30 (RSSI relative strength), coinciding with the operation of the facility's wireless security system (900 MHz), the same frequency band used for transmission and reception of telemetry data. Replacement of the security system with hardware operating at 433 MHz resulted in a negligible interference signal, with RSSI values averaging below 8, similar to previous facility values. An improvement in sensitivity at the purpose-built facility was observed. The MDD for QTcI prolongation was reduced to 6.2 ms, surpassing findings at previous facility (10.8 ms). Additionally, the LSD demonstrated enhanced sensitivity at the new facility (QTcI, 4.5 ms). Transitioning to a purpose-built telemetry facility has demonstrated tangible benefits in enhancing sensitivity. The optimized and characterized environment minimizes extraneous variables, enhancing the detection of QTcI prolongation induced by dofetilide.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107789"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The translation of QTc across species - Impact of subject number and exposure multiple tested on discriminatory sensitivity","authors":"Derek J. Leishman","doi":"10.1016/j.vascn.2025.107774","DOIUrl":"10.1016/j.vascn.2025.107774","url":null,"abstract":"<div><div>Small, relatively insensitive studies can be useful in safety assessment when multiples of the therapeutic clinical concentration are tested. This is a fundamental principle in safety testing in animals which is equally valid for early clinical evaluations in healthy volunteers. It is often less practical to increase the number of test subjects than to increase the exposure tested. Both, when combined with the analysis method, can have an impact on the sensitivity to detect an effect. The objective is that the relationship between statistical power, analysis method, number of animals and exposure multiple explored can be illustrated using the example of QTc assessment in animals. The statistical power to detect an effect on the electrocardiogram QTc interval in nonhuman primates (NHP) for different analyses methods was known. The concentration-QTc relationship was also known for reference agents in NHP. Lastly, the critical concentration associated with a 10 ms QTc interval change in man was known for these same reference agents. This information was combined to illustrate how doubling the number of NHP used or increasing the exposure tested would support a conclusion concerning the presence or absence of an effect on the QTc interval for a test agent. In NHP, the most sensitive analysis methods have &gt;80 % power (at <em>p</em> &lt; 0.05) to detect an effect of the reference agent at the critical concentration using only 4 animals. Less sensitive techniques can detect an effect with the same power when either more animals are used or where higher multiples of the critical concentration are tested. This illustrates the principle that even with only 4 animals and an insensitive technique an effect can be detected provided higher exposures are tested. Conversely, a study using more animals, or a more sensitive analysis needn't require a higher exposure in animals to exclude an effect in man. Rather than focusing on a fixed QTc threshold sensitivity regardless of experimental design these analyses demonstrate that investigators have the flexibility to use the simplest available combination of exposures, animal numbers and analysis to achieve an effective QTc assessment.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107774"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticoagulant activity of Eucalyptus essential oils: An in vitro approach and a bioinformatics-based pharmacokinetic-pharmacodynamic analysis","authors":"Jhonatan Felipe dos Santos ,&nbsp;Maria Eduarda Dias Possate ,&nbsp;Maysa Barbosa de Almeida ,&nbsp;Eveline Maria de Melo ,&nbsp;Ricardo Andrade Furtado ,&nbsp;Lays da Silva Moreira Santos ,&nbsp;Isabela Cristina Gomes Honório ,&nbsp;Silvio de Almeida-Junior","doi":"10.1016/j.vascn.2025.108381","DOIUrl":"10.1016/j.vascn.2025.108381","url":null,"abstract":"<div><div>Coagulation disorders pose significant health risks, requiring effective therapies. Natural products emerge as promising anticoagulant agents, standing out in the search for innovative and safe alternatives, integrating <em>in vitro studies</em>, pharmacological analyses and bioinformatics for therapeutic advances. In this context, a study was conducted on the anticoagulant and toxicological activity of three essential oils of <em>Eucalyptus spp.</em>: <em>Eucalyptus citriodora</em>, <em>Eucalyptus globulus</em> and <em>Eucalyptus staigeriana</em>, commercially acquired. The chemical composition was analyzed by gas chromatography coupled to mass spectrometry. The anticoagulant activity was evaluated by <em>in vitro</em> assays of prothrombin time (PT) and activated partial thromboplastin time (aPTT) at concentrations of 0.19 % to 100 %, performed in triplicate. The mechanism of action was investigated by <em>in silico</em> analysis of activated Factor X, and the toxicological potential was evaluated with bioinformatics tools. The major compound identified was citronellal (57.77 %) in <em>E. citriodora</em> essential oil, eucalyptol (77.03 %) in <em>E. globulus</em> oil, and <span>d</span>-limonene (20.89 %) and geranial (10.54 %) in <em>E. staigeriana</em> oil. <em>E. globulus</em> showed greater anticoagulant efficacy, with prolongation of 256 % in aPTT and 147 % in PT, while the other oils showed prolongation of 117 % in PT. The pharmacokinetic parameters showed similarity with commercial anticoagulants, and the ΔG values in the <em>in-silico</em> model for activated Factor X were comparable to those of warfarin. The results confirm the anticoagulant potential of the three essential oils, especially <em>E. globulus</em> oil, which is more indicated for the prospection of new drugs.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108381"},"PeriodicalIF":1.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144522950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"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":"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":"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":"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":"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}