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https://www.readbyqxmd.com/read/29758944/the-conundrum-of-gsk3-inhibitors-is-it-the-dawn-of-a-new-beginning
#1
Ratan V Bhat, Ulf Andersson, Shalini Andersson, Laurent Knerr, Udo Bauer, Anna Sundgren Andersson
Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials...
May 11, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29755536/preclinical-study-of-ibuprofen-loaded-transnasal-mucoadhesive-microemulsion-for-neuroprotective-effect-in-mptp-mice-model
#2
Surjyanarayan Mandal, Snigdha Das Mandal, Krishna Chuttani, Krutika K Sawant, Bharat Bhushan Subudhi
Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM)...
2018: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/29742447/the-discovery-of-nitro-fatty-acids-as-products-of-metabolic-and-inflammatory-reactions-and-mediators-of-adaptive-cell-signaling
#3
REVIEW
Bruce A Freeman, Valerie B O'Donnell, Francisco J Schopfer
Foundational advances in eicosanoid signaling, the free radical biology of oxygen and nitric oxide and mass spectrometry all converged to enable the discovery of nitrated unsaturated fatty acids. Due to the unique biochemical characteristics of fatty acid nitroalkenes, these species undergo rapid and reversible Michael addition of biological nucleophiles such as cysteine, leading to the post-translational modification of low molecular weight and protein thiols. This capability has led to the present understanding that nitro-fatty acid reaction with the alkylation-sensitive cysteine proteome leads to physiologically-beneficial alterations in transcriptional regulatory protein function, gene expression and in vivo rodent model responses to metabolic and inflammatory stress...
May 6, 2018: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/29729263/enhanced-endocannabinoid-tone-as-a-potential-target-of-pharmacotherapy
#4
REVIEW
Marek Toczek, Barbara Malinowska
The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms. Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases...
May 2, 2018: Life Sciences
https://www.readbyqxmd.com/read/29723251/spatiotemporal-assessment-of-spontaneous-metastasis-formation-using-multimodal-in-vivo-imaging-in-her2-and-triple-negative-metastatic-breast-cancer-xenograft-models-in-mice
#5
Inga B Fricke, Raquel De Souza, Lais Costa Ayub, Giulio Francia, Robert Kerbel, David A Jaffray, Jinzi Zheng
BACKGROUND: Preclinical breast cancer models recapitulating the clinical course of metastatic disease are crucial for drug development. Highly metastatic cell lines forming spontaneous metastasis following orthotopic implantation were previously developed and characterized regarding their biological and histological characteristics. This study aimed to non-invasively and longitudinally characterize the spatiotemporal pattern of metastasis formation and progression in the MDA-MB-231-derived triple negative LM2-4 and HER2+ LM2-4H2N cell lines, using bioluminescence imaging (BLI), contrast enhanced computed tomography (CT), fluorescence imaging, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography ([18F]FDG-PET)...
2018: PloS One
https://www.readbyqxmd.com/read/29710775/novel-ex-vivo-human-osteochondral-explant-model-of-knee-and-spine-osteoarthritis-enables-assessment-of-inflammatory-and-drug-treatment-responses
#6
Jeroen Geurts, Doria Jurić, Miriam Müller, Stefan Schären, Cordula Netzer
Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a disease-modifying pharmacological treatment remains an unmet clinical need. A major challenge for drug development includes selection of appropriate preclinical models that accurately reflect clinical phenotypes of human disease. The aim of this study was to establish an ex vivo explant model of human knee and spine osteoarthritis that enables assessment of osteochondral tissue responses to inflammation and drug treatment. Equal-sized osteochondral fragments from knee and facet joints (both n = 6) were subjected to explant culture for 7 days in the presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of transforming growth factor-beta (TGF-β) receptor type I signaling...
April 28, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29702045/positron-emission-tomography-pet-and-pharmacokinetics-classical-blood-sampling-versus-image-derived-analysis-of-18f-faza-and-18f-fdg-in-a-murine-tumor-bearing-model
#7
Hans-Soenke Jans, Xiao-Hong Yang, Dion R Brocks, Piyush Kumar, Melinda Wuest, Leonard I Wiebe
PURPOSE: Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi-quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues...
2018: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29689315/stress-as-risk-factor-for-alzheimer-s-disease
#8
REVIEW
Alessandra Caruso, Ferdinando Nicoletti, Dalila Mango, Amira Saidi, Rosamaria Orlando, Sergio Scaccianoce
Prolonged stress predisposes susceptible individuals to a number of physiological disorders including cardiovascular disease, obesity and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders. Preclinical studies have suggested that manipulation of the glucocorticoid milieu can trigger cellular, molecular and behavioral derangement resembling the hallmarks of Alzheimer's Disease (AD). For example, stress or glucocorticoid administration can increase amyloid ß precursor protein and tau phosphorylation which are involved in synaptic dysfunction and neuronal death associated with AD...
April 21, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29684379/effect-of-a-long-term-treatment-with-metformin-in-dystrophic-mdx-mice-a-reconsideration-of-its-potential-clinical-interest-in-duchenne-muscular-dystrophy
#9
Paola Mantuano, Francesca Sanarica, Elena Conte, Maria Grazia Morgese, Roberta Francesca Capogrosso, Anna Cozzoli, Adriano Fonzino, Angelo Quaranta, Jean-Francois Rolland, Michela De Bellis, Giulia Maria Camerino, Luigia Trabace, Annamaria De Luca
The pharmacological stimulation of AMP-activated protein kinase (AMPK) via metabolic enhancers has been proposed as potential therapeutic strategy for Duchenne muscular dystrophy (DMD). Metformin, a widely-prescribed anti-hyperglycemic drug which activates AMPK via mitochondrial respiratory chain, has been recently tested in DMD patients in synergy with nitric oxide (NO)-precursors, with encouraging results. However, preclinical data supporting the use of metformin in DMD are still poor, and its actions on skeletal muscle appear controversial...
April 20, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29680449/modeling-tumor-growth-inhibition-and-toxicity-outcome-after-administration-of-anticancer-agents-in-xenograft-mice-a-dynamic-energy-budget-deb-approach
#10
N Terranova, E M Tosca, E Borella, E Pesenti, M Rocchetti, P Magni
Host features, such as cell proliferation rates, caloric intake, metabolism and energetic conditions, significantly influence tumor growth; at the same time, tumor growth may have a dramatic impact on the host conditions. For example, in clinics, at certain stages of the tumor growth, cachexia (body weight reduction) may become so relevant to be considered as responsible for around 20% of cancer deaths. Unfortunately, anticancer therapies may also contribute to the development of cachexia due to reduced food intake (anorexia), commonly observed during the treatment periods...
April 19, 2018: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/29662787/steroid-associated-osteonecrosis-animal-model-in-rats
#11
Li-Zhen Zheng, Jia-Li Wang, Ling Kong, Le Huang, Li Tian, Qian-Qian Pang, Xin-Luan Wang, Ling Qin
Objective: Established preclinical disease models are essential for not only studying aetiology and/or pathophysiology of the relevant diseases but more importantly also for testing prevention and/or treatment concept(s). The present study proposed and established a detailed induction and assessment protocol for a unique and cost-effective preclinical steroid-associated osteonecrosis (SAON) in rats with pulsed injections of lipopolysaccharide (LPS) and methylprednisolone (MPS). Methods: Sixteen 24-week-old male Sprague-Dawley rats were used to induce SAON by one intravenous injection of LPS (0...
April 2018: Journal of Orthopaedic Translation
https://www.readbyqxmd.com/read/29662021/roles-of-polyploid-multinucleated-giant-cancer-cells-in-metastasis-and-disease-relapse-following-anticancer-treatment
#12
Razmik Mirzayans, Bonnie Andrais, David Murray
Tumors and tumor-derived cell lines contain polyploid giant cells with significantly elevated genomic content, often with multiple nuclei. The frequency of giant cells can increase markedly following anticancer treatment. Although giant cells enter a dormant phase and therefore do not form macroscopic colonies (aggregates of ≥50 cells) in the conventional in vitro colony formation assay, they remain viable and metabolically active. The purpose of this commentary is to underscore the potential importance of polyploid/multinucleated giant cells in metastasis and cancer recurrence following exposure to anticancer agents...
April 15, 2018: Cancers
https://www.readbyqxmd.com/read/29660405/microbiome-mediated-bile-acid-modification-role-in-intestinal-drug-absorption-and-metabolism
#13
REVIEW
Elaine F Enright, Brendan T Griffin, Cormac G M Gahan, Susan A Joyce
Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research...
April 13, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29655914/importance-of-cynomolgus-monkeys-in-development-of-monoclonal-antibody-drugs
#14
REVIEW
Kazuhide Iwasaki, Yasuhiro Uno, Masahiro Uto, Hiroshi Yamazaki
Animal species used in the preclinical studies for development of monoclonal antibody (mAb) drugs are surveyed in this review. Relevant animal species for preclinical studies of mAb candidates are those express desired epitope of mAb candidates. Cynomolgus monkeys cross-react with mAb drugs much higher than other animal species commonly used in preclinical studies such as absorption, distribution, metabolism and excretion (ADME), efficacy, and toxicity studies, for development of new drugs. Moreover, plasma exposure of the mAb drugs in humans is predicted well from the exposure in the monkeys, and the placental transfer of immunoglobulin G (IgG, all the mAb drugs contain IgG) from mother to fetus is similar between humans and the monkeys from a viewpoint of time course and plasma level of IgG transferred...
March 20, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29655610/structure-based-drug-design-and-in-vitro-metabolism-study-discovery-of-n-4-methylthiophenyl-n-2-dimethyl-cyclopenta-d-pyrimidine-as-a-potent-microtubule-targeting-agent
#15
Weiguo Xiang, Shruti Choudhary, Ernest Hamel, Susan L Mooberry, Aleem Gangjee
We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4'-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC50 values for antiproliferative effects in MDA-MB-435 melanoma cells...
April 4, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29650275/metformin-for-non-small-cell-lung-cancer-patients-opportunities-and-pitfalls
#16
REVIEW
Antonin Levy, Jérôme Doyen
Despite exciting advances of the anticancer armamentarium in the recent years, mortality of non-small cell lung cancer (NSCLC) remains high and novel treatments are requisite. Therapy intensification is explored with promising, but expensive and potentially toxic new compounds. Repositioning already existing drugs for cancer treatment could save money and improve patient outcomes in specific contexts. Observational data suggest that use of the standard antidiabetic agent metformin decreases lung cancer incidence and mortality...
May 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29649683/modulation-of-udp-glucuronidation-by-acridinone-antitumor-agents-c-1305-and-c-1311-in-hepg2-and-ht29-cell-lines-despite-slight-impact-in-noncellular-systems
#17
Anna Bejrowska, Monika Pawłowska, Anna Mróz, Zofia Mazerska
BACKGROUND: Among the studied antitumor acridinone derivatives developed in our laboratory, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) exhibited cytotoxic and antitumor properties against several cancer types and were selected to be evaluated in preclinical and early-phase clinical trials. In the present work, we investigated the impact of C-1305 and C-1311 on UDP-glucuronosyltransferase (UGT) activity...
November 22, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/29628435/dependence-on-the-pyrimidine-biosynthetic-enzyme-dhodh-is-a-synthetic-lethal-vulnerability-in-mutant-kras-driven-cancers
#18
Malvika Koundinya, Judith Sudhalter, Albane Courjaud, Bruno Lionne, Gaetan Touyer, Luc Bonnet, Isabelle Menguy, Isabelle Schreiber, Christelle Perrault, Stephanie Vougier, Brigitte Benhamou, Bailin Zhang, Timothy He, Qiang Gao, Patricia Gee, Daniel Simard, M Paola Castaldi, Ronald Tomlinson, Stephan Reiling, Matthieu Barrague, Richard Newcombe, Hui Cao, Yanjun Wang, Fangxian Sun, Joshua Murtie, Mark Munson, Eric Yang, David Harper, Monsif Bouaboula, Jack Pollard, Claudine Grepin, Carlos Garcia-Echeverria, Hong Cheng, Francisco Adrian, Christopher Winter, Stuart Licht, Ivan Cornella-Taracido, Rosalia Arrebola, Aaron Morris
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH)...
April 3, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29626440/in-vivo-and-in-vitro-diclofenac-5-hydroxylation-mediated-primarily-by-cytochrome-p450-3a-enzymes-in-common-marmoset-livers-genotyped-for-p450-2c19-variants
#19
Kazuyuki Nakanishi, Shotaro Uehara, Takashi Kusama, Takashi Inoue, Kanami Shimura, Yusuke Kamiya, Norie Murayama, Makiko Shimizu, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4'-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models...
April 4, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29626326/development-of-a-physiologically-based-pharmacokinetic-model-for-sinogliatin-a-first-in-class-glucokinase-activator-by-integrating-allometric-scaling-in-vitro-to-in-vivo-exploration-and-steady-state-concentration-mean-residence-time-methods-mechanistic-understanding
#20
Ling Song, Yi Zhang, Ji Jiang, Shuang Ren, Li Chen, Dongyang Liu, Xijing Chen, Pei Hu
AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css -MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css -MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms...
April 6, 2018: Clinical Pharmacokinetics
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