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Journal of Pharmacological and Toxicological Methods

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https://www.readbyqxmd.com/read/29462667/a-proximity-extension-assay-pea-based-method-for-quantification-of-bevacizumab
#1
Ivana Mikačić, Robert Belužić, Oliver Vugrek, Đuro Plavljanić
INTRODUCTION: Proximity Extension Assay (PEA) is a direct one-step protein quantification method using a pair of DNA oligonucleotides linked to antibodies against the target molecule. It requires polyclonal or two monoclonal antibodies (mAbs) that bind to target epitopes close enough to form a DNA duplex which is quantified by real-time PCR. Bevacizumab, an anti-cancer drug, is a mAb against vascular endothelial growth factor with common cardiovascular adverse effects. It is widely used off-label to treat neovascular eye disorders by intravitreal application of small doses...
February 17, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29438745/an-automated-epifluorescence-microscopy-imaging-assay-for-the-identification-of-phospho-akt-level-modulators-in-breast-cancer-cells
#2
Elke Kaemmerer, Dane Turner, Amelia A Peters, Sarah J Roberts-Thomson, Gregory R Monteith
AKT is an enzyme of the PI3K/pAKT pathway, regulating proliferation and cell survival. High basal levels of active, phosphorylated AKT (pAKT) are associated with tumor progression and therapeutic resistance in some breast cancer subtypes, including HER2 positive breast cancers. Various stimuli can increase pAKT levels and elevated basal pAKT levels are a feature of PTEN-deficient breast cancer cell lines. The aim of this study was to develop an assay able to identify modulators of pAKT levels using an automated epifluorescence microscope and high content analysis...
February 10, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29438744/lipopolysaccharide-interferes-with-the-use-of-the-human-cell-line-activation-test-to-determine-the-allergic-potential-of-proteins
#3
Hanae Tsukumo, Natsumi Matsunari, Kunihiko Yamashita, Hajime Kojima, Hiroshi Itagaki
It was believed that high molecular weight molecules including proteins cannot penetrate the skin. However, protein penetration through disrupted/ruptured skin has been reported recently, thus carrying the potential for inducing an allergic response. We used the human Cell Line Activation Test (h-CLAT), an in vitro skin sensitization test, to assess the allergic potential of proteins by measuring levels of CD86 and CD54 in the human monocytic leukemia cell line THP-1. Six allergens including ovalbumin (OVA) and human serum albumin (HSA; negative control) upregulated CD86 and/or CD54; a false-positive result was obtained using HSA...
February 10, 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
#4
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...
February 6, 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
#5
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...
February 5, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29408384/single-tube-biosynthesis-and-extraction-of-u-13c-and-u-14c-arachidonic-acid-from-microcultures-of-mortierella-alpina-for-in-vivo-pharmacology-and-metabolic-tracing-studies
#6
Rani J Qasem
Heavy and radioisotope labeling are commonly used methods to trace the pharmacological activity and metabolic fate of a biochemical or pharmaceutical in vivo. Recent years witnessed increased demand for molecules uniformly labeled with heavy carbon-13 (U-13C) or radioactive carbon-14 (U-14C) isotopes over singly labeled isotopic versions. Polyunsaturated fatty acids (PUFAs) represent one classic example where uniform 13C or 14C isotopic enrichment of the hydrocarbon backbone has numerous technical, metabolic and pharmacological advantages...
February 3, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29407728/strain-differences-in-the-development-of-cisplatin-induced-pica-behavior-in-mice
#7
Kouichi Yamamoto, Atsushi Yamatodani
INTRODUCTION: Pica behavior, kaolin ingestion, in rats and mice can be used as an assessment of nausea and vomiting; however, we observed that the incidence of pica behavior in ICR strain mice varied markedly. We investigated the susceptibility of four strains of mice (ICR, BALB/c, C57BL/6, and DBA/2) to the development of pica behavior. METHODS: Mice received cisplatin (7.5 mg/kg, i.p.) with or without a serotonin 5-HT3 receptor antagonist (granisetron: 0.1 mg/kg, i...
January 30, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29382548/development-of-pharmacological-screening-method-for-evaluation-of-effect-of-drug-on-elevated-pulse-pressure-and-arterial-stiffness
#8
Sanjay K Gupta, Surendra H Bodakhe
INTRODUCTION: Elevated pulse pressure (PP) and amplification of arterial stiffness (AS) are responsible for various cardiovascular disease and deaths. Numerous investigations have identified that different antihypertensive agents influence PP and AS differently. None of the previous studies described any reliable animal model particularly to screen drugs having effects on PP and AS. In present study, we developed an animal model to screen such drugs particularly affecting PP and AS. METHODS: Elevation of PP and amplification of AS were induced in rats by uninephrectomy along with high salt intake (NaCl 4% w/v) for a period of six weeks, and weekly changes in body weight, PP, systolic, diastolic, mean pressure and pulse wave velocity (PWV) were estimated...
January 27, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29378341/nagarse-treatment-of-cardiac-subsarcolemmal-and-interfibrillar-mitochondria-leads-to-artefacts-in-mitochondrial-protein-quantification
#9
Gábor Koncsos, Zoltán V Varga, Tamás Baranyai, Péter Ferdinandy, Rainer Schulz, Zoltán Giricz, Kerstin Boengler
INTRODUCTION: In the heart, subsarcolemmal (SSM), interfibrillar (IFM) and perinuclear mitochondria represent three subtypes of mitochondria. The most commonly used protease during IFM isolation is the nagarse, however, its effect on the detection of mitochondrial proteins is still unclear. Therefore, we investigated whether nagarse treatment influences the quantification of mitochondrial proteins. METHODS: SSM and IFM were isolated from hearts of mice and rats...
January 26, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29371052/analytical-performance-of-a-commercial-multiplex-luminex-based-cytokine-panel-in-the-rat
#10
Tim Erkens, Nick Goeminne, Ann Kegels, Martine Byloos, Petra Vinken
INTRODUCTION: Multiplex immunoassays are an important tool in biomarker research during preclinical drug development. However, information regarding analytical performance of commercial multiplex assays for animal species is often limited. To be able to correctly interpret study results, a fit-for-purpose validation approach is recommended. The objective of our study was to provide a realistic example of what level of validation can be expected from this type of assay, using a rat cytokine panel...
January 22, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29355722/predicting-cardiac-safety-using-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-combined-with-multi-electrode-array-mea-technology-a-conference-report
#11
REVIEW
Petra Mulder, Tessa de Korte, Elena Dragicevic, Udo Kraushaar, Richard Printemps, Maria L H Vlaming, Stefan R Braam, Jean-Pierre Valentin
Safety pharmacology studies that evaluate drug candidates for potential cardiovascular liabilities remain a critical component of drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have recently emerged as a new and promising tool for preclinical hazard identification and risk assessment of drugs. Recently, Pluriomics organized its first User Meeting entitled 'Combining Pluricyte® Cardiomyocytes & MEA for Safety Pharmacology applications', consisting of scientific sessions and live demonstrations, which provided the opportunity to discuss the application of hiPSC-CMs (Pluricyte® Cardiomyocytes) in cardiac safety assessment to support early decision making in safety pharmacology...
January 17, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29330133/the-evaluation-of-drug-induced-changes-in-left-ventricular-function-in-pentobarbital-anesthetized-dogs
#12
Yevgeniya E Koshman, Brett R Herzberg, Terese R Seifert, James S Polakowski, Scott W Mittelstadt
INTRODUCTION: The goal of this study was to determine whether assessment of myocardial contractility and hemodynamics in an anesthetized dog model, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. METHODS: Derived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end-diastolic LVP, and LVdP/dtmax as the primary contractility index...
January 9, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29330132/an-overview-of-the-safety-pharmacology-society-strategic-plan
#13
M K Pugsley, S Authier, J E Koerner, W S Redfern, C G Markgraf, T Brabham, K Correll, M V Soloviev, A Botchway, M Engwall, M Traebert, J-P Valentin, T J Mow, A Greiter-Wilke, D J Leishman, H M Vargas
Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology...
January 9, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29330131/response-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-to-several-pharmacological-agents-when-intrinsic-syncytial-pacing-is-overcome-by-acute-external-stimulation
#14
Haoyu Zeng, Bharathi Balasubramanian, Armando Lagrutta, Frederick Sannajust
We challenged human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) syncytia, mainly, CDI iCells with several classes of well-characterized pharmacological agents (including hERG blocker, Nav1.5 blocker, Cav1.2 blocker and opener, β-adrenergic agonist, and If blocker) under pacing conditions, utilizing the Cardio-ECR instrument, a non-invasive platform featuring simultaneous and continuous measurement of synchronized beating rate and contractility (both signals were acquired simultaneously and well aligned) ...
January 9, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29288713/the-effects-of-gentamicin-and-penicillin-streptomycin-on-the-electrophysiology-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-in-manual-patch-clamp-and-multi-electrode-array-system
#15
Soo-Wang Hyun, Bo-Ram Kim, Dan Lin, Sung-Ae Hyun, Seong Shoon Yoon, Joung-Wook Seo
INTRODUCTION: Cell culture media usually contains antibiotics including gentamicin or penicillin/streptomycin (PS) to protect cells from bacterial contamination. However, little is known about the effects of antibiotics on action potential and field potential parameters in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: The present study examined the effects of gentamicin (10, 25, and 50μg/ml) and PS (50, 100, and 200U/μg/ml) on electrophysiological activity in spontaneously beating hiPSC-CMs using manual patch clamp and multi-electrode array...
December 27, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29278742/evaluation-of-the-suitability-of-a-sprague-dawley-rat-model-to-assess-intravenous-iron-preparations
#16
Kimberley Span, Ebel H E Pieters, Vera Brinks, Wim E Hennink, Huub Schellekens
The aim of the study was to examine the reproducibility of a rat model to assess the preclinical similarity in safety profiles and tissue accumulation of iron products. Accordingly, the effect of several doses of intravenously administered Venofer® and of Ferrlecit® on blood parameters, and on kidney and particularly liver toxicity were examined in non-anemic Sprague Dawley rats. The different analysis showed neither a clear treatment nor a dose effect after multiple injections. The parameters measured in this rat strain showed some iron induced adverse effects, but these could not be correlated to treatment specific differences...
December 23, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29274391/electrophysiological-characteristics-and-pharmacological-sensitivity-of-two-lines-of-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-coming-from-two-different-suppliers
#17
Sonia Goineau, Vincent Castagné
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as preclinical tool for predicting drug-induced QT prolongation and arrhythmias. This study was conducted to assess the electrophysiological characteristics and the pharmacological sensitivity of two commercialized hiPSC-CMs. The baseline electrophysiological characteristics measured with a multi-electrode array (MEA) technology differ between Cor.4U and iCell2: higher beat rate (+32bpm) and shorter field potential duration (FPD, -201ms) for Cor...
December 20, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29203451/an-improved-cprg-colorimetric-ligand-receptor-signal-transduction-assay-based-on-beta-galactosidase-activity-in-mammalian-bwz-reporter-cells
#18
Charlotte Jendresen, Michael R Daws, Lars N G Nilsson
INTRODUCTION: Reporter cells expressing a chimeric receptor that activates a reporter can be used for screening ligand-mediated signal transduction. In this study, we used reporter cells harboring an NFAT/lacZ construct that express β-galactosidase when the chimeric receptor is stimulated. A colorimetric β-galactosidase substrate, chlorophenol-red β-d-galactopyranoside (CPRG), was used to detect enzymatic activity. Sub-optimal conditions have unfortunately extensively been reported with such reporter-based β-galactosidase assays...
December 1, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29203450/the-drug-discrimination-assay-interpretative-value-of-partial-generalization-for-drug-schedule-control-actions
#19
David V Gauvin, Zachary J Zimmermann, Robert Code, Theodore J Baird
The U.S. Food & Drug Administration (FDA) has issued a final guidance document on the preclinical determination of abuse potential that must be conducted in animals for all new molecular entities (NMEs) submitted for a new drug application (NDA). Under statutory restrictions government guidance documents serve only as a guide or an expression of the agency's current thinking on the topic. Guidelines do not legally bind the agency or its registrants to any content in the guidance. There are no statutory (legal) descriptions of what study designs or methodology must be submitted to the Drug Enforcement Administration with respect to drug scheduling review...
December 1, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29155283/comparative-analysis-of-media-effects-on-human-induced-pluripotent-stem-cell-derived-cardiomyocytes-in-proarrhythmia-risk-assessment
#20
Derek Schocken, Jayna Stohlman, Jose Vicente, Dulciana Chan, Dakshesh Patel, Murali Krishna Matta, Vikram Patel, Mathew Brock, Daniel Millard, James Ross, David G Strauss, Ksenia Blinova
INTRODUCTION: Cardiotoxicity assessment using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) forms a key component of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). A potentially impactful factor on iPSC-CM testing is the presence of serum in the experimental media. Generally, serum-free media is used to most accurately reproduce "free" drug concentration. However, caution is needed; drug solubility and cardiomyocyte electrophysiology could be affected by media formulation, potentially impacting interpretation of drug-induced effects...
November 16, 2017: Journal of Pharmacological and Toxicological Methods
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