Journal of pharmacological and toxicological methods最新文献

{"title":"The translation of hERG block and APD90 in vitro to clinical QTc prolongation in man","authors":"Derek J. Leishman ,&nbsp;Najah Abi-Gerges","doi":"10.1016/j.vascn.2025.107804","DOIUrl":"10.1016/j.vascn.2025.107804","url":null,"abstract":"<div><div>The core ICH S7B in vitro assay is a hERG assessment which has associated best practice recommendations. Three reference agents are being used to compare margins based on concentrations associated with 10 ms QTc prolongation in man. The objective of the current analyses was to compare the margins for best practice hERG patch-clamp data with those for other in vitro assessments. The unbound critical concentrations shared as part of the Training Materials were used as the denominator throughout. The numerators were: the hERG IC₅₀ generated in a study conforming to current best practice guidance, the pKi from published dofetilide-binding data, the concentrations associated with either published rate corrected APD₉₀ prolongation in isolated IPD-derived human cardiomyocytes, or with a 25 ms change in APD₉₀ in human ventricular trabeculae tissue. The respective margins for dofetilide, moxifloxacin and ondansetron in the patch-clamp study were 45, 32 and 4.2. The dofetilide-binding displacement pKi, gave margins of 11, 15 and 10. In isolated cardiomyocytes the margins were 0.5, 5.2 and 1.3. In human trabeculae tissue the margins were 14, 4.5 and 9. There is an underlying assumption that for selective hERG blocking drugs the amount of hERG block (and associated hERG margin) would be similar for the same 10 ms change in QTc. The consistent margin determined using the dofetilide-binding displacement pKi and the concentration associated with a 25 ms APD90 prolongation in human trabeculae would tend to support that assessment. There was more variability in isolated cardiomyocytes where there was an 11-fold difference between dofetilide and moxifloxacin margins while the ondansetron margin lay in between these margins. The hERG patch-clamp study had skewed variability with a margin for ondansetron 11-fold and 8-fold different from the margins for dofetilide and moxifloxacin, respectively. The small margin for ondansetron caused wider confidence intervals for the pooled margin of 18-fold. Overall, these data suggest that any of these assays might realistically be used to predict a QTc prolongation in man. The hERG patch-clamp study is the required study. Where there are ‘ondansetron-like’ blocking characteristics an additional assay may be warranted to clarify the prediction.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107804"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094931","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":"Comprehensive protocol for culturing and functionally characterizing primary mixed neural cells from the neonatal rat cortex","authors":"Thaynan Silva Ramos ,&nbsp;Matheus Heidemann Tempone ,&nbsp;Hercules Rezende Freitas ,&nbsp;Monique Fonseca-Teixeira ,&nbsp;Patricia Fernanda Schuck ,&nbsp;Ricardo Augusto de Melo Reis ,&nbsp;Gustavo Costa Ferreira","doi":"10.1016/j.vascn.2025.108390","DOIUrl":"10.1016/j.vascn.2025.108390","url":null,"abstract":"<div><div><em>In vitro</em> models using purified neurons or glial cells are crucial for studying neurological functions but often overlook intercellular interactions. Mixed neural cell cultures offer a more physiologically relevant system by preserving cell-to-cell communication and providing deeper insights into neural behavior. Here, we present a protocol for culturing mixed primary cells from the neonatal rat cerebral cortex and functionally characterizing them <em>via</em> calcium imaging. This method enables cell phenotyping, spatial distribution analysis, and activity monitoring in response to stimuli. Our model maintained a cellular composition resembling the native rat cortex, with 35.4 % neurons, 44.3 % astrocytes, and 20.3 % other cell types. Calcium imaging showed that ATP (100 μM) and BzATP (100 μM) evoked stronger calcium transients than KCl (50 mM). BzATP induced a sustained response mediated by P2X7 receptor activation, while ATP activated a broader range of P2 receptors. Unlike purified or enriched cultures, this mixed-cell system better replicates the cellular environment of the brain, ensuring reproducibility and biological relevance. This protocol provides a straightforward platform for investigating neuron-glia interactions and neural signaling, bridging the gap between simplified <em>in vitro</em> models and the complexity of neural networks. Its applications may advance research into neurobiological disease mechanisms and therapeutic development.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 108390"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144984058","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":"Elucidating the challenges with categorizing drugs that block cardiac sodium channels − The impact of temperature on drug-cardiac sodium channel interactions","authors":"Huimei Yu,&nbsp;Claudia Alvarez Baron,&nbsp;Jun Zhao,&nbsp;Jose Vicente,&nbsp;Lars Johannesen,&nbsp;Wendy W. Wu,&nbsp;Donglin Guo","doi":"10.1016/j.vascn.2025.107805","DOIUrl":"10.1016/j.vascn.2025.107805","url":null,"abstract":"<div><div>Class I antiarrhythmic drugs (AADs) are categorized into Class IA, IB and IC subgroups based on their distinct electrophysiological consequences on the heart that are thought to arise from distinct interaction characteristics with cardiac sodium channels (Na_V). The original categorization centered on assessing electrophysiological features including drug effects on the maximal upstroke velocity of action potential (AP), AP duration, and effective refractory period using ventricular preparations from animals performed at physiological temperature (PT). Subsequently, categorization assessing drug binding and unbinding kinetics in patch clamp assays in Na_V overexpressing cells at room temperature (RT) was proposed. Temperature is known to impact Na_V gating, hence potentially affecting use- and state-dependence of drug interactions. Whether RT patch clamp data adequately capture drug-Na_V interaction characteristics that allows for the same subgroup categorization as in the original categorization using native tissues is unclear. Similarly, a systematic assessment of the effects on other cardiac ion channels following best practices is also lacking. This study characterized drug-Na_V (Na_V1.5) interaction characteristics of quinidine (IA), mexiletine (IB) and flecainide (IC) at near PT and RT using manual patch clamp. Additionally, drug's potencies on inhibiting the late Na_V1.5, hERG, and Ca_V1.2 currents were conducted at near PT following ICH S7B Q&amp;A 2.1 best practices. At RT, use-dependent block of Na_V1.5 currents and unbinding kinetics were fastest for mexiletine, followed by quinidine, and flecainide. At near PT, use-dependent block and unbinding kinetics of quinidine remained faster than flecainide. Surprisingly, mexiletine showed no use-dependent block and no apparent unbinding at near PT. Preliminary assessment revealed that the three drugs have different effects on other cardiac ionic currents. The three Class I AADs showed distinct interaction characteristics with Na_V1.5 currents. Importantly, temperature-dependent binding and unbinding kinetics for mexiletine and different effects on other cardiac ionic currents for all three drugs were observed. These data provide mechanistic insights to drug-induced changes in myocyte APs that led to Class I AADs categorization, and lay a foundation for future research to identify the commonalities and differences of Class I AADs interacting with Na_V1.5 channels.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107805"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094934","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":"Application for drug evaluation of human-induced pluripotent stem cell-derived cardiomyocytes cultured by anisotropic orientation","authors":"Hisako Tokuno ,&nbsp;Hidenori Hiranuma ,&nbsp;Akari Hasegawa ,&nbsp;Ayano Satsuka","doi":"10.1016/j.vascn.2025.107807","DOIUrl":"10.1016/j.vascn.2025.107807","url":null,"abstract":"<div><div>Human-induced pluripotent stem cell-derived cells (hiPSC) are expected to have applications in the fields of regenerative medicine and drug discovery. Due to the recent trend of reducing or eliminating animal testing, hiPSC is also expanded to use as the alternative method for animal testing. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are especially effective as an alternative assay of human cardiomyocytes which are not easily available. hiPS-CMs are, however, considered immature, hence the maturation of hiPS-CMs is an important issue for proper assessment of drug response. To induce maturation of hiPS-CMs, various methods have been developed, including long-term culturing, three-dimensional (3D) tissue engineering, mechanical loading, electrical stimulation, modulation of substrate stiffness, and treatment with neurohormonal factors. In these context, we attempted an anisotropic orientation culture, in which the cultured cells are aligned in one orientation resembling <em>in vivo</em> cardiomyocytes. Culture substrate for anisotropic orientation culture was developed by applying our original nanofabrication technology (CellArray-Heart™, Oji Holdings Corporation), and the alignment and maturation of hiPS-CMs were evaluated with the culture substrate. The hiPS-CMs cultured in anisotropic orientation on CellArray-Heart™ showed elongated morphology and unidirectional contraction using cell motion vector analysis and increase of mRNA related to maturation of hiPS-CMs including KCNJ2, ATP2A2, and GJA1. Furthermore, in Ca²⁺ transient assay with isoproterenol (0.1 μM, 1 μM), the hiPS-CMs cultured in anisotropic orientation showed 1.5- to 2.4-fold change in beating rate and 1.1- to 1.4-fold change in amplitude, the parameters of contraction force, compared to hiPS-CMs treated with DMSO. The hiPS-CMs cultured in anisotropic orientation might have induced the expression of positive inotropy by beta-receptor stimulation. These results indicate the hiPS-CMs cultured in anisotropic orientation on CellArray-Heart™ are induced maturation and are suitable for drug evaluation.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107807"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094940","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":"Development of drug toxicity evaluation platform using hiPSC-derived cardiac organoids","authors":"Hyun-lee Lee ,&nbsp;Ji-hye Park ,&nbsp;Hyun-su Kang ,&nbsp;Ki-suk Kim","doi":"10.1016/j.vascn.2025.107809","DOIUrl":"10.1016/j.vascn.2025.107809","url":null,"abstract":"<div><div>Cardiotoxicity is a critical aspect of safety evaluation in drug development. Traditional cardiotoxicity assessment methods rely primarily on animal models and 2D cell culture systems, which fail to replicate the complex physiological characteristics of human cardiac tissue fully. This study aims to generate human Cardiac Organoids (hCOs) derived from human induced Pluripotent Stem Cells (hiPSCs) and to use them to enhance the sensitivity of drug testing. hCOs were successfully cultured for up to 12 weeks, with a stable increase in heart rate observed over the cultivation period. Differentiation conditions were optimized by confirming the expression of cardiac markers (TNNT2), smooth muscle cell markers (aSMA), fibroblast markers (VIM), and endothelial markers (PECAM). The differentiation rate into cardiomyocytes was higher than that of conventional 2D cell culture methods. In calcium imaging using the positive drug nifedipine, the intensity of the calcium signal response of hCOs was confirmed to change depending on the concentration (1, 5, 10uM). This can be inferred that hCOs well reflects changes in various ion channels. Utilizing optimized hCOs conditions, we measured the changes in BPM induced by positive (Quinidine, Moxifloxacin, Nifedipine, E-4031), false positive (Diltiazem), false negative (Bepridil), and negative (Levofloxacin) drugs, comparing these to existing iCM data. The results demonstrated that hCOs exhibited more sensitive changes, suggesting that cardiac organoids can more sensitively and accurately reflect drug-induced cardiotoxicity than traditional 2D cell culture systems. This study presents a cardiotoxicity assessment platform using human-derived cardiac organoids. This approach can enhance the accuracy of cardiotoxicity assessment in the early stages of drug development, ultimately contributing to the development of safe and effective new drugs. Future research will measure electrophysiological changes to further optimize the evaluation platform and present an advanced cardiotoxicity evaluation platform.</div><div>This research was supported by a grant (22213MFDS391) from Ministry of Food and Drug Safety in 2024.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107809"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094943","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":"Pair housing large adult male cynomolgus monkeys is possible!, the use of telemetry to assess the benefits","authors":"Peter Harris ,&nbsp;Rosemary Santos ,&nbsp;Thi Dong-Binh Tran ,&nbsp;Dingzhou Li ,&nbsp;Jan Bernal ,&nbsp;Steven Kreuser ,&nbsp;Erin Ricciardi ,&nbsp;Siri Skowronek ,&nbsp;Kiran Palyada ,&nbsp;John Capitanio","doi":"10.1016/j.vascn.2025.107769","DOIUrl":"10.1016/j.vascn.2025.107769","url":null,"abstract":"<div><div>Long term pair housing of sexually mature, cynomolgus monkeys in male-male pairs is a common practice based on social needs of the species and research design. This housing paradigm does include risks of aggression, trauma, and impact to studies. Some facilities may forgo attempting to socially house males due to these risks. We sought to leverage the often-easier task of male-female pairing to create longer term, stable pairs as an option to address the social housing needs of sexually mature males. To understand the risk/benefit of this practice, seven vasectomized male monkeys previously implanted with telemetry devices were housed with female counterparts. These animals were selected based on good health, and a history of single housing in a male only study room. The pairing process was gradual with increasing levels of interactions between the male and female occurring over 45 days. At various stages of the pairing process, telemetry data was collected to characterize heart rate, blood pressure, activity, and temperature with data averaged into 2 timebins, 12 am–4 am and 2 pm–6 pm. Initial telemetry was collected when female monkeys were not present in the room and was used for baseline values. A second and third study with different male monkeys were conducted to assess male-male pairing and the influence of cage size on the parameters collected previously. When the females were paired with the males, decreases in blood pressure (−9 mmHg), and increases in body temperature (+0.7 °C) were observed. No significant pairing effects were found for heart rate or physical activity. During the second study, when male animals were re-paired with their male counterparts, blood pressure decreased (−5 mmHg) similar to the male – female pairing study. In the third study, no significant cage size effect was noted on physiologic parameters. These reductions in blood pressure indicate a lower stress in paired animals unrelated to sex or cage size. This further supports the benefits of pair housing monkeys in a research environment. In conclusion, pairing vasectomized male monkeys with female monkeys is a viable option for long term telemetry colonies using single housed male animals.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107769"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094992","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":"QTc least significant difference in stand-alone implanted telemetry safety pharmacology and jacketed external telemetry regulatory toxicology studies in dogs","authors":"Abdel-Ilah El Amrani ,&nbsp;Ana Gueorguieva-Apostolova ,&nbsp;Camille Lagard ,&nbsp;Anson Phillips ,&nbsp;Francine El Amrani Callens","doi":"10.1016/j.vascn.2025.107770","DOIUrl":"10.1016/j.vascn.2025.107770","url":null,"abstract":"<div><div>The use of least significant difference (LSD) as the metric for variability of specific study, especially in the context of ICH E14/S7B Q&amp;As studies, is considered as part of best practice. This parameter represents not only the threshold of statistical significance for a given parameter, but also reflects the intrinsic study variability. LSD is commonly used to evaluate the variability of QTc changes in standalone 4 × 4 cross-over (XO) Q&amp;As studies. To our knowledge, LSD evaluations are not commonly performed when jacketed external telemetry (JET) in parallel groups is used during safety pharmacology studies integrated in regulatory toxicology studies, despite the complementarity between this approach and standalone XO safety pharmacology studies. The use of one and/or the other approach could prove necessary depending on the nature and/or the PK/PD of the drug candidate. Therefore, we calculated LSDs for QT and QTc in 7 randomly selected telemetry investigations, including 3 XO design studies and 4 JET studies in a parallel design. Four male dogs and 32 dogs (16 males and 16 females) were used in each XO and JET investigation, respectively. Animals received vehicle with no impact on ECG parameters and/or 3 doses of test items. LSD is calculated using repeated measure ANOVA over 24 h in several intervals. LSDs for QT interval per study were 5 ± 2, 12 ± 5 and 8 ± 3 msec in XO and 11 ± 6, 8 ± 3, 13 ± 6 and 8 ± 4 msec in JET. LSDs for QTc (with Miyazaki correction) per study were 4 ± 2, 5 ± 2 and 5 ± 2 msec in XO and 3 ± 1, 6 ± 3, 12 ± 6 and 2 ± 1 msec in JET. Mathematical sensitivity comparisons between both approaches might be difficult. However, the threshold for detecting statistically significant increases in QT/QTc from JET cardiovascular studies was close to that shown in XO studies. This investigation shows that jacketed ECG can be as adequate as cross-over implanted cardiovascular studies to support an integrative risk assessment of QT prolongation in the dog. However, this first set of LSD values will need to be completed with the same analysis, based on a larger cohort of studies.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107770"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094993","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":"QTc data sensitivity: Is animal screening important to ensure reduced data variability?","authors":"Heather C. Heckt,&nbsp;Douglas E. Regalia,&nbsp;London E. Maberto,&nbsp;Stephen D. Tichenor","doi":"10.1016/j.vascn.2025.107787","DOIUrl":"10.1016/j.vascn.2025.107787","url":null,"abstract":"<div><div>The ICH E14/S7B Q&amp;As recommend a positive control study to demonstrate the assay sensitivity at a Test Site to detect changes in ECG parameters, namely QTc to enable translatability to the clinic. The objective of this study was to demonstrate the effectiveness of QT prolongation detection using telemetry implants (Physiotel: Data Sciences International) and manually restrained (snapshot) technology in non-human primates (NHP) dosed with moxifloxacin. Two Latin square positive control groups (cohorts 1 and 2) were simultaneously dosed (i.e., same room, drug formulation, technical staff, etc.) with moxifloxacin; 8 NHPs implanted with either the M-11 telemetry device or the L-21 telemetry device. Doses occurred every 7 days for a total of 4 doses and cardiovascular data were collected for 24 h on each occasion on unrestrained animals. Both groups showed measurable QT/QTc prolongation but a higher than anticipated least significant difference (LSD) of 22.4 msec for cohort 1 and 12.60 msec for cohort 2. It was determined that some of the animals had inherently longer QTc intervals than other animals leading to larger individual animal variability. Both cohorts had a maximum standard deviation (SD) of 25.68 and 14.62, respectively. To accurately determine sensitivity capabilities, subjects with similar QT intervals and the same dosing rotation were grouped together in a hybrid Latin square consisting of 2 animals from cohort 1 and 2 animals from cohort 2. The re-assigned animals with similar QT variability (maximum SD = 11.54) resulted in an LSD of 9.8 msec. Pre-screening subjects for inherent ECG waveform variability could allow for greater data sensitivity ensuring adherence to expected industry standard sensitivity. In addition to implanted telemetry, the same 8 subjects had manually restrained, snapshot data collected. All subjects demonstrated similar QT/QTc values from predose to postdose with no observation of QT variability (QTc of 281.4 to 272.7 msec respectively) and as such, could not detect measurable changes in QTc, compared to unrestrained techniques, which did provide measurable changes even with the highest calculated SD. Collectively, these data demonstrate diminished sensitivity of manually restrained, snapshot data as opposed to telemetry data from unrestrained, freely moving animals.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"135 ","pages":"Article 107787"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145095179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced 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}