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Journal of Pharmacological and Toxicological Methods

Christinna V Jørgensen, Hong Zhou, Markus J Seibel, Hans Bräuner-Osborne
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...
April 1, 2019: Journal of Pharmacological and Toxicological Methods
H M Himmel, A Delaunois, M Deurinck, T Dinklo, T M Eriksson Faelker, C Habermann, C Heers, K Hempel, H Lorenz, A Rosch, H Schauerte, G Teuns, M Traebert, C van Amsterdam, H van der Linde
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...
March 27, 2019: Journal of Pharmacological and Toxicological Methods
Simon Authier, Joseph Arezzo, Mylène Pouliot, Michael V Accardi, Emmanuel Boulay, Eric Troncy, Michelle Dubuc Mageau, Wendy Tan, Audrey Sanfacon, Stephanie Mignault Goulet, Dominique Paquette
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). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%)...
March 25, 2019: Journal of Pharmacological and Toxicological Methods
Kata Kozma, Ferenc Kassai, Aliz J Ernyey, István Gyertyán
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. Conditioning took place first with naive-naive pairs, then with naive-experienced and finally with experienced-experienced pairs, when the task was familiar for both rats...
March 22, 2019: Journal of Pharmacological and Toxicological Methods
Ala A Alhusban, Ola A Tarawneh, Sanabel O Dawabsheh, Ahmad A Alhusban, Feras W Abumhareb
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. However, the selection of a single entity and proper regimen is not specified in medical guidelines. The objective of this study is to develop a rapid and selective simultaneous high-performance liquid chromatography-tandem mass spectroscopic method to explore the bioavailability of 4 fluoroquinolones, including 0...
March 20, 2019: Journal of Pharmacological and Toxicological Methods
David V Gauvin, Zachary J Zimmermann
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...
March 15, 2019: Journal of Pharmacological and Toxicological Methods
Shinichi Sato
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. The MDEP sensor is a rectangular plate with 15 gold-plated stripe pattern electrodes, on which a mouse can walk around freely, and detects ECG whenever ≥2 paws (footpads) come in contact with the electrodes...
March 14, 2019: Journal of Pharmacological and Toxicological Methods
David V Gauvin, Zachary J Zimmermann, Mary Jeanne Kallman
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...
February 21, 2019: Journal of Pharmacological and Toxicological Methods
Yusuke Yamamoto, Sayaka Wanibuchi, Masaharu Fujita, Yasuhiro Katsuoka, Atsushi Ono, Toshihiko Kasahara
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...
February 20, 2019: Journal of Pharmacological and Toxicological Methods
Cecelia Jackson, Cherish Ardinger, Kristin M Winter, John H McDonough, Hilary S McCarren
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...
February 18, 2019: Journal of Pharmacological and Toxicological Methods
Matt Skinner, Peter Ceuppens, Peter White, Helen Prior
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...
February 16, 2019: Journal of Pharmacological and Toxicological Methods
Masaharu Fujira, Yusuke Yamamoto, Sayaka Wanibuchi, Yasuhiro Katsuoka, Toshihiko Kasahara
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...
February 15, 2019: Journal of Pharmacological and Toxicological Methods
Xiuying Ma, Shahid Tannu, John Allocco, Jie Pan, Janet Dipiero, Pancras Wong
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...
February 6, 2019: Journal of Pharmacological and Toxicological Methods
Chang-Ning Liu, Jeffrey Morin, Melba Dokmanovich, Crystal T Bluette, Richard Goldstein, Balasubramanian Manickam, Cedo M Bagi
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. Phagocytosis and accumulation of the contrast agent by Kupffer cells in the liver, as well as macrophages in the spleen, increase the soft tissue X-ray attenuation for up to 6 months...
February 6, 2019: Journal of Pharmacological and Toxicological Methods
Mirjana Malnar, Tadeja Režen
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...
February 6, 2019: Journal of Pharmacological and Toxicological Methods
Luis F Díaz-Peña, Alejandro García-Arredondo, Juan R Riesgo-Escovar
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. There is also no guarantee that the effects observed in the bioassay reflect the true nature of the venom's intended effects, as the animals used for assessment might not be the prey items to which the venom has evolved. METHODS: We harvested tarantula venoms from the Indian Poecilotheria regalis and the Mexican Bonnetina papalutlensis using light anesthesia and electrical stimulation...
January 30, 2019: Journal of Pharmacological and Toxicological Methods
Sapana P Bansod, Amit Khurana, Chandraiah Godugu
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. The severity of damage was assessed by biochemical assays and histopathology. The expression of pro-inflammatory cytokine and fibrotic proteins was assessed by IHC and western blotting...
January 23, 2019: Journal of Pharmacological and Toxicological Methods
Anna Šuláková, Lucie Fojtíková, Barbora Holubová, Kateřina Bártová, Oldřich Lapčík, Martin Kuchař
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. Therefore, simple, cost-effective and reliable methods are needed for rapid determination of abused hallucinogens...
January 2019: Journal of Pharmacological and Toxicological Methods
Lydmila Kazavchinsky, Anat Dafna, Haim Einat
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. One of the frequently used models for screening antidepressants and interventions related to depression is the forced swim test (FST)...
January 2019: Journal of Pharmacological and Toxicological Methods
Akihito Yamashita, Jiro Deguchi, Yayoi Honda, Toru Yamada, Izuru Miyawaki, Yuhei Nishimura, Toshio Tanaka
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. In this study, we established zebrafish deficient in the nuclear factor erythroid 2-related factor 2a (nrf2a), a key antioxidant-responsive gene, and its potential to detect oxidative stress-mediated toxicity was examined...
December 27, 2018: Journal of Pharmacological and Toxicological Methods
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