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https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#1
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28629389/cancer-chemoprevention-through-dietary-flavonoids-what-s-limiting
#2
REVIEW
Haneen Amawi, Charles R Ashby, Amit K Tiwari
Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e...
June 19, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28592260/recent-advances-in-the-use-of-pi3k-inhibitors-for-glioblastoma-multiforme-current-preclinical-and-clinical-development
#3
REVIEW
Hua-Fu Zhao, Jing Wang, Wei Shao, Chang-Peng Wu, Zhong-Ping Chen, Shing-Shun Tony To, Wei-Ping Li
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism...
June 7, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28570275/long-term-culture-of-human-liver-tissue-with-advanced-hepatic-functions
#4
Soon Seng Ng, Anming Xiong, Khanh Nguyen, Marilyn Masek, Da Yoon No, Menashe Elazar, Eyal Shteyer, Mark A Winters, Amy Voedisch, Kate Shaw, Sheikh Tamir Rashid, Curtis W Frank, Nam Joon Cho, Jeffrey S Glenn
A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus...
June 2, 2017: JCI Insight
https://www.readbyqxmd.com/read/28552479/biopharmaceutic-parameters-pharmacokinetics-transport-and-cyp-mediated-drug-interactions-of-iiim-017-a-novel-nitroimidazooxazole-analogue-with-anti-tuberculosis-activity
#5
Gurleen Kour, Parvinder Pal Singh, Asha Bhagat, Zabeer Ahmed
Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...
May 26, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28552429/prediction-of-renal-transporter-mediated-drug-drug-interactions-for-a-drug-which-is-an-oat-substrate-and-inhibitor-using-pbpk-modelling
#6
Kathryn Ball, Tanguy Jamier, Yannick Parmentier, Claire Denizot, Agnes Mallier, Marylore Chenel
A PBPK modelling approach was used to predict organic anion transporter (OAT) mediated drug-drug interactions involving S44121, a substrate and an inhibitor of OAT1 and OAT3. Model predictions were then compared to the results of a clinical DDI study which was carried out to investigate the interaction of S44121 with probenecid, tenofovir and ciprofloxacin. PBPK models were developed and qualified using existing clinical data, and inhibition constants were determined in vitro. The model predictions for S44121 as an OAT inhibitor were similar to the results obtained from the clinical DDI study, with no interaction observed for tenofovir or ciprofloxacin in the presence of S44121...
May 25, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28544603/metabolic-reprogramming-of-macrophages-exposed-to-silk-poly-lactic-co-glycolic-acid-and-silica-nanoparticles
#7
Raquel Saborano, Thidarat Wongpinyochit, John D Totten, Blair F Johnston, F Philipp Seib, Iola F Duarte
Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications...
May 8, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28537883/preclinical-characterization-of-abemaciclib-in-hormone-receptor-positive-breast-cancer
#8
Raquel Torres-Guzmán, Bruna Calsina, Ana Hermoso, Carmen Baquero, Beatriz Alvarez, Joaquín Amat, Ann M McNulty, Xueqian Gong, Karsten Boehnke, Jian Du, Alfonso de Dios, Richard P Beckmann, Sean Buchanan, María José Lallena
Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28536862/mechanisms-of-hepatotoxicity-associated-with-the-monocyclic-%C3%AE-lactam-antibiotic-bal30072
#9
Franziska Paech, Simon Messner, Jochen Spickermann, Mathias Wind, Anne-Hortense Schmitt-Hoffmann, Anne Therese Witschi, Brett A Howell, Rachel J Church, Jeff Woodhead, Marc Engelhardt, Stephan Krähenbühl, Martina Maurer
BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations...
May 23, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28536775/catechol-o-methyltransferase-and-udp-glucuronosyltransferases-in-the-metabolism-of-baicalein-in-different-species
#10
Ruiya Zhang, Yonglei Cui, Yan Wang, Xiangge Tian, Lu Zheng, HaiJian Cong, Bin Wu, Xiaokui Huo, Chao Wang, BaoJing Zhang, Xiaobo Wang, Zhonghui Yu
BACKGROUND: Baicalein is the major bioactive flavonoid in some herb medicines and dietary plants; however, the detailed metabolism pathway of its major metabolite oroxylin A-7-O-β-D-glucuronide in human was not clear. It was important to illustrate the major metabolic enzymes that participate in its elimination for the clinic use of baicalein. OBJECTIVES: We first revealed a two-step metabolism profile for baicalein and illustrated the combination of catechol-O-methyltransferase (COMT) and uridine diphosphate-glucuronosyltransferases (UGTs) in drug metabolism, further evaluated its bioactivity variation during drug metabolism...
May 23, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28508321/trpc-channels-and-glioma
#11
Shanshan Li, Xia Ding
Glioma is the most common type of brain tumors and malignant glioma is extremely lethal, with patients' 5-year survival rate less than 10%. Treatment of gliomas poses remarkable clinical challenges, not only because of their particular localization but also because glioma cells possess several malignant biological features, including highly proliferative, highly invasive, highly angiogenic, and highly metabolic aberrant. All these features make gliomas highly recurrent and drug resistant. Finding new and effective molecular drug targets for glioma is an urgent and critical task for both basic and clinical research...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28507103/nicotinic-acid-phosphoribosyltransferase-regulates-cancer-cell-metabolism-susceptibility-to-nampt-inhibitors-and-dna-repair
#12
Francesco Piacente, Irene Caffa, Silvia Ravera, Giovanna Sociali, Mario Passalacqua, Valerio G Vellone, Pamela Becherini, Daniele Reverberi, Fiammetta Monacelli, Alberto Ballestrero, Patrizio Odetti, Antonia Cagnetta, Michele Cea, Aimable Nahimana, Michel A Duchosal, Santina Bruzzone, Alessio Nencioni
In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+ producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature...
May 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28504983/serum-inhibitory-factor-1-high-density-lipoprotein-and-cardiovascular-diseases
#13
Laurent O Martinez, Annelise Genoux, Jean Ferrières, Thibaut Duparc, Bertrand Perret
PURPOSE OF REVIEW: The atheroprotective properties of HDL are supported by epidemiological and preclinical research. However, the results of interventional trials paradoxically indicate that drugs increasing HDL-cholesterol (HDL-C) do not reduce coronary artery disease (CAD) risk. Moreover, Mendelian randomization studies have shown no effect of HDL-C-modifying variants on CAD outcome. Thus, the protective effects of HDL particles are more governed by their functional status than their cholesterol content...
May 12, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28497107/ngp-555-a-%C3%AE-secretase-modulator-lowers-the-amyloid-biomarker-a%C3%AE-42-in-cerebrospinal-fluid-while-preventing-alzheimer-s-disease-cognitive-decline-in-rodents
#14
Maria Z Kounnas, Courtney Lane-Donovan, Dan W Nowakowski, Joachim Herz, William T Comer
INTRODUCTION: Alzheimer's disease (AD) is defined by the progressive accumulation of amyloid plaques and neurofibrillary tangles in the brain which precedes cognitive decline by years. METHODS: Using amyloid biomarkers, chemical modeling, mouse behavioral models, and drug development techniques we investigate the properties of NGP 555, a clinical-stage γ-secretase modulator. RESULTS: NGP 555 shifts amyloid peptide production to the smaller, non-aggregating forms of amyloid...
January 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/28487309/molecular-cloning-and-characterization-of-marmoset-aldehyde-oxidase
#15
Shotaro Uehara, Yasuhiro Uno, Eriko Okamoto, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus), New world monkeys, are a promising primate model for preclinical drug metabolism studies due to the similarities of cytochrome P450 (P450) enzyme function to those of humans. Despite an increasing number of drug candidates catalyzed by non-P450 enzymes, drug metabolizing enzymes other than P450s have been hardly identified or characterized in marmosets. In this study, we identified aldehyde oxidase (AOX) 1 gene by marmoset genome analysis. AOX1 cDNA was cloned from marmoset livers by reverse transcription-polymerase chain reaction...
May 9, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28485193/preclinical-absorption-distribution-metabolism-excretion-and-pharmacokinetics-of-a-novel-selective-inhibitor-of-breast-cancer-resistance-protein-bcrp
#16
Mingxiang Liao, Bei-Ching Chuang, Qing Zhu, Yuexian Li, Emily Guan, Shaoxia Yu, Johnny Yang, Shimoga Prakash, Cindy Q Xia
1. Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma. 2. In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2(-/-)) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog)...
May 31, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28474789/functional-characterization-and-tissue-expression-of-marmoset-cytochrome-p450-2e1
#17
Shotaro Uehara, Yasuhiro Uno, Etsuko Tomioka, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) have attracted increasing attention as a useful small non-human primate model in preclinical research. However, studies on marmoset cytochrome P450 (P450) 2E enzyme have scarcely been conducted. In this study, the full-length cDNA encoding P450 2E1 enzyme was isolated from marmoset livers by reverse transcription (RT)-polymerase chain reaction (PCR). Marmoset P450 2E1 amino acid sequences were highly identical (>88%) to those of cynomolgus monkey and human P450 2E1 enzymes...
May 5, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28470516/high-throughput-spheroid-screens-using-volume-resazurin-reduction-and-acid-phosphatase-activity
#18
Delyan P Ivanov, Anna M Grabowska, Martin C Garnett
Mainstream adoption of physiologically relevant three-dimensional models has been slow in the last 50 years due to long, manual protocols with poor reproducibility, high price, and closed commercial platforms. This chapter describes high-throughput, low-cost, open methods for spheroid viability assessment which use readily available reagents and open-source software to analyze spheroid volume, metabolism, and enzymatic activity. We provide two ImageJ macros for automated spheroid size determination-for both single images and images in stacks...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28463419/micropatterned-co-cultures-of-human-hepatocytes-and-stromal-cells-for-the-assessment-of-drug-clearance-and-drug-drug-interactions
#19
Christine Lin, Salman R Khetani
Drug clearance rates from the body can determine drug exposure that can affect efficacy or toxicity. Thus, accurate prediction of drug clearance during preclinical development can help guide dose selection in humans, but animal testing is not always predictive of human outcomes. Because hepatic drug metabolism is a rate-limiting step in the overall clearance of many drugs, primary human hepatocytes (PHHs) in suspension cultures or monolayers are used for drug clearance predictions. Yet, the precipitous decline in drug metabolism capacity can lead to significant underestimation of clearance rates, particularly for low turnover compounds that have desirable one-pill-a-day dosing regimens...
May 2, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28450578/integrated-assessment-of-diclofenac-biotransformation-pharmacokinetics-and-omics-based-toxicity-in-a-three-dimensional-human-liver-immunocompetent-coculture-system
#20
Ujjal Sarkar, Kodihalli C Ravindra, Emma Large, Carissa L Young, Dinelia Rivera-Burgos, Jiajie Yu, Murat Cirit, David J Hughes, John S Wishnok, Douglas A Lauffenburger, Linda G Griffith, Steven R Tannenbaum
In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography-tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans...
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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