Open label, Multicenter, Prospective Study to Characterize the Pharmacokinetics and Pharmacodynamics of Cufence (Trientine Dihydrochloride) and to Investigate the Efficacy and Safety in Wilson’s Disease Patients - TR-004 UNITED Study

开始日期2021-10-08

申办/合作机构-

CTR20211406 / Active, not recruiting临床2期

一项在心力衰竭和射血分数降低患者中评价 INL1（Trientine）效果的随机化、双盲、安慰剂对照研究

目的：主要目的：评价12周时INL1（盐酸曲恩汀）与安慰剂相比在NYHA 心功能分级Ⅱ～Ⅲ级伴左心室射血分数降低（LVEF<40%）的心力衰竭患者中的疗效。次要目的：评价INL1（盐酸曲恩汀）与安慰剂相比在心力衰竭患者中的安全性和耐受性。描述12周治疗期间INL1（盐酸曲恩汀）的药代动力学（PK）特征

开始日期2021-07-01

申办/合作机构

Frontage Laboratories, Inc.

[+2]

NCT04706429 / Active, not recruiting临床2期IIT

A Randomised, Double-blind, Placebo-controlled, Phase 2 Evaluation of the Efficacy and Mechanism of Trientine in Patients With Hypertrophic Cardiomyopathy

This research study has been designed to test whether a drug called trientine dihydrochloride (also called Cufence) reduces heart muscle thickening, improves exercise capacity, improves heart function and reduces abnormal heart rhythms in patients with hypertrophic cardiomyopathy (HCM). The study is also assessing how trientine works in HCM. Participants will be prescribed either trientine or placebo, for a period of 12 months.

开始日期2020-12-01

申办/合作机构

Manchester University NHS Foundation Trust

[+5]

100 项与 HIF-1α x Cu 相关的临床结果

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100 项与 HIF-1α x Cu 相关的转化医学

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0 项与 HIF-1α x Cu 相关的专利（医药）

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项与 HIF-1α x Cu 相关的文献（医药）

2000-07-01·Journal of Biological Chemistry2区 · 生物学

Role of Hypoxia-inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency

2区 · 生物学

Article

作者: Chinmay K. Mukhopadhyay ; Barsanjit Mazumder ; Paul L. Fox

A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these observations.

PLoS ONE3区 · 综合性期刊

Copper Deficiency Induced Emphysema Is Associated with Focal Adhesion Kinase Inactivation

3区 · 综合性期刊

ArticleOA

作者: Aysar Alhussaini ; Donatas Kraskauskas ; Laszlo Farkas ; Daniela Farkas ; Masanori Yasuo ; Norbert F. Voelkel ; Harm J. Bogaard ; Jose Gomez-Arroyo ; Shiro Mizuno

BACKGROUNDCopper is an important regulator of hypoxia inducible factor 1 alpha (HIF-1α) dependent vascular endothelial growth factor (VEGF) expression, and is also required for the activity of lysyl oxidase (LOX) to effect matrix protein cross-linking. Cell detachment from the extracellular matrix can induce apoptosis (anoikis) via inactivation of focal adhesion kinase (FAK).METHODOLOGYTo examine the molecular mechanisms whereby copper depletion causes the destruction of the normal alveolar architecture via anoikis, Male Sprague-Dawley rats were fed a copper deficient diet for 6 weeks while being treated with the copper chelator, tetrathiomolybdate. Other groups of rats were treated with the inhibitor of auto-phosphorylation of FAK, 1,2,4,5-benzenetetraamine tetrahydrochloride (1,2,4,5-BT) or FAK small interfering RNA (siRNA).PRINCIPAL FINDINGSCopper depletion caused emphysematous changes, decreased HIF-1α activity, and downregulated VEGF expression in the rat lungs. Cleaved caspase-3, caspase-8 and Bcl-2 interacting mediator of cell death (Bim) expression was increased, and the phosphorylation of FAK was decreased in copper depleted rat lungs. Administration of 1,2,4,5-BT and FAK siRNA caused emphysematous lung destruction associated with increased expression of cleaved capase-3, caspase-8 and Bim.CONCLUSIONSThese data indicate that copper-dependent mechanisms contribute to the pathogenesis of emphysema, which may be associated with decreased HIF-1α and FAK activity in the lung.