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https://www.readbyqxmd.com/read/27909650/pbpk-modeling-and-simulation-in-drug-research-and-development
#1
REVIEW
Xiaomei Zhuang, Chuang Lu
Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development...
September 2016: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/27903235/erythropoietin-enhances-the-cytotoxic-effect-of-hydrogen-peroxide-on-colon-cancer-cells
#2
Tankiewicz-Kwedlo Anna, Hermanowicz Justyna Magdalena, Surażynski Arkadiusz, Kwedlo Wojciech, Rożkiewicz Dariusz, Pawlak Krystyna, Domaniewski Tomasz, Pawlak Dariusz
BACKGROUND: Cancer patients treated with alkylating agents and radiotherapy are exposed to high level of reactive oxygen species (ROS) in tissues. ROS can involve superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide and hydrogen peroxide. It is well documented that increased exposure to oxygen through a high metabolic rate could lead to a shortened life span. Ionizing radiation, use of drugs and the development of cancer can lead to cancer-induced anemia. Recombinant human erythropoietin (Epo) supplementation is one of the methods for treating anemia...
November 15, 2016: Current Pharmaceutical Biotechnology
https://www.readbyqxmd.com/read/27901175/adme-studies-and-preliminary-safety-pharmacology-of-ldt5-a-lead-compound-for-the-treatment-of-benign-prostatic-hyperplasia
#3
F Noël, J B Nascimento-Viana, L A S Romeiro, R O Silva, L F N Lemes, A S Oliveira, T B S Giorno, P D Fernandes, C L M Silva
This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells...
2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/27888307/monitoring-doxorubicin-cellular-uptake-and-trafficking-using-in-vitro-raman-microspectroscopy-short-and-long-time-exposure-effects-on-lung-cancer-cell-lines
#4
Zeineb Farhane, Franck Bonnier, Hugh J Byrne
Raman microspectroscopy is a non-invasive, in vitro analytical tool which is being increasingly explored for its potential in clinical applications and monitoring the uptake, mechanism of action and cellular interaction at a molecular level of chemotherapeutic drugs, ultimately as a potential label-free preclinical screening and companion diagnostic tool. In this study, doxorubicin (DOX), a "gold standard" chemotherapeutic drug, is employed as a model in the in vitro lung cancer cell line A549 in order to demonstrate the potential of Raman microspectroscopy to screen and identify spectroscopic markers of its trafficking and mechanism of action...
November 25, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27882460/development-of-a-specific-substrate-inhibitor-panel-liver-on-a-chip-for-evaluation-of-cytochrome-p450-activity
#5
A A Zakhariants, O A Burmistrova, M Y Shkurnikov, A A Poloznikov, D A Sakharov
We developed a cytochrome P450 substrate-inhibitor panel for preclinical in vitro evaluation of drugs in a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). The concentrations of substrates and inhibitors were optimized to ensure reliable detection of the principal metabolites by HPLC-mass-spectroscopy. The selected specific substrate-inhibitor pairs, namely bupropion/2-phenyl-2-(1-piperidinyl)propane) for evaluation of CYP2B6B activity, tolbutamide/sulfaphenazole for CYP2C9, omeprazole/(+)-N-benzylnirvanol for CYP2C19, and testosterone/ketoconazole for CYP3A4, enable reliable evaluation of the drug metabolism pathway...
November 23, 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27872127/targeting-cancer-metabolism-dietary-and-pharmacologic-interventions
#6
REVIEW
Claudio Vernieri, Stefano Casola, Marco Foiani, Filippo Pietrantonio, Filippo de Braud, Valter Longo
: Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacologic approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs, and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies...
December 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27863668/nanotechnologies-for-the-treatment-of-colon-cancer-from-old-drugs-to-new-hope
#7
Larissa Kotelevets, Eric Chastre, Didier Desmaële, Patrick Couvreur
Colorectal cancer is a wide-reaching health problem due to its incidence and to the high mortality rates. Adjuvant chemotherapies have considerably improved the prognosis and/or the overall survival of patients with locally advanced and metastatic cancers. Nevertheless, their efficiency remains limited due to intrinsic and emerging multidrug resistance (MDR) of cancer cells, and to major adverse effects and dose limiting toxicities. The present review discusses the knowledge of clinically relevant mechanisms of resistance to cytotoxic and targeted therapies for the treatment of colorectal cancer, and focuses on the benefit of nanomedicine approach to circumvent these processes...
November 30, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27849439/liver-proteome-in-diabetes-type-1-rat-model-insulin-dependent-and-independent-changes
#8
Camila Pereira Braga, Cory H T Boone, Ryan A Grove, Dana Adamcova, Ana Angélica Henrique Fernandes, Jiri Adamec, Pedro de Magalhães Padilha
Diabetes mellitus type 1 (DM1) is a major public health problem that continues to burden the healthcare systems worldwide, costing exponentially more as the epidemic grows. Innovative strategies and omics system diagnostics for earlier diagnosis or prognostication of DM1 are essential to prevent secondary complications and alleviate the associated economic burden. In a preclinical study design that involved streptozotocin (STZ)-induced DM1, insulin-treated STZ-induced DM1, and control rats, we characterized the insulin-dependent and -independent changes in protein profiles in liver samples...
November 16, 2016: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/27847844/potential-role-of-local-estrogen-in-enhancement-of-fracture-healing-preclinical-study-in-rabbits
#9
Mohammad Tahami, Behrooz Haddad, Armin Abtahian, Ali Hashemi, Amir Aminian, Sujith Konan
BACKGROUND: Effects of estrogen on bone metabolism and its protective role on prevention of osteoporosis are well documented. However, the efficacy of estrogen treatment on bone healing is not well investigated. The drug can be delivered both systemically or locally to the bone with differences in concentrations and side effects. The aim of this study was to investigate the effect of local and systemic administration of estrogen on the fracture healing process. METHODS: Standardized tibial fractures with 4 millimeter gaps were created in twenty four adult male Dutch rabbits...
October 2016: Archives of Bone and Joint Surgery
https://www.readbyqxmd.com/read/27843803/randomized-phase-ii-study-of-duligotuzumab-mehd7945a-vs-cetuximab-in-squamous-cell-carcinoma-of-the-head-and-neck-mehgan-study
#10
Jérôme Fayette, Lori Wirth, Cristina Oprean, Anghel Udrea, Antonio Jimeno, Danny Rischin, Christopher Nutting, Paul M Harari, Tibor Csoszi, Dana Cernea, Paul O'Brien, William D Hanley, Amy V Kapp, Maria Anderson, Elicia Penuel, Bruce McCall, Andrea Pirzkall, Jan B Vermorken
BACKGROUND: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. METHODS: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27830575/neuropharmacology-of-3-4-methylenedioxypyrovalerone-mdpv-its-metabolites-and-related-analogs
#11
Michael H Baumann, Mohammad O Bukhari, Kurt R Lehner, Sebastien Anizan, Kenner C Rice, Marta Concheiro, Marilyn A Huestis
3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects...
November 10, 2016: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/27786597/targeting-cardiac-natriuretic-peptides-in-the-therapy-of-diabetes-and-obesity
#12
Cedric Moro
Atrial and B-type Natriuretic Peptides (NP) are cardiac hormones with potent cardiovascular and metabolic effects. They signal through the NPRA/cGMP system and are inactivated by a clearance receptor NPRC and neutral endopeptidases (NEP). Recombinant ANP and BNP are currently used as drug treatment for acute decompensated congestive heart failure. Recent literature indicate that a defective NP system is linked to obesity and predict the risk of type 2 diabetes (T2D). Areas covered: This article reviews recent epidemiological, clinical and preclinical evidences that NP system deficiency may be causal of obesity and T2D...
December 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/27784240/biohybrid-membrane-systems-and-bioreactors-as-tools-for-in-vitro-drug-testing
#13
Simona Salerno, Loredana De Bartolo
In drug development, in vitro human model systems are absolutely essential prior to the clinical trials, considering the increasing number of chemical compounds in need of testing, and, keeping in mind that animals cannot predict all the adverse human health effects and reactions, due to the species-specific differences in metabolic pathways. The liver plays a central role in the clearance and biotransformation of chemicals and xenobiotics. In vitro liver model systems by using highly differentiated human cells could have a great impact in preclinical trials...
October 25, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27775354/in-vivo-and-in-vitro-optimization-of-screening-antimalarial-hits-toward-lead-molecules-for-preclinical-development
#14
Tony Fröhlich, Svetlana B Tsogoeva
In order to overcome one of the greatest challenges in malaria treatment, drug resistance, new drug candidates are urgently needed, which should preferably act via novel mechanisms. Successful optimization of a phenotypic screening hit based on a quinoline-4-carboxamide derivative resulted in the highly promising lead structure 4, which according to the Medicines for Malaria Venture (MMV) met the efficacy and drug metabolism and pharmacokinetics (DMPK) requirements for a malaria drug target candidate and consequently was selected for preclinical development...
October 24, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27770217/partial-adenosine-a1-agonist-in-heart-failure
#15
Wilfried Dinh, Barbara Albrecht-Küpper, Mihai Gheorghiade, Adriaan A Voors, Michael van der Laan, Hani N Sabbah
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels...
October 22, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27759439/drug-induced-steatohepatitis
#16
Ajit Dash, Robert A Figler, Arun J Sanyal, B R Wamhoff
Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH). Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved...
October 19, 2016: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/27750412/differences-in-toxicological-and-pharmacological-responses-mediated-by-polymorphic-cytochromes-p450-and-related-drug-metabolizing-enzymes
#17
Hiroshi Yamazaki
Research over the past 30 years has elucidated the roles of polymorphic human liver cytochrome P450 (P450) enzymes associated with toxicological and/or pharmacological actions. Thalidomide exerts its various pharmacological and toxic actions in primates through multiple mechanisms, including nonspecific modification of many protein networks after bioactivation by autoinduced human P450 enzymes. To overcome species-differences between rodents, currently, nonhuman primates and/or mouse models with transplanted human hepatocytes are used...
October 17, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27749467/agomelatine-a-new-opportunity-to-reduce-neuropathic-pain-preclinical-evidence
#18
Chouki Chenaf, Eric Chapuy, Frédéric Libert, Fabien Marchand, Christine Courteix, Marianne Bertrand, Cecilia Gabriel, Elisabeth Mocaër, Alain Eschalier, Nicolas Authier
Antidepressants are first-line treatments of neuropathic pain but not all of these drugs are really effective. Agomelatine is an antidepressant with a novel mode of action, acting as a MT1/MT2 melatonergic receptor agonist and a 5-HT2C receptor antagonist that involves indirect noradrenaline release. Melatonin, serotonin and noradrenaline have been involved in the pathophysiology of neuropathic pain. Yet no study has been conducted to determine agomelatine effects on neuropathic pain in animal models.Using three rat models of neuropathic pain of toxic (oxaliplatin/OXA), metabolic (streptozocin/STZ) and traumatic (sciatic nerve ligation/CCI) etiologies, we investigated the anti-hypersensitivity effect of acute and repeated agomelatine administration...
October 1, 2016: Pain
https://www.readbyqxmd.com/read/27742642/partnerships-to-design-novel-regimens-to-treat-childhood-tuberculosis-sui-generis-the-road-ahead
#19
Tawanda Gumbo, Mamodikoe K Makhene, James A Seddon
There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development...
November 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/27737930/lack-of-exposure-in-a-first-in-man-study-due-to-aldehyde-oxidase-metabolism-investigated-by-use-of-14c-microdose-humanized-mice-monkey-pharmacokinetics-and-in-vitro-methods
#20
Klaus Gjervig Jensen, Anne-Marie Jacobsen, Christoffer Bundgaard, Dorrit Ostergaard Nilausen, Zia Thale, Gamini Chandrasena, Martin Jorgensen
Inclusion of a microdose of (14)C-labeled drug in the first-in-man study of new investigational drugs and subsequent analysis by accelerator mass spectrometry has become an integrated part of drug development at Lundbeck. It has been found to be highly informative with regards to investigations of the routes and rates of excretion of the drug and the human metabolite profiles according to MIST guidance, and also when additional metabolism related issues needed to be addressed. In the first-in-man study with the NCE Lu AF09535, contrary to anticipated, surprisingly low exposure was observed when measuring the parent compound using conventional bioanalysis...
October 13, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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