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https://www.readbyqxmd.com/read/28508321/trpc-channels-and-glioma
#1
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
#2
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
#3
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
#4
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
#5
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
#6
Mingxiang Liao, Bei-Ching Chuang, Qing Zhu, Yuexian Li, Emily Guan, Shaoxia Yu, Johnny Yang, Prakash Shimoga, 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 the present 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 9, 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
#7
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
#8
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
#9
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-3d-human-liver-immunocompetent-co-culture-system
#10
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 immuno-competent co-culture 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 h of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans...
April 27, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28447074/chidamide-tablets-hdac-inhibition-to-treat-lymphoma
#11
Y Xu, P Zhang, Y Liu
Chidamide is the first oral subtype-selective histone deacetylase inhibitor (HDACI) approved in China as well as the first HDACI of the benzamide class approved for the treatment of relapsed and refractory peripheral T-cell lymphoma (PTCL). This review addresses detailed information regarding chidamide, including the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, clinical studies and application, safety, drug interactions and ongoing clinical trials. Although twice-weekly chidamide monotherapy has been recommended based on the evidence from preclinical and clinical studies with tolerable toxicities, its clinical efficacy could be further increased by combination with multidrug chemotherapy or chemo-free regimens...
March 2017: Drugs of Today
https://www.readbyqxmd.com/read/28444639/metformin-and-prostate-cancer-a-new-role-for-an-old-drug
#12
REVIEW
Jessica Whitburn, Claire M Edwards, Prasanna Sooriakumaran
PURPOSE OF REVIEW: Since epidemiological studies first demonstrated a potential positive effect of metformin in reducing cancer incidence and mortality, there has been an increased interest in not only better understanding metformin's mechanisms of action but also in exploring its potential anti-cancer effects. In this review, we aim to summarise the current evidence exploring a role for metformin in prostate cancer therapy. RECENT FINDINGS: Preclinical studies have demonstrated a number of antineoplastic biological effects via a range of molecular mechanisms...
June 2017: Current Urology Reports
https://www.readbyqxmd.com/read/28440988/-how-safe-is-the-recombinant-human-growth-hormone
#13
Raúl Calzada-León
In this paper, several aspects related to the safety of the use of biosynthetic human growth hormone are reviewed. For example, its classification as a biosynthetic drug, the phases that need to be performed in Mexico to verify its safety (obtaining, purification, preclinical studies, clinical trials, and finally observational clinical studies), as well as the evidence that exists in relation to the association of intracranial hypertension, muscular events, scoliosis, slipped capital femoral epiphysis, obstructive sleep apnea, pancreatitis, alterations in cortisol, thyroid hormones alterations, cardiovascular disease, metabolic risk, mortality and cancer, adverse events not related to its use, and finally dosing and safety...
May 2017: Revista Médica del Instituto Mexicano del Seguro Social
https://www.readbyqxmd.com/read/28438049/ocular-non-p450-oxidative-reductive-hydrolytic-and-conjugative-drug-metabolizing-enzymes
#14
Upendra A Argikar, Jennifer L Dumouchel, Christine E Dunne, Andrea J Bushee
Metabolism in the eye for any species, laboratory animals or human, is gaining rapid interest as pharmaceutical scientists aim to treat a wide range of so-called incurable ocular diseases. Over a period of decades, reports of metabolic activity toward various drugs and biochemical markers have emerged in select ocular tissues of animals and humans. Ocular P450 enzymes and transporters have been recently reviewed. However, there is a dearth of collated information on non-P450 drug metabolizing enzymes in eyes of various preclinical species and humans in health and disease...
April 24, 2017: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/28432595/what-animal-models-have-taught-us-about-the-safety-and-efficacy-of-bisphosphonates-in-chronic-kidney-disease
#15
REVIEW
Matthew R Allen, Mohammad W Aref
PURPOSE OF REVIEW: Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. RECENT FINDINGS: Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models...
April 21, 2017: Current Osteoporosis Reports
https://www.readbyqxmd.com/read/28428366/in-vitro-metabolism-of-oprozomib-an-oral-proteasome-inhibitor-role-of-epoxide-hydrolases-and-cytochrome-p450s
#16
Zhican Wang, Ying Fang, Juli Teague, Hansen Wong, Christophe Morisseau, Bruce D Hammock, Dan A Rock, Zhengping Wang
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic therefore a thorough investigation of pathways responsible for metabolism is required...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28422962/docosahexaenoic-acid-blocks-progression-of-western-diet-induced-nonalcoholic-steatohepatitis-in-obese-ldlr-mice
#17
Kelli A Lytle, Carmen P Wong, Donald B Jump
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments...
2017: PloS One
https://www.readbyqxmd.com/read/28408224/one-drug-for-two-targets-biological-evaluation-of-antiretroviral-agents-endowed-with-antiproliferative-activity
#18
Lorenzo Botta, Giorgio Maccari, Pierpaolo Calandro, Marika Tiberi, Annalaura Brai, Claudio Zamperini, Filippo Canducci, Mario Chiariello, Rosa Martí-Centelles, Eva Falomir, Miguel Carda
AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28399020/therapeutic-micrornas-in-polycystic-kidney-disease
#19
Matanel Yheskel, Vishal Patel
PURPOSE OF REVIEW: microRNAs (miRNAs) are short noncoding RNAs that function as sequence-specific inhibitors of gene expression. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage kidney failure with limited treatment options. The realization that miRNA upregulation, and thus its gain-of-function, can drive the progression of ADPKD has raised the possibility that anti-miRs represent a novel drug class for this disorder. RECENT FINDINGS: A common set of miRNAs are aberrantly expressed in various murine models of polycystic kidney disease...
April 8, 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28397099/maturation-of-human-pluripotent-stem-cell-derived-cardiomyocytes-is-improved-in-cardiovascular-construct
#20
Hanna Vuorenpää, Kirsi Penttinen, Tuula Heinonen, Mari Pekkanen-Mattila, Jertta-Riina Sarkanen, Timo Ylikomi, Katriina Aalto-Setälä
In order to translate preclinical data into the clinical studies, relevant in vitro models with structure and key functional properties similar to native human tissue should be used. In vitro cardiac models with vascular structures mimic the highly vascularized myocardium and provide interactions between endothelial cells, stromal cells and cardiomyocytes. Currently, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been shown to present immature morphology and fetal-like electrophysiological properties that may limit their use as physiological test platform...
April 10, 2017: Cytotechnology
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