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Evaluation of the translation of multiple cardiovascular regulatory mechanisms in the anesthetized dog J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2024-03-11 Olivera Antic, Yevgeniya E. Koshman, Brandan M. Bird, Geena Jasiek, Amanda S. Wilsey, Scott W. Mittelstadt, C. Michael Foley
The strategic and targeted use of an anesthetized canine cardiovascular model early in drug discovery enables a comprehensive cardiovascular and electrophysiological assessment of potential safety liabilities and guides compound selection prior to initiation of chronic toxicological studies. An ideal model would enable exposure-response relationships to guide safety margin calculations, have a low
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Improved seizure liability detection by combining rat hippocampal brain slice electrophysiology with in vivo behavior observation following intracerebroventricular drug administration J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2024-03-02 Tadashi Tsubouchi, Keigo Ikeda, Yasuhiro Sasaki, Hitoshi Watanabe, Kazuhiro Chihara, Izuru Miyawaki
An adverse effect of drug candidates, seizure is a serious issue in drug development. Improving evaluation systems for seizure liability is crucial for selecting good candidates. Firstly, electrophysiological measurement by a multielectrode array system in rat hippocampal brain slices was employed to confirm an increase in electrically evoked population spike (PS) area, the occurrence of multiple population
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Virtual clinical QT exposure-response studies – A translational computational approach J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2024-03-01 Jazmin Aguado-Sierra, Paula Dominguez-Gomez, Ani Amar, Constantine Butakoff, Michael Leitner, Stefan Schaper, Jan M. Kriegl, Borje Darpo, Mariano Vazquez, Georg Rast
A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is
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The visual field-testing maze and vision maze: Feasible techniques to evaluate visual field loss in animals J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2024-02-17 Shivani Behera, Ashmita Das, Jaya Shree, Pranay Soni, Devi Prasad Pandey, Surendra H. Bodakhe
Visual field loss due to glaucoma is a severe and concerning problem, leading to limited visual range and poor quality vision. The progression of this loss begins with a para-central arcuate scotoma which eventually advances to a ring scotoma and constricted visual fields in later stages. Currently, no animal model is available for screening this pattern of vision loss. However, we have successfully
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A personal reflection on 23 years of the Journal of pharmacological and toxicological methods J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2024-01-06 Michael J. Curtis
Abstract not available
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A highly efficient liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for etomidate and etomidate acid in urine, liver and kidney J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-12-21 Tian-Fu He, Huan-hui Zhu, Xian-wen Lin, Yuan-yuan Tian, Li-min Sun, Xu Guan, Hai-Yan Zhang, Li Tan, Song-cai Wang
Etomidate (ETO) is a highly-efficient drug that can induce anesthesia with increasing doses, thus subject to strict regulation. However, an accurate and efficient method for ETO intake detection is currently lacking. Therefore, this study developed a straightforward sample preparation method using LC-MS/MS to analyze ETO and its primary metabolite, etomidate acid (ETA), in urine, liver, and kidney
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Editorial Board J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-12-06
Abstract not available
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Validation of a simple spectrophotometric method for the rapid determination of salicylates in plasma J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-11-21 Younes Zebbiche, Abderrahmane Kori Yahia, Nour El Yakine Keraghel, Fiala Sarah, Chebli Akli Islam, Achouri Mohammed Yacine
Introduction The determination of salicylate concentrations constitutes a critical aspect of medical diagnostics, particularly in emergency settings. High-performance liquid chromatography (HPLC) and spectrophotometry are efficient methods commonly utilized for this purpose. In emergency laboratories with limited resources, the validation of a cost-effective and reliable spectrophotometric method for
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Telemetric long-term assessment of autonomic function in experimental heart failure J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-11-16 Katharina Boden, Pailin Pongratanakul, Julia Vogel, Nicola Willemsen, Eva-Maria Jülke, Jakob Balitzki, Hanna Tinel, Hubert Truebel, Wilfried Dinh, Thomas Mondritzki
Despite medical advances in the treatment of heart failure (HF), mortality remains high. It has been shown that alterations of the autonomic-nervous-system (ANS) are associated with HF progression and increased mortality. Preclinical models are required to evaluate the effectiveness of novel treatments modulating the autonomic imbalance. However, there are neither standard models nor diagnostic methods
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A generalized canine transfer function accurately reconstructs central aortic pressure waveforms to enable enhanced pulse wave analysis J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-11-04 Julia C. Hotek, Theodore J. Detwiler, Julio A. Chirinos, Christopher P. Regan
Routine preclinical blood pressure evaluation is an important risk assessment tool. Although proximal aortic pressure is most relevant for key target organs, abdominal aortic pressures are more commonly recorded. Pulse pressure amplification and waveform distortion in abdominal waveforms make it inappropriate for central hemodynamic analytical methods without the use of a mathematical transfer function
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Isolation and electrophysiological recording of Ixodes ricinus synganglion neurons J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-10-20 Khalid Boussaine, Maria Taha, Cáinà Nìng, Alison Cartereau, Sabine Rakotobe, Lourdes Mateos-Hernandez, Emiliane Taillebois, Ladislav Šimo, Steeve H. Thany
The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has dramatically improved over the last two decades, this is the first time that isolation and electrophysiological recordings have been carried out on tick neurons from the synganglion. Method: We developed a simple protocol for synganglion
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Comparison of cell viability methods for human mesenchymal/stromal stem cells and human A549 lung carcinoma cells after freeze-thaw stress J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-10-20 Markus Kardorff, Hanns-Christian Mahler, Jörg Huwyler, Léa Sorret
For the safety and efficacy of frozen cell therapy products, determination of cellular viability is key. However, results of cell viability measurements do not only depend on the cell line or on the inflicted stress, but also on the assay used, making inter-experimental comparisons difficult. The aim of this study was thus to assess commonly used viability assays in clinically relevant human mesenchymal/stromal
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Comparison of SYBR green I and lactate dehydrogenase antimalarial in vitro assay in Plasmodium falciparum field isolates J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-09-29 Joseph Hawadak, Shewta Chaudhry, Veena Pande, Vineeta Singh
Several assay methods are in use for monitoring the drug sensitivity of malaria parasites and screening new antimalarial drugs. Plasmodium lactate dehydrogenase (pLDH) and SYBR Green I in vitro assays were used to evaluate the drug efficacy of Chloroquine, Artemisinin and Azadirachta indica silver nano particles against Plasmodium falciparum 3D7 strain. The half-maximal inhibitory concentration (IC50)
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Performance and feasibility of three different approaches for computer based semi-automated analysis of ventricular arrhythmias in telemetric long-term ECG in cynomolgus monkeys J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-09-09 Jörg Eiringhaus, Anna-Lena de Vries, Stephan Hohmann, Dietmar Böthig, Johanna Müller-Leisse, Henrike A.K. Hillmann, Andreas Martens, Robert Zweigerdt, Annette Schrod, Ulrich Martin, David Duncker, Ina Gruh, Christian Veltmann
Computer-based analysis of long-term electrocardiogram (ECG) monitoring in animal models represents a cost and time-consuming process as manual supervision is often performed to ensure accuracy in arrhythmia detection. Here, we investigate the performance and feasibility of three ECG interval analysis approaches A) attribute-based, B) attribute- and pattern recognition-based and C) combined approach
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Quantification of anti-drug antibodies against E6011, an anti-fractalkine monoclonal antibody, in monkey and human serum, by an electrochemiluminescence assay J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-09-07 Muneo Aoyama, Yuji Mano
E6011, a humanized anti-fractalkine monoclonal antibody, is under development for the treatment of various inflammatory diseases, such as rheumatoid arthritis. Therapeutic antibodies may induce production of anti-drug antibodies (ADA) that may deteriorate efficacy and/or enhance immunogenic reaction. It is important to have an ADA assay to understand the characteristics of biotherapeutics under development
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Adaptation of closed-chest infarction porcine model to adult Pannon minipigs J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-08-19 Dénes Kőrösi, András Vorobcsuk, Dániel Fajtai, Ottó Tátrai, Emőke Bodor, Kornélia Farkas, Rita Garamvölgyi
The aim of the recent study was to collect data on the genotype characteristics of the Hungarian self-bred Pannon minipigs by adapting a standardized infarct model procedure. Closed chest AMI was induced by balloon occlusion for 90 min in the left anterior descendent coronary artery (LAD) in 24 adult intact female minipigs followed by reperfusion. To assess the left ventricular (LV) function, serial
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Off-target pharmacological activity at various kinases: Potential functional and pathological side effects J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-08-06 Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Sujatha M. Gopalakrishnan, Michael J. Liguori, Scott W. Mittelstadt, Eric A.G. Blomme, Terry R. Van Vleet
In drug discovery, during the lead optimization and candidate characterization stages, novel small molecules are frequently evaluated in a battery of in vitro pharmacology assays to identify potential unintended, off-target interactions with various receptors, transporters, ion channels, and enzymes, including kinases. Furthermore, these screening panels may also provide utility at later stages of
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Safety pharmacology 2023 and implementation of the ICH E14/S7B Q&A guidance document J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-29 Michael K. Pugsley, Yevgeniya E. Koshman, C. Michael Foley, Brett R. Winters, Simon Authier, Michael J. Curtis
This editorial prefaces the annual themed issue on safety pharmacology (SP) methods published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). We highlight here the content derived from the recent 2022 Safety Pharmacology Society (SPS) and Canadian Society of Pharmacology and Therapeutics (CSPT) joint meeting held in Montreal, Quebec, Canada. The meeting also generated
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Comparative study for the IMI2-NeuroDeRisk project on microelectrode arrays to derisk drug-induced seizure liability J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-25 Jin Zhai, Martin Traebert, Kurt Zimmermann, Annie Delaunois, Leandro Royer, Giorgia Salvagiotto, Coby Carlson, Armando Lagrutta
Introduction In the framework of the IMI2-NeuroDeRisk consortium, three in vitro electrophysiology assays were compared to improve preclinical prediction of seizure-inducing liabilities. Methods Two cell models, primary rat cortical neurons and human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with hiPSC-derived astrocytes were tested on two different microelectrode
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Comparing the sensitivity of cross-over and parallel study designs for QTc assessment: An analysis based on a single large study of moxifloxacin in 48 nonhuman primates J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-24 Derek J. Leishman, David Holdsworth, Derek D. Best, Brian Roche
The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only
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Optimization of bioanalysis of dried blood samples J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-22 Elham Ataei Alizadeh, Georg Rast, Chris Cantow, Jessica Schiwon, Florian Krause, Guido R.Y. De Meyer, Pieter-Jan Guns, Brian D. Guth, Michael Markert
Introduction Pharmacokinetic/pharmacodynamic modelling has emerged as a valuable technique for understanding drug exposure and response relationships in drug development. Pharmacokinetic data are often obtained by taking multiple blood samples, which may disturb physiological parameters and complicate study designs. Wearable automatic blood sampling systems can improve this limitation by collecting
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Blood microsampling in cynomolgus monkey and evaluation of plasma PK parameters in comparison to conventional sampling J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-21 Simone Bertani, Alberto Donadi, Jessica Franchi, Federica Vinco, Rossella Cardin, Denise Federico, Alessia Tagliavini, Simone Zannoni, Marco Pergher, Michela Pecoraro, Massimo Breda
Microsampling, a reduced volume sampling method, has successfully gained attention at the International Conference on Harmonization (ICH) level and established benefits support its use in Toxicokinetic (TK) studies. These improved sampling techniques are less invasive and in large animal species improve animal welfare (refinement). To evaluate if the plasma concentrations of drugs were influenced by
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Common chemistry, manufacturing, and control deficiencies in abbreviated new drug applications assessed by the US Food and drug administration: Hurdle to access cost-effective medicines J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-17
To market a generic product in the United States, it must be registered in Common Technical Document (CTD) format with the US Food and Drug Administration. The Generic Drug User Fee Act went into force in 2012, to expedite the timely review of Abbreviated New Drug Applications (ANDA) by communicating potential defects in the application to the applicant through deficiency letters at different time
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Overview of the bioanalytical methods used for the determination of benzodiazepines in biological samples and their suitability for emergency toxicological analysis J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-17 Mohamed Yafout, Rachid Aït Mouss, Houda Bouchafra, Lhoussaine Zarayby, Ibrahim Sbai El-Otmani
Benzodiazepines are one of the most widely used classes of drugs around the world. They are medically used in different therapeutic areas including insomnia, anxiety, epilepsy, and anesthesia. Unfortunately, these drugs are very widespread in the illicit market for recreational purposes and cause drug dependence, traffic accidents, and criminality. Furthermore, benzodiazepine misuse leads to acute
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hERG agonists pose challenges to web-based machine learning methods for prediction of drug-hERG channel interaction J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-17 Aziza El Harchi, Jules C. Hancox
Pharmacological blockade of the IKr channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities
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Species comparison of compounds with known blood pressure effects in a vascular smooth muscle cell collagen contraction assay J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-12
Introduction There is a great need for new approaches early in drug discovery that have the potential to improve clinical translation of compound-mediated cardiovascular effects. Current approaches frequently rely on in vivo animal models or in vitro tissue bath preparations, both of which are low throughput and costly. An in vitro surrogate screen for blood pressure using primary human cells may serve
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Editorial Board J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-11
Abstract not available
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Enhancing the functional maturity of hiPSC-derived cardiomyocytes to assess inotropic compounds J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-07-06 Xiaoyu Zhang, Praful Aggarwal, Ulrich Broeckel, Yama A. Abassi
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present an attractive in vitro platform to model safety and toxicity assessments—notably screening pro-arrhythmic compounds. The utility of the platform is stymied by a hiPSC-CM contractile apparatus and calcium handling mechanism akin to fetal phenotypes, evidenced by a negative force-frequency relationship. As such, hiPSC-CMs
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Comparative assessment of Ca2+ oscillations in 2- and 3-dimensional hiPSC derived and isolated cortical neuronal networks J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-06-29 John P. Imredy, Gautier Roussignol, Holly Clouse, Giorgia Salvagiotto, Ludmilla Mazelin-Winum
Human induced Pluripotent Stem Cell (hiPSC) derived neural cells offer great potential for modelling neurological diseases and toxicities and have found application in drug discovery and toxicology. As part of the European Innovative Medicines Initiative (IMI2) NeuroDeRisk (Neurotoxicity De-Risking in Preclinical Drug Discovery), we here explore the Ca2+ oscillation responses of 2D and 3D hiPSC derived
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Evaluation of three different 99mTc-based mock-venom agents for lymphoscintigraphy studies in preclinical models of peripheral snakebite envenomation J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-06-07 Nidhi Tiwari, Abhinav Jaimini, Gaurav Kumar Jain, Geeta Aggarwal, Gaurav Mittal
Snakebite envenomation is one of the major public health concerns across many countries; with the WHO designating it as a ‘priority neglected tropical disease’ and stressing for a need to develop novel therapeutic strategies to reduce death and disability rate by end of 2030. Since a major component of venom; the high molecular weight (HMw) toxins enter the bloodstream through lymphatic system, research
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Assessment of sarcomere shortening and calcium transient in primary human and dog ventricular myocytes J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-06-01 BaoXi Gao, Najah Abi-Gerges, Ky Truong, Alexa Stafford, William Nguyen, Weston Sutherland, Hugo M. Vargas, Yusheng Qu
Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca2+ dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ
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Thirty years of telemetry-based data acquisition for cardiovascular drug safety evaluation: Applications and optimization J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-05-29 Elham Ataei Alizadeh, Karin Graf, Jessica Schiwon, Thomas Trautmann, Florian Krause, Werner Mayer, Katrin Christ, Eric Martel, Brian D. Guth, Michael Markert
Conducting safety evaluations of new drugs using conscious animals has been a specialty of our working group for thirty years. In this article, we review the various technical challenges and solutions dealt with over the years to improve both the data quality and the well being of our animal subjects. Of particular interest for us has been the use of telemetry-based data acquisition for conducting
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HS-GC-FID method for quantification of HFA-152a in cell culture media, and plasma from a range of species and regulatory compliant validations J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-05-15 Philip J. Kuehl, Stuart Corr, Jabari Farrar, Jacob D. McDonald, Tim Wermer, Derek Weber, Chet Leach
Introduction 1,1-Difluoroethane (HFA-152a) is being developed as an alternative propellant in pressurized metered dose inhalers (pMDIs). As a part of the regulatory development pathway, pharmacology, toxicology and clinical studies have been conducted with inhaled HFA-152a. These studies require fit for purpose regulatory compliant (GxP validated) methods for quantification of HFA-152a from blood.
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Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-05-08 Eric I. Rossman, Todd A. Wisialowski, Hugo M. Vargas, Jean-Pierre Valentin, Michael G. Rolf, Brian M. Roche, Steve Riley, Michael K. Pugsley, Jill Nichols, Dingzhou Li, Derek J. Leishman, Robert B. Kleiman, Andrea Greiter-Wilke, Gary A. Gintant, Michael J. Engwall, Annie Delaunois, Simon Authier
The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a “double negative” nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical “double negative” data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute
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Simultaneous assessment of central nervous and respiratory systems using jacketed telemetry in socially-housed rats: Application of the “3Rs” principles in core battery safety pharmacology studies J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-05-03 Raafat Fares, Pascal Champéroux
Central nervous (CNS) and respiratory systems are routinely investigated in safety pharmacology core battery studies. For small molecules, the assessment of both vital organ systems is frequently done in rats in two distinct studies. With the advent of a miniaturized technology of jacketed external telemetry for rats (DECRO system), the simultaneous assessment of modified Irwin's or functional observational
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“Appraisal of state-of-the-art” 2021 safety pharmacology society - distinguished service award safety and secondary pharmacology: Reflecting on the past to tackle challenges ahead J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-05-05 Jean-Pierre Valentin, Alicia Sibony, Marie-Luce Rosseels, Annie Delaunois
This appraisal of state-of-the-art manuscript highlights and expands upon the thoughts conveyed in the lecture of Dr. Jean-Pierre Valentin, recipient of the 2021 Distinguished Service Award from the Safety Pharmacology Society, given on the 2nd December 2021. The article reflects on the strengths, weaknesses, opportunities, and threats that surrounded the evolution of safety and secondary pharmacology
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Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-03-28 Hugo M. Vargas, Eric I. Rossman, Todd A. Wisialowski, Jill Nichols, Michael K. Pugsley, Brian Roche, Gary A. Gintant, Andrea Greiter-Wilke, Robert B. Kleiman, Jean-Pierre Valentin, Derek J. Leishman
Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more
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The impact of environmental and biological factors on the resting heart rate of dogs as assessed using 20 years of data from safety pharmacology studies J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-03-24 Elham Ataei Alizadeh, Thomas Trautmann, Florian Krause, Benjamin Knoeferl, Pieter-Jan Guns, Guido De Meyer, Brian D. Guth, Michael Markert
Introduction A safety pharmacology study detects and evaluates potential side effects of a new drug on physiological function at therapeutic levels and above and, in most cases, prior to the initiation of clinical trials. The aim of this study was to investigate the effects of environmental and biological factors on resting heart rate (HR), a representative cardiac parameter in cardiovascular safety
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Sensitive and rapid method for the quantitation of amoxicillin in minipig plasma and milk by LC-MS/MS: A contribution from the IMI ConcePTION project J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-03-22 Yeghig Armoudjian, Qi Lin, Bart Lammens, Johan Van Daele, Pieter Annaert
The IMI project ConcePTION was launched to fill the knowledge gap of using medicines during pregnancy and lactation. To achieve this goal, several studies are being conducted, including the bioanalysis of amoxicillin in minipig plasma and milk. A high-throughput, robust and reliable liquid chromatography tandem mass spectrometry method was developed and validated according to FDA and EMA guidelines
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The incidence of spontaneous arrhythmias in telemetered beagle dogs, Göttingen Minipigs and Cynomolgus non-human primates: A HESI consortium retrospective analysis J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-03-22 Emmanuel Boulay, Loïs S. Miraucourt, Michael K. Pugsley, Matthew M. Abernathy, Ray Chui, Jill Dalton, Marjorie Demers, Noel Dybdal, Elissa Gazaille, Andrea Greiter-Wilke, Peter Hoffmann, Hai Huang, Carrie LaDuke, Kevin Norton, Jennifer B. Pierson, Isabelle Reeves, Brian Roche, Eric I. Rossman, Albert E. Schultze, Hai-Ming Tang, Simon Authier
Introduction Characterization of the incidence of spontaneous arrhythmias to identify possible drug-related effects is often an important part of the analysis in safety pharmacology studies using telemetry. Methods A retrospective analysis in non-clinical species with and without telemetry transmitters was conducted. Electrocardiograms (24 h) from male and female beagle dogs (n = 131), Göttingen minipigs
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Editorial Board J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-03-12
Abstract not available
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Validation of an LC–MS/MS method for quantitation of fostemsavir in plasma J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-02-28 Siddhartha Lolla, Kumar Shiva Gubbiyappa, Shankar Cheruku, D.V.R.N. Bhikshapathi
Background A novel, sensitive and specific LC-MS/MS technique was developed and validated for the quantification of fostemsavir in human plasma and its pharmacokinetic application in rabbits. Methods Chromatographic separation of the fostemsavir and fosamprenavir (internal standard) were achieved on Zorbax C18 (50 mm × 2 mm × 5 μm) column with 0.80 mL/min flow rate and coupled with API6000 triple quadrupole
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Comparison of validity of standard nonclinical group size selection versus standard clinical group sizes for nonhuman primate QTc prolongation evaluation J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-02-16 David Holdsworth, Derek D. Best, Katarina Haist, Kyle O'Donohue, Anson Phillips, Matthew M. Abernathy, Brian Roche, Derek J. Leishman
The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4–8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40–60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity
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Disconnect between COX-2 selective inhibition and cardiovascular risk in preclinical models J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-02-13 Yevgeniya E. Koshman, Aimee L. Bielinski, Brandan M. Bird, Jonathon R. Green, Kenneth L. Kowalkowski, Jie Lai-Zhang, Prathap Kumar Mahalingaiah, James W. Sawicki, Nari N. Talaty, Amanda S. Wilsey, Mark T. Zafiratos, Terry R. Van Vleet
Introduction Secondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant
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Revisiting the high-fat diet/low streptozotocin prediabetic rat model: A bioanalytical adjustment J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-01-27 Alejandra M. Preciado-Saldaña, José A. López-Díaz, J. Abraham Domínguez-Avila, J. Fernando Ayala-Zavala, Humberto F. Astiazaran-García, Gustavo A. González-Aguilar, Abraham Wall-Medrano
Insulin resistance (IR) is the main feature of prediabetes (PD), which ultimately leads to diabetes. High-dose streptozotocin-treated rodents often show irreversible β-cell mass loss and function, leaving the premorbid diabetic state (PD/IR) unnoticed. This study aimed to re-evaluate the synergistic/independent effect of a sub-chronic consumption (1–5 weeks) of a high-fat diet (60% gross energy from
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Simultaneous quantification of thalidomide, lenalidomide and pomadomide in plasma by LC-MS/MS J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2023-01-07 Bin Wang, Wanting Qiang, Jia Yi, Shouhong Gao, Bosu Meng, Yuhui Mu, Bolong Wang, Zhipeng Wang, Xia Tao
Objective To develop a new method for quantitatively analyzing three immunomodulators (thalidomide, lenalidomide and pomadomide) by liquid chromatography tandem mass spectrometry (LC-MS/MS). Methods Using thalidomide-d4 as internal standard, the three analytes were separated on Agilent Zorbax SB-C18(2.1 mm × 100 mm, 3.5 μm, Agilent, USA) column and monitored in multiple reactions monitoring mode in
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Editorial Board J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-12-27
Abstract not available
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Reference intervals and method sensitivity for electrocardiology, hemodynamics, and body temperature parameters in healthy cynomolgus monkeys J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-12-26 Xiefan Fang, Stephen D. Tichenor
In nonclinical studies, electrocardiograms (ECG) of cynomolgus monkey are recorded intermittently by external leads in manually restrained animals (snapshot recording) or continuously by jacketed external telemetry (JET) or implanted radiotelemetry transmitter in freely moving animals. With the implanted device, blood pressure and core body temperature can be monitored simultaneously. Despite the frequent
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An electrochemiluminescence assay for quantification of Denileukin Diftitox and its anti-drug antibodies in rat serum J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-12-13 Yuji Mano
Denileukin Diftitox (DD), comprising fragments of diphtheria toxin (DT) and interleukin-2 (IL2), was developed for the treatment of lymphoma and has been approved for marketing in Japan. Toxicological evaluation including pharmacokinetics and immunogenicity in preclinical animals is important for drug development and thus the assays of DD and anti-drug antibody (ADA) were developed by electrochemiluminescence
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Non-uniformity in in vitro drug-induced cytotoxicity as evidenced by differences in IC50 values – implications and way forward J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-12-12 T. Arokia Femina, V. Barghavi, K. Archana, N.G. Swethaa, Ravi Maddaly
Cell lines have proven indispensable for in vitro experiments and their utility as experimental models range from understanding the fundamental cell functioning to drug discovery. One of the most common utility of cell lines is for in vitro drug testing. Drug testing involves determining the cytotoxic effects of the drugs and such a measurement is expressed as the IC50 values of drugs. Although determination
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Protein malnutrition in BALB/C mice: A model mimicking clinical scenario of marasmic-kwashiorkor malnutrition J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-11-19 Madhura R.J., Varsha A., Anirban Chakraborthy, Mohana Kumar B., Veena Shetty A., Murali Badanthadka
Protein malnutrition continues to be a major global issue. A stable animal model to address protein malnutrition and its effect on various disease conditions is necessary. In the present study, we have formulated and standardized a low protein diet (LPD) to develop a protein malnutrition model using Balb/C mice. Healthy male Balb/C mice were weaned and exposed to LPD combinations while another group
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Determination of five positive control drugs in hERG external solution (buffer) by LC-MS/MS to support in vitro hERG assay as recommended by ICH S7B J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-11-09 Tamara I. King, Amruta Indapurkar, Isra Tariq, Ryan DePalma, Sabyasachy Mistry, Claudia Alvarez-Baron, Omnia A. Ismaiel, Wendy Wu, Kimberly Chiu, Vikram Patel, Rodney Rouse, David G. Strauss, Murali K. Matta
ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QTC prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to
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An optimized method for intratracheal instillation in mice J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-10-30 Yi Zeng, Huidong Jin, Jia Wang, Chengwei Guo, Weiyan Chen, Yao Tan, Lingqiao Wang, Ziyuan Zhou
Non-invasive intratracheal instillation is an important method for direct exposure of the respiratory tract which is commonly used in toxicology, environmental science, and other research fields. However, there is no standard operating process for non-invasive intratracheal instillation. To keep the reliability and accuracy of intratracheal instillation is vital, especially, for animal models of sub-chronic
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Importance of beating rate control for the analysis of drug effects on contractility in human induced pluripotent stem cell-derived cardiomyocytes J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-10-20 Yuto Hinata, Yuki Kagawa, Hirotsugu Kubo, Eriko Kato, Atsushi Baba, Daisuke Sasaki, Katsuhisa Matsuura, Kohei Sawada, Tatsuya Shimizu
Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control
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Contractility assessment of human iPSC-derived cardiomyocytes by using a motion vector system and measuring cell impedance J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-10-13 Ayano Satsuka, Sayo Hayashi, Shota Yanagida, Atsushi Ono, Yasunari Kanda
Predicting drug-induced cardiotoxicity during the non-clinical stage is important to avoid severe consequences in the clinical trials of new drugs. Human iPSC-derived cardiomyocytes (hiPSC-CMs) hold great promise for cardiac safety assessments in drug development. To date, multi-electrode array system (MEA) has been a widely used as a tool for the assessment of proarrhythmic risk with hiPSC-CMs. Recently
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Development of a medium throughput whole-cell microtiter plate Thr286 autophosphorylation assay for CaMKIIα using ELISA J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-09-27 Line B. Palmelund, Geeske M. van Woerden, Hans Bräuner-Osborne, Petrine Wellendorph
Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a multifunctional Ser/Thr kinase involved in several neuronal signaling pathways including synaptic plasticity. CaMKIIα autonomous activity is highly dependent on Thr286 autophosphorylation (pThr286), which is widely used as a readout for its enzymatic activity. To readily characterise compounds and potential drug candidates targeting CaMKIIα
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Less invasive, simultaneous, and continuous measurements of locomotor activity and body temperature using the nano tag® small accelerometer device in cynomolgus monkeys J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-09-15 Tomoyuki Kishida, Yoshiyuki Motokawa, Ryohei Yokoi, Shinji Souma
Locomotor activity and body temperature evaluations of cynomolgus monkeys are useful to understand the effects of drugs on the central nervous system. Here, we describe a simple, inexpensive, and less invasive evaluation method using the nano tag® (KISSEI COMTEC Co., Ltd.), a small three-axis accelerometer device with a temperature sensor. Nano tags® were subcutaneously implanted in four cynomolgus
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A mouse model of allergic conjunctivitis permitting tear eosinophil quantification J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-09-18 Atsushi Ogura, Yukio Sugimoto
Introduction Allergic conjunctivitis is an immune-mediated inflammatory disease of the conjunctiva that is induced by antigens. Allergic conjunctivitis can cause various symptoms such as ocular itching, hyperemia and edema. Developing experimental animal models that show clinical symptoms and methods for quantitative and objective evaluation is important for understanding allergic conjunctivitis. Therefore
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Electrocardiography and heart rate variability in Göttingen Minipigs: Impact of diurnal variation, lead placement, repeatability and streptozotocin-induced diabetes J. Pharmacol. Toxicol. Methods (IF 1.9) Pub Date : 2022-09-11 Mille Kronborg Lyhne, Karina Poulsdóttir Debes, Terese Helgogaard, Andreas Vegge, Jonas Kildegaard, Ulrik Pedersen-Bjergaard, Lisbeth Høier Olsen
Background The Göttingen Minipig is widely used in preclinical research and safety pharmacology, but standardisation of porcine electrocardiography (ECG) is lacking. The aim of this study was to investigate diurnal effects, change over time and choice of lead on ECG morphology and heart rate variability (HRV) in healthy and streptozotocin (STZ) induced diabetic Göttingen Minipigs. Methods Diabetes