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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
Michael K Pugsley, Marci L Harter, Tessa de Korte, Chantelle Connaughton, Simon Authier, Michael J Curtis
This editorial is a preface to the annual themed issue on safety pharmacology (SP) methods published in the Journal of Pharmacological and Toxicological Methods (JPTM). The content is derived from the recent 2017 Safety Pharmacology Society (SPS) annual general meeting held in Berlin, Germany. It is evident from the content that the evolution of SP methods is increasingly driven by, and in turn exerts influence upon, regulatory requirements. It will be interesting to observe how this interaction evolves in coming years...
June 21, 2018: Journal of Pharmacological and Toxicological Methods
John M David, Xian Chen
No abstract text is available yet for this article.
June 15, 2018: Journal of Pharmacological and Toxicological Methods
BaoXi Gao, Yusheng Qu, Weston Sutherland, Ray W Chui, Kim Hoagland, Hugo M Vargas
Contractility measurements using primary isolated cardiac myocytes (CM) have commonly been used in understanding the physiology and pharmacology of cellular mechanics. In the majority of studies, CM from healthy animals were used, and fewer studies were performed with CM from diseased hearts. To better understand the translational value of contractility on the cellular level of a diseased animal model, myocytes were isolated from left ventricles of a tachypacing-induced heart failure (HF) canine model, and their contractility was measured by recording sarcomere shortening using an image-based IonOptix video system...
June 13, 2018: Journal of Pharmacological and Toxicological Methods
Sayed Masoud Hosseini, Hamid Gholami Pourbadie, Nima Naderi, Mohammad Sayyah, Mohammad Ismail Zibaii
INTRODUCTION: The vulnerability of hippocampal formation to ischemic insult has been documented in both humans and animal models. Ischemic injury induction through photothrombosis is an invasive and reproducible model of ischemic stroke which provides the ability to induce ischemia selectively in any desired area. In this study, we describe a method to induce selective unilateral hippocampal ischemia in rat through modified photothrombotic model. METHODS: Male wistar rats (n = 66) were subjected to stereotaxic surgery to insert a guide cannula just above the ascending part of hippocampal fissure...
June 12, 2018: Journal of Pharmacological and Toxicological Methods
Borje Darpo, Jean-Philippe Couderc
INTRODUCTION: This paper is based on a presentation held at the Annual Safety Pharmacology Society meeting in September 2017, at which challenges for the clinical component of CiPA were presented. FDA has published an automated algorithm for measurement of the J-Tpeak interval on a median beat from a vector magnitude lead derived from a 12-lead ECG. CiPA proposes that J-Tpeak prolongation < 10 ms can be used for drugs with a QTc effect < 20 ms to differentiate between safe and unsafe delayed repolarization and to reduce the level of ECG monitoring in late stage clinical trials...
June 4, 2018: Journal of Pharmacological and Toxicological Methods
Yuri Hase, Kuniaki Suzuki, Nobuhito Kamekura, Makiko Shibuya, Yu Takahashi, Kosuke Namba, Toshiaki Fujisawa
INTRODUCTION: It is difficult to quantify poorly soluble volatile anesthetics in aqueous solutions; this necessitates the development of alternative prompt methods to analyze the in vivo blood concentrations of anesthetics for the clinical assessment of anesthesia depth. In this study, we demonstrated that the difficulties can be overcome by using volatile organic compound (VOC) sensors, which allow the levels of vaporized VOCs to be quantified in several seconds and obviate the need for conventional techniques such as gas chromatography or nuclear magnetic resonance (NMR)...
June 1, 2018: Journal of Pharmacological and Toxicological Methods
Tully Erwin, Satish P Rekulapally, Thomas S Abraham, Qinfeng Liu
INTRODUCTION: Calcium/Calmodulin-dependent protein kinase II (CaMKII) is a multifunctional protein kinase that phosphorylates and regulates activity of many substrates in various tissues. Traditional CaMKII activity assays rely on incorporation of radioactivity onto a CaMKII substrate by utilizing γ-32 P ATP, which has a short half-life and can pose health risks to the researchers. METHODS: An 8-minute HPLC-MS method was developed to measure a CaMKII-specific peptide substrate autocamtide-2 (AC-2) and its phosphorylated form, phosphoautocamtide-2 (PAC-2)...
May 24, 2018: Journal of Pharmacological and Toxicological Methods
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 and 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
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
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 4, 2018: Journal of Pharmacological and Toxicological Methods
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
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 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
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