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Journal of Pharmacological and Toxicological Methods

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https://www.readbyqxmd.com/read/29753134/the-use-of-human-tissue-in-safety-assessment
#1
Samuel J Jackson, Helen Prior, Anthony Holmes
INTRODUCTION: The safety-related failure of drugs during clinical phases of development is a significant contributor to drug attrition, wasting resources, preventing treatments from reaching patients. A lack of concordance between results from animal models and adverse events in the clinic has been identified as one potential cause of attrition. In vitro models using human tissue or cells have the potential to replace some animal models and improve predictivity to humans. METHODS: To gauge the current use of human tissue models in safety pharmacology and the barriers to greater uptake, an electronic survey of the international safety assessment community was carried out and a Safety Pharmacology Society European Regional Meeting was organised entitled 'The Use of Human Tissue in Safety Assessment'...
May 9, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29751085/a-predictive-index-of-biomarkers-for-ictogenesis-from-tier-i-safety-pharmacology-testing-that-may-warrant-tier-ii-eeg-studies
#2
REVIEW
David V Gauvin, Zachary J Zimmermann, Joshua Yoder, Marci Harter, David Holdsworth, Quinn Kilgus, Jonelle May, Jill Dalton, Theodore J Baird
Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240) . These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies...
May 8, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29730318/a-real-time-screening-assay-for-cannabinoid-cb1-receptor-mediated-signaling
#3
Haley K Andersen, Kenneth B Walsh
The cannabinoid CB1 receptor is expressed throughout the central nervous system where it functions to regulate neurotransmitter release and synaptic plasticity. While the CB1 receptor has been identified as a target for both natural and synthetic cannabinoids, the specific downstream signaling pathways activated by these various ligands have not been fully described. In this study, we developed a real-time membrane potential fluorescent assay for cannabinoids using pituitary AtT20 cells that endogenously express G protein-gated inward rectifier K+ (GIRK) channels and were stably transfected with the CB1 receptor using a recombinant lentivirus...
May 3, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29704608/comparison-of-one-and-three-lead-ecg-to-measure-cardiac-intervals-and-differentiate-drug-induced-multi-channel-block
#4
Robert Brockway, Marina Brockway, Brian Brockway, Robert Hamlin
INTRODUCTION: FDA has established initiatives to characterize clinical and non-clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi-channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived ​from a spatial vectorcardiogram computed using multiple leads...
April 25, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29684554/short-term-oral-gavage-administration-of-adenine-induces-a-model-of-fibrotic-kidney-disease-in-rats
#5
Chang Z Zhu, Kelly J Doyle, Arthur L Nikkel, Lauren Olsen, Marian T Namovic, Katherine Salte, Deborah Widomski, Zhi Su, Diana L Donnelly-Roberts, Murali M Gopalakrishnan, Steve McGaraughty
INTRODUCTION: The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage administration over a short period in an attempt to induce robust renal pathology while addressing variability and viability of the animals. METHODS: Adenine (150 or 200 mg/kg) was administered via oral gavage for 10 consecutive days, and assessed over a total of 20 days...
April 20, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29660397/a-pharmacology-guided-approach-for-setting-limits-on-product-related-impurities-for-bispecific-antibody-manufacturing
#6
Sharmila Rajan, Junichiro Sonoda, Timothy Tully, Ambrose J Williams, Feng Yang, Frank Macchi, Terry Hudson, Mark Z Chen, Shannon Liu, Nicole Valle, Kyra Cowan, Thomas Gelzleichter
INTRODUCTION: bFKB1 is a humanized bispecific IgG1 antibody, created by conjoining an anti-Fibroblast Growth Factor Receptor 1 (FGFR1) half-antibody to an anti-Klothoβ (KLB) half-antibody, using the knobs-into-holes strategy. bFKB1 acts as a highly selective agonist for the FGFR1/KLB receptor complex and is intended to ameliorate obesity-associated metabolic defects by mimicking the activity of the hormone FGF21. An important aspect of the biologics product manufacturing process is to establish meaningful product specifications regarding the tolerable levels of impurities that copurify with the drug product...
April 13, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29630936/the-rabbit-vagina-as-an-in-vivo-model-for-vaginal-fenticonazole-permeability-and-toxicity
#7
Rafael Campos, Samara F Bittencourt, Julio Alejandro Rojas-Moscoso, Lorenzo Pissinatti, Lu Shi Chen, Marcovan Porto, Ronilson Agnaldo Moreno, Gustavo Mendes, Gilberto De Nucci
INTRODUCTION: Vaginal route is often used in topical antifungal formulations. Vaginal permeability assays are generally performed as in vitro tests. METHOD: An in vivo vaginal permeability assay was developed using female rabbits. Fenticonazole permeability was evaluated by assessing fenticonazole bioavailability in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Toxicity was monitored histopathologically after 8 consecutive days of antifungal treatment (20 mg/animal)...
April 6, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29630935/real-time-monitoring-and-quantification-of-reactive-oxygen-species-in-breast-cancer-cell-line-mcf-7-by-2-7-dichlorofluorescin-diacetate-dcfda-assay
#8
Daniela Figueroa, Mohammad Asaduzzaman, Fiona Young
The detection of reactive oxygen species (ROS) using 2',7'-dichlorofluorescin diacetate (DCFDA) is commonly performed by a single measurement of fluorescence but this fails to capture a profile of ROS generation over time. This study aimed to develop a real-time monitoring method to increase the utility of the assay, to incorporate cytotoxicity screening and to describe the combined effects of DCFDA and the ROS generator, Ter-butyl hydrogen peroxide (TBHP). Breast cancer MCF-7 cells were loaded with DCFDA (0-50 μM) for 45 min, and then exposed to TBHP (0-50 μM)...
April 6, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29614334/safety-pharmacology-in-and-for-africa-establishment-of-the-pre-clinical-drug-development-platform
#9
REVIEW
Brian D Guth, Anne Grobler
Southern Africa (South Africa as well as neighboring countries) has not had an infrastructure for testing the safety of new drugs or other therapeutic entities, including plant-based or herbal treatments coming from the indigenous cultures, according to the current practice and regulatory requirements. Simultaneously, Southern Africa is challenged by very high rates of immune deficiency diseases which have further led to the resurgence of diseases such as tuberculosis, which is commonly thought to be eradicated, at least in Western cultures...
March 31, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29614333/pharmacological-validation-of-individual-animal-locomotion-temperature-and-behavioural-analysis-in-group-housed-rats-using-a-novel-automated-home-cage-analysis-system-a-comparison-with-the-modified-irwin-test
#10
Karen Tse, Rowland Sillito, Amy Keerie, Rachel Collier, Claire Grant, Natasha A Karp, Cathy Vickers, Kathryn Chapman, J Douglas Armstrong, William S Redfern
BACKGROUND: The ActualHCA™ system continuously monitors the activity, temperature and behaviour of group-housed rats without invasive surgery. The system was validated to detect the contrasting effects of sedative and stimulant test agents (chlorpromazine, clonidine and amphetamine), and compared with the modified Irwin test (mIT) with rectal temperature measurements. METHODS: Six male Han Wistar rats per group were used to assess each test agent and vehicle controls in separate ActualHCA™ recordings and mIT...
March 31, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29597013/a-new-telemetry-based-system-for-assessing-cardiovascular-function-in-group-housed-large-animals-taking-the-3rs-to-a-new-level-with-the-evaluation-of-remote-measurement-via-cloud-data-transmission
#11
Michael Markert, Thomas Trautmann, Florian Krause, Marius Cioaga, Sebastien Mouriot, Miriam Wetzel, Brian D Guth
INTRODUCTION: A newly developed total implant telemetry system for cardiovascular (CV), electrophysiological and body temperature measurement was evaluated. A cloud-based transmission of the physiological signals allowed an assessment of the quality of the physiological signals despite the physical separation between the instrumented animals and the evaluating home laboratory. The new system is intended to be used for safety pharmacological evaluations of drug candidates in various species...
March 26, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29580877/establishment-of-a-novel-microscale-thermophoresis-ligand-binding-assay-for-characterization-of-slc-solute-carriers-using-oligopeptide-transporter-pept1-slc15-family-as-a-model-system
#12
Benjamin Clémençon, Benjamin P Lüscher, Matthias A Hediger
INTRODUCTION: Membrane proteins represent roughly one third of the human proteome and many of them serve as targets of therapeutic drugs. An exception is the SLC solute carrier superfamily with only a handful of approved drugs targeting SLCs. Indeed, for many of the SLCs, the natural transport substrates are still unknown. A major limitation for SLCs has been the difficulty to thoroughly characterize these multimembrane spanning proteins. The intrinsic properties of membrane proteins with alternative hydrophobic and hydrophilic domains lead to instability, making the purification tasks even more challenging compared to soluble proteins...
March 23, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29580876/regulatory-respiratory-data-refinement-with-reduced-animal-usage
#13
Louise Sladen, Rommel Matheson, Kevin Norton, Aileen Milne
INTRODUCTION: Assessment of effects of potential drug candidates on the respiratory system is part of the regulatory preclinical safety assessment conducted prior to first in human trials (FTIH). Commonly, this is carried out utilizing head out plethysmography (HOP) or whole body plethysmography (WBP) which record only ventilatory parameters. When dosing via the inhaled route a more thorough respiratory assessment, including a direct measure of airway mechanics, is desirable. The aim of the present work was to improve the strategy for respiratory safety testing by a) evaluating a telemetered pleural pressure - HOP (PP-HOP) model and b) evaluating a crossover study design protocol in the WBP model to reduce variability and animal usage...
March 23, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29555537/development-of-serotonin-transporter-reuptake-inhibition-assays-using-jar-cells
#14
Ann M Decker, Bruce E Blough
INTRODUCTION: The development and validation of serotonin transporter reuptake inhibition assays in 96-well format using commercially available human placental choriocarcinoma JAR cells is described. METHODS: AR cells were first shown to uptake [3 H]serotonin in a saturable fashion with a KM value of 1 μM as determined by a Michaelis-Menten kinetic analysis. The cells were then utilized to determine the reuptake inhibition potencies of known ligands and the results were compared with results previously generated in the two most commonly used transporter assays (rat brain synaptosomes and transfected HEK293 cells)...
March 16, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29555536/mrna-transfection-retrofits-cell-based-assays-with-xenobiotic-metabolism
#15
Danica E DeGroot, Adam Swank, Russell S Thomas, Mark Strynar, Mi-Young Lee, Paul L Carmichael, Steven O Simmons
The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to false positive (chemical is detoxified in vivo) as well as false negative results (chemical is bioactivated in vivo) and thus potential mischaracterization of chemical hazard. To address this challenge, the ten most prevalent human liver cytochrome P450 (CYP) enzymes were introduced into a human cell line (HEK293T) with low endogenous metabolic capacity...
March 16, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29550466/a-spontaneous-metastatic-mathematical-model-in-mice-for-screening-anti-metastatic-agents
#16
Yao Li, Zhiqiang Yue, Hua Yu, Xiaojian Liu, Li Tao, Zhijie Zhu, Fangtian Fan, Cunsi Shen, Aiyun Wang, Wenxing Chen, Yin Lu
PURPOSE: A computational model based on clinical data from pancreatic cancer patients has been successfully created and used for predicting tumor sizes in primary and metastasis sites and survival time from kinetics of tumor cells, such as growth rate, metastasis rate and mutation rate, etc. Whether this computational model could be fitted or necessary modification of some parameters for fitting in mice is unknown. Here, we developed a computational model in mice for spontaneous metastasis to simulate the process of tumor metastasis based on the mathematical frameworks...
March 14, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29534860/corrigendum-to-a-new-rat-model-of-neonatal-bilirubin-encephalopathy-kernicterus-j-pharmacol-toxicol-methods-84-2017-44-50
#17
Naser Amini, Nasim Vousooghi, Mansoureh Soleimani, Ali Samadikuchaksaraei, Mehdi Akbari, Hosein Safakheil, Pezhman Atafimanesh, Ali Shahbazi, Peiman Brouki Milan, Sara Ramezani, Masoud Mozafari, Mohammad Taghi Joghataei
No abstract text is available yet for this article.
March 11, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29505899/the-evaluation-of-endpoint-variability-and-implications-for-study-statistical-power-and-sample-size-in-conscious-instrumented-dogs
#18
Alan Y Chiang, Brian D Guth, Michael K Pugsley, C Michael Foley, Jennifer M Doyle, Michael J Engwall, John E Koerner, Stanley T Parish, R Dustan Sarazan
INTRODUCTION: The sensitivity of a given test to detect a treatment-induced effect in a variable of interest is intrinsically related to the variability of that variable observed without treatment and the number of observations made in the study (i.e. number of animals). To evaluate test sensitivity to detect drug-induced changes in myocardial contractility using the variable LVdP/dtmax , a HESI-supported consortium designed and conducted studies in chronically instrumented, conscious dogs using telemetry...
March 2, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29425689/an-easy-to-use-liquid-chromatography-method-with-fluorescence-detection-for-the-simultaneous-determination-of-five-neuroactive-amino-acids-in-different-regions-of-rat-brain
#19
Beatriz M Fonseca, Ana C Cristóvão, Gilberto Alves
INTRODUCTION: To comprehend the normal function and pathological characteristics of certain neurological disorders it is important to evaluate the neuroactive amino acids levels in animal models. METHODS: This work describes a simple liquid chromatography-fluorescence detection (LC-FLD) method for the simultaneous determination of aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), taurine (Tau) and γ-aminobutyric acid (GABA), using methyl-L-arginine as internal standard, in samples of rat brain tissue...
May 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29421525/impact-of-calcium-sensitive-dyes-on-the-beating-properties-and-pharmacological-responses-of-human-ips-derived-cardiomyocytes-using-the-calcium-transient-assay
#20
Ivan Kopljar, An N Hermans, Ard Teisman, David J Gallacher, Hua Rong Lu
INTRODUCTION: Calcium-based screening of hiPS-CMs is a useful preclinical safety evaluation platform with the ability to generate robust signals that facilitates high-throughput screening and data analysis. However, due to the potential inherent toxicities, it is important to understand potential effects of different calcium-sensitive dyes on the hiPS-CMs model. METHODS: We compared three calcium-sensitive fluorescence dyes (Cal520, ACTOne and Calcium 5) for their impact on the variability, the beating properties and the pharmacological responses of hiPS-CMs using the Hamamatsu FDSS/μCell imaging platform...
May 2018: Journal of Pharmacological and Toxicological Methods
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