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drug metabolism, preclinical

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https://www.readbyqxmd.com/read/28221362/disrupted-iron-regulation-in-the-brain-and-periphery-in-cocaine-addiction
#1
K D Ersche, J Acosta-Cabronero, P S Jones, H Ziauddeen, R P L van Swelm, C M M Laarakkers, R Raha-Chowdhury, G B Williams
Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery...
February 21, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28220713/the-influence-of-targeted-temperature-management-on-the-pharmacokinetics-of-drugs-administered-during-and-after-cardiac-arrest-a-systematic-review
#2
Tessa Crombez, Said Hachimi-Idrissi
OBJECTIVE: Pharmacokinetic parameters of drugs are widely investigated under normothermic conditions and normal hemodynamic parameters. The European Resuscitation Council recommends the use of targeted temperature management (TTM) with a target temperature of 34 °C in cardiac arrest (CA) patients. The aim of this literature review is to investigate the influence of CA combined with TTM on the pharmacokinetics of drugs. Results of preclinical and clinical studies are compared with each other...
February 21, 2017: Acta Clinica Belgica
https://www.readbyqxmd.com/read/28213330/drug-discovery-strategies-in-the-field-of-tumor-energy-metabolism-limitations-by-metabolic-flexibility-and-metabolic-resistance-to-chemotherapy
#3
REVIEW
N D Amoedo, E Obre, R Rossignol
The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28196306/effects-of-isoflurane-anesthesia-and-intravenous-morphine-self-administration-on-regional-glucose-metabolism-18-f-fdg-pet-of-male-sprague-dawley-rats
#4
Thomas Y Park, Kevin S Nishida, Colin M Wilson, Shalini Jaiswal, Jessica Scott, Andrew R Hoy, Reed G Selwyn, Bernard J Dardzinski, Kwang H Choi
Although certain drugs of abuse are known to disrupt brain glucose metabolism (BGluM), the effects of opiates on BGluM are not well characterized. Moreover, preclinical positron emission tomography (PET) studies anesthetize animals during the scan, which limits clinical applications. We investigated the effects of 1) isoflurane anesthesia and 2) intravenous morphine self-administration (MSA) on BGluM in rats. Jugular vein cannulated adult male Sprague-Dawley rats self-administered either saline (SSA) or morphine (0...
February 14, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28191664/direct-arterial-injection-of-hyperpolarized-13-c-labeled-substrates-into-rat-tumors-for-rapid-mr-detection-of-metabolism-with-minimal-substrate-dilution
#5
Steven Reynolds, Stephen Metcalf, Edward J Cochrane, Rebecca C Collins, Simon Jones, Martyn N J Paley, Gillian M Tozer
PURPOSE: A rat model was developed to enable direct administration of hyperpolarized (13) C-labeled molecules into a tumor-supplying artery for magnetic resonance spectroscopy (MRS) studies of tumor metabolism. METHODS: Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized (13) C-molecules were either infused directly to the tumor through the epigastric artery or systemically through the contralateral femoral vein...
February 12, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28190577/dilated-cardiomyopathy
#6
REVIEW
Robert G Weintraub, Christopher Semsarian, Peter Macdonald
Dilated cardiomyopathy is defined by the presence of left ventricular dilatation and contractile dysfunction. Genetic mutations involving genes that encode cytoskeletal, sarcomere, and nuclear envelope proteins, among others, account for up to 35% of cases. Acquired causes include myocarditis and exposure to alcohol, drugs and toxins, and metabolic and endocrine disturbances. The most common presenting symptoms relate to congestive heart failure, but can also include circulatory collapse, arrhythmias, and thromboembolic events...
February 9, 2017: Lancet
https://www.readbyqxmd.com/read/28179883/new-microrna-biomarkers-for-drug-induced-steatosis-and-their-potential-to-predict-the-contribution-of-drugs-to-non-alcoholic-fatty-liver-disease
#7
Mireia López-Riera, Isabel Conde, Laia Tolosa, Ángela Zaragoza, José V Castell, María J Gómez-Lechón, Ramiro Jover
Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28176881/functional-coupling-of-human-microphysiology-systems-intestine-liver-kidney-proximal-tubule-blood-brain-barrier-and-skeletal-muscle
#8
Lawrence Vernetti, Albert Gough, Nicholas Baetz, Sarah Blutt, James R Broughman, Jacquelyn A Brown, Jennifer Foulke-Abel, Nesrin Hasan, Julie In, Edward Kelly, Olga Kovbasnjuk, Jonathan Repper, Nina Senutovitch, Janet Stabb, Catherine Yeung, Nick C Zachos, Mark Donowitz, Mary Estes, Jonathan Himmelfarb, George Truskey, John P Wikswo, D Lansing Taylor
Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media...
February 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28167510/preclinical-development-of-a-non-toxic-oral-formulation-of-monoethanolamine-a-lipid-precursor-for-prostate-cancer-treatment
#9
Roopali Saxena, Chunhua Yang, Mukkavilli Rao, Ravi Chakra C Turaga, Chakravarthy Garlapati, Sushma Reddy Gundala, Kimberly Myers, Ahmed Ghareeb, Shristi Bhattarai, Golnaz Kamilinia, Sangina Bristi, Dan Su, Giovanni Gadda, Padmashree Cg Rida, Guilherme Cantuaria, Ritu Aneja
PURPOSE: Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory...
February 6, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28165728/hepatoprotective-effect-of-%C3%AF-glutathione-in-a-murine-model-of-acetaminophen-induced-liver-toxicity
#10
Swati S More, Jaime Nugent, Ashish P Vartak, Steffan M Nye, Robert Vince
Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios...
February 16, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28161274/valproate-acid-vpa-induced-dysmetabolic-function-in-clinical-and-animal-studies
#11
Rong Li, Lisheng Liang, Xinmou Wu, Xianli Ma, Min Su
BACKGROUND: Valproate acid (VPA), a commonly used antiepileptic medicine, is found to be linked to developing dysmetabolic risk. However, the proposed mechanism remains completely unknown. METHODS: In this study, we collected data from patients with epilepsy and further investigated the preclinical study in mice. RESULTS: As results, the clinical data showed that VPA-used patients resulted in higher levels of blood glucose, urine acid, triglyceride (TG), and immune cells (leucocyte, neutrophil leucocyte) when compared to clinically diagnosed references, while circulating apolipoprotein A1 (Apob A1) and fatty acid binding protein 4 (FABP4) were reduced without visible drug-induced liver injury (DILI)...
February 2, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28152562/a-comparative-evaluation-of-models-to-predict-human-intestinal-metabolism-from-nonclinical-data
#12
Estelle Yau, Carl Petersson, Hugues Dolgos, Sheila Annie Peters
Extensive gut metabolism is often associated with the risk of low and variable bioavailability. Prediction of the fraction of drug escaping gut wall metabolism as well as transporter-mediated secretion (Fg ) has been challenged by the lack of appropriate preclinical models. The purpose of this study is to compare the performance of models that are widely employed in the pharmaceutical industry today to estimate Fg , and based on the outcome to provide recommendations for the prediction of human Fg during drug discovery and early drug development...
February 2, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28145791/human-plasma-metabolic-profiles-of-benzydamine-a-flavin-containing-monooxygenase-probe-substrate-simulated-with-pharmacokinetic-data-from-control-and-humanized-liver-mice
#13
Miho Yamazaki-Nishioka, Makiko Shimizu, Hiroshi Suemizu, Megumi Nishiwaki, Marina Mitsui, Hiroshi Yamazaki
1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine...
February 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28139372/in%C3%A2-vitro-ocular-metabolism-and-bioactivation-of-ketoconazole-in-rat-rabbit-and-human
#14
Amanda L Cirello, Jennifer L Dumouchel, Mithat Gunduz, Christine E Dunne, Upendra A Argikar
Oral ketoconazole is clinically administered for treatment of severe cases for fungal keratitis. Pharmacodynamics and efficacy of oral and topical (ocular) ketoconazole have been explored in rabbit. However, metabolism of ketoconazole in the eye in any species is not well explored in any preclinical species or human. An understanding of ocular drug metabolism in the eye is crucial for ocular therapeutics to facilitate the risk assessment and development of potential drug candidates for the clinic. We aimed to investigate the metabolism of ketoconazole in rat, rabbit and human ocular S9 fractions...
November 19, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28138743/an-efficient-liquid-chromatography-high-resolution-mass-spectrometry-approach-for-the-optimization-of-the-metabolic-stability-of-therapeutic-peptides
#15
Simone Esposito, Riccardo Mele, Raffaele Ingenito, Elisabetta Bianchi, Fabio Bonelli, Edith Monteagudo, Laura Orsatti
In drug discovery, there is increasing interest in peptides as therapeutic agents due to several appealing characteristics that are typical of this class of compounds, including high target affinity, excellent selectivity, and low toxicity. However, peptides usually present also some challenging ADME (absorption, distribution, metabolism, and excretion) issues such as limited metabolic stability, poor oral bioavailability, and short half-lives. In this context, early preclinical in vitro studies such as plasma metabolic stability assays are crucial to improve developability of a peptidic drug...
January 30, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28138152/it-s-all-druggable
#16
EDITORIAL
(no author information available yet)
Current medicines are small chemicals that target the activity of proteins in the body, resulting in therapeutic and off-target changes in metabolism and gene expression. Now, however, gene expression levels can be raised or lowered at almost any point in the genome by sequence-targeted therapeutics, and the effects of these agents can be tested in preclinical models generated by gene editing of experimental animals and human cells. Genome-wide association studies (GWAS) of disease predisposition, metabolism and gene expression have a key role in explaining how current protein-targeting drugs work and in using the regulatory variation in human genomes to guide the therapeutic future of targeted gene regulation...
January 31, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28137721/transcriptional-functional-and-mechanistic-comparisons-of-stem-cell-derived-hepatocytes-heparg-cells-and-3d-human-hepatocyte-spheroids-as-predictive-in-vitro-systems-for-drug-induced-liver-injury
#17
Catherine C Bell, Volker M Lauschke, Sabine U Vorrink, Henrik Palmgren, Roger Duffin, Tommy B Andersson, Magnus Ingelman-Sundberg
Reliable and versatile hepatic in vitro systems for the prediction of drug pharmacokinetics and toxicity are essential constituents of preclinical safety assessment pipelines for new medicines. Here, we compared three emerging cell systems, hepatocytes derived from induced pluripotent stem cells (hiPS-Hep), HepaRG cells and 3D primary human hepatocyte (PHH) spheroids at transcriptional and functional levels in a multi-center study to evaluate their potential as predictive models for drug-induced hepatotoxicity...
January 30, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28131847/inhibition-of-11%C3%AE-hydroxysteroid-dehydrogenase-2-by-the-fungicides-itraconazole-and-posaconazole
#18
Katharina R Beck, Murielle Bächler, Anna Vuorinen, Sandra Wagner, Muhammad Akram, Ulrich Griesser, Veronika Temml, Petra Klusonova, Hideaki Yamaguchi, Daniela Schuster, Alex Odermatt
Impaired 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)-dependent cortisol inactivation can lead to electrolyte dysbalance, hypertension and cardiometabolic disease. Furthermore, placental 11β-HSD2 essentially protects the fetus from high maternal glucocorticoid levels, and its impaired function has been associated with altered fetal growth and a higher risk for cardio-metabolic diseases in later life. Despite its important role, 11β-HSD2 is not included in current off-target screening approaches. To identify potential 11β-HSD inhibitors amongst approved drugs, a pharmacophore model was used for virtual screening, followed by biological assessment of selected hits...
January 25, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28119362/lkb1-expression-correlates-with-increased-survival-in-advanced-non-small-cell-lung-cancer-patients-treated-with-chemotherapy-and-bevacizumab
#19
Laura Bonanno, Angela De Paoli, Elisabetta Zulato, Giovanni Esposito, Fiorella Calabrese, Adolfo Favaretto, Antonio Santo, Alessandro Del Conte, Marco Chilosi, Francesco Oniga, Gabriella Sozzi, Massimo Moro, Francesco Ciccarese, Giorgia Nardo, Roberta Bertorelle, Cinzia Candiotto, Gian Luca De Salvo, Alberto Amadori, PierFranco Conte, Stefano Indraccolo
PURPOSE: LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC). EXPERIMENTAL DESIGN: We retrospectively analyzed LKB1 expression by immunohistochemistry in 98 samples out of 125 aNSCLC patients, including 59 patients treated with chemotherapy (CT) and 39 treated with CT plus bevacizumab...
January 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28115222/discovery-and-development-of-pyrotinib-anovel-irreversible-egfr-her2-dual-tyrosine-kinase-inhibitor-with-favorable-safety-profiles-for-the-treatment-of-breast-cancer
#20
Xin Li, Changyong Yang, Hong Wan, Ge Zhang, Jun Feng, Lei Zhang, Xiaoyan Chen, Dafang Zhong, Liguang Lou, Weikang Tao, Lianshan Zhang
The discovery and development of a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor SHR1258 (pyrotinib) for the treatment of HER2-postive breast cancer is presented. The structure-activity relationship of lead series and their pharmacokinetic properties were evaluated to identify the potential candidates for further in vivo efficacy studies and preclinical safety assessments. Metabolic pathway and drug-drug interaction were also investigated in preclinical settings. In particular, major metabolites in human and animal species were assessed with regard to potential toxicity or off-target side effects...
January 20, 2017: European Journal of Pharmaceutical Sciences
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