1,721 results match your criteria Journal of Pharmacological and Toxicological Methods [Journal]


Simultaneous assessment of compound activity on cardiac Nav1.5 peak and late currents in an automated patch clamp platform.

J Pharmacol Toxicol Methods 2019 Apr 15. Epub 2019 Apr 15.

Drug Safety Research and Development, Pfizer Inc., La Jolla, CA 92121, United States of America.

Introduction: High throughput in vitro profiling of the cardiac Nav1.5 peak sodium current (I) is widely used in cardiac safety screening. However, there is no standardized high throughput method to measure late I. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.04.001DOI Listing

Label-free dynamic mass redistribution analysis of endogenous adrenergic receptor signaling in primary preadipocytes and differentiated adipocytes.

J Pharmacol Toxicol Methods 2019 Apr 1;97:59-66. Epub 2019 Apr 1.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address:

Introduction: Adipose tissues release adipokines, which regulate energy intake and expenditure. G protein-coupled receptors (GPCRs) and associated signaling pathways in adipocytes are potentially important drug targets for conditions with disturbed energy metabolism.

Methods: The aim of the current study was to compare signaling of endogenously expressed GPCRs between primary preadipocytes and differentiated adipocytes using a novel state-of-the-art unbiased method that measures dynamic mass redistribution (DMR) in real-time. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.03.005DOI Listing
April 2019
3 Reads

Variability of non-clinical behavioral CNS safety assessment: An intercompany comparison.

J Pharmacol Toxicol Methods 2019 Mar 27. Epub 2019 Mar 27.

Janssen, Global Safety Pharmacology, Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address:

Introduction: Irwin/FOB testing is routinely conducted to investigate the neurofunctional integrity of laboratory animals during preclinical development of new drugs, however, the study design frequently varies to meet specific needs. Representatives of several European-based pharmaceutical companies performed a "state-of-the-art" assessment of how they conduct their CNS safety evaluation using Irwin/FOB tests.

Methods: This assessment consisted of (1) a survey of current/historical practice, (2) an evaluation of historical studies with reference compounds (amphetamine, chlorpromazine) to determine intercompany reproducibility of results, and (3) an interlaboratory test using reference compounds (MK-801, chlorpromazine) to determine whether partially standardized conditions (animals, sex, doses, vehicles, administration route, observation time points, systemic exposure) might reduce variability of results. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.03.002DOI Listing
March 2019
2 Reads

EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates.

J Pharmacol Toxicol Methods 2019 Mar 26;97:52-58. Epub 2019 Mar 26.

Citoxlab North America, 445 Armand-Frappier, Laval, QC, Canada.

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). Read More

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http://dx.doi.org/10.1016/j.vascn.2019.03.004DOI Listing
March 2019
1 Read

Establishment of a rodent cooperation assay as a model of social cognition.

J Pharmacol Toxicol Methods 2019 Mar 22;97:44-51. Epub 2019 Mar 22.

MTA-SE NAP B Cognitive Translational Behavioural Pharmacology Group, Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary; Institute of Cognitive Neuroscience and Psychology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, 1117, Hungary. Electronic address:

Introduction: Impaired cooperative skills form a characteristic symptom in autism, which lacks adequate treatment. The objective of this study was to establish a rat cooperation assay which fits the feasibility and capacity requirements of drug development.

Methods: Long-Evans and Lister Hooded rats were trained in pairs to simultaneously perform nose-pokes (within 1 s) for reward in a Skinner box equipped with two nose-poke modules. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.03.003DOI Listing
March 2019
3 Reads

Liquid chromatography-tandem mass spectrometry for rapid and selective simultaneous determination of fluoroquinolones level in human aqueous humor.

J Pharmacol Toxicol Methods 2019 Mar 20;97:36-43. Epub 2019 Mar 20.

Department of Ophthalmology, King Talal Military Hospital, Royal Medical Services, Almafraq, Jordan.

Endophthalmitis, an intraocular infection, may lead to irreversible loss of vision. Antimicrobial chemotherapy is prescribed prior to ocular surgical procedures to avoid endophthalmitis. Fluoroquinolones are the most commonly prescribed and used antibiotics during such procedures. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.03.001DOI Listing
March 2019
2.150 Impact Factor

FOB vs modified Irwin: What are we doing?

J Pharmacol Toxicol Methods 2019 Mar 16;97:24-28. Epub 2019 Mar 16.

Neurobehavioral Sciences, Charles River Laboratories, Inc., Mattawan, MI, USA.

There is a general sentiment in the nonclinical safety assessment literature and the proponents of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), that the "Modified Irwin" and the Functional Observation Battery are distinct and unique assays for the nonclinical assessment of the central nervous system (CNS). We identify and defend the position that the Irwin screen was developed as an FOB and both terms refer to a single, unitary functional assay. In giving credit to one prominent contributor to any one significant discipline of science for a specific assay, orientation, or theory may have an exclusionary influence on the merits of other prominent contributors within the same research arena. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.008DOI Listing

Multi-dry-electrode plate sensor for non-invasive electrocardiogram and heart rate monitoring for the assessment of drug responses in freely behaving mice.

Authors:
Shinichi Sato

J Pharmacol Toxicol Methods 2019 Mar 14;97:29-35. Epub 2019 Mar 14.

Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Electronic address:

Monitoring of electrocardiogram (ECG) and heart rate (HR) is essential in a wide range of experiments. For conscious animal studies, telemetry is the preferred approach; however, it requires 1-3 weeks of recovery after surgical device-implantation. The present paper describes a novel multi-dry-electrode plate (MDEP) sensor system to monitor ECG/HR in freely behaving mice without the need for surgery for device/electrode implantation. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.009DOI Listing
March 2019
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Establishing performance characteristics for positive control article selection in drug self-administration studies.

J Pharmacol Toxicol Methods 2019 Feb 21;97:13-23. Epub 2019 Feb 21.

Kallman Preclinical Consulting, CEO, VP, 1569 E. 300 North, Greenfield, IN 46140, United States.

The selection of a controlled substance (CS) for use as the positive control article in a nonclinical drug abuse liability (DAL) assessment study should be contemplated carefully and with full understanding of the stated intent of the study design. Any CS that can maintain day-to-day stable baseline responding of voluntary intravenous intakes in animals may be selected under the current guidelines. Schedule I - IV CNS stimulants, depressants, and sedative/hypnotics can serve as maintenance drugs in these protocols, but not all of these compounds will provide comparatively efficient, robust, and stable daily intakes. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.007DOI Listing
February 2019
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Expanding the applicability of the amino acid derivative reactivity assay: Determining a weight for preparation of test chemical solutions that yield a predictive capacity identical to the conventional method using molar concentration and demonstrating the capacity to detect sensitizers in liquid mixtures.

J Pharmacol Toxicol Methods 2019 Feb 21;97:67-79. Epub 2019 Feb 21.

Safety Evaluation Center, Fujifilm Corporation, Kanagawa, Japan. Electronic address:

Introduction: The amino acid derivative reactivity assay (ADRA) is a novel in chemico alternative to animal testing for assessment of skin sensitization potential. The conventional ADRA protocol stipulates that test chemical solutions should be prepared to a specific molar concentration, allowing only for use of test chemicals with known molecular weights. Since many potential test substances are prepared by weight concentration or contain multiple unknown chemicals, this study was conducted to verify if it is possible to accurately assess the sensitization potential of test chemical solutions prepared at a specific weight concentration. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.01.001DOI Listing
February 2019

Validating a model of benzodiazepine refractory nerve agent-induced status epilepticus by evaluating the anticonvulsant and neuroprotective effects of scopolamine, memantine, and phenobarbital.

J Pharmacol Toxicol Methods 2019 Feb 19;97:1-12. Epub 2019 Feb 19.

Neuroscience Branch, Nerve Agent Countermeasures, U.S. Army Medical Research Institute of Chemical Defense, MD, USA. Electronic address:

Introduction: Organophosphorus nerve agents (OPNAs) irreversibly block acetylcholinesterase activity, resulting in accumulation of excess acetylcholine at neural synapses, which can lead to a state of prolonged seizures known as status epilepticus (SE). Benzodiazepines, the current standard of care for SE, become less effective as latency to treatment increases. In a mass civilian OPNA exposure, concurrent trauma and limited resources would likely cause a delay in first response time. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.006DOI Listing
February 2019
4 Reads

Social-housing and use of double-decker cages in rat telemetry studies.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:87-94. Epub 2019 Feb 16.

National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Rd, London NW1 2BE, UK.

Rat telemetry is widely used for biomedical research purposes and is used routinely in early pre-clinical drug development to screen for the potential cardiovascular risk of candidate drugs. Historically, these studies have been conducted in individually housed conditions which can impact significantly on an animal's welfare. Here we present data from a survey of pharmaceutical companies and contract research organisations to define current industry practices relating to the housing of rats during telemetry studies and to expand and complement a similar project in non-rodents. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.005DOI Listing
February 2019
2.150 Impact Factor

The underlying factors that explain why nucleophilic reagents rarely co-elute with test chemicals in the ADRA.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:95-105. Epub 2019 Feb 15.

Safety Evaluation Centre, Ecology & Quality Management Division, CSR Division, FUJIFILM Corporation, 210 Nakanuma, Minamiashigara-shi, Kanagawa, Japan.

The Amino acid Derivative Reactivity Assay (ADRA) is an in chemico alternative to animal testing for skin sensitization potential that uses two different nucleophilic reagents and it is known that ADRA hardly exhibts co-elution compared with the Direct Peptide Reactivity Assay (DPRA) based on the same scientific principles. In this study, we have analyzed the factors underlying why co-elution, which is sometimes an issue during DPRA testing, virtually never occurs during ADRA testing. Chloramine T and dimethyl isophthalate both exhibited co-elution during DPRA testing, but when quantified at both DPRA's 220 nm and ADRA's 281 nm, we found that when the later detection wavelength was used, these test chemicals produced extremely small peaks that did not interfere with quantification of the peptides. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.004DOI Listing
February 2019
7 Reads

A mouse model of heart failure exhibiting pulmonary edema and pleural effusion: Useful for testing new drugs.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:78-86. Epub 2019 Feb 6.

Cardiovascular & Fibrosis Discovery Biology, Research & Development, Bristol-Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534, USA. Electronic address:

Introduction: Mouse models of chronic heart failure (HF) have been widely used in HF research. However, the current HF models most often use the C57BL/6 mouse strain and do not show the clinically relevant characteristics of pulmonary congestion. In this study, we developed a robust mouse model of HF in the BALB/c mouse strain, exhibiting pulmonary edema and pleural effusion, and we validated the model using the standard pharmacological therapies in patients with chronic HF and reduced ejection fraction (HFrEF) or acute decompensated HF. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.001DOI Listing
February 2019
3 Reads

Nanoparticle contrast-enhanced micro-CT: A preclinical tool for the 3D imaging of liver and spleen in longitudinal mouse studies.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:67-77. Epub 2019 Feb 7.

Comparative Medicine, Pfizer Worldwide R&D, Groton, CT 06340, USA.

In drug discovery and development, X-ray micro-computed tomography (micro-CT) has gained increasing importance over the past decades. In recent years, micro-CT imaging of soft tissues has become popular due to the introduction of a variety of radiopaque contrast agents. More recently, nanoparticle-based ExiTron nano 12,000 has become commercially available for the nonclinical micro-CT imaging of soft tissues in rodents. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.003DOI Listing
February 2019
9 Reads

Factors affecting RNA quantification from tissue long-term stored in formalin.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:61-66. Epub 2019 Feb 6.

Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Zaloška 4, SI-1000 Ljubljana, Slovenia. Electronic address:

Introduction: FFPE samples represent a rich pool of tissue samples for retrospective analyses of mRNA and miRNA analyses. However, the initial formalin fixation introduces a chemical modification of RNA and causes its degradation, therefore, a longer storage of tissue in formalin is predicted to render ribonucleic acids lost for isolation and subsequent analyses.

Methods: Herein, we tested the impact of several factors on isolation of total RNA and detection with RT-qPCR from mouse liver tissue stored for over two years in formalin at room temperature. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.02.002DOI Listing
February 2019
1 Read

Drosophila bioassays are very sensitive methods to assess tarantula species venoms.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:56-60. Epub 2019 Jan 30.

Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM Juriquilla, Boulevard Juriquilla #3001, 76230 Querétaro, Querétaro, Mexico. Electronic address:

Introduction: Assaying venom toxicity in a suitable model system is often tricky, since normally the amount of venom is in short supply, and the assay subjects, i.e., typically mice, require large amounts. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.01.003DOI Listing
January 2019

Cerulein-induced chronic pancreatitis in Swiss albino mice: An improved short-term model for pharmacological screening.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:46-55. Epub 2019 Jan 23.

Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India. Electronic address:

There is a need for short-term, reliable and reproducible animal model of chronic pancreatitis (CP) in small animals like mice. This study was aimed to establish the 9 exposures of cerulein-induced CP in mice. Repeated intraperitoneal cerulein injections were performed at 6 consecutive doses (50 μg/kg)/day, 3 days a week for 3 weeks to induce chronic pancreatitis in Swiss albino mice. Read More

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http://dx.doi.org/10.1016/j.vascn.2019.01.002DOI Listing
January 2019
1 Read

Increased susceptibility to oxidative stress-induced toxicological evaluation by genetically modified nrf2a-deficient zebrafish.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:34-45. Epub 2018 Dec 27.

Department of Systems Pharmacology, Mie University Graduate School of Medicine, Mie, Japan; Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie, Japan; Mie University Medical Zebrafish Research Center, Mie, Japan; Department of Bioinformatics, Mie University Life Science Research Center, Mie, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation Institute, Mie, Japan.

Introduction: Oxidative stress plays an important role in drug-induced toxicity. Oxidative stress-mediated toxicities can be detected using conventional animal models but their sensitivity is insufficient, and novel models to improve susceptibility to oxidative stress have been researched. In recent years, gene targeting methods in zebrafish have been developed, making it possible to generate homozygous null mutants. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.006DOI Listing
December 2018
18 Reads

Availability of multistep light stimulus method for evaluation of visual dysfunctions.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:27-33. Epub 2018 Dec 22.

Preclinical Research Unit, Drug Research Division, Sumitomo Dainippon Pharma Co. Ltd., Osaka, Japan.

In the field of drug safety research, electroretinography (ERG) is commonly conducted according to the international standard method propounded by the International Society for Clinical Electrophysiology of Vision (ISCEV) in recent years. However, various ERG methods other than the ISCEV standard method are also utilized depending on the intended purpose of the evaluation. In this study, we investigated the availability of a multistep light stimulus method for evaluation of rod function in Long-Evans rats using sildenafil, which is known to inhibit phosphodiesterase 6 (PDE6) in phototransduction and induce visual dysfunctions in humans. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.005DOI Listing
December 2018
9 Reads

Impact of disease state on arrhythmic event detection by action potential modelling in cardiac safety pharmacology.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:15-26. Epub 2018 Dec 21.

Nova Research Laboratories LLC, 1441 Canal Street, New Orleans, LA 70112, USA. Electronic address:

Introduction: The use of in silico cardiac action potential simulations is one of the pillars of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) currently under evaluation designed to detect more accurately proarrhythmic liabilities of new drug candidate. In order to take into account the variability of clinical situations, we propose to improve this method by studying the impact of various disease states on arrhythmic events induced by 30 torsadogenic or non-torsadogenic compounds.

Method: In silico modelling was done on the human myocytes using the Dutta revised O'Hara-Rudy algorithm. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.004DOI Listing
December 2018
2 Reads

Assessing the risk of drug crystallization in vivo.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:1-8. Epub 2018 Dec 13.

Research & Development, Bristol-Myers Squibb Company, Princeton, NJ, USA; University of Kansas, Lawrence, KS, USA.

Introduction: Low intrinsic solubility leading to poor oral bioavailability is a common challenge in drug discovery that can often be overcome by formulation strategies, however, it remains a potential limitation that can pose challenges for early risk assessment and represent a significant obstacle to drug development. We identified a selective inhibitor (BMS-986126) of the IL-1 receptor-associated kinase 4 (IRAK4) with favorable properties as a lead candidate, but with unusually low intrinsic solubility of <1 μg/mL.

Methods: Conventional histopathology identified the issue of crystal formation in vivo. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.003DOI Listing
December 2018
10 Reads

Protocol for evaluation of topical ophthalmic drug products in different compartments of fresh eye tissues in a rabbit model.

J Pharmacol Toxicol Methods 2019 Mar - Apr;96:9-14. Epub 2018 Dec 13.

Office of Translational Science, Office of Clinical Pharmacology, Division of Applied Regulatory Science, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak Federal Research Center, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA. Electronic address:

Topical ophthalmic drugs are the most commonly used dosage form to treat diseases of the anterior segment of the eye. Although this dosage form has the advantages of ease of application, small volume dose, and rapid action and is largely devoid of systemic adverse effects, the bioavailability is low due to pre-corneal anatomical barriers and the nature of the drug formulation itself. Some complex generic formulations (suspensions, ointments, gels) for topical ophthalmic products face impediments to rapid regulatory approval because of the complex nature of the formulations and difficulties in determining bioequivalence with the innovator product. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.002DOI Listing
December 2018
10 Reads

Hydrophobic drug adsorption loss to syringe filters from a perspective of drug delivery.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:79-85. Epub 2018 Dec 5.

Institute of Ocular Pharmacology, School of Ophthalmology and Optometry, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, Zhejiang 325027, China; Jacob's Retina Center at Shiley Eye Institute, Department of Ophthalmology, University of California San Diego, 9415 Campus Point Drive, La Jolla, CA 92037-0946, United States. Electronic address:

Filtering with a syringe filter is a common operation in pharmaceutical analysis. Ophthalmic research often has a limited amount of sample and low amount of drug which is vulnerable to filtering membrane adsorption loss but not well recognized in the research community. Current study investigated drug adsorption by 11 types of syringe filters for 4 hydrophobic compounds commonly encountered in transscleral drug delivery. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.12.001DOI Listing
March 2019
5 Reads

Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:66-69. Epub 2018 Nov 28.

Departments of Pharmaceutics, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298-0533, USA. Electronic address:

Introduction: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites.

Methods: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis.

Results: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.009DOI Listing
March 2019
4 Reads

Development of a bioreactor system for cytotoxic evaluation of pharmacological compounds in living cells using NMR spectroscopy.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:70-78. Epub 2018 Nov 28.

CICS-UBI - Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, Covilhã, Portugal. Electronic address:

Introduction: The evaluation of drug's cytotoxicity is a crucial step in the development of new pharmacological compounds. P NMR can be a tool for toxicological screening, as it enables the study of drugs' cytotoxicity and their effect on cell energy metabolism in a real-time, in a non- invasive and non-destructive way. This paper details a step-by-step protocol to implement a bioreactor system able to maintain cell viability during NMR acquisitions, at high cell densities and for several hours, enabling toxicological evaluation of pharmacological compounds in living cells. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.004DOI Listing
March 2019
19 Reads

Larval zebrafish model for studying the effects of valproic acid on neurodevelopment: An approach towards modeling autism.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:56-65. Epub 2018 Nov 27.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address:

Introduction: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder of early onset, characterized by impaired sociability, cognitive function and stereotypies. The etiology of ASD involves a multidimensional link between genetic, neurobiological and environmental factors. Since existing, comprehensive animal models for ASD are time consuming and laborious, the need for simple, quick approaches to study subsets of ASD-associated characteristics has always been in demand for better understanding of disease. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.006DOI Listing
March 2019
3 Reads

Two immunoassays for the detection of 2C-B and related hallucinogenic phenethylamines.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:36-46. Epub 2018 Nov 24.

Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, 166 28 Praha 6, Dejvice, Czechia; Forensic Laboratory of Biologically Active Substances, University of Chemistry and Technology Prague, Technická 3, 166 28 Praha 6, Dejvice, Czechia; Department of Experimental Neurobiology, National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czechia. Electronic address:

Introduction: The use of new psychoactive substances as drugs of abuse has dramatically increased over the last years. Hallucinogenic phenethylamines gained particular popularity as they have both stimulating and psychedelic effects. Although generally perceived as safe, these illicit drugs pose a serious health risk; they have been linked to cases of severe poisoning or even deaths. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.001DOI Listing
March 2019
16 Reads

A novel high-content imaging-based technique for measuring binding of Dickkopf-1 to low-density lipoprotein receptor-related protein 6.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:47-55. Epub 2018 Nov 23.

Alzheimer's Research UK Oxford Drug Discovery Institute, University of Oxford, NDM Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7FZ, UK. Electronic address:

Introduction: Dickkopf-related protein 1 (Dkk1) is a secreted protein ligand of low-density lipoprotein receptor-related protein 6 (LRP6), which antagonises canonical Wnt signalling. Elevated Dkk1 levels have been linked to Alzheimer's disease (AD), with protein blockade protective in pre-clinical AD models, suggesting inhibitors of Dkk1-LRP6 binding may have therapeutic utility against AD. Cell-based Dkk1-LRP6 assays reported in the literature use either modified Dkk1 protein and/or do not possess suitable throughput for drug screening. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.003DOI Listing
March 2019
17 Reads

Relative equivalence of CNS safety (FOB) assessment outcomes in male and female Wistar-Han and Sprague-Dawley rats.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:2-11. Epub 2018 Nov 23.

Drug Safety Assessment, United States.

In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.002DOI Listing
March 2019
22 Reads

A novel experimental intraperitoneal infection model for Haemophilus parasuis in neutropenic guinea pigs.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:27-35. Epub 2018 Nov 23.

National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. Electronic address:

Introduction: Haemophilus parasuis, one of the major swine pathogens, has at least fifteen different types, all of which have significant economic effects on the global swine industry. The aim of this study was to establish an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.008DOI Listing
March 2019
10 Reads

Influence of incubation conditions on microsomal metabolism of xanthine-derived A adenosine receptor ligands.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:16-26. Epub 2018 Nov 23.

Institute of Neuroscience and Medicine, Nuclear Chemistry (INM-5), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428 Jülich, Germany. Electronic address:

Introduction: In vitro metabolism models such as liver microsomes represent an important tool for the development of novel radioligands. Comparability and physiological relevance of in vitro metabolism data critically depend on the careful evaluation and optimization of assay protocols. We therefore investigated the influence of incubation conditions on the microsomal stability of xanthine-derived A adenosine receptor (AAR) ligands which have been developed for positron emission tomography (PET). Read More

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http://dx.doi.org/10.1016/j.vascn.2018.11.005DOI Listing
March 2019
2 Reads

Individual variability in female and male mice in a test-retest protocol of the forced swim test.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:12-15. Epub 2018 Nov 23.

School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, Israel; Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Israel. Electronic address:

Background: The challenges to embody the complexity of symptoms and biological mechanism of affective disorders question the value of animal models as well as their reproducibility and validity. Validity is further hindered by large individual variability in many models. Whereas individual variability presents a challenge, it can also be used to study susceptibility and resistance. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10568719183069
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http://dx.doi.org/10.1016/j.vascn.2018.11.007DOI Listing
March 2019
16 Reads

Challenges in designing and executing clinical trials in a dish studies.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):73-82. Epub 2018 Sep 26.

Coyne Scientific, 1899 Powers Ferry Road SE, Atlanta, GA 30339, USA.

The ever-increasing cost of drug discovery and development represents a significant challenge for the pharmaceutical industry and new strategies to bridge studies between preclinical testing and clinical trials are needed to reduce the knowledge gap prior to first human exposures, and to allow earlier decisions to be made on the further development of drugs. A number of studies have demonstrated that various cell types differentiated from human induced pluripotent stem cells (iPSCs) do not just respond similarly to human tissues in general, but rather recapitulate the drug response of their specific donor's, when exposed to the same drug in vivo. This recapitulation opens the doors to Clinical Trials in a Dish (CTiD), a platform which involves testing, in vitro, medical therapies for safety on cells collected from a sample of human patients, before moving into clinical trials. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.09.002DOI Listing
March 2019
17 Reads

Revisiting the binding kinetics and inhibitory potency of cardiac glycosides on Na,K-ATPase (α1β1): Methodological considerations.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):64-72. Epub 2018 Sep 20.

Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovoth, Israel. Electronic address:

Introduction: Ouabain and digoxin are classical inhibitors of the Na,K-ATPase. In addition to their conventional uses as therapeutic agents or experimental tools there is renewed interest due to evidence suggesting they could be endogenous hormones. Somewhat surprisingly, different publications show large discrepancies in potency for inhibiting Na,K-ATPase activity (IC), particularly for the slow binding inhibitors, ouabain and digoxin. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.09.001DOI Listing
March 2019
9 Reads

Integration of cardiac energetics, function and histology from isolated rat hearts perfused with doxorubicin and doxorubicin-ol; a model for use in drug safety evaluations.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):54-63. Epub 2018 Sep 6.

Charles River Laboratories, Ashland, OH 44805, United States.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.08.004DOI Listing
March 2019
19 Reads

A simple UHPLC-PDA method with a fast dilute-and-shot sample preparation for the quantification of canrenone and its prodrug spironolactone in human urine samples.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):29-35. Epub 2018 Aug 28.

Laboratory of Clinical Pharmacology and Pharmacogenetics(1), University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.08.003DOI Listing
March 2019
12 Reads

Comparison of subjective and objective measures of constipation - Employing a new method for categorizing gastrointestinal symptoms.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):23-28. Epub 2018 Aug 24.

Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Mølleparkvej 4, Aalborg 9000, Denmark; Department of Clinical Medicine, Aalborg University, Søndre Skovvej 15, Aalborg 9000, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160/162, Copenhagen 2100, Denmark. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.08.002DOI Listing
March 2019
2 Reads

The gold-standard in preclinical abuse liability testing: It's all relative.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):36-53. Epub 2018 Aug 18.

Drug Safety Evaluation, Neurobehavioral Sciences, MPI Research (A Charles River Company), Mattawan, MI, USA.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.08.001DOI Listing
March 2019
22 Reads

A highly sensitive and selective high pressure liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method for the direct peptide reactivity assay (DPRA).

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):1-15. Epub 2018 Aug 9.

Toxicology and Environmental Research & Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674, USA.

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). The final results were compared with the results from the traditional HPLC/UV-based guideline DPRA. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.07.004DOI Listing
March 2019
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Comparison of different microscopy approaches to quantification of inhibitory effect on thrombus formation under flow conditions by the example of adenosine receptor agonist HE-NECA.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):94-104. Epub 2018 Jul 19.

Department of Haemostatic Disorders, Chair of Biomedical Sciences, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka Street, 92-235 Lodz, Poland.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.07.003DOI Listing
December 2018
7 Reads

Zebrafish models: do we have valid paradigms for depression?

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 2):16-22. Epub 2018 Jul 18.

School of Pharmacy, Southwest University, Chongqing, China; Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Center, St. Petersburg, Russia; Ural Federal University, Ekaterinburg, Russia; Granov Russian National Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia; ZENEREI Research Center, Slidell, LA, USA; Laboratory of Translational Biopsychiatry, Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.07.002DOI Listing
March 2019
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In vitro secondary pharmacological profiling: An IQ-DruSafe industry survey on current practices.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:7-14. Epub 2018 Jul 17.

Novartis Institutes for Biomedical Research, Pre-Clinical Safety, Cambridge, MA, USA.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.07.001DOI Listing
January 2019
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CiPA challenges and opportunities from a non-clinical, clinical and regulatory perspectives. An overview of the safety pharmacology scientific discussion.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:15-25. Epub 2018 Jun 27.

UCB-Biopharma SPRL, Non-Clinical Development, 1420 Braine L'Alleud, Belgium.

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10568719183062
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http://dx.doi.org/10.1016/j.vascn.2018.06.005DOI Listing
January 2019
29 Reads

Cross - site comparison of excitation-contraction coupling using impedance and field potential recordings in hiPSC cardiomyocytes.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:46-58. Epub 2018 Jun 22.

Nanion Technologies GmbH, Ganghoferstrasse 70A, 80339 Munich, Germany. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146285PMC
January 2019
7 Reads

Safety pharmacology methods and regulatory considerations evolve together.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:1-6. Epub 2018 Jun 21.

Cardiovascular Division, Rayne Institute, St Thomas' Hospital, London SE17EH, UK.

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http://dx.doi.org/10.1016/j.vascn.2018.06.004DOI Listing
June 2018
8 Reads

Decreased contractility and altered responses to inotropic agents in myocytes from tachypacing-induced heart failure canines.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:98-107. Epub 2018 Jun 14.

Integrated Discovery and Safety Pharmacology, Amgen. Inc., Thousand Oaks, CA 91320, United States.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.06.001DOI Listing
January 2019
2 Reads

Evaluation of warming devices for lateral tail vein blood collection in mice (Mus musculus).

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):87-93. Epub 2018 Jun 15.

Department of Comparative Medicine, Pfizer Inc, Cambridge, MA, United States.

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http://dx.doi.org/10.1016/j.vascn.2018.06.002DOI Listing
June 2018
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Photothrombotically induced unilateral selective hippocampal ischemia in rat.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):77-86. Epub 2018 Jun 12.

Laser and Plasma Research Institute, Shahid Beheshti University, Tehran, Iran.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.06.003DOI Listing
December 2018
16 Reads