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Journal of Pharmacological and Toxicological Methods

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https://www.readbyqxmd.com/read/27913272/the-northeast-regional-sps-meeting-update-safety-pharmacology-innovations-and-applications
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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/27773845/harmonised-high-throughput-microsomal-stability-assay
#7
Beth Williamson, Claire Wilson, Gayle Dagnell, Robert J Riley
INTRODUCTION: Prediction of human pharmacokinetics from in vitro assays and pre-clinical data is an integral part of drug discovery. In vitro stability metabolic studies can provide an estimate of in vivo hepatic intrinsic clearance through inclusion of biological scaling factors. Many labs have personalised stability protocols including marker compounds and have adopted QC criteria and assay limits to ensure data integrity. Contract research organisations (CRO's) provide integrated drug discovery support to academic and pharmaceutical/biotechnology institutions to progress their in-house projects...
October 20, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27773844/a-murine-model-of-type-2-diabetes-mellitus-developed-using-a-combination-of-high-fat-diet-and-multiple-low-doses-of-streptozotocin-treatment-mimics-the-metabolic-characteristics-of-type-2-diabetes-mellitus-in-humans
#8
Sayantan Nath, Sankar Kumar Ghosh, Yashmin Choudhury
INTRODUCTION: A murine model of type 2 diabetes mellitus was used to compare the antidiabetic effects of the dipeptidyl peptidase-4 (DPP4) inhibitor vildagliptin and biguanide, metformin. METHODS: Swiss albino mice (n=20 males; n=25 females) were given high fat diet (HFD) ad libitum for 3weeks followed by low dose (40mgkg(-1) body weight, bw daily) of streptozotocin (STZ) intraperitoneally five times from the 22nd day of treatment onwards, with HFD continued up to 26th day...
October 20, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27773843/using-tiletamine-zolazepam-xylazine-anesthesia-compared-to-co2-inhalation-for-terminal-clinical-chemistry-hematology-and-coagulation-analysis-in-mice
#9
Oksana N Khokhlova, Elena A Tukhovskaya, Irina N Kravchenko, Elena S Sadovnikova, Irina A Pakhomova, Elena A Kalabina, Alexander V Lobanov, Elvira R Shaykhutdinova, Alina M Ismailova, Arkady N Murashev
INTRODUCTION: It is important that the method of anesthesia of mice does not considerably alter the animal's physiological and metabolic status before terminal blood sampling taken in order to analyze clinical pathology parameters. METHODS: Hematology, hemostasis, and clinical chemistry parameters were compared in male and female BALB/c mice exposed to either tiletamine-zolazepam-xylazine (TZX) anesthesia or euthanasia in carbon dioxide (CO2) chamber to reveal an alternative method of anesthesia vs...
October 20, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27756610/promising-approach-for-the-preclinical-assessment-of-cardiac-risks-using-left-ventricular-pressure-volume-loop-analyses-in-anesthetized-monkeys
#10
Tomomichi Ishizaka, Yu Yoshimatsu, Yu Maeda, Wataru Takasaki, Katsuyoshi Chiba, Kazuhiko Mori
INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a β-blocker), or dl-sotalol (a β+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug)...
October 15, 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
#11
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...
October 15, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27746217/a-new-rat-model-of-neonatal-bilirubin-encephalopathy-kernicterus
#12
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
INTRODUCTION: Hemolytic kernicterus, an indirect bilirubin-induced brain dysfunction, is associated with hyper-bilirubinemia in mammalian neonates. In this study, a new model of kernicterus has been developed using intra-peritoneal injections of phenyl hydrazine and subcutaneous injections of sulfisoxazole. These drugs can potentially induce kernicterus in neonatal through changes in hemolysis and hypo-albumin. METHODS: For this purpose, 7-day-old male Wistar rats (n=72; mean weight 11±1g) were used...
October 13, 2016: 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
#13
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...
October 11, 2016: 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
#14
Frederick J Ehlert, Richard Sl 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...
October 7, 2016: 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
#15
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...
September 26, 2016: 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
#16
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...
September 23, 2016: 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
#17
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...
September 19, 2016: 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
#18
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...
September 17, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27641113/pharmacokinetic-applications-of-cutaneous-microdialysis-continuous-intermittent-vs-continuous-only-sampling
#19
Abhay Joshi, Hiren Patel, Amit Joshi, Grazia Stagni
INTRODUCTION: Microdialysis is a technique that allows interstitial-fluid sampling with minimal tissue-damage. In a microdialysis study, samples are collected serially (continuous microdialysis, CMD) and participant's movements are reduced for the entire study. Intermittent Cutaneous Microdialysis (IMD) is a modified version of CMD, which allows for unrestrained periods in between samples. However, in separate experiments, pharmacokinetic parameters estimated with IMD showed higher variability than with CMD...
September 15, 2016: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/27622857/assessment-of-extracellular-field-potential-and-ca-2-transient-signals-for-early-qt-pro-arrhythmia-detection-using-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#20
Najah Abi-Gerges, Amy Pointon, Karen L Oldman, Martin R Brown, Mark A Pilling, Clare E Sefton, Helen Garside, Christopher E Pollard
Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free microelectrode array (parameters measured were beating period (BP), field potential duration (FPD), fast Na(+) amplitude and slope) and live cell, fast kinetic fluorescent Ca(2+) transient FLIPR® Tetra (parameters measured were peak count, width, amplitude) systems...
September 10, 2016: Journal of Pharmacological and Toxicological Methods
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