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Roxadustat

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https://www.readbyqxmd.com/read/28331872/induction-of-erythropoiesis-by-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitors-without-promotion-of-tumor-initiation-progression-or-metastasis-in-a-vegf-sensitive-model-of-spontaneous-breast-cancer
#1
Todd W Seeley, Mark D Sternlicht, Stephen J Klaus, Thomas B Neff, David Y Liu
The effects of pharmacological hypoxia-inducible factor (HIF) stabilization were investigated in the MMTV-Neu(ndl)-YD5 (NeuYD) mouse model of breast cancer. This study first confirmed the sensitivity of this model to increased vascular endothelial growth factor (VEGF), using bigenic NeuYD;MMTV-VEGF-25 mice. Tumor initiation was dramatically accelerated in bigenic animals. Bigenic tumors were also more aggressive, with shortened doubling times and increased lung metastasis as compared to NeuYD controls. In separate studies, NeuYD mice were treated three times weekly from 7 weeks of age until study end with two different HIF prolyl hydroxylase inhibitors (HIF-PHIs), FG-4497 or roxadustat (FG-4592)...
2017: Hypoxia
https://www.readbyqxmd.com/read/28290095/a-new-approach-to-the-management-of-anemia-in-ckd-patients-a-review-on-roxadustat
#2
REVIEW
Kimberly Becker, Maha Saad
This article informs the reader of the current information available on a novel therapeutic agent and new class of drug for the treatment of anemia. The data show promising results for alternative erythropoietin-stimulating agents and offers a time line of when Phase III data will be available. The information on this new drug and new drug class will change how nephrologists approach treating anemia within their patients.
March 13, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/27918992/investigation-of-the-metabolites-of-the-hif-stabilizer-fg-4592-roxadustat-in-five-different-in-vitro-models-and-in-a-human-doping-control-sample-using-high-resolution-mass-spectrometry
#3
Annelie Hansson, Mario Thevis, Holly Cox, Geoff Miller, Daniel Eichner, Ulf Bondesson, Mikael Hedeland
FG-4592 is a hypoxia-inducible factor (HIF) stabilizer, which can increase the number of red blood cells in the body. It has not been approved by regulatory authorities, but is available for purchase on the Internet. Due to its ability to improve the oxygen transportation mechanism in the body, FG-4592 is of interest for doping control laboratories, but prior to this study, little information about its metabolism was available. In this study, the metabolism of FG-4592 was investigated in a human doping control sample and in five in vitro models: human hepatocytes and liver microsomes, equine liver microsomes and S9 fraction and the fungus Cunninghamella elegans...
February 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/27470678/hypoxia-inducible-factor-1-plays-a-role-in-phosphate-induced-vascular-smooth-muscle-cell-calcification
#4
Sophie Mokas, Richard Larivière, Laurent Lamalice, Stéphane Gobeil, David N Cornfield, Mohsen Agharazii, Darren E Richard
Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification...
September 2016: Kidney International
https://www.readbyqxmd.com/read/27352308/effect-of-moderate-hepatic-impairment-on-the-pharmacokinetics-and-pharmacodynamics-of-roxadustat-an-oral-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor
#5
Dorien Groenendaal-van de Meent, Martin den Adel, Jan Noukens, Sanne Rijnders, Axel Krebs-Brown, Lyudmila Mateva, Assen Alexiev, Marloes Schaddelee
BACKGROUND AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability. METHODS: This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child-Pugh score 7-9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions...
September 2016: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27122198/investigational-therapies-for-renal-disease-induced-anemia
#6
REVIEW
Holger Schmid, Wolfgang Jelkmann
INTRODUCTION: The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs. AREAS COVERED: By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis...
August 2016: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/27094610/oral-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-roxadustat-fg-4592-for-the-treatment-of-anemia-in-patients-with-ckd
#7
Robert Provenzano, Anatole Besarab, Chao H Sun, Susan A Diamond, John H Durham, Jose L Cangiano, Joseph R Aiello, James E Novak, Tyson Lee, Robert Leong, Brian K Roberts, Khalil G Saikali, Stefan Hemmerich, Lynda A Szczech, Kin-Hung Peony Yu, Thomas B Neff
BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly...
June 6, 2016: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/27091985/comparative-systems-pharmacology-of-hif-stabilization-in-the-prevention-of-retinopathy-of-prematurity
#8
COMPARATIVE STUDY
George Hoppe, Suzy Yoon, Banu Gopalan, Alexandria R Savage, Rebecca Brown, Kelsey Case, Amit Vasanji, E Ricky Chan, Randi B Silver, Jonathan E Sears
Retinopathy of prematurity (ROP) causes 100,000 new cases of childhood blindness each year. ROP is initiated by oxygen supplementation necessary to prevent neonatal death. We used organ systems pharmacology to define the transcriptomes of mice that were cured of oxygen-induced retinopathy (OIR, ROP model) by hypoxia-inducible factor (HIF) stabilization via HIF prolyl hydroxylase inhibition using the isoquinolone Roxadustat or the 2-oxoglutarate analog dimethyloxalylglycine (DMOG). Although both molecules conferred a protective phenotype, gene expression analysis by RNA sequencing found that Roxadustat can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect hepatic HIF-1 stabilization and increased serum angiokines...
May 3, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26947173/the-hypoxia-inducible-factor-prolyl-hydroxylase-inhibitor-roxadustat-fg-4592-and-warfarin-in-healthy-volunteers-a-pharmacokinetic-and-pharmacodynamic-drug-drug-interaction-study
#9
Dorien Groenendaal-van de Meent, Martin den Adel, Sanne Rijnders, Axel Krebs-Brown, Virginie Kerbusch, Georg Golor, Marloes Schaddelee
PURPOSE: Roxadustat is a small-molecule hypoxia-inducible factor prolyl-hydroxylase inhibitor in late-stage clinical development for the treatment of anemia in patients with chronic kidney disease (CKD). Warfarin is an oral anticoagulant with a narrow therapeutic window that is often prescribed to treat coexisting cardiovascular diseases in patients with CKD. This clinical trial was designed to evaluate the effect of roxadustat on warfarin pharmacokinetic and pharmacodynamic parameters...
2016: Clinical Therapeutics
https://www.readbyqxmd.com/read/26846333/roxadustat-fg-4592-versus-epoetin-alfa-for-anemia-in-patients-receiving-maintenance-hemodialysis-a-phase-2-randomized-6-to-19-week-open-label-active-comparator-dose-ranging-safety-and-exploratory-efficacy-study
#10
Robert Provenzano, Anatole Besarab, Steven Wright, Sohan Dua, Steven Zeig, Peter Nguyen, Lona Poole, Khalil G Saikali, Gopal Saha, Stefan Hemmerich, Lynda Szczech, K H Peony Yu, Thomas B Neff
BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. STUDY DESIGN: Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. SETTING & PARTICIPANTS: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa...
June 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/26494833/roxadustat-fg-4592-correction-of-anemia-in-incident-dialysis-patients
#11
RANDOMIZED CONTROLLED TRIAL
Anatole Besarab, Elena Chernyavskaya, Igor Motylev, Evgeny Shutov, Lalathaksha M Kumbar, Konstantin Gurevich, Daniel Tak Mao Chan, Robert Leong, Lona Poole, Ming Zhong, Khalil G Saikali, Marietta Franco, Stefan Hemmerich, Kin-Hung Peony Yu, Thomas B Neff
Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb≤10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks...
April 2016: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/26238121/randomized-placebo-controlled-dose-ranging-and-pharmacodynamics-study-of-roxadustat-fg-4592-to-treat-anemia-in-nondialysis-dependent-chronic-kidney-disease-ndd-ckd-patients
#12
RANDOMIZED CONTROLLED TRIAL
Anatole Besarab, Robert Provenzano, Joachim Hertel, Raja Zabaneh, Stephen J Klaus, Tyson Lee, Robert Leong, Stefan Hemmerich, Kin-Hung Peony Yu, Thomas B Neff
BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects. METHODS: NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1...
October 2015: Nephrology, Dialysis, Transplantation
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