1,710 results match your criteria Journal of Pharmacological and Toxicological Methods [Journal]


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

J Pharmacol Toxicol Methods 2019 Feb 16. 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

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

J Pharmacol Toxicol Methods 2019 Feb 15. 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
2 Reads

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

J Pharmacol Toxicol Methods 2019 Feb 6;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
1 Read

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 Feb 7;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

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

J Pharmacol Toxicol Methods 2019 Feb 6;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 Jan 30;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 Jan 23;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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January 2019
1 Read

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

J Pharmacol Toxicol Methods 2018 Dec 27;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
6 Reads

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

J Pharmacol Toxicol Methods 2018 Dec 22;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
5 Reads

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

J Pharmacol Toxicol Methods 2018 Dec 21;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

Assessing the risk of drug crystallization in vivo.

J Pharmacol Toxicol Methods 2018 Dec 13;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
3 Reads

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

J Pharmacol Toxicol Methods 2018 Dec 13;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
2 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
December 2018

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
November 2018
2 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
November 2018
14 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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November 2018
1 Read

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
November 2018
11 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
November 2018
7 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
November 2018
15 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
November 2018
9 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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November 2018

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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November 2018
10 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
September 2018
10 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
September 2018
7 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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September 2018
17 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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August 2018
10 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
August 2018
1 Read

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
August 2018
15 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
August 2018
2 Reads

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
5 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

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
10 Reads

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
21 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
5 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
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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

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
14 Reads

Challenges in implementing and obtaining acceptance for J-Tpeak assessment as the clinical component of CiPA.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:75-79. Epub 2018 Jun 4.

iCardiac Technologies, Inc., Rochester, NY, USA; Heart Research Follow-up Program, University of Rochester Medical Center, Rochester, NY, USA.

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10568719183058
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http://dx.doi.org/10.1016/j.vascn.2018.05.006DOI Listing
January 2019
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Quantitation of sevoflurane in whole blood and aqueous solutions by volatile organic compound sensing.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):71-76. Epub 2018 Jun 1.

Department of Dental Anesthesiology, Faculty of Dental Medicine, Hokkaido University, Kita 13 Nishi 7, Kita-ku, Sapporo, Hokkadido 060-8586, Japan. Electronic address:

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).

Methods: The concentrations of a volatile general anesthetic (sevoflurane) in aqueous solutions containing human blood components and rabbit blood were measured using a VOC sensor and those in distilled water and phosphatidylcholine suspension were compared to those determined by NMR. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.05.005DOI Listing
December 2018
18 Reads

A non-radioactive in vitro CaMKII activity assay using HPLC-MS.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):64-70. Epub 2018 May 24.

Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Campbell University, Buies Creek, NC 27506, USA. Electronic address:

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-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). Read More

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http://dx.doi.org/10.1016/j.vascn.2018.05.004DOI Listing
December 2018
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The use of human tissue in safety assessment.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:29-34. Epub 2018 May 9.

The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), Gibbs Building, 215 Euston Road, London NW1 2BE, United Kingdom. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.05.003DOI Listing
January 2019
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A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):50-63. Epub 2018 May 8.

Drug Safety Assessment, MPI Research (A Charles Rivers Company), Mattawan, MI, United States.

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. This review is about "ictogenesis" not "epileptogenesis". Read More

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http://dx.doi.org/10.1016/j.vascn.2018.05.002DOI Listing
December 2018
1 Read

A real time screening assay for cannabinoid CB1 receptor-mediated signaling.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):44-49. Epub 2018 May 4.

Department of Pharmacology, Physiology & Neuroscience, University of South Carolina, School of Medicine, Columbia, SC, United States. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.05.001DOI Listing
December 2018
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Comparison of one- and three-lead ECG to measure cardiac intervals and differentiate drug-induced multi-channel block.

J Pharmacol Toxicol Methods 2018 Sep - Oct;93:80-89. Epub 2018 Apr 25.

The Ohio State University and QTest Labs, Columbus, OH, United States.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.04.004DOI Listing
January 2019
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Short-term oral gavage administration of adenine induces a model of fibrotic kidney disease in rats.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):34-43. Epub 2018 Apr 22.

Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.

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. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.04.003DOI Listing
December 2018
6 Reads

A pharmacology guided approach for setting limits on product-related impurities for bispecific antibody manufacturing.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):19-25. Epub 2018 Apr 13.

Safety Assessment, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:

Introduction: bFKB1 is a humanized bispecific IgG1 antibody, created by conjoining an anti-Fibroblast Growth Factor Receptor 1 (FGFR1) half-antibody to an anti-Klothoβ (KLB) half-antibody, using the knobs-into-holes strategy. bFKB1 acts as a highly selective agonist for the FGFR1/KLB receptor complex and is intended to ameliorate obesity-associated metabolic defects by mimicking the activity of the hormone FGF21. An important aspect of the biologics product manufacturing process is to establish meaningful product specifications regarding the tolerable levels of impurities that copurify with the drug product. Read More

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http://dx.doi.org/10.1016/j.vascn.2018.04.002DOI Listing
December 2018
9 Reads

The rabbit vagina as an in vivo model for vaginal fenticonazole permeability and toxicity.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):14-18. Epub 2018 Apr 7.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil; Galeno Research Unit, Latino Coelho St., 1301, Parque Taquaral, 13087-010 Campinas, SP, Brazil; Faculty of Medical Sciences, São Leopoldo Mandic, São Paulo, Brazil. Electronic address:

Introduction: Vaginal route is often used in topical antifungal formulations. Vaginal permeability assays are generally performed as in vitro tests.

Method: An in vivo vaginal permeability assay was developed using female rabbits. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10568719183000
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http://dx.doi.org/10.1016/j.vascn.2018.04.001DOI Listing
December 2018
25 Reads

Real time monitoring and quantification of reactive oxygen species in breast cancer cell line MCF-7 by 2',7'-dichlorofluorescin diacetate (DCFDA) assay.

J Pharmacol Toxicol Methods 2018 Nov - Dec;94(Pt 1):26-33. Epub 2018 Apr 7.

Department of Medical Biotechnology, College of Medicine and Public Health, Flinders University, Adelaide, SA 5052, Australia. Electronic address:

The detection of reactive oxygen species (ROS) using 2',7'-dichlorofluorescin diacetate (DCFDA) is commonly performed by a single measurement of fluorescence but this fails to capture a profile of ROS generation over time. This study aimed to develop a real-time monitoring method to increase the utility of the assay, to incorporate cytotoxicity screening and to describe the combined effects of DCFDA and the ROS generator, Ter-butyl hydrogen peroxide (TBHP). Breast cancer MCF-7 cells were loaded with DCFDA (0-50 μM) for 45 min, and then exposed to TBHP (0-50 μM). Read More

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http://dx.doi.org/10.1016/j.vascn.2018.03.007DOI Listing
December 2018
4 Reads