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drug metabolism, preclinical

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https://www.readbyqxmd.com/read/29342230/metformin-as-an-anti-cancer-agent-actions-and-mechanisms-targeting-cancer-stem-cells
#1
Nipun Saini, Xiaohe Yang
Metformin, a first line medication for type II diabetes, initially entered the spotlight as a promising anti-cancer agent due to epidemiologic reports that found reduced cancer risk and improved clinical outcomes in diabetic patients taking metformin. To uncover the anti-cancer mechanisms of metformin, preclinical studies determined that metformin impairs cellular metabolism and suppresses oncogenic signaling pathways, including receptor tyrosine kinase, PI3K/Akt, and mTOR pathways. Recently, the anti-cancer potential of metformin has gained increasing interest due to its inhibitory effects on cancer stem cells (CSCs), which are associated with tumor metastasis, drug resistance, and relapse...
October 7, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#2
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29334372/pharmacological-blockade-of-asct2-dependent-glutamine-transport-leads-to-antitumor-efficacy-in-preclinical-models
#3
Michael L Schulte, Allie Fu, Ping Zhao, Jun Li, Ling Geng, Shannon T Smith, Jumpei Kondo, Robert J Coffey, Marc O Johnson, Jeffrey C Rathmell, Joe T Sharick, Melissa C Skala, Jarrod A Smith, Jordan Berlin, M Kay Washington, Michael L Nickels, H Charles Manning
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2...
January 15, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29322647/max-bergmann-award-lecture-macromolecular-medicinal-chemistry-as-applied-to-metabolic-diseases
#4
REVIEW
Richard D DiMarchi, John P Mayer, Vasily M Gelfanov, Matthias Tschöp
This review presents the scope of research presented in an October 2016 lecture pertaining to the award of the 2015 Max Bergmann Medal. The advancement in synthetic and biosynthetic chemistry as applied to the discovery of novel macromolecular drug candidates is reviewed. The evolution of the technology from the design, synthesis, and development of the first biosynthetic peptides through the emergence of peptide-based incretin agonists that function by multiple biological mechanisms is exemplified by the progression of such peptides from preclinical to clinical study...
January 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/29318906/cefiderocol-a-novel-siderophore-cephalosporin
#5
Justin J Choi, Matthew W McCarthy
The emergence of multidrug-resistant bacterial pathogens has led to a global public health emergency and novel therapeutic options and drug-delivery systems are urgently needed. Cefiderocol is a siderophore cephalosporin antibiotic that has recently been developed to combat a variety of bacterial pathogens, including β-lactam- and carbapenem-resistant organisms. Areas covered: This paper provides an overview of the mutational and plasmid-mediated mechanisms of β-lactam and carbapenem resistance, the biochemical pathways of siderophores in bacterial iron metabolism, and how cefiderocol may be able to provide better targeted antimicrobial therapy that escape these drug-resistant mechanisms...
January 10, 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29311137/late-occurring-and-long-circulating-metabolites-of-gabaa%C3%AE-2-3-receptor-modulator-azd7325-involving-metabolic-cyclization-and-aromatization-relevance-to-mist-analysis-and-application-for-patient-compliance
#6
Chungang Gu, Markus Artelsmair, Charles S Elmore, Richard J Lewis, Patty Davis, James E Hall, Bruce T Dembofsky, Greg Christoph, Mark A Smith, Marc Chapdelaine, Maria Sunzel
AZD7325 [4-amino-8-(2-fluoro-6-methoxyphenyl)-N-propylcinnoline-3-carboxamide] is a selective GABAAα2,3 receptor modulator intended for the treatment of anxiety disorders through oral administration. An interesting metabolic cyclization and aromatization pathway led to the tricyclic core of M9, i.e. 2-ethyl-7-(2-fluoro-6-methoxyphenyl)pyrimido[5,4-c]cinnolin-4(3H)-one. Further oxidative metabolism generated M10 via O-demethylation and M42 via hydroxylation. An authentic standard of M9 was synthesized to confirm the novel structure of M9 and that of M10 and M42 by liver microsomal incubation of the M9 standard...
January 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29311093/characterization-of-the-preclinical-pharmacology-of-the-new-2-aminomethylphenol-jpc-3210-for-malaria-treatment-and-prevention
#7
Geoffrey W Birrell, Gavin D Heffernan, Guy A Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin van Breda, Marina Chavchich, Laura R Jacobus, G Dennis Shanks, David P Jacobus, Michael D Edstein
The new 2-aminomethylphenol JPC-3210 has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and in vitro screening assays including the inhibition of cytochrome (CYP) P450 isozymes. In mice JPC-3210 is rapidly absorbed, has extensive tissue distribution with a brain tissue to plasma concentration ratio of about 5.4 and a lengthy plasma elimination half-life of about 4...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29303950/cns-drug-development-lessons-learned-part-4-the-role-of-brain-circuitry-and-genes-tasimelteon-as-an-example
#8
Sheldon H Preskorn
This is the fourth in a series of columns discussing the rational and targeted development of drugs to affect specific central nervous system (CNS) circuits in specific ways based on knowledge gained by molecular biology and the human genome project. The first column in this series described 6 CNS drugs with novel mechanisms of action developed over the last 25 years. The second column discussed differences between syndromic diagnoses as exemplified by the third through the fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM III through DSM-5) and the new approach to psychiatric diagnoses championed by the National Institute of Mental Health in their Research Domain Criteria Initiative...
November 2017: Journal of Psychiatric Practice
https://www.readbyqxmd.com/read/29295482/lipid-metabolism-and-lipid-droplets-in-pancreatic-cancer-and-stellate-cells
#9
REVIEW
Yoshiaki Sunami, Artur Rebelo, Jörg Kleeff
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed...
December 23, 2017: Cancers
https://www.readbyqxmd.com/read/29286054/meropenem-vaborbactam-fixed-combination-for-the-treatment-of-patients-with-complicated-urinary-tract-infections
#10
M W McCarthy, T J Walsh
On August 29, 2017, the United States Food and Drug Administration (FDA) approved meropenem/ vaborbactam fixed combination for the treatment of adults with complicated urinary tract infections (cUTI). The decision was based on substantial preclinical and clinical data, including two recent trials involving hundreds of adults with cUTI. Meropenem/ vaborbactam represents a powerful new treatment option to address antibiotic-resistant pathogens, including Klebsiella pneumoniae carbapenemase-producing bacteria...
October 2017: Drugs of Today
https://www.readbyqxmd.com/read/29277691/genetic-polymorphisms-of-drug-metabolizing-cytochrome-p450-enzymes-in-cynomolgus-and-rhesus-monkeys-and-common-marmosets-in-preclinical-studies-for-humans
#11
REVIEW
Yasuhiro Uno, Shotaro Uehara, Hiroshi Yamazaki
Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes...
December 22, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29277574/human-cytochrome-p450-kinetic-studies-on-six-n-2-methoxybenzyl-nbome-derived-new-psychoactive-substances-using-the-substrate-depletion-approach
#12
Achim T Caspar, Markus R Meyer, Hans H Maurer
A huge number of new chemical derivatives of known drugs of abuse, so-called new psychoactive substances (NPS), are sold and consumed without prior preclinical and clinical testing. For assessing the elimination behaviors, determination of the kinetic constants Km and Vmax of the cytochrome P450 (CYP) isoforms involved in the hepatic metabolism of NPS could help to predict their contributions to hepatic clearance, drug-drug interactions and polymorphisms. Therefore, the aims of the present study were to determine the Km and Vmax values for CYP isoforms using the substrate depletion approach for the six N-2-methoxybenzyl (NBOMe)-derived NPS 25B-NBOMe, 25C-NBOMe, 25I-NBOMe, 3,4-DMA-NBOMe, 4-EA-NBOMe, and 4-MMA-NBOMe...
December 22, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29259982/pharmacokinetics-tissue-distribution-and-metabolism-study-of-icariin-in-rat
#13
Shunjun Xu, Jiejing Yu, Jingjing Zhan, Liu Yang, Longgang Guo, Yijuan Xu
Icariin is one of the predominant flavonoids contained in Herba Epimedii (Yin-yang-huo in Chinese), a well-known Chinese medicine for the treatment of cancers and immune system diseases. Although Herba Epimedii has been widely used in China and there are so many and various research reports on the herbal drug and its main flavones, very limited data is available on the tissue distribution and biotransformation of icariin. In the present study, a liquid chromatographic method combined with electrospray ionization tandem mass spectrometry was developed to quantify the concentration of icariin in rat plasma and various tissues collected at different time points after oral administration of the total flavonoid extract of Herba Epimedii at a dose of 0...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29258509/chemotherapy-diminishes-lipid-storage-capacity-of-adipose-tissue-in-a-preclinical-model-of-colon-cancer
#14
Maryam Ebadi, Catherine J Field, Richard Lehner, Vera C Mazurak
BACKGROUND: Accelerated loss of adipose tissue in cancer is associated with shorter survival, and reduced quality of life. Evidence is emerging suggesting tumour association with alterations in adipose tissue, but much less is known about drug-related mechanisms contributing to adipose atrophy. Identification of mechanisms by which tumour and cancer treatments, such as chemotherapy, affect adipose tissue are required to develop appropriate therapeutic interventions to prevent fat depletion in cancer...
December 19, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29234895/intestinal-stem-cells-to-advance-drug-development-precision-and-regenerative-medicine-a-paradigm-shift-in-translational-research
#15
Jonathan P Mochel, Albert E Jergens, Dawn Kingsbury, Hyun Jung Kim, Martín G Martín, Karin Allenspach
Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies...
December 12, 2017: AAPS Journal
https://www.readbyqxmd.com/read/29226720/memantine-induces-apoptosis-and-inhibits-cell-cycle-progression-in-lncap-prostate-cancer-cells
#16
G Albayrak, E Konac, A U Dikmen, C Y Bilen
Deregulated cancer cell metabolism plays an important role in cancer progression. Cancer cell metabolism has been in the centre of attention in therapeutical cancer cell targeting. Repurposed chemical agents, such as metformin and aspirin, have been studied extensively as preventive and therapeutic agents. Metformin is Food and Drug administration (FDA)-approved antidiabetic drug cheaper than other chemotherapeutic agents that were shown to have anticancer effects. Memantine is an FDA-approved Alzheimer's drug...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/29223921/metabolism-and-pharmacokinetics-of-alantolactone-and-isoalantolactone-in-rats-thiol-conjugation-as-a-potential-metabolic-pathway
#17
Bailun Zhou, Ji Ye, Niao Yang, Liping Chen, Zhiguo Zhuo, Ling Mao, Qun Liu, Gongcai Lan, Jing Ning, Guangbo Ge, Ling Yang, Yunheng Shen, Shumei Wang, Weidong Zhang
Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR)...
December 2, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29203658/molecular-and-functional-resemblance-of-differentiated-cells-derived-from-isogenic-human-ipscs-and-scnt-derived-escs
#18
Ming-Tao Zhao, Haodong Chen, Qing Liu, Ning-Yi Shao, Nazish Sayed, Hung-Ta Wo, Joe Z Zhang, Sang-Ging Ong, Chun Liu, Youngkyun Kim, Huaxiao Yang, Tony Chour, Hong Ma, Nuria Marti Gutierrez, Ioannis Karakikes, Shoukhrat Mitalipov, Michael P Snyder, Joseph C Wu
Patient-specific pluripotent stem cells (PSCs) can be generated via nuclear reprogramming by transcription factors (i.e., induced pluripotent stem cells, iPSCs) or by somatic cell nuclear transfer (SCNT). However, abnormalities and preclinical application of differentiated cells generated by different reprogramming mechanisms have yet to be evaluated. Here we investigated the molecular and functional features, and drug response of cardiomyocytes (PSC-CMs) and endothelial cells (PSC-ECs) derived from genetically relevant sets of human iPSCs, SCNT-derived embryonic stem cells (nt-ESCs), as well as in vitro fertilization embryo-derived ESCs (IVF-ESCs)...
December 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29203236/amylin-its-role-in-the-homeostatic-and-hedonic-control-of-eating-and-recent-developments-of-amylin-analogs-to-treat-obesity
#19
REVIEW
Christina Neuner Boyle, Thomas Alexander Lutz, Christelle Le Foll
BACKGROUND: Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. One of its best-characterized effects is the reduction in eating and body weight seen in preclinical and clinical studies. Amylin activates specific receptors, a portion of which it shares with calcitonin gene-related peptide (CGRP). Amylin's role in the control of energy metabolism relates to its satiating effect, but recent data indicate that amylin may also affect hedonic aspects in the control of eating, including a reduction of the rewarding value of food...
November 23, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29190376/p53-promotes-akt-and-sp1-dependent-metabolism-through-the-pentose-phosphate-pathway-that-inhibits-apoptosis-in-response-to-nutlin-3a
#20
Lei Duan, Ricardo E Perez, Ling Chen, Lothar A Blatter, Carl G Maki
Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway (PPP) produces NADPH that can protect cells from potentially lethal reactive oxygen species (ROS). We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a...
November 27, 2017: Journal of Molecular Cell Biology
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