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Journal of Pharmacological and Toxicological Methods

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
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
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
Michael V Accardi, Hai Huang, Simon Authier
INTRODUCTION: Traditionally, rat hippocampal tissue slice models are used as an in vitro electrophysiology assay to assess seizurogenic potential in early drug development despite non-clinical species-specific differences noted during in vivo seizure studies. METHODS: Hippocampal tissue slices were acutely isolated from rats, minipigs, dogs and nonhuman primates (NHP). Population spikes (PS) were evoked through stimulation of the CA3 Schaffer collateral pathway and recorded using in vitro electrophysiological techniques via an extracellular electrode placed within the CA1 stratum pyramidale cell body layer...
November 16, 2017: Journal of Pharmacological and Toxicological Methods
Robert J Goodrow, Suveer Desai, Jacqueline A Treat, Brian K Panama, Mayurika Desai, Vladislav V Nesterenko, Jonathan M Cordeiro
INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for safety pharmacology and to investigate genetic diseases affecting cardiac ion channels. It is unclear whether adult myocytes or hiPSC-CMs are the better platform for cardiac safety pharmacology. We examined the biophysical and molecular properties of INa in adult myocytes and hiPSC-CMs. METHODS: hiPSC-CMs were plated at low density. Atrial and ventricular cells were obtained from dog hearts...
November 8, 2017: Journal of Pharmacological and Toxicological Methods
Shinjini Pilon, Alison C Holloway, Errol M Thomson
INTRODUCTION: Metabolic effects of anthropogenic chemicals are a focus of environmental health research due to the significant public health implications. Conventional glucose tolerance tests (GTTs) do not generally examine multiple metabolic, inflammatory, and endocrine factors; however, responses to exogenous glucose can provide insight into mode-of-action and disease processes, and warrant consideration in developing models for toxicological assessment. METHODS: GTTs were conducted on male Fischer-344 rats to 1) assess the feasibility of measuring multiple analytes in small sample volumes; 2) monitor analyte response; and 3) determine whether route of glucose delivery (oral, OGTT vs...
November 2, 2017: Journal of Pharmacological and Toxicological Methods
Josué A Velázquez-Moyado, Andrés Navarrete
INTRODUCTION: The development of electrochemical sensors for the detection of small molecules has already had a significant effect on the study of biology because of their selectivity and ability to measure low concentrations of small molecules that regulate various functions in living organisms. Hydrogen sulfide (H2S) is a gasotransmitter produced at low levels in several tissues including the stomach. Here, we propose a new method for detecting low concentrations of this transmitter in the rat stomach, in-vivo and in real time, with applications in pharmacology and physiology...
October 31, 2017: Journal of Pharmacological and Toxicological Methods
Thomas Mondritzki, Sarah M L Steinbach, Philip Boehme, Jessica Hoffmann, Maximilian Kullmann, Daniel Schock-Kusch, Julia Vogel, Peter Kolkhof, Peter Sandner, Erwin Bischoff, Jörg Hüser, Wilfried Dinh, Hubert Truebel
INTRODUCTION: Quantitative assessment of renal function by measurement of glomerular filtration rate (GFR) is an important part of safety and efficacy evaluation in preclinical drug development. Existing methods are often time consuming, imprecise and associated with animal burden. Here we describe the comparison between GFR determinations with sinistrin (PS-GFR) and fluorescence-labelled sinistrin-application and its transcutaneous detection (TD-GFR) in a large animal model of chronic kidney disease (CKD)...
October 31, 2017: Journal of Pharmacological and Toxicological Methods
Ricardo O Lima, Francisco V Fechine, Mario R Lisboa, Fernando K Leitão, Mariana L Vale
INTRODUCTION: In studies with experimental models of pressure ulcer, until date, there is no validated instrument to assess the various visual aspects of the healing process. Measure of wound area is the most used method for this purpose. Thus, we aimed to develop and validate a visual assessment tool for the evaluation of healing in experimental models of pressure ulcer. METHODS: The Experimental Wound Assessment Tool (EWAT) was developed based on tools used in clinical practice...
October 31, 2017: Journal of Pharmacological and Toxicological Methods
Marlies Oorts, Janneke Keemink, Neel Deferm, Robin Adriaensen, Lysiane Richert, Patrick Augustijns, Pieter Annaert
INTRODUCTION: Sandwich-cultured rat hepatocytes (SCRH) have become an invaluable in vitro model to study hepatic drug disposition. SCRH are maintained between two layers of extracellular matrix. In this configuration, culture periods of 4days are typically applicable. The aim of the present study was to modify conventional SCRH by applying an additional collagen overlay to prolong the hepatic phenotype in SCRH and thus to extend the applicability of the model. METHODS: The cultures receiving an extra top layer ('SCRH-plus' cultures) were compared with the conventional SCRH by testing the morphology, cell functionality, metabolic capacity and Mrp2-activity...
October 25, 2017: Journal of Pharmacological and Toxicological Methods
Emanuela Abbate, Muriel Boulakia, Yves Coudière, Jean-Frédéric Gerbeau, Philippe Zitoun, Nejib Zemzemi
We propose a mathematical approach for the analysis of drugs effects on the electrical activity of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) based on multi-electrode array (MEA) experiments. Our goal is to produce an in silico tool able to simulate drugs action in MEA/hiPSC-CM assays. The mathematical model takes into account the geometry of the MEA and the electrodes' properties. The electrical activity of the stem cells at the ion-channel level is governed by a system of ordinary differential equations (ODEs)...
October 21, 2017: Journal of Pharmacological and Toxicological Methods
Eveline P van Poelgeest, Marlous R Dillingh, Marieke de Kam, Karen E Malone, Marleen Kemper, Erik S G Stroes, Jacobus Burggraaf, Matthijs Moerland
INTRODUCTION: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low- to moderate dose (0.5, 1 or 2ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers...
October 19, 2017: Journal of Pharmacological and Toxicological Methods
Daniel D Bravo, Tania Chernov-Rogan, Jun Chen, Jianyong Wang
INTRODUCTION: Many cell types (including muscle cells and fibroblasts) can contract at physiological conditions and their contractility may change during tissue injury and repair or other diseases such as allergy and asthma. The conventional gel contraction assay is commonly used to monitor the cellular contractility. It is a manual assay and the experiment usually takes hours even days to complete. As its readout is not always accurate and reliable, the gel contraction assay is often used to qualitatively (but not quantitatively) characterize cellular contractility under various conditions...
October 19, 2017: Journal of Pharmacological and Toxicological Methods
Stephen Jenkinson, Asser Bassyouni, Jason Cordes, Bernard Fermini, Donglin Guo, David M Potter, David S Ramirez, Jill Steidl-Nichols, Sunny Sun, Todd Wisialowski
INTRODUCTION: Cardiac sodium channel antagonists have historically been used to treat cardiac arrhythmias by preventing the reentry of the electrical impulse that could occur following myocardial damage. However, clinical studies have highlighted a significant increase in mortality associated with such treatment. Cardiac sodium channel antagonist activity is now seen as an off-target pharmacology that should be mitigated during the drug development process. The aim of this study was to examine the correlation between in vitro/ex vivo assays that are routinely used to measure Nav1...
October 16, 2017: Journal of Pharmacological and Toxicological Methods
Viktoria Planz, Jing Wang, Maike Windbergs
INTRODUCTION: Predictive in vitro testing of novel wound therapeutics requires adequate cell-based bio-assays. Such assays represent an integral part during preclinical development as pre-step before entering in vivo studies. Simple "scratch tests" based on defected skin cell monolayers exist, however these can solely be used for testing liquids, as cell monolayer destruction and excessive hydration limit their applicability for (semi-)solid systems like wound dressings. In this context, a cell-based wound healing assay is introduced for rapid and predictive testing of wound therapeutics independent of their physical state in a bio-relevant environment...
October 14, 2017: Journal of Pharmacological and Toxicological Methods
Kwenga Sichilongo, Elliott Mwando, Enoch Sepako, Amos Massele
INTRODUCTION: Sample preparation in bio analytical chemistry poses a challenge because it can be compound dependent. We compared six sample extraction techniques i.e. QuEChERS (Q), liquid extraction (LE), protein precipitation (PPT), Q-PPT, Q-LE and LE-PPT for the extraction of antiretroviral drugs emtricitabine, tenofovir, efavirenz, lopinavir and rotinavir in human blood plasma. METHOD: A multiple reaction monitoring liquid chromatography- tandem mass spectrometry method for the determination of the same antiretroviral drugs developed and validated in this laboratory was used...
October 5, 2017: Journal of Pharmacological and Toxicological Methods
Pushkar Kulkarni, Raghavender Medishetti, Nagaraju Nune, Swapna Yellanki, Vijaykumar Sripuram, Pallavi Rao, Dharmarajan Sriram, Uday Saxena, Srinivas Oruganti, Perumal Yogeeswari
INTRODUCTION: Adult zebrafish pharmacology is evolving rapidly for creating efficacy and safety models for drug discovery. However, there is very limited research in understanding pharmacokinetics (PK) in adult zebrafish. Methods for understanding PK will help in conducting pharmacokinetic - pharmacodynamic (PK-PD) correlations and improving the quality and applicability of data obtained using zebrafish. METHODS: We conducted adult zebrafish PK and brain penetration studies on two known compounds (irinotecan and lorcaserin) with distinct PK and brain penetration properties using validated LCMS/MS method...
September 30, 2017: Journal of Pharmacological and Toxicological Methods
Tatsuya Maekawa, Hironobu Tadaki, Tomohiko Sasase, Yu Motohashi, Katsuhiro Miyajima, Takeshi Ohta, Shinichi Kume
INTRODUCTION: To establish an animal model for diabetic peripheral neuropathy (DPN) at an earlier stage, we performed functional and pathophysiological evaluations in Spontaneously Diabetic Torii (SDT) fatty rats before 16weeks of age. METHODS: Male SDT fatty rats were treated with vehicle or phlorizin (100 to 150mg/kg/day) from 5 to 16weeks. Sprague-Dawley (SD) rats were used as age-matched controls. Body weights and biochemical parameters were measured over time...
September 29, 2017: Journal of Pharmacological and Toxicological Methods
Tamás Kőszegi, Nikolett Sali, Maja Raknić, Zoltán Horváth-Szalai, Rita Csepregi, Marijana Zovko Končić, Nóra Papp, Miklós Poór
INTRODUCTION: Reactive oxygen species (ROS) are normal metabolic products of living cells. However, a decrease of the defense mechanisms against the effects of ROS or increased ROS production maybe one important causative factor of cellular damage. A non-enzymatic scavenger system is considered to be responsible for the maintenance of total antioxidant capacity (TAC) as a protection against oxidative injuries that exist in all higher plants and in mammals as well. METHODS: In our work, we optimized and validated a luminol-peroxidase-4-iodophenol-H2O2 enhanced chemiluminescence-based (ECL) TAC measurement technique...
September 28, 2017: Journal of Pharmacological and Toxicological Methods
Kyohei Yasuno, Erika Takahashi, Isao Igarashi, Takuma Iguchi, Yoshimi Tsuchiya, Kiyonori Kai, Kazuhiko Mori
INTRODUCTION: Immediate early genes are widely used as neuronal cell activity markers in neuroscience. The present study investigated the relationship between their expression and abnormality in context fear conditioning. METHODS: The learning test (two-way active avoidance test) was conducted in male rats administered with nonselective muscarinic antagonist scopolamine or selective dopamine D1-like receptor antagonist SCH 23390 at a dose level of 2.0 or 0.1mg/kg, respectively, for 4days...
September 27, 2017: Journal of Pharmacological and Toxicological Methods
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