Read by QxMD icon Read


Daisuke Saigusa, Norio Suzuki, Yotaro Matsumoto, Keiko Umeda, Yoshihisa Tomioka, Seizo Koshiba, Masayuki Yamamoto
No abstract text is available yet for this article.
June 1, 2018: Journal of Biochemistry
Dorien Groenendaal-van de Meent, Martin den Adel, Jan van Dijk, Begona Barroso-Fernandez, Rachid El Galta, Georg Golor, Marloes Schaddelee
BACKGROUND AND OBJECTIVES: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat. METHODS: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat...
May 11, 2018: European Journal of Drug Metabolism and Pharmacokinetics
Amit Arvind Joharapurkar, Vrajesh Bhaskarbhai Pandya, Vishal J Patel, Ranjit C Desai, Mukul R Jain
Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia-inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent the novel pharmacological treatment of anemia of chronic diseases...
May 1, 2018: Journal of Medicinal Chemistry
Yunwen Yang, Xiaowen Yu, Yue Zhang, Guixia Ding, Chunhua Zhu, Songming Huang, Zhanjun Jia, Aihua Zhang
Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active small-molecule HIF PHD inhibitor for the treatment of anemia in patients with CKD...
March 26, 2018: Clinical Science (1979-)
Daisuke Saigusa, Norio Suzuki, Yotaro Matsumoto, Keiko Umeda, Yoshihisa Tomioka, Seizo Koshiba, Masayuki Yamamoto
Roxadustat (FG-4592, Rox) is a stabilizer for hypoxia-inducible transcription factors (HIFs), which induce production of the erythroid growth factor erythropoietin, and has been listed by the World Anti-Doping Agency as a prohibited substance for athletes since 2011. Although the detection technologies for Rox and its glucuronide-conjugated metabolite (Rox-Gluc) have been developed exploiting triple quadrupole mass spectrometry (MS/MS), the production of metabolites from Rox in the human body remains to be clarified...
February 9, 2018: Journal of Biochemistry
James Beck, Carroll Henschel, James Chou, Al Lin, Ughetta Del Balzo
The carcinogenic potential of roxadustat (FG-4592), a novel orally active, heterocyclic small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzymes in clinical development for treatment of anemia, was evaluated in CD-1 mice and Sprague Dawley rats. Inhibition of HIF-PH by roxadustat leads to a rapid increase in cytoplasmic HIF-α concentrations, followed by translocation of HIF-α to the nucleus and upregulation of HIF-responsive genes, including erythropoietin. Roxadustat was dosed by oral gavage 3 times weekly (TIW) for up to 104 weeks in mice at 0, 15, 30, and 60 mg/kg and in rats at 0, 2...
November 2017: International Journal of Toxicology
Daniel Eichner, Ryan M Van Wagoner, Mitch Brenner, James Chou, Scott Leigh, Lee R Wright, Lee A Flippin, Michael Martinelli, Oliver Krug, Wilhelm Schänzer, Mario Thevis
The utility of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors as a therapeutic means of treating patients suffering from anaemia has been demonstrated for various clinical settings. However, besides this intended use, HIF stabilizers can be the subject of misuse in amateur and elite sports due to their erythropoietic properties, as recently proven by several cases of adverse analytical findings in doping control testing. Consequently, to allow for adequate and comprehensive test methods, knowledge of the drug candidates' metabolism and analytical options enabling appropriate detection windows in sports drug testing samples (i...
November 2017: Drug Testing and Analysis
Nan Chen, Jiaqi Qian, Jianghua Chen, Xueqing Yu, Changlin Mei, Chuanming Hao, Gengru Jiang, Hongli Lin, Xinzhou Zhang, Li Zuo, Qiang He, Ping Fu, Xuemei Li, Dalvin Ni, Stefan Hemmerich, Cameron Liu, Lynda Szczech, Anatole Besarab, Thomas B Neff, Kin-Hung Peony Yu, Frank H Valone
Background: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). Methods: In the NDD study, 91 participants were randomized to low (1...
August 1, 2017: Nephrology, Dialysis, Transplantation
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
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.
April 2017: Advances in Therapy
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
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
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
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
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
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
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
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
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
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
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"