Journal of pharmacological and toxicological methods最新文献

{"title":"Development and validation of a quantitative UHPLC-HRMS bioanalytical method for equine anti-doping control","authors":"Wafaa El-Ghaly ,&nbsp;Taha El Kamli ,&nbsp;Ange Melisse Ariane Gongbe ,&nbsp;Lamia Zaari Lambarki ,&nbsp;Maha El Hamdani ,&nbsp;Fatima-ezzahra Lahkak ,&nbsp;Najib Al Idrissi ,&nbsp;Adnane Benmoussa ,&nbsp;Lhousaine Balouch ,&nbsp;Fadil Bakkali ,&nbsp;Taoufiq Saffaj ,&nbsp;Fayssal Jhilal","doi":"10.1016/j.vascn.2025.107759","DOIUrl":"10.1016/j.vascn.2025.107759","url":null,"abstract":"<div><div>The quantification of banned substances in equine antidoping control, especially in racehorse urine, necessitates robust analytical methods with high detection levels due to the extremely low concentrations of the target substances and the significant impact of minor variations on doping test results. Reliable quantification is important for substances near regulatory thresholds, which, if exceeded, are prohibited.</div><div>This study presents the development and validation of a bioanalytical UHPLC-HRMS method for quantifying doping substances in equine urine, including diazepam and acepromazine with a regulatory limit level of 10 ng.mL⁻¹ (validated at 6, 8, 10, 12, and 14 ng.mL⁻¹); ketoprofen, flunixin, and caffeine with a permissible limit of 100 ng.mL⁻¹ (validated at 60, 80, 100, 120, and 140 ng.mL⁻¹); and meloxicam and lidocaine with a detection threshold of 25 ng.mL⁻¹ (validated at 15, 20, 25, 30, and 35 ng.mL⁻¹) using the accuracy profile. Different β values were applied to determine the proportion of future measurements that will fall within predefined acceptance limits, set at ±30 % (for a biological matrix). Method validation was carefully carried out and rigorously demonstrated in compliance with the French Society of Pharmaceutical Sciences and Techniques (SFSTP) commission in compliance with the ISO 17025 standard.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"134 ","pages":"Article 107759"},"PeriodicalIF":1.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145276","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":"Telemetry in toxicology studies – A comparison of data across species, technologies and time","authors":"Derek D. Best,&nbsp;Matthew M. Abernathy,&nbsp;Derek J. Leishman","doi":"10.1016/j.vascn.2025.107757","DOIUrl":"10.1016/j.vascn.2025.107757","url":null,"abstract":"<div><div>Telemetry technology allows collection of quantitative cardiovascular safety pharmacology data in repeat dose toxicology studies. The ICH M3(R2) guideline suggests that inclusion of safety pharmacology endpoints into toxicology studies should be considered wherever feasible, and where similar rigor can be achieved, to reduce animal use. The objective of the current analyses was a comparison of the cardiovascular data collected using telemetry technology in stand-alone and toxicology studies.</div><div>Pretreatment and vehicle control data were gathered from 75 studies for 780 dogs and 1059 nonhuman primates (NHP), and over 4503 days. Three technologies were used: a dual pressure implant used in stand-alone studies, a smaller single pressure implant and jacketed external telemetry. The latter was coupled with a minimally invasive blood pressure implant in a few studies.</div><div>Mean QTc values were practically identical between L21, M11 and JET® telemetry data in NHP (differences of 1–3 ms). In dog, M11 and JET® telemetry had mean QTc values which were different by 2 ms. These were 5–7 ms shorter than for L21 telemetry. All the confidence intervals for the different technologies had substantial overlap (68–91 % overlap for dog and 92–97 % overlap for NHP). The QTc data were also stable over time. The predicted change from baseline QTc for a 100-day span between assessments was 0.07 ± 0.15 ms for dog and 1.22 ± 0.19 ms for NHP. The mean arterial blood pressure (MAP) was also similar across all technologies and stable over time (0.56 and − 2.18 mmHg for 100-day span in dog and NHP).</div><div>These analyses demonstrate that the technology used in toxicology studies provides similar data to that in stand-alone studies and the data is stable over long periods. Longitudinal assessment is important for new modalities where pharmacodynamic effects can be delayed, and in assessment of potential chronic blood pressure changes.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"134 ","pages":"Article 107757"},"PeriodicalIF":1.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107567","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":"High-content cell imaging for chemical toxicity screening in the model organism Caenorhabditis elegans","authors":"Camiryn J. Kardal ,&nbsp;Spencer R. Dmytruk ,&nbsp;Abdullah Qureshi ,&nbsp;Cheng-Wei Wu","doi":"10.1016/j.vascn.2025.107756","DOIUrl":"10.1016/j.vascn.2025.107756","url":null,"abstract":"<div><div>The use of animal models for screening environmental chemicals for toxicity is an important step towards determining potential hazards to humans. Due to the large number of environmental chemicals with unknown biological activity, high-throughput screening has served as the primary method in toxicity testing for the past decades. However, with the emergence of diverse cellular targets that have been shown to be adversely affected by chemicals, a transition towards high-throughput screening that incorporates high-content analysis provides an array of cutting-edge experimental advantages. Here, we utilized the genetic model organism <em>Caenorhabditis elegans</em> to demonstrate how high-content screening can be utilized to identify new chemical modifiers of RNA splicing with the U.S. ToxCast chemical library. Through this semi-automated workflow, we highlight areas where modern high-content screening platforms provide advantages that improves on traditional methodology in high-throughput screening assays to maximize quantitative and qualitative data types collected.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"134 ","pages":"Article 107756"},"PeriodicalIF":1.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103379","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":"Computational modelling for improved translation of cardiac inotropic and lusitropic drug effects from rats to humans","authors":"Alexander Jung ,&nbsp;Christoph M. Augustin ,&nbsp;Julia Voglhuber-Höller ,&nbsp;Mara Kiessling ,&nbsp;Senka Ljubojevic-Holzer ,&nbsp;Gary R. Mirams ,&nbsp;Steven A. Niederer ,&nbsp;Gernot Plank","doi":"10.1016/j.vascn.2025.107747","DOIUrl":"10.1016/j.vascn.2025.107747","url":null,"abstract":"<div><div>Telemetered rats are widely used for early drug screenings but pronounced physiological differences between rat and human hearts limit translational relevance. To address this, the study investigates the potential of computer modelling to improve the translation of inotropic and lusitropic drug effects from rats to humans, beginning at the cellular scale. To this end, computer models of rat and human left ventricular cardiomyocytes were constructed to reproduce experimental data. First, global sensitivity analyses identified distinctive differences in inotropic and lusitropic responses to the inhibition of ion channels and transporters in rats and humans. Then, the computer models were used to address the translation challenge by predicting human responses based on sarcomere length and intracellular [Ca²⁺] data obtained from rats. This process, referred to as computational drug effect translation, involved identifying the drug's blocking potencies on potential targets. Focussing on the identifiable targets RyR2, SERCA2, and NCX1, evaluations on synthetic data showed high translation accuracy across all biomarkers and drug concentrations. For example, coefficients of determination were ≥ 0.997 for predicted human effects compared to ≤0.771 for rat effects for percentage sarcomere shortening, and ≥ 0.905 compared to ≤0.418 for the time from peak to 90 % relaxation. Evaluations on experimental data collected for thapsigargin largely corroborated these findings. The results demonstrate that computer modelling can improve the translation of inotropic and lusitropic drug effects from rats to humans, offering potential benefits for augmenting the current drug development pipeline.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"134 ","pages":"Article 107747"},"PeriodicalIF":1.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082454","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":"Taking a deep breath: Evidence-based approaches to respiratory safety assessment","authors":"John J. Kremer ,&nbsp;Matt Bridgland-Taylor ,&nbsp;Matt Clark ,&nbsp;Mike G. Rolf ,&nbsp;Martin Traebert ,&nbsp;Gregory S. Friedrichs","doi":"10.1016/j.vascn.2025.107744","DOIUrl":"10.1016/j.vascn.2025.107744","url":null,"abstract":"<div><div>Modernization of the necessity and conduct of nonclinical respiratory assays should be undertaken to enhance their translational impact for clinical outcomes, optimize animal and development costs, and ultimately strengthen regulatory relevance. This manuscript offers a perspective on why the International Conference on Harmonization (ICH) S7A mandated respiratory assay should be updated, offering a potential streamlined approach for putative therapeutics with minimal expected risks, and recommendations on more rigorous, supplemental investigations of respiratory safety hazards.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"134 ","pages":"Article 107744"},"PeriodicalIF":1.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904034","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":"Detection of abnormal behavior and convulsion in cynomolgus monkeys using video-based deep learning","authors":"Yusaku Matsushita ,&nbsp;Tetsuo Kitamura ,&nbsp;Motohiro Shiotani ,&nbsp;Hiroshi Mizuno ,&nbsp;Munehiro Nakagawa ,&nbsp;Shoji Asakura ,&nbsp;Takashi Yoshinaga","doi":"10.1016/j.vascn.2025.107627","DOIUrl":"10.1016/j.vascn.2025.107627","url":null,"abstract":"<div><div>Drug-induced behavior changes in nonclinical safety studies could correlate to serious side effects in humans and hence must be detected prior to clinical trials. We investigated a video analysis using deep learning to assess locomotor activity (LA) and convulsions in conscious non-human primates (NHPs). The training data was created by annotating the waist landmarks for pose estimation based on the video data from each cage. The time series of 2D coordinates was calculated with the deep learning-based pose estimation model. Study 1. LA evaluation: Apomorphine hydrochloride (APO, 0 or 1 mg/kg, sc), non-selective dopamine agonist, was dosed (<em>n</em> = 4). Animal behaviors were recorded for 4 h after dosing. A momentum was calculated from the difference between the frames of 2D coordinates, and a trajectory was created from transition of 2D coordinates for each 1-h epoch. Study 2. Convulsion detection: Pentylenetetrazole (PTZ, 60 to 70 mg/kg, sc), GABAA receptor antagonist as a convulsant agent, was dosed (n = 4). Animal behaviors were recorded until the occurrence of convulsion under light-on or -off (with infrared radiation) condition. A convulsion was determined when the number of frames was greater than the threshold for ten seconds using 2D coordinates and vibration intensity calculated with wavelet transformation. In Study 1, behavioral changes characteristic of APO (circling, jumping, cage licking, etc.) were observed differently between animals. The LA increased in two NHPs, showing different trajectories correlated with circling or jumping in the cage. In Study 2, PTZ induced convulsions within about 1-h postdose in all NHPs and the algorithm could detect the convulsions in all animals under both light-on and -off conditions while this algorithm did not falsely detect any convulsions in movie files in the animals in study 1. Our deep learning model using video data is considered useful to assess LA and convulsion in NHPs.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107627"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927388","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":"Best practice considerations for nonclinical in vivo cardiovascular telemetry studies with alternative study designs in non-rodent species","authors":"Steve Tichenor ,&nbsp;Christopher Regan ,&nbsp;C. Michael Foley ,&nbsp;Jill Nichols ,&nbsp;Kim Henderson ,&nbsp;Sridharan Rajamani ,&nbsp;Pascal Champeroux ,&nbsp;Dingzhou Li ,&nbsp;Brian Roche ,&nbsp;Korynne Rollins","doi":"10.1016/j.vascn.2025.107607","DOIUrl":"10.1016/j.vascn.2025.107607","url":null,"abstract":"<div><div>The recently published ICH E14/S7B Q&amp;As incorporated an additional thorough QT (TQT) substitution path for compounds that are double negative in nonclinical studies (hERG and in vivo QT). To increase regulatory confidence in such an approach, general requirements for nonclinical telemetry studies were detailed in the Q&amp;As that focus on model sensitivity, data analysis techniques, and clinical translation. Briefly, criteria for the integrated risk assessment include prescriptive in vitro hERG requirements, and an in vivo evaluation at sufficient multiples over the highest clinical exposure with demonstrated adequate sensitivity to detect an effect of a similar magnitude as a dedicated clinical QT study. Harmonization of best practices for a Latin square crossover study design were recently published by industry subject matter experts (SMEs) to ensure high quality QTc data to support an ICH E14/S7B Q&amp;A 5.1 scenario that meets regulatory expectations. However, there is no industry consensus on best practices for alternate study designs (ascending dose, parallel groups, etc.) routinely utilized for oncology small molecule, large molecule, oligonucleotide, and peptide modalities. To increase industry consistency and ensure data quality, SMEs are collaborating to review current methodologies for alternative study designs where continuous data collection is required in implanted and jacketed telemetry studies. A survey was generated by members of the working group to gather information on alternative study designs employed, data analysis processes, QT interval correction and statistical methods, individual study and test facility sensitivity, and use of pharmacokinetic sampling. The most common current alternative designs included escalating dose (vehicle plus 3 doses levels, <em>N</em> = 4) and parallel (2–3 treatment groups plus concurrent vehicle, N = 4–8/group) which have been submitted to satisfy the ICH S7B, S6, S9, and to a limited extent, the S7B 5.1/6.1 Q&amp;As. Escalating dose designs were typically applied to small molecules, whereas parallel designs were used to test oligonucleotides, large and small molecules. Data from this survey will be used as a starting point for the working group to recommend best practices for alternate study designs in the context of supporting the ICH E14/S7B Q&amp;A 5.1 and 6.1 scenarios and build regulatory confidence in nonclinical QTc data.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107607"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927602","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":"Marmoset (a small size NHP): Incorporation of safety pharmacology endpoints in toxicology studies","authors":"Raafat Fares,&nbsp;Pascal Champéroux","doi":"10.1016/j.vascn.2025.107614","DOIUrl":"10.1016/j.vascn.2025.107614","url":null,"abstract":"<div><div>The common marmoset (<em>Callithrix jacchus</em>) is a nonhuman primate species that is already used in biomedical research. Due to the constrained supply of Cynomolgus monkey and the acute shortage of sexually mature animals arisen during the COVID-19 Pandemic, the marmoset has been increasingly used for toxicity testing of biotherapeutic proteins. However, incorporating safety pharmacology endpoints in marmoset toxicology studies was not as optimal as in Cynomolgus. Therefore, the purpose of this study was to test a jacketed telemetry system (DECRO system) which enables the simultaneous recordings of respiratory, ECG and activity parameters in freely moving marmosets. Ten animals (5 females and 5 males) were fitted with the Decro system and recorded for 14 h. Respiratory rate (RespR), expiratory and inspiratory times, tidal volume, minute ventilation, ECG analysis and intervals calculation, heart rate (HR), and activity level (AL) were assessed in all animals. During the light phase, the mean values ± SEM of HR and RespR varied from 271 ± 12 beat per min (bpm) to 318 ± 14 bpm, and from 63 ± 3 breath per min (brpm) to 73 ± 2 brpm, respectively based on the AL. During the dark cycle where AL was nearly null, the HR and RespR decreased to 247 ± 12 bpm and 53 ± 4 bpm, respectively. All the remaining parameters were successfully assessed using the different algorithms provided by the software. Overall, our results provided evidence that there were no clinical findings caused by the jacket. This preliminary study yielded promising results to support the use of the GLP software version of this jacketed telemetry system, in line with the 3Rs principles, in regulatory toxicology studies. With this development, the use of marmosets as an alternative to Cynomolgus in drug development is reinforced especially if considering that marmosets are one of the very few species capable of showing drug-induced torsades de pointes in healthy animals.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107614"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927609","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":"Multiplexed cell-based assays for evaluating the structure and function of excitable cells","authors":"Kjell Steps,&nbsp;Austin Passaro,&nbsp;Daniel Millard,&nbsp;Denise Sullivan,&nbsp;Ben Streeter,&nbsp;Stacie Chvatal","doi":"10.1016/j.vascn.2025.107666","DOIUrl":"10.1016/j.vascn.2025.107666","url":null,"abstract":"<div><div>The flexibility and accessibility of induced pluripotent stem cell technology has allowed complex human biology to be reproduced <em>in vitro</em> at high throughput scales. Indeed, rapid advances in stem cell technology have led to widespread adoption for the development of <em>in vitro</em> models of neuron and cardiomyocyte electrophysiology to be used in screening applications in drug discovery and safety. Furthermore, advanced cell preparations, such as organoids, are under investigation with aims toward establishing mature human phenotypes <em>in vitro</em>. For the development and validation of relevant <em>in vitro</em> neuronal and cardiac models, it is critical to evaluate the structure and function of neuronal synapses and networks, as well as cardiomyocyte viability, electrophysiology, and contractility. The objective of this work is to develop and validate a multiplexed structure-function assay as an efficient approach for evaluating neuronal and cardiomyocyte models <em>in vitro</em>. A planar grid of microelectrodes embedded in the substrate of each well interfaces with cultured cellular networks to continuously monitor both electrophysiological function and structural viability. The electrodes detect the raw electrical activity from the cells to identify changes in function, while structural effects, such as morphological changes and cell viability, are detected as changes in impedance at the cell-electrode interface. Here, we characterized and validated this multiplexed assay using known control compounds that differentially affected cell structure and function. For iPSC-derived neuronal models, all compounds tested (DMSO, glutamate, tributyltin, ionomycin, and Triton X-100) altered functional spiking activity. Glutamate, ionomycin, and tributyltin all produced a dose- and time-dependent decrease in viability, as measured <em>via</em> impedance, with Triton X-100 serving as the positive control for complete loss of membrane integrity. For cardiomyocytes, all compounds (E-4031, nifedipine, isoproterenol, doxorubicin, and blebbistatin) affected aspects of electrical or contractile function, but only doxorubicin decreased cell viability. These results support the continued development and use of human iPSC-derived neuronal and cardiomyocyte assays for high throughput drug discovery and safety assessment.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107666"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927612","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":"Cardiovascular effects of Zenalpha® compared to dexmedetomidine in ventricular tachy-paced dogs","authors":"Sydney E. St. Clair","doi":"10.1016/j.vascn.2025.107676","DOIUrl":"10.1016/j.vascn.2025.107676","url":null,"abstract":"<div><div>Dexmedetomidine is used in veterinary medicine to produce sedation, analgesia, and muscle relaxation but elicits hypertension, bradycardia, and decreased cardiac output, which can create concern when given to animals with cardiomyopathies. Zenalpha combines vatinoxan with medetomidine to produce sedation and analgesic effects, but it has a different cardiovascular profile than that seen with dexmedetomidine alone in healthy animals. The effects of Zenalpha in heart failure animals are unknown. Thus, this study aims to compare the cardiovascular effects of intramuscular Zenalpha compared to dexmedetomidine, in dogs with mild-to-moderate heart failure induced by ventricular tacypacing. Seven purpose-bred beagle-dogs were implanted with radiotelemetry units to measure conscious central aortic pressure, left ventricular pressure, and single‑lead electrocardiograms. Mild-to-moderate heart failure was induced <em>via</em> right-ventricular tachypacing before being studied. The dogs were studied in a prospective, randomized cross-over incorporating intramuscular treatments with Zenalpha compared to dexmedetomidine. Prior to drug administration, dogs were anaesthetized for Swan-Ganz placement and allowed to recover. Treatment was administered, and the dogs were monitored for two-hours with continuous telemetry recordings, brief echocardiograms, and assessments of sedation and analgesia. At 45 min post-dose, dexmedetomidine administration alone led to hypertension (↑ MAP 14 ± 7 % Δ BL), bradycardia (↓ HR −37 ± 7), decreased cardiac output (↓ CO -56 ± 5), elevated left-ventricular filling pressures (↑ EDP 160 ± 46), and decreased left-ventricular function (↓ EF -17 ± 6) with adequate sedation and analgesic scores (↑ MNT 130 ± 52). Zenalpha decreased blood pressure (↓ MAP -33 ± 3 % Δ BL), caused bradycardia (↓ HR -27 ± 5[SR3]) decreased cardiac output (↓ CO -21 ± 5), reduced left-ventricular filling pressures (↓ EDP -9 ± 75), and slightly increased left-ventricular function (↑ EF 5 ± 6) with adequate sedation and analgesic scores (↑ MNT 56 ± 34) at the same timepoint. Zenalpha provides adequate sedation and analgesic properties when compared to dexmedetomidine in animals with mild-to-moderate heart failure, while mitigating the decrease in heart rate and cardiac output typically seen with dexmedetomidine. Zenalpha also maintained left-ventricular function and had minimal effects on the ventricular filling pressures. Although the effects are shorter than those seen with dexmedetomidine, Zenalpha could be considered a safer choice for animals with cardiomyopathies in a clinical setting.</div></div>","PeriodicalId":16767,"journal":{"name":"Journal of pharmacological and toxicological methods","volume":"133 ","pages":"Article 107676"},"PeriodicalIF":1.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927672","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}