keyword
MENU ▼
Read by QxMD icon Read
search

drug metabolism, preclinical

keyword
https://www.readbyqxmd.com/read/28808818/first-in-human-study-of-the-epichaperome-inhibitor-pu-h71-clinical-results-and-metabolic-profile
#1
Giovanna Speranza, Larry Anderson, Alice P Chen, Khanh Do, Michelle Eugeni, Marcie Weil, Larry Rubinstein, Eva Majerova, Jerry Collins, Yvonne Horneffer, Lamin Juwara, Jennifer Zlott, Rachel Bishop, Barbara A Conley, Howard Streicher, Joseph Tomaszewski, James H Doroshow, Shivaani Kummar
Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments...
August 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28792505/fluorescence-imaging-of-bombesin-and-transferrin-receptor-expression-is-comparable-to-18f-fdg-pet-in-early-detection-of-sorafenib-induced-changes-in-tumor-metabolism
#2
Jen-Chieh Tseng, Nara Narayanan, Guojie Ho, Kevin Groves, Jeannine Delaney, Bagna Bao, Jun Zhang, Jeffrey Morin, Sylvie Kossodo, Milind Rajopadhye, Jeffrey D Peterson
Physical measurement of tumor volume reduction is the most commonly used approach to assess tumor progression and treatment efficacy in mouse tumor models. However, it is relatively insensitive, and often requires long treatment courses to achieve gross physical tumor destruction. As alternatives, several non-invasive imaging methods such as bioluminescence imaging (BLI), fluorescence imaging (FLI) and positron emission tomography (PET) have been developed for more accurate measurement. As tumors have elevated glucose metabolism, 18F-fludeoxyglucose (18F-FDG) has become a sensitive PET imaging tracer for cancer detection, diagnosis, and efficacy assessment by measuring alterations in glucose metabolism...
2017: PloS One
https://www.readbyqxmd.com/read/28776444/curcumin-as-a-clinically-promising-anti-cancer-agent-pharmacokinetics-and-drug-interactions
#3
Jeffry Adiwidjaja, Andrew J McLachlan, Alan V Boddy
Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations...
August 10, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28762864/progesterone-hydroxylation-by-cytochromes-p450-2c-and-3a-enzymes-in-marmoset-liver-microsomes
#4
Kazuyuki Nakanishi, Shotaro Uehara, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical drug metabolism studies. However, the roles of marmoset cytochrome P450 (P450) isoforms in the oxidation of endobiotic progesterone have not been fully investigated. In this study, the roles of marmoset P450 isoforms in progesterone hydroxylation were extensively determined. 2. The activities of liver microsomes from individual marmosets with respect to progesterone 21/17α- and 16α/6β-hydroxylation were significantly correlated with those for flurbiprofen 4-hydroxylation and midazolam 1'-hydroxylation, respectively, as similar correlations have been found in humans...
August 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28758057/the-opportunities-of-metabolomics-in-drug-safety-evaluation
#5
Pengcheng Wang, Amina I Shehu, Xiaochao Ma
Although safety of drug candidates is carefully monitored in preclinical and clinical studies using a variety of approaches, drug toxicity may still occur in clinical practice. Therefore, novel approaches are needed to complement the current drug safety evaluation system. Metabolomics comprehensively analyzes the metabolites altered by drug exposure, which can therefore be used to profile drug metabolism, endobiotic metabolism, and drug-microbiota interactions. The information from metabolomic analysis can be used to determine the off-targets of a drug candidate, and thus provide a mechanistic understanding of drug toxicity...
February 2017: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28754670/gemcitabine-and-chk1-inhibitor-azd7762-synergistically-suppress-the-growth-of-lkb1-deficient-lung-adenocarcinoma
#6
Kwok-Kin Wong, Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M Quinn, Fei Li, Ashley A Merlino, Cyril H Benes, Qingsong Liu, Nathanael S Gray
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model (GEMM) of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in Kras/p53/Lkb1 tumors, synergizing with the DNA damaging drug gemcitabine to reduce tumor size in these models...
July 28, 2017: Cancer Research
https://www.readbyqxmd.com/read/28747210/the-medical-food-souvenaid-affects-brain-phospholipid-metabolism-in-mild-alzheimer-s-disease-results-from-a-randomized-controlled-trial
#7
Anne Rijpma, Marinette van der Graaf, Marieke M Lansbergen, Olga Meulenbroek, Aysun Cetinyurek-Yavuz, John W Sijben, Arend Heerschap, Marcel G M Olde Rikkert
BACKGROUND: Synaptic dysfunction contributes to cognitive impairment in Alzheimer's disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer's disease. METHODS: Thirty-four drug-naive patients with mild Alzheimer's disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study...
July 26, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28736828/genomic-and-metabolic-characterization-of-a-chromophobe-renal-cell-carcinoma-cell-line-model-uok276
#8
Youfeng Yang, Cathy D Vocke, Christopher J Ricketts, Darmood Wei, Hesed M Padilla-Nash, Martin Lang, Carole Sourbier, J Keith Killian, Shawna L Boyle, Robert Worrell, Paul S Meltzer, Thomas Ried, Maria J Merino, Adam R Metwalli, W Marston Linehan
Chromophobe renal cell carcinoma (ChRCC) represents 5% of all RCC cases and frequently demonstrates multiple chromosomal losses and an indolent pattern of local growth, but can demonstrate aggressive features and resistance to treatment in a metastatic setting. Cell line models are an important tool for the investigation of tumor biology and therapeutic drug efficacy. Currently, there are few ChRCC-derived cell lines and none is well characterized. This study characterizes a novel ChRCC-derived cell line model, UOK276...
October 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28733523/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#9
Jair Machado Espindola-Netto, Claudia C S Chini, Mariana Tarragó, Enfeng Wang, Shamit Dutta, Krishnendu Pal, Debabrata Mukhopadhyay, Mauro Sola-Penna, Eduardo N Chini
NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28732807/pharmacology-and-toxicology-of-%C3%AE-and-%C3%AE-asarone-a-review-of-preclinical-evidence
#10
REVIEW
Ranjithkumar Chellian, Vijayapandi Pandy, Zahurin Mohamed
BACKGROUND: Asarone is one of the most researched phytochemicals and is mainly present in the Acorus species and Guatteria gaumeri Greenman. In preclinical studies, both α- and β-asarone have been reported to have numerous pharmacological activities and at the same time, many studies have also revealed the toxicity of α- and β-asarone. PURPOSE: The purpose of this comprehensive review is to compile and analyze the information related to the pharmacokinetic, pharmacological, and toxicological studies reported on α- and β-asarone using preclinical in vitro and in vivo models...
August 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28718949/high-dosage-of-vitamin-d-regulates-the-energy-metabolism-and-increases-insulin-sensitivity-but-are-associated-with-high-levels-of-kidney-damage
#11
Rafael Calais Gaspar, José Diego Botezelli, Gabriel Keine Kuga, Vitor Rosetto Muñoz, Andressa Coope, Rodrigo Martins Pereira, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Leandro Pereira de Moura, Eduardo Rochete Ropelle, José Rodrigo Pauli
Preclinical Research Metabolic disorders are responsible for more than 60% of all deaths worldwide. Calcitriol or vitamin D (vitD) deficiency is associated with a large proportion of these diseases is an important therapeutic target for exploration. This study evaluated the administration of high doses of vitD (3000 IU/kg) in obese and insulin-resistant C57BL/6J mice. Our results demonstrated that although high doses of vitD provided metabolic benefits such as increased insulin sensitivity and decreased body mass, this was associated with significant damage in the kidneys of obese mice...
July 18, 2017: Drug Development Research
https://www.readbyqxmd.com/read/28707063/liquid-chromatography-mass-spectrometry-methods-for-the-intracellular-determination-of-drugs-and-their-metabolites-a-focus-on-antiviral-drugs
#12
REVIEW
Pierre-André Billat, Franck Saint-Marcoux
Understanding the efficacy and/or toxicity of most drugs requires effective intracellular measurements of the drug and its metabolites. Nevertheless, the most common plasma marker of the biological effect of the drug is the area under the curve. Compared with drug determination in whole blood or urine, various difficulties occur in the development of analytical methods for intracellular measurements. We propose step-by-step guidelines to develop an analytical method exploring intracellular concentrations of antivirals and/or their metabolites...
July 13, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28699698/reduced-dosing-and-liability-in-methadone-maintenance-treatment-by-targeting-oestrogen-signal-for-morphine-addiction
#13
Yao-Chang Chiang, Ruey-Yun Wang, Chieh-Liang Huang, Shue-Hwa Chen, Wen-Jing Ho, Hsien-Yuan Lane, Ing-Kang Ho, Hwei-Ting Yang, Wen-Lung Ma
Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28689458/marmoset-pulmonary-cytochrome-p450-2f1-oxidizes-biphenyl-and-7-ethoxycoumarin-and-hepatic-human-p450-substrates
#14
Shotaro Uehara, Yasuhiro Uno, Toru Oshio, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. A potentially useful animal model for preclinical studies is the common marmoset (Callithrix jacchus). In this study, using reverse-transcription polymerase chain reaction from marmoset livers, we identified a novel cytochrome P450 (P450) 2F1 cDNA with an open reading frame of 1473 bp. 2. High sequence identities of 92-94% with primate P450 2F amino acid sequences were indicated by deduced amino acid sequences of P450 2F1 cDNA. Phylogenetic analysis indicates that marmoset P450 2F1 is more congruent with primate P450 2F forms than those of other species such as rodents...
July 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28687459/mouse-models-of-nonalcoholic-steatohepatitis-in-preclinical-drug-development
#15
REVIEW
Henrik H Hansen, Michael Feigh, Sanne S Veidal, Kristoffer T Rigbolt, Niels Vrang, Keld Fosgerau
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH...
July 4, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28682065/discovery-of-clinical-candidate-4-2-5-amino-1h-pyrazol-4-yl-4-chlorophenoxy-5-chloro-2-fluoro-n-1-3-thiazol-4-ylbenzenesulfonamide-pf-05089771-design-and-optimization-of-diaryl-ether-aryl-sulfonamides-as-selective-inhibitors-of-nav1-7
#16
Nigel A Swain, Dave Batchelor, Serge Beaudoin, Bruce M Bechle, Paul A Bradley, Alan D Brown, Bruce Brown, Ken J Butcher, Richard P Butt, Mark L Chapman, Stephen Denton, David Ellis, Sebastien R G Galan, Steven M Gaulier, Ben S Greener, Marcel J de Groot, Mel S Glossop, Ian K Gurrell, Jo Hannam, Matthew S Johnson, Zhixin Lin, Christopher J Markworth, Brian E Marron, David S Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J Rawson, Sarah J Ransley, Steven M Reister, Kosuke Sasaki, R Ian Storer, Paul A Stupple, Christopher W West
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics...
August 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28678794/ammonium-tetrathiomolybdate-following-ischemia-reperfusion-injury-chemistry-pharmacology-and-impact-of-a-new-class-of-sulfide-donor-in-preclinical-injury-models
#17
Alex Dyson, Felipe Dal-Pizzol, Giovanni Sabbatini, Anna B Lach, Federica Galfo, Juliano Dos Santos Cardoso, Bruna Pescador Mendonça, Iain Hargreaves, Bernardo Bollen Pinto, Daniel I Bromage, John F Martin, Kevin P Moore, Martin Feelisch, Mervyn Singer
BACKGROUND: Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. METHODS AND FINDINGS: In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner...
July 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28675556/prospective-clinical-trials-to-investigate-clinical-and-molecular-biomarkers
#18
Stéphane Auvin, Lauren Walker, William Gallentine, Sergiusz Jozwiak, Mario Tombini, Graeme J Sills
Among clinical studies, randomized studies as well as well-designed observational studies are providing the highest quality data. In addition, these studies represent a good opportunity to examine biomarkers of ictogenesis and epileptogenesis. To date, no validated molecular or cellular biomarker exists for any aspect of epilepsy. We provide an overview of the inflammatory biomarkers under investigation in prospective clinical studies in epilepsy: proinflammatory cytokines in prolonged febrile seizure; High Mobility Group Box 1 (HMGB1) as a prognosis biomarker in epilepsy and the interaction between inflammation and metabolism, in particular, iron metabolism, in epilepsy...
July 2017: Epilepsia
https://www.readbyqxmd.com/read/28674030/s-nitrosoglutathione-reductase-gsnor-deficiency-confers-improved-survival-and-neurological-outcome-in-experimental-cerebral-malaria
#19
Robyn E Elphinstone, Rickvinder Besla, Eric A Shikatani, Ziyue Lu, Alfred Hausladen, Matthew Davies, Clinton S Robbins, Mansoor Husain, Jonathan S Stamler, Kevin C Kain
Artesunate remains the mainstay of treatment for cerebral malaria, but is less effective in later stages of disease when the host inflammatory response and blood brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione (GSNO) reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria...
July 3, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28668397/interleukin-6-c-ebp-%C3%AE-and-ppar-%C3%AE-expression-correlates-with-intramuscular-liposarcoma-growth-in-mice-the-impact-of-voluntary-physical-activity-levels
#20
Mohamad Assi, Moussa Kenawi, Mickaël Ropars, Amélie Rébillard
IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS...
August 26, 2017: Biochemical and Biophysical Research Communications
keyword
keyword
96222
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"