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https://www.readbyqxmd.com/read/28937442/orally-active-epoxyeicosatrienoic-acid-analogs
#1
William B Campbell, John D Imig, James M Schmitz, John R Falck
Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial, and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size after ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance, and reduce the renal injury...
September 19, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28927276/alkoxycarbonate-ester-prodrugs-of-preclinical-drug-candidate-elq-300-for-prophylaxis-and-treatment-of-malaria
#2
Lisa Frueh, Yuexin Li, Michael Mather, Qigui Li, Sovitj Pou, Aaron Nilsen, Rolf W Winter, Isaac Forquer, April Pershing, Lisa H Xie, Martin J Smilkstein, Diana Caridha, Robert F Campbell, Richard J Sciotti, Mara Kreishman-Deitrick, Jane X Kelly, Brian Andrew Vesely, Akhil Vaidya, Michael K Riscoe
ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multi-dose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host...
September 19, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28922023/fatty-acid-synthase-fasn-as-a-therapeutic-target-in-breast-cancer
#3
Javier A Menendez, Ruth Lupu
Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to explain how FASN is intertwined with various signaling networks to cell-autonomously regulate breast cancer initiation and progression, FASN has received considerable attention as a therapeutic target. However, despite the ever-growing evidence demonstrating the involvement of FASN as part of the cancer-associated metabolic reprogramming, translation of the basic science-discovery aspects of FASN blockade to the clinical arena remains a challenge...
September 18, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28918016/therapeutic-mirna-and-sirna-moving-from-bench-to-clinic-as-next-generation-medicine
#4
REVIEW
Chiranjib Chakraborty, Ashish Ranjan Sharma, Garima Sharma, C George Priya Doss, Sang-Soo Lee
In the past few years, therapeutic microRNA (miRNA) and small interfering RNA (siRNA) are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA-based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28901277/repositioning-of-tak-475-in-mevalonate-kinase-disease-translating-theory-into-practice
#5
Annalisa Marcuzzi, Claudia Loganes, Claudio Celeghini, Giulio Kleiner
Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase (MK), due to a mutation in the MVK gene, leads to the shortage of mevalonate-derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-1 (IL-1) can significantly reduce inflammation, they cannot completely control the clinical symptoms that affects the nervous system...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28893642/enzyme-inducing-effects-of-berberine-on-cytochrome-p450-1a2-in-vitro-and-in-vivo
#6
Bo Jiang, Liyuan Meng, Feng Zhang, Xiaoling Jin, Guiliang Zhang
AIMS: Berberine (BER) is an important anti-bacterial drug from Chinese herbal medicine and a novel drug candidate for preclinical development in recent years. Here we provide evidence that the effects of berberine on cytochrome P450 (CYP) 1A2 in vitro and in vivo. MAIN METHODS: Real-time polymerase chain reaction and western blotting analysis were employed to evaluate the CYP1A2 mRNA levels and protein expression. The enzyme activity was assessed by the metabolic rate of phenacetin to acetaminophen by LC-MS/MS method...
September 8, 2017: Life Sciences
https://www.readbyqxmd.com/read/28891437/investigation-of-ocular-bioactivation-potential-and-the-role-of-cytochrome-p450-2d-enzymes-in-rat
#7
Jennifer L Dumouchel, Upendra A Argikar, Jaimie Spear, Ann Brown, Christine E Dunne, Valerie M Kramlinger, Amanda L Cirello, Mithat Gunduz
BACKGROUND: Timolol is clinically administered topically (ocular) to reduce intraocular pressure and treat open-angle glaucoma. Ocular administration of timolol in low doses (0.5% w/v in the form of eye drops) has led to challenges for in vivo metabolite identification. An understanding of drug metabolism in the eye is important for clinical ocular therapeutics and potential drug candidates. METHODS: We aimed to investigate the metabolism of timolol in rat ocular and liver S9 fractions, as well as rat ocular tissue and plasma following a 0...
September 11, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/28884164/ecoao-a-simple-system-for-the-study-of-human-aldehyde-oxidases-role-in-drug-metabolism
#8
Erickson M Paragas, Sara C Humphreys, Joshua Min, Carolyn A Joswig-Jones, Silke Leimkühler, Jeffrey P Jones
Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO's preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles...
August 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28865281/design-strategies-in-the-prodrugs-of-hiv-1-protease-inhibitors-to-improve-the-pharmaceutical-properties
#9
REVIEW
Murugaiah A M Subbaiah, Nicholas A Meanwell, John F Kadow
Combination antiretroviral therapy (cART) is currently the most effective treatment for HIV-1 infection. HIV-1 protease inhibitors (PIs) are an important component of some regimens of cART. However, PIs are known for sub-optimal ADME properties, resulting in poor oral bioavailability. This often necessitates high drug doses, combination with pharmacokinetic enhancers and/or special formulations in order to effectively deliver PIs, which may lead to a high pill burden and reduced patient compliance. As a remedy, improving the ADME properties of existing drugs via prodrug and other approaches has been pursued in addition to the development of next generation PIs with improved pharmacokinetic, resistance and side effect profiles...
July 22, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28860341/targeting-metabolism-and-survival-in-chronic-lymphocytic-leukemia-and-richter-syndrome-cells-by-a-novel-nf-kb-inhibitor
#10
Tiziana Vaisitti, Federica Gaudino, Samedy Ouk, Maria Moscvin, Nicoletta Vitale, Sara Serra, Francesca Arruga, Johannes L Zakrzewski, Hsiou-Chi Liou, John N Allan, Richard R Furman, Silvia Deaglio
IT-901 is a novel and selective NF-kB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells with IT-901 effectively interrupts NF-kB transcriptional activity. Chronic lymphocytic leukemia cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production and activate intrinsic apoptosis. Inhibition of NF-kB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-kB-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche...
August 31, 2017: Haematologica
https://www.readbyqxmd.com/read/28837150/three-dimensional-tumor-cell-growth-stimulates-autophagic-flux-and-recapitulates-chemotherapy-resistance
#11
Corinna Bingel, Emily Koeneke, Johannes Ridinger, Annika Bittmann, Martin Sill, Heike Peterziel, Jagoda K Wrobel, Inga Rettig, Till Milde, Uta Fernekorn, Frank Weise, Andreas Schober, Olaf Witt, Ina Oehme
Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions...
August 24, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28819370/metformin-inhibits-gemcitabine-induced-apoptosis-in-pancreatic-cancer-cell-lines
#12
Dietmar Zechner, Ann-Christin Albert, Florian Bürtin, Brigitte Vollmar
Many preclinical and clinical studies are currently evaluating metformin in combination with classical therapeutic agents as anti-cancer therapy. In this study we used three distinct pancreatic cancer cell lines and evaluated cell death by trypan blue assay and Western Blots using antibodies directed against cleaved caspase 3 and PARP. Surprisingly, we observed that 20mM metformin did not enhance, but rather inhibited gemcitabine induced cell death in murine 7265PDA, 6606PDA and 6606l cells. Microenvironmental aspects such as oxygen supply or the pH value did not influence the inhibition of cancer cell apoptosis by metformin...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28819274/distinct-carbon-sources-affect-structural-and-functional-maturation-of-cardiomyocytes-derived-from-human-pluripotent-stem-cells
#13
Cláudia Correia, Alexey Koshkin, Patrícia Duarte, Dongjian Hu, Ana Teixeira, Ibrahim Domian, Margarida Serra, Paula M Alves
The immature phenotype of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) constrains their potential in cell therapy and drug testing. In this study, we report that shifting hPSC-CMs from glucose-containing to galactose- and fatty acid-containing medium promotes their fast maturation into adult-like CMs with higher oxidative metabolism, transcriptional signatures closer to those of adult ventricular tissue, higher myofibril density and alignment, improved calcium handling, enhanced contractility, and more physiological action potential kinetics...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808818/first-in-human-study-of-the-epichaperome-inhibitor-pu-h71-clinical-results-and-metabolic-profile
#14
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
#15
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
#16
REVIEW
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...
September 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
#17
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
#18
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
#19
Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M Quinn, Fei Li, Ashley A Merlino, Cyril Benes, Qingsong Liu, Nathanael S Gray, Kwok-Kin Wong
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 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 pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models...
September 15, 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
#20
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
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