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Journal of Pharmacological and Toxicological Methods

Kim A Henderson, R Brandon Borders, John B Ross, Amir Abdulalil, Seth Gibbs, Anthony J Skowronek, Katherine Knostman, Jay Bailey, Jeremy Smith, Tom Vinci, Brandon Wood, Michael V Knopp, Brian M Roche
The isolated rat heart (Langendorff) assay combined with NMR spectroscopy and histology were used to elucidate functional, metabolic, and histological signs of cardiotoxicity resulting from acute exposure to clinically relevant concentrations of doxorubicin and its metabolite dox-ol. Doxorubicin blood concentrations and pharmacokinetic parameters were assessed following a clinically relevant dose of 2 mg/kg in order to select concentrations for isolated heart perfusions. Isolated rat hearts were exposed to 1 or 10 μM of doxorubicin or 0...
September 6, 2018: Journal of Pharmacological and Toxicological Methods
Valeria Avataneo, Amedeo De Nicolò, Franco Rabbia, Mauro Sciandra, Francesco Tosello, Jessica Cusato, Elisa Perlo, Giovanna Fatiguso, Sarah Allegra, Fabio Favata, Paolo Mulatero, Franco Veglio, Giovanni Di Perri, Antonio D'Avolio
INTRODUCTION: Nowadays, the treatment of hypertension represents an important issue, particularly in developed countries. While in most cases the standard therapeutic approaches, consisting in the administration of 1 to 3 drugs, are adequate to reach adequate blood pressure levels, in some cases more drugs are needed: this condition is called "resistant hypertension". In this context, the administration of a diuretic, such as spironolactone or canrenoate salts, represents a standard practice...
August 28, 2018: Journal of Pharmacological and Toxicological Methods
Debbie Grønlund, Lene Vase, Stine Abildgaard Knudsen, Maria Christensen, Asbjørn Mohr Drewes, Anne Estrup Olesen
INTRODUCTION: Correlations between subjective and objective measures of constipation have seldom been demonstrated. This could be due to multiple confounding factors in clinical studies and the broad span of symptoms represented in questionnaires used to assess constipation. We developed a new method for categorizing gastrointestinal (GI) symptoms into relevant symptom groups, and used this in a controlled experimental study aimed to investigate whether GI transit times and colonic volumes were correlated to self-reported GI symptoms...
August 24, 2018: Journal of Pharmacological and Toxicological Methods
David V Gauvin, Zachary J Zimmermann, Theodore J Baird
All new molecular entities (NMEs) with targeted or indirect effects on the central nervous system (CNS) must be evaluated for their abuse liability as a part of their nonclinical development plan. Inherently key in the drug control review is the term "relative abuse liability". The basis for determination of drug control is critically dependent on the nonclinical assessment of the reinforcing attributes of the NME in animals (rat is the regulatory preferred species) in a standard operant conditioning paradigm...
August 18, 2018: Journal of Pharmacological and Toxicological Methods
Fagen Zhang, Tim Erskine, Joanna Klapacz, Raja Settivari, Sue Marty
While the HPLC/UV (high performance liquid chromatography coupled with ultra-violet spectrometry)-based DPRA (Direct Peptide Reactivity Assay) identifies dermal sensitizers with approximately 80% accuracy, the low selectivity and sensitivity of the HPLC/UV-based DPRA poses challenges to accurately identify the sensitization potential of certain chemicals. In this study, a high performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS-MS)-based DPRA was developed and validated according to the test guideline (OECD TG 442C)...
August 9, 2018: Journal of Pharmacological and Toxicological Methods
Tomasz Przygodzki, Nina Wolska, Marcin Talar, Dawid Polak, Magdalena Gapinska, Cezary Watala
INTRODUCTION: Thrombus formation in vitro in flow conditions and its visualization and quantification with the use of microscopy are widely utilized to evaluate activity of compounds with a potential antithrombotic activity. Visualization and quantification of thrombi can be performed with the use of wide-field or confocal microscopy. Acquiring reliable numerical data from wide-field microscopy images of objects which have a complex three-dimensional structure is strongly influenced by the methods used for image analysis...
July 19, 2018: Journal of Pharmacological and Toxicological Methods
Murilo S de Abreu, Ashton J Friend, Konstantin A Demin, Tamara G Amstislavskaya, Wandong Bao, Allan V Kalueff
Depression is a wide-spread, debilitating psychiatric disorder. Mainly rodent-based, experimental animal models of depression are extensively used to probe the pathogenesis of this disorder. Here, we emphasize the need for innovative approaches to studying depression, and call for a wider use of novel model organisms, such as the zebrafish (Danio rerio), in this field. Highly homologous to humans and rodents, zebrafish are rapidly becoming a valuable tool in translational neuroscience research, but have only recently been utilized in depression research...
July 18, 2018: Journal of Pharmacological and Toxicological Methods
Jean-Pierre Valentin, Jean-Michel Guillon, Stephen Jenkinson, Vivek Kadambi, Peri Ravikumar, Sonia Roberts, Lyn Rosenbrier-Ribeiro, Friedemann Schmidt, Duncan Armstrong
INTRODUCTION: In 2015, IQ DruSafe conducted a survey of its membership to identify industry practices related to in vitro off target pharmacological profiling of small molecules. METHODS: An anonymous survey of 20 questions was submitted to IQ-DruSafe representatives. Questions were designed to explore screening strategies, methods employed and experience of regulatory interactions related to in vitro secondary pharmacology profiling. RESULTS: The pharmaceutical industry routinely utilizes panels of in vitro assays to detect undesirable off-target interactions of new chemical entities that are deployed at all stages of drug discovery and early development...
July 17, 2018: Journal of Pharmacological and Toxicological Methods
Rob Wallis, Charles Benson, Borje Darpo, Gary Gintant, Yasunari Kanda, Krishna Prasad, David G Strauss, Jean-Pierre Valentin
The Safety Pharmacology Society organized a scientific session at its annual conference in 2017 to discuss the challenges and opportunities of the Comprehensive In-Vitro Proarrhythmia Assay (CiPA) paradigm. Our intention was to raise awareness of this initiative with its members and also to gauge the extent to which safety pharmacologists have incorporated the CiPA testing strategy within the pharmaceutical industry. CiPA offers many potential opportunities including 1) a focus on proarrhythmic risk (as opposed to QTc prolongation), 2) providing scientific rationale to support the continued development of compounds that may have a poor selectivity over hERG whilst also blocking other inward currents and 3) reducing the extent of ECG monitoring in clinical trials with a greater influence of the non-clinical studies...
June 26, 2018: Journal of Pharmacological and Toxicological Methods
Corina T Bot, Krisztina Juhasz, Fabian Haeusermann, Liudmila Polonchuk, Martin Traebert, Sonja Stoelzle-Feix
INTRODUCTION: Since 2005 the S7B and E14 guidances from ICH and FDA have been in place to assess a potential drug candidate's ability to cause long QT syndrome. To refine these guidelines, the FDA proposed the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, where the assessment of drug effects on cardiac repolarization was one subject of investigation. Within the myocyte validation study, effects of pharmaceutical compounds on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were assessed and this article will focus on the evaluation of the proarrhythmic potential of 23 blinded drugs in four hiPSC-CM cell lines...
June 22, 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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: JAR 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)...
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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.
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
Kyung Yuk Ko, MiHye Hong, Tae Sung Kim, Ki Taek Nam, GaYoung Lee, Jung-Sun Yi, Il Young Ahn, Joo Hwan Kim, Jong Kwon Lee
INTRODUCTION: A variety of in vitro tests to replace the Draize test have been developed; however, there is no available method for assessing the full spectrum of Globally Harmonized System (GHS) categories. Human cornea-like three-dimensional (3D) reconstructed tissue models are the most promising in vitro systems. The objective of this study was to evaluate the ocular toxicity of 11 test substances using the EpiOcular™ model after performing proficiency tests. We further evaluated the effectiveness of ezrin staining as a complementary marker in histological analysis to overcome the limitation of eye irritation tests using 3D reconstructed human corneal epithelium models...
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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...
July 2018: Journal of Pharmacological and Toxicological Methods
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