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[PMID]:29254377
[Au] Autor:Del Vecchio L; Locatelli F
[Ad] Endereço:a Department of Nephrology and Dialysis , A. Manzoni Hospital , Lecco , Italy.
[Ti] Título:Roxadustat in the treatment of anaemia in chronic kidney disease.
[So] Source:Expert Opin Investig Drugs;27(1):125-133, 2018 Jan.
[Is] ISSN:1744-7658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia-inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies.
[Mh] Termos MeSH primário: Anemia/tratamento farmacológico
Glicina/análogos & derivados
Isoquinolinas/uso terapêutico
Insuficiência Renal Crônica/complicações
[Mh] Termos MeSH secundário: Anemia/etiologia
Animais
Doenças Cardiovasculares/etiologia
Doenças Cardiovasculares/prevenção & controle
Eritropoetina/metabolismo
Glicina/efeitos adversos
Glicina/farmacologia
Glicina/uso terapêutico
Hematínicos/efeitos adversos
Hematínicos/uso terapêutico
Seres Humanos
Isoquinolinas/efeitos adversos
Isoquinolinas/farmacologia
Inibidores de Prolil-Hidrolase/efeitos adversos
Inibidores de Prolil-Hidrolase/farmacologia
Inibidores de Prolil-Hidrolase/uso terapêutico
Qualidade de Vida
Diálise Renal
Insuficiência Renal Crônica/terapia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FG-4592); 0 (Hematinics); 0 (Isoquinolines); 0 (Prolyl-Hydroxylase Inhibitors); 11096-26-7 (Erythropoietin); TE7660XO1C (Glycine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171220
[St] Status:MEDLINE
[do] DOI:10.1080/13543784.2018.1417386


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[PMID]:28449418
[Au] Autor:Haase VH
[Ad] Endereço:Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
[Ti] Título:HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
[So] Source:Hemodial Int;21 Suppl 1:S110-S124, 2017 Jun.
[Is] ISSN:1542-4758
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
[Mh] Termos MeSH primário: Eritropoese/efeitos dos fármacos
Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia
Ferro/metabolismo
Inibidores de Prolil-Hidrolase/uso terapêutico
[Mh] Termos MeSH secundário: Anemia/tratamento farmacológico
Barbitúricos/efeitos adversos
Barbitúricos/uso terapêutico
Ensaios Clínicos como Assunto
Eritropoetina/biossíntese
Glicina/efeitos adversos
Glicina/análogos & derivados
Glicina/uso terapêutico
Seres Humanos
Isoquinolinas/efeitos adversos
Isoquinolinas/uso terapêutico
Ácidos Picolínicos/efeitos adversos
Ácidos Picolínicos/uso terapêutico
Diálise Renal/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Barbiturates); 0 (EPO protein, human); 0 (FG-4592); 0 (GSK1278863); 0 (Isoquinolines); 0 (Picolinic Acids); 0 (Prolyl-Hydroxylase Inhibitors); 0 (vadadustat); 11096-26-7 (Erythropoietin); E1UOL152H7 (Iron); EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases); TE7660XO1C (Glycine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1111/hdi.12567


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[PMID]:28880966
[Au] Autor:Zhou J; Li J; Rosenbaum DM; Zhuang J; Poon C; Qin P; Rivera K; Lepore J; Willette RN; Hu E; Barone FC
[Ad] Endereço:Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America.
[Ti] Título:The prolyl 4-hydroxylase inhibitor GSK360A decreases post-stroke brain injury and sensory, motor, and cognitive behavioral deficits.
[So] Source:PLoS One;12(9):e0184049, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is interest in pharmacologic preconditioning for end-organ protection by targeting the HIF system. This can be accomplished by inhibition of prolyl 4-hydroxylase (PHD). GSK360A is an orally active PHD inhibitor that has been previously shown to protect the failing heart. We hypothesized that PHD inhibition can also protect the brain from injuries and resulting behavioral deficits that can occur as a result of surgery. Thus, our goal was to investigate the effect of pre-stroke surgery brain protection using a verified GSK360A PHD inhibition paradigm on post-stroke surgery outcomes. Vehicle or an established protective dose (30 mg/kg, p.o.) of GSK360A was administered to male Sprague-Dawley rats. Initially, GSK360A pharmacokinetics and organ distribution were determined, and then PHD-HIF pharmacodynamic markers were measured (i.e., to validate the pharmacological effects of the GSK360A administration regimen). Results obtained using this validated PHD dose-regimen indicated significant improvement by GSK360A (30mg/kg); administered at 18 and 5 hours prior to transient middle cerebral artery occlusion (stroke). GSK360A exposure and plasma, kidney and brain HIF-PHD pharmacodynamics endpoints (e.g., erythropoietin; EPO and Vascular Endothelial Growth Factor; VEGF) were measured. GSK360A provided rapid exposure in plasma (7734 ng/ml), kidney (45-52% of plasma level) and brain (1-4% of plasma level), and increased kidney EPO mRNA (80-fold) and brain VEGF mRNA (2-fold). We also observed that GSK360A increased plasma EPO (300-fold) and VEGF (2-fold). Further assessments indicated that GSK360A reduced post-stroke surgery neurological deficits (47-64%), cognitive dysfunction (60-75%) and brain infarction (30%) 4 weeks later. Thus, PHD inhibition using GSK360A pretreatment produced long-term post-stroke brain protection and improved behavioral functioning. These data support PHD inhibition, specifically by GSK360A, as a potential strategy for pre-surgical use to reduce brain injury and functional decline due to surgery-related cerebral injury.
[Mh] Termos MeSH primário: Comportamento Animal
Lesões Encefálicas/tratamento farmacológico
Lesões Encefálicas/etiologia
Transtornos Cognitivos/tratamento farmacológico
Glicina/análogos & derivados
Atividade Motora
Inibidores de Prolil-Hidrolase/uso terapêutico
Quinolonas/uso terapêutico
Acidente Vascular Cerebral/complicações
[Mh] Termos MeSH secundário: Administração Oral
Animais
Comportamento Animal/efeitos dos fármacos
Encéfalo/efeitos dos fármacos
Encéfalo/metabolismo
Encéfalo/patologia
Lesões Encefálicas/sangue
Lesões Encefálicas/fisiopatologia
Transtornos Cognitivos/etiologia
Eritropoetina/sangue
Eritropoetina/genética
Glicina/administração & dosagem
Glicina/farmacocinética
Glicina/farmacologia
Glicina/uso terapêutico
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Infarto da Artéria Cerebral Média/sangue
Infarto da Artéria Cerebral Média/complicações
Infarto da Artéria Cerebral Média/patologia
Infarto da Artéria Cerebral Média/fisiopatologia
Masculino
Atividade Motora/efeitos dos fármacos
Especificidade de Órgãos/efeitos dos fármacos
Prolil Hidroxilases/metabolismo
Inibidores de Prolil-Hidrolase/administração & dosagem
Inibidores de Prolil-Hidrolase/farmacologia
Quinolonas/administração & dosagem
Quinolonas/farmacocinética
Quinolonas/farmacologia
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos Sprague-Dawley
Sensação/efeitos dos fármacos
Acidente Vascular Cerebral/sangue
Acidente Vascular Cerebral/fisiopatologia
Fator A de Crescimento do Endotélio Vascular/sangue
Fator A de Crescimento do Endotélio Vascular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (N-((1-(cyclopropylethyl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl)glycine); 0 (Prolyl-Hydroxylase Inhibitors); 0 (Quinolones); 0 (RNA, Messenger); 0 (Vascular Endothelial Growth Factor A); 11096-26-7 (Erythropoietin); EC 1.14.11.- (Prolyl Hydroxylases); TE7660XO1C (Glycine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184049


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[PMID]:28527810
[Au] Autor:Nowlan B; Futrega K; Brunck ME; Walkinshaw G; Flippin LE; Doran MR; Levesque JP
[Ad] Endereço:Stem Cell Therapies Laboratory, Translational Research Institute, Queensland University of Technology, Woolloongabba, Queensland, Australia; Mater Research Institute, Translational Research Institute, University of Queensland, Woolloongabba, Queensland, Australia.
[Ti] Título:HIF-1α-stabilizing agent FG-4497 rescues human CD34 cell mobilization in response to G-CSF in immunodeficient mice.
[So] Source:Exp Hematol;52:50-55.e6, 2017 Aug.
[Is] ISSN:1873-2399
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Granulocyte colony-stimulating factor (G-CSF) is used routinely in the clinical setting to mobilize hematopoietic stem progenitor cells (HSPCs) into the patient's blood for collection and subsequent transplantation. However, a significant proportion of patients who have previously received chemotherapy or radiotherapy and require autologous HSPC transplantation cannot mobilize the minimal threshold of mobilized HSPCs to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are used in the clinical setting. We have shown previously in mice that administration of prolyl 4-hydroxylase domain enzyme (PHD) inhibitors, which stabilize hypoxia-inducible factor (HIF)-1α, synergize with G-CSF in vivo to enhance mouse HSPC mobilization into blood, leading to enhanced engraftment via an HSPC-intrinsic mechanism. To evaluate whether PHD inhibitors could be used to enhance mobilization of human HSPCs, we humanized nonobese, diabetic severe combined immune-deficient Il2rg mice by transplanting them with human umbilical cord blood CD34 HSPCs and then treating them with G-CSF with and without co-administration of the PHD inhibitor FG-4497. We observed that combination treatment with G-CSF and FG-4497 resulted in significant mobilization of human lineage-negative (Lin ) CD34 HSPCs and more primitive human Lin CD34 CD38 HSPCs into blood and spleen, whereas mice treated with G-CSF alone did not mobilize human HSPCs significantly. These results suggest that the PHD inhibitor FG-4497 also increases human HSPC mobilization in a xenograft mouse model, suggesting the possibility of testing PHD inhibitors to boost HSPC mobilization in response to G-CSF in humans.
[Mh] Termos MeSH primário: Fator Estimulador de Colônias de Granulócitos/farmacologia
Mobilização de Células-Tronco Hematopoéticas
Células-Tronco Hematopoéticas/efeitos dos fármacos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Isoquinolinas/farmacologia
Inibidores de Prolil-Hidrolase/farmacologia
[Mh] Termos MeSH secundário: Animais
Antígenos CD34/metabolismo
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos
Feminino
Sangue Fetal/citologia
Sangue Fetal/metabolismo
Citometria de Fluxo
Células-Tronco Hematopoéticas/metabolismo
Seres Humanos
Subunidade gama Comum de Receptores de Interleucina/deficiência
Subunidade gama Comum de Receptores de Interleucina/genética
Camundongos
Camundongos Endogâmicos NOD
Camundongos Knockout
Camundongos SCID
Fatores de Tempo
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD34); 0 (FG-4497); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Il2rg protein, mouse); 0 (Interleukin Receptor Common gamma Subunit); 0 (Isoquinolines); 0 (Prolyl-Hydroxylase Inhibitors); 143011-72-7 (Granulocyte Colony-Stimulating Factor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170522
[St] Status:MEDLINE


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[PMID]:28488896
[Au] Autor:Patel H; Soni K; Trivedi R; Heading H; Geue J; Kansagra K; Gupta RJ; Pandya VB; Srinivas NR; Patel PR; Desai RC
[Ad] Endereço:Zydus Research Centre, Bioanalytical Laboratory, Ahmedabad-382 210, India.
[Ti] Título:A sensitive assay for ZYAN1 in human whole blood and urine utilizing positive LC-MS/MS electrospray ionization.
[So] Source:Bioanalysis;9(9):719-732, 2017 May.
[Is] ISSN:1757-6199
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: A sensitive LC-MS/MS method was developed and validated for estimation of ZYAN1 in human blood/urine. METHODS: An analog internal standard IOX2 along with ZYAN1 was quantified using selective reaction monitoring in positive mode. The chromatographic separation was performed by gradient elution with C analytical column (3 µm, 50 mm × 2.0 mm) with 4-min run time using an acidified mobile phase consisting of ammonium formate and acetonitrile. Protein precipitation enabled extraction of analytes from diluted blood/urine. RESULTS: Calibration curve of ZYAN1 was linear (2-5000 ng/ml). The recovery of ZYAN1 and IOX2 was between 87 and 104%. Interday and intraday accuracy and precision was found well within the acceptance criteria. CONCLUSION: The validated assay was applied for clinical pharmacokinetics of ZYAN1 in healthy volunteers.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão/métodos
Inibidores de Prolil-Hidrolase/sangue
Inibidores de Prolil-Hidrolase/urina
Quinolonas/sangue
Quinolonas/urina
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Seres Humanos
Limite de Detecção
Reprodutibilidade dos Testes
Espectrometria de Massas por Ionização por Electrospray/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Prolyl-Hydroxylase Inhibitors); 0 (Quinolones); 0 (ZYAN1 compound)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.4155/bio-2017-0014


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[PMID]:28368464
[Au] Autor:Schaible B; Rodriguez J; Garcia A; von Kriegsheim A; McClean S; Hickey C; Keogh CE; Brown E; Schaffer K; Broquet A; Taylor CT
[Ad] Endereço:Conway Institute and.
[Ti] Título:Hypoxia Reduces the Pathogenicity of Pseudomonas aeruginosa by Decreasing the Expression of Multiple Virulence Factors.
[So] Source:J Infect Dis;215(9):1459-1467, 2017 May 01.
[Is] ISSN:1537-6613
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Our understanding of how the course of opportunistic bacterial infection is influenced by the microenvironment is limited. We demonstrate that the pathogenicity of Pseudomonas aeruginosa strains derived from acute clinical infections is higher than that of strains derived from chronic infections, where tissues are hypoxic. Exposure to hypoxia attenuated the pathogenicity of strains from acute (but not chronic) infections, implicating a role for hypoxia in regulating bacterial virulence. Mass spectrometric analysis of the secretome of P. aeruginosa derived from an acute infection revealed hypoxia-induced repression of multiple virulence factors independent of altered bacterial growth. Pseudomonas aeruginosa lacking the Pseudomonas prolyl-hydroxylase domain-containing protein, which has been implicated in bacterial oxygen sensing, displays reduced virulence factor expression. Furthermore, pharmacological hydroxylase inhibition reduces virulence factor expression and pathogenicity in a murine model of pneumonia. We hypothesize that hypoxia reduces P. aeruginosa virulence at least in part through the regulation of bacterial hydroxylases.
[Mh] Termos MeSH primário: Hipóxia Celular/fisiologia
Infecções por Pseudomonas/microbiologia
Pseudomonas aeruginosa/efeitos dos fármacos
Pseudomonas aeruginosa/patogenicidade
Fatores de Virulência/metabolismo
[Mh] Termos MeSH secundário: ADP Ribose Transferases/metabolismo
Doença Aguda
Animais
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/metabolismo
Toxinas Bacterianas/metabolismo
Microambiente Celular/fisiologia
Doença Crônica
Exotoxinas/metabolismo
Camundongos
Oxigênio/farmacologia
Prolil Hidroxilases/metabolismo
Inibidores de Prolil-Hidrolase/metabolismo
Pseudomonas aeruginosa/metabolismo
Sideróforos/metabolismo
Fatores de Virulência/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Bacterial Toxins); 0 (Exotoxins); 0 (Prolyl-Hydroxylase Inhibitors); 0 (Siderophores); 0 (Virulence Factors); EC 1.14.11.- (Prolyl Hydroxylases); EC 2.4.2.- (ADP Ribose Transferases); EC 2.4.2.31 (toxA protein, Pseudomonas aeruginosa); S88TT14065 (Oxygen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1093/infdis/jix139


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[PMID]:28266966
[Au] Autor:Harnoss JM; Platzer LK; Burhenne J; Radhakrishnan P; Cai J; Strowitzki MJ; Weiss J; Ritter AS; Mollenhauer M; Schmidt T; Ulrich A; Haefeli WE; Schneider M
[Ad] Endereço:*Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany †Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
[Ti] Título:Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth.
[So] Source:Ann Surg;265(4):782-791, 2017 Apr.
[Is] ISSN:1528-1140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: We sought to assess whether pharmacological inhibition of hypoxia-inducible transcription factor (HIF)-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) is a suitable strategy to stimulate liver regeneration after partial hepatectomy for colorectal liver metastases (CRLM). BACKGROUND: Liver regeneration occurs in a hypoxic environment. PHD1 to PHD3 are molecular oxygen sensors and increasingly considered as putative therapeutic targets. However, little is known about the effect of pharmacological PHD inhibition on tumor expansion, and on liver regeneration after surgical resection. METHODS: Various mouse models of liver regeneration after extended partial hepatectomy and portal vein ligation for multiple bilobar CRLM were applied to assess the effect of the small molecule pan-PHD inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on liver regeneration and metastatic tumor growth. Metabolism and biodistribution of EDHB were analyzed using liquid chromatography coupled to tandem mass spectrometry. RESULTS: EDHB selectively augmented liver regeneration after partial hepatectomy and portal vein ligation, and increased the expression of cell cycle-promoting cyclin proteins, without enhancing metastatic tumor growth. Systemically administered EDHB and its active metabolite 3,4-dihydroxybenzoic acid accumulated in the liver to selectively induce hepatoprotective effects in the liver, but not in tumor tissue, without humoral adverse effects. CONCLUSIONS: Pharmacological inhibition of PHDs using EDHB might represent a novel and safe strategy in the treatment of multiple bilobar CRLM.
[Mh] Termos MeSH primário: Neoplasias Colorretais/patologia
Hepatectomia/métodos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Neoplasias Hepáticas/secundário
Regeneração Hepática/efeitos dos fármacos
Inibidores de Prolil-Hidrolase/farmacologia
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Western Blotting
Neoplasias Colorretais/cirurgia
Modelos Animais de Doenças
Feminino
Neoplasias Hepáticas/cirurgia
Camundongos
Camundongos Endogâmicos BALB C
Distribuição Aleatória
Reação em Cadeia da Polimerase em Tempo Real
Sensibilidade e Especificidade
Células Tumorais Cultivadas/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (Prolyl-Hydroxylase Inhibitors)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170612
[Lr] Data última revisão:
170612
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170308
[St] Status:MEDLINE
[do] DOI:10.1097/SLA.0000000000001696


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[PMID]:27548524
[Au] Autor:Olcina MM; Giaccia AJ
[Ti] Título:Reducing radiation-induced gastrointestinal toxicity - the role of the PHD/HIF axis.
[So] Source:J Clin Invest;126(10):3708-3715, 2016 Oct 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain-containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail.
[Mh] Termos MeSH primário: Trato Gastrointestinal/patologia
Inibidores de Prolil-Hidrolase/farmacologia
Lesões por Radiação/prevenção & controle
Protetores contra Radiação/farmacologia
[Mh] Termos MeSH secundário: Animais
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Trato Gastrointestinal/metabolismo
Trato Gastrointestinal/efeitos da radiação
Seres Humanos
Neoplasias/radioterapia
Prolil Hidroxilases/metabolismo
Inibidores de Prolil-Hidrolase/uso terapêutico
Estabilidade Proteica
Lesões por Radiação/metabolismo
Protetores contra Radiação/uso terapêutico
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Prolyl-Hydroxylase Inhibitors); 0 (Radiation-Protective Agents); EC 1.14.11.- (Prolyl Hydroxylases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


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[PMID]:27454299
[Au] Autor:Taylor CT; Doherty G; Fallon PG; Cummins EP
[Ti] Título:Hypoxia-dependent regulation of inflammatory pathways in immune cells.
[So] Source:J Clin Invest;126(10):3716-3724, 2016 Oct 03.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.
[Mh] Termos MeSH primário: Imunidade
Inflamação/metabolismo
Macrófagos/metabolismo
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/farmacologia
Hipóxia Celular
Seres Humanos
Fator 1 Induzível por Hipóxia/fisiologia
Inflamação/tratamento farmacológico
Macrófagos/imunologia
Prolil Hidroxilases/metabolismo
Inibidores de Prolil-Hidrolase/farmacologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Hypoxia-Inducible Factor 1); 0 (Prolyl-Hydroxylase Inhibitors); EC 1.14.11.- (Prolyl Hydroxylases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160726
[St] Status:MEDLINE


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[PMID]:27352308
[Au] Autor:Groenendaal-van de Meent D; Adel MD; Noukens J; Rijnders S; Krebs-Brown A; Mateva L; Alexiev A; Schaddelee M
[Ad] Endereço:Astellas Pharma Europe B.V., Leiden, The Netherlands.
[Ti] Título:Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
[So] Source:Clin Drug Investig;36(9):743-751, 2016 Sep.
[Is] ISSN:1179-1918
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo: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. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function. RESULTS: In subjects with moderate hepatic impairment, area under the concentration-time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (C max) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1-175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5-104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t ½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (V z/F) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (E max) were 31 % (GMR 68.95 %; 90 % CI 29.29-162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95-94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated. CONCLUSIONS: This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.
[Mh] Termos MeSH primário: Glicina/análogos & derivados
Fator 1 Induzível por Hipóxia/antagonistas & inibidores
Isoquinolinas/farmacocinética
Hepatopatias/metabolismo
Inibidores de Prolil-Hidrolase/farmacologia
Inibidores de Prolil-Hidrolase/farmacocinética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Área Sob a Curva
Eritropoetina/metabolismo
Feminino
Glicina/efeitos adversos
Glicina/farmacocinética
Glicina/farmacologia
Meia-Vida
Seres Humanos
Isoquinolinas/efeitos adversos
Isoquinolinas/farmacologia
Cirrose Hepática/metabolismo
Masculino
Meia-Idade
Inibidores de Prolil-Hidrolase/efeitos adversos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FG-4592); 0 (Hypoxia-Inducible Factor 1); 0 (Isoquinolines); 0 (Prolyl-Hydroxylase Inhibitors); 11096-26-7 (Erythropoietin); TE7660XO1C (Glycine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170525
[Lr] Data última revisão:
170525
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160629
[St] Status:MEDLINE
[do] DOI:10.1007/s40261-016-0422-y



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