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Journal of Pharmacological and Toxicological Methods

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https://www.readbyqxmd.com/read/28065822/detecting-drug-induced-changes-in-ecg-parameters-using-jacketed-telemetry-effect-of-different-data-reduction-techniques
#1
Matthew Skinner, Guozhen Xing, Jing Lu, Jin Ren, Karen Oldman
INTRODUCTION: Continuous cardiovascular data is routinely collected during preclinical safety assessment of new medicines. This generates large datasets, which must be summarised to analyse and interpret drug effects. We assessed four methods of data reduction of continuous electrocardiogram (ECG) data and examined the impact on the statistical power of the assay. METHODS: Continuous ECG data were collected from a validation study in 6 cynomolgus monkeys using jacketed telemetry...
January 5, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28065821/an-evaluation-of-the-utility-of-lvdp-dt40-qa-interval-lvdp-dtmin-and-tau-as-indicators-of-drug-induced-changes-in-contractility-and-lusitropy-in-dogs
#2
Michael K Pugsley, Brian Guth, Alan Y Chiang, Jennifer M Doyle, Michael Engwall, Jean-Michel Guillon, Peter K Hoffmann, John E Koerner, Scott W Mittelstadt, Jennifer Beck Pierson, Eric I Rossman, Dustan R Sarazan, Stanley T Parish
INTRODUCTION: The importance of drug-induced effects on the inotropic state of the heart is well known. Unlike hemodynamic and cardiac electrophysiological methods, which have been routinely used in drug safety testing for years, the non-clinical assessment of drug effects on myocardial contractility is used less frequently with no established translation to humans. The goal of these studies was to determine whether assessment of alternate measures of cardiac inotropy could detect drug-induced changes in the contractile state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility...
January 5, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28063918/simultaneous-in-vivo-receptor-occupancy-assays-for-serotonin-1a-2a-and-dopamine-2-receptors-with-the-use-of-non-radiolabelled-tracers-proposed-method-in-screening-antipsychotics
#3
Jagadeesh Babu Thentu, Ramakrishna Nirogi, Gopinadh Bhyrapuneni, Devender Reddy Ajjala, Raghupathi Reddy Aleti, Veera Raghava Choudary Palacharla
INTRODUCTION: Conventionally, receptor occupancy assays employ radiolabelled tracer.However, recent advances with non-radiolabelled tracers brought a revolution in target engagement assays.Non-radiolabelled tracer based receptor occupancy uses LC-MS/MS based quantification.It offers simultaneous quantification of more than one tracer; thus, provides the feasibility of evaluating multiple targets in a single animal.In the present study, we demonstrated simultaneous measurement of serotonin 1A, serotonin 2A, and dopamine 2 receptor occupancy using non-radiolabelled tracers in rats...
January 4, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27956204/a-new-paradigm-for-drug-induced-torsadogenic-risk-assessment-using-human-ips-cell-derived-cardiomyocytes
#4
Hiroyuki Ando, Takashi Yoshinaga, Wataru Yamamoto, Keiichi Asakura, Takaaki Uda, Tomohiko Taniguchi, Atsuko Ojima, Raku Shinkyo, Kiyomi Kikuchi, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Norimasa Miyamoto, Hiroyuki Tashibu, Daiju Yamazaki, Atsushi Sugiyama, Yasunari Kanda, Kohei Sawada, Yuko Sekino
INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are anticipated to be a useful tool for conducting proarrhythmia risk assessments of drug candidates. However, a torsadogenic risk prediction paradigm using hiPSC-CMs has not yet been fully established. METHODS: Extracellular field potentials (FPs) were recorded from hiPSC-CMs using the multi-electrode array (MEA) system. The effects on FPs were evaluated with 60 drugs, including 57 with various clinical torsadogenic risks...
December 10, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27956205/early-echocardiographic-predictors-of-outcomes-in-the-mouse-transverse-aortic-constriction-heart-failure-model
#5
Caryn Hampton, Raymond Rosa, Barry Campbell, Richard Kennan, Loise Gichuru, Xiaoli Ping, Xiaolan Shen, Kersten Small, Jeffrey Madwed, Joseph J Lynch
INTRODUCTION: Mouse transverse aortic constriction (TAC) is a widely-used model of pressure overload-induced heart failure. An intrinsic limitation of the model is variability in the response to pressure overload even when employing a standard severity of stenosis. Few literature studies have explicitly reported the use of entry criteria or early predictors to mitigate variability and enrich outcomes in this model. METHODS: Eleven-week-old male C57BL/6J mice underwent TAC or sham surgery...
December 9, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27940076/a-rapid-assessment-for-predicting-drug-induced-hepatotoxicity-using-zebrafish
#6
Yun Zhang, Liwen Han, Qiuxia He, Weiyun Chen, Chen Sun, Xue Wang, Xiqiang Chen, Rongchun Wang, Chung-Der Hsiao, Kechun Liu
INTRODUCTION: Zebrafish have been used as a model to access drug-induced hepatotoxicity. However, individual differences occur in the liver development of zebrafish. METHODS: We used a transgenic line of zebrafish that expressed enhanced green fluorescent protein (EGFP) in the liver and then used a calculation of the liver index area, a potentially new endpoint of hepatotoxicity, to evaluate drug-induced liver injury. To further validate the reliability of the liver area index as a quick evaluation of zebrafish liver function damage, the liver area index level was correlated with hepatic transaminase activities using the Pearson correlation coefficient and confirmed by histopathology...
December 8, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27913272/the-northeast-regional-sps-meeting-update-safety-pharmacology-innovations-and-applications
#7
REVIEW
Malar Pannirselvam, Tiffini Brabham, Alfred W Botchway, Donald B Hodges, Martin Traebert, Michael K Pugsley
The Safety Pharmacology Society (SPS) held a Northeast (NE) regional meeting in Boston, MA on May 13, 2016 at the Vertex Pharmaceuticals Incorporated site. There were 103 attendees from the pharmaceutical industry, contract research organizations (CROs), academia, and global regulatory agencies. An assortment of scientific topics were presented by 7 speakers that included broad topics in the cardiovascular (organ on chip, statistical power and translation of rat cardiovascular telemetry data and dual inhibition of IKr and IKs on QT interval prolongation) and central nervous system (in vitro platform for neurotoxicity, an integrated risk assessment of suicidal ideation and behavior, and EEG advances in safety pharmacology) and a novel topic discussing preclinical challenges faced in the development of a novel gene therapy...
November 29, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27884773/an-intelligent-prognostic-system-for-analyzing-patients-with-paraquat-poisoning-using-arterial-blood-gas-indexes
#8
Lufeng Hu, Feiyan Lin, Huaizhong Li, Changfei Tong, Zhifang Pan, Jun Li, Huiling Chen
The arterial blood gas (ABG) test is used to assess gas exchange in the lung, and the acid-base level in the blood. However, it is still unclear whether or not ABG test indexes correlate with paraquat (PQ) poisoning. This study investigates the predictive value of ABG tests in prognosing patients with PQ poisoning; it also identifies the most significant indexes of the ABG test. An intelligent machine learning-based system was established to effectively give prognostic analysis of patients with PQ poisoning based on ABG indexes...
November 21, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27865847/functional-characterisation-and-application-of-an-ex-vivo-perfusion-superfusion-system-in-murine-airways
#9
Esther Y Cheah, Tracy S Mann, Philip C Burcham, Peter J Henry
INTRODUCTION: The aim of this study was to develop two dynamic ex vivo airway explant systems, a perfusion-superfusion system and a ventilation-superfusion system, for the study of toxic airborne substances, such as the prevalent smoke constituent acrolein. METHODS: Mouse isolated tracheal segments were perfused with physiological media or ventilated with humidified air at 37°C to mimic dynamic flow conditions, and superfused with media over the exterior surface...
November 16, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27856310/l-type-calcium-channel-antagonism-translation-from-in-vitro-to-in-vivo
#10
Bernard Fermini, David S Ramirez, Sunny Sun, Asser Bassyouni, Michelle Hemkens, Todd Wisialowski, Stephen Jenkinson
INTRODUCTION: Although therapeutically beneficial in the treatment of certain diseases, L-type calcium channel antagonism can result in unwanted off-target pharmacology leading to adverse drug reactions and to the termination of the development of otherwise promising compounds. In the present study three marketed calcium channel inhibitors, nifedipine, verapamil and diltiazem were profiled in a series of in vitro and ex-vivo assays in an effort to determine the ability of these assays to discriminate, between dihydropyridine versus non-dihydropyridine-like compounds, and how well they can predict the cardiovascular effects observed in a conscious telemetered rat model...
November 15, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27838457/drug-selected-cell-line-panels-for-evaluation-of-the-pharmacokinetic-consequences-of-multidrug-resistance-proteins
#11
Andrzej Błauż, Błażej Rychlik
Through the selection with five chemotherapeutics of diverse chemical structures and modes of action (cis-diamminedichloroplatinum, doxorubicin, etoposide, methotrexate and vincristine), four multidrug-resistant cell line panels were developed. Cancer cell lines of different species (human and murine) as well as tissue/organ (skin, colon) origin, characterized by low endogenous expression of multidrug resistance (MDR) proteins and high sensitivity to anticancer agents, were used as parental cell lines. A selection process resulted in the upregulation of several ABC transporters (ABCB1/Abcb1a, ABCC1/Abcc1 and ABCG2/Abcg2), which was confirmed by a number of molecular and cell biology methods...
November 9, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27810394/validation-of-a-na-shift-binding-assay-for-estimation-of-the-intrinsic-efficacy-of-ligands-at-the-a2a-adenosine-receptor
#12
François Noël, Fernando M do Monte
INTRODUCTION: Determination of the intrinsic efficacy of ligands at the A2A receptor is important for selecting drug candidates, e.g. in the case of inflammatory diseases where agonists are searched for or in Parkinson disease (antagonists). METHODS: Three functional binding assays were compared with up to seven ligands with different efficacies: the GTP-shift method based on the decrease of affinity observed with agonists when GTP is added to the competition binding assay; the Ki ratio method based on the different affinity states of the receptor when using an agonist or antagonist radioligand and the Na(+)-shift assay based on the difference of affinity of agonists when tested in a medium containing a divalent cation (50mM MgCl2) favoring the G protein coupled agonist-receptor complex or sodium (100mM NaCl) as negative allosteric modulator...
November 1, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27989852/cortical-and-spinal-assessment-a-comparative-study-using-encephalography-and-the-nociceptive-withdrawal-reflex
#13
I W Fischer, M Gram, T M Hansen, A Brokjaer, C Graversen, L P Malver, C D Mørch, L L Christrup, A M Drewes, A E Olesen
BACKGROUND: Standardized objective methods to assess the analgesic effects of opioids, enable identification of underlying mechanisms of drug actions in the central nervous system. Opioids may exert their effect on both cortical and spinal levels. In this study actions of morphine at both levels were investigated, followed by analysis of a possible correlation between the cortical processing and spinal transmission. METHODS: The study was conducted after a double-blinded, two-way crossover design in thirty-nine healthy participants...
October 29, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27756609/early-life-exposure-to-permethrin-a-progressive-animal-model-of-parkinson-s-disease
#14
Cinzia Nasuti, Gloria Brunori, Piera Eusepi, Lisa Marinelli, Roberto Ciccocioppo, Rosita Gabbianelli
INTRODUCTION: Oxidative stress, alpha-synuclein changes, mitochondrial complex I defects and dopamine loss, observed in the striatum of rats exposed to the pesticide permethrin in early life, could represent neuropathological hallmarks of Parkinson's disease (PD). Nevertheless, an animal model of PD should also fulfill criteria of face and predictive validities. This study was designed to: 1) verify dopaminergic status in the striatum and substantia nigra pars compacta; 2) recognize non-motor symptoms; 3) investigate the time-course development of motor disabilities; 4) assess L-Dopa effectiveness on motor symptoms in rats previously exposed to permethrin in early life...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27737794/human-neuron-astrocyte-3d-co-culture-based-assay-for-evaluation-of-neuroprotective-compounds
#15
Ana Paula Terrasso, Ana Carina Silva, Augusto Filipe, Pedro Pedroso, Ana Lúcia Ferreira, Paula Marques Alves, Catarina Brito
INTRODUCTION: Central nervous system drug development has registered high attrition rates, mainly due to the lack of efficacy of drug candidates, highlighting the low reliability of the models used in early-stage drug development and the need for new in vitro human cell-based models and assays to accurately identify and validate drug candidates. 3D human cell models can include different tissue cell types and represent the spatiotemporal context of the original tissue (co-cultures), allowing the establishment of biologically-relevant cell-cell and cell-extracellular matrix interactions...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27725245/estimation-of-the-receptor-state-affinity-constants-of-ligands-in-functional-studies-using-wild-type-and-constitutively-active-mutant-receptors-implications-for-estimation-of-agonist-bias
#16
Frederick J Ehlert, Richard S L Stein
We describe a method for estimating the affinities of ligands for active and inactive states of a G protein-coupled receptor (GPCR). Our protocol involves measuring agonist-induced signaling responses of a wild type GPCR and a constitutively active mutant of it under control conditions and after partial receptor inactivation or reduced receptor expression. Our subsequent analysis is based on the assumption that the activating mutation increases receptor isomerization into the active state without affecting the affinities of ligands for receptor states...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27686045/the-influence-of-facility-and-home-pen-design-on-the-welfare-of-the-laboratory-housed-dog
#17
Laura E M Scullion Hall, Sally Robinson, John Finch, Hannah M Buchanan-Smith
We have an ethical and scientific obligation to Refine all aspects of the life of the laboratory-housed dog. Across industry there are many differences amongst facilities, home pen design and husbandry, as well as differences in features of the dogs such as strain, sex and scientific protocols. Understanding how these influence welfare, and hence scientific output is therefore critical. A significant proportion of dogs' lives are spent in the home pen and as such, the design can have a considerable impact on welfare...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27670369/simultaneous-quantification-of-gatifloxacin-moxifloxacin-and-besifloxacin-concentrations-in-cornea-and-aqueous-humor-by-lc-qtof-ms-after-topical-ocular-dosing
#18
Luisa C Domingos, Matheus Vilardo L Moreira, Kelly M Keller, Fernando Antônio B Viana, Marília M Melo, Benito Soto-Blanco
The fourth-generation fluoroquinolones are widely used as ophthalmic antimicrobials. This study aimed to validate a new analytical technique for simultaneous quantification of gatifloxacin, moxifloxacin, and besifloxacin concentrations in the cornea and aqueous humor by liquid chromatography (LC) coupled to quadrupole time-of-flight mass spectrometry (QTOF/MS) at 10min and 1h after instillation of topical ophthalmic antimicrobial suspensions. It was used twenty-two male dogs without ocular lesions verified by ophthalmic and histologic examinations...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27659846/15-th-annual-meeting-of-the-safety-pharmacology-society-focus-on-traditional-sensory-systems
#19
Icilio Cavero, Henry Holzgrefe
INTRODUCTION: This report summarizes and comments key talks on the five traditional senses (ear, vestibular system, vision, taste, olfaction, and touch) which were delivered during the 2015 Annual Meeting of the Safety Pharmacology (SP) Society. AREAS COVERED: The functional observational battery (FOB) can detect major candidate drug liabilities only on ear, touch and vision. Anatomy, physiology, pharmacology, and pathology notions on each sensory system introduce speaker talks...
January 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27646297/comprehensive-in-vitro-cardiac-safety-assessment-using-human-stem-cell-technology-overview-of-csahi-heart-initiative
#20
REVIEW
Kiyoshi Takasuna, Keiichi Asakura, Seiichi Araki, Hiroyuki Ando, Katsuyuki Kazusa, Takashi Kitaguchi, Takeshi Kunimatsu, Shinobu Suzuki, Norimasa Miyamoto
Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities...
January 2017: Journal of Pharmacological and Toxicological Methods
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