Cardio-Renal Effects of Torsemide vs. Furosemide: A TRANSFORM-HF Mechanistic Sub-Study

托塞米与呋塞米的心肾效应：TRANSFORM-HF 机制子研究

基本信息

批准号：
10199884
负责人：
JEFFREY M TESTANI
金额：
$ 79.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199884
关键词：
Acute Address Albumins Aldosterone Animals Applications Grants Binding Biological Biological Assay Biological Availability Blood Plasma Volume Body Fluids Body Water Bolus Infusion Cessation of life Clinical Congestive Continuous Infusion Controlled Environment Data Defect Deuterium Oxide Diet Distal Diuresis Diuretics Dose Drug Kinetics Excretory function Financial compensation Funding Furosemide Goals Gold Half-Life Heart failure Henle&apos s loop Heterogeneity Hospitalization Human Hypertrophy I131 isotope In Vitro Inferior Infusion procedures Inpatients Iothalamate Kidney Kinetics Liquid substance Lithium Low Cardiac Output Measurement Measures Medical Minor Nephrons Outcome Participant Patients Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Population Potassium Property Proteins Proxy Randomized Research Technics Resistance Role SLC12A3 gene Signal Transduction Sodium Sodium Channel Structure Symptoms Tissues Translating Tubular formation United States National Institutes of Health Up-Regulation Water absorption clinical practice clinically relevant design extracellular improved in vivo insight kidney dysfunction member pharmacokinetics and pharmacodynamics prevent receptor standard measure urinary

项目摘要

Despite being the cornerstone of decongestive therapy in heart failure (HF), loop diuretics are paradoxically one of the least well-studied classes of HF medications and substantial differences exist between members of the class. Compared to furosemide, torsemide has 1) superior bioavailability and absorption, 2) significantly longer half-life and 3) potential broad spectrum “anti-aldosterone” effects. These theoretical advantages of torsemide, in part, motivated the NIH funded 6000 participant TRANSFORM-HF study, which will definitively establish the value of torsemide on hard outcomes. At first glance, the above differences would imply a self- evident superiority of torsemide. However, it is also known that severe within-dose diuretic resistance occurs in healthy subjects administered torsemide during its long half-life; indeed, animal studies have demonstrated massive adverse structural remodeling of the distal tubule with prolonged loop diuretic exposure. We have recently demonstrated that distal tubular compensation is in fact the dominant mechanism of loop diuretic resistance in human HF and pharmacokinetic defects are relegated to a minor role. Additionally, while there may be in vitro anti-aldosterone effects, it is unclear if this translates into clinically relevant effects in HF patients on contemporary medical therapy. Lastly, furosemide also has unique properties such as promiscuous antagonism of sodium channels proximal and distal to the loop of Henle and a paradoxical improvement in relative potency with progressive renal dysfunction. As such, with currently available data, a biologically plausible case for superiority or inferiority of torsemide can be made. The overarching goal of this proposal is to rigorously characterize candidate mechanisms by which torsemide may influence outcome within the TRANSFORM-HF population. To achieve this goal, we propose a three center, 150 patient mechanistic sub study of TRANSFORM-HF which will query a detailed set of mechanistic parameters both at randomization and again at 30 days to answer the following questions: 1) What are the net effects of known and unknown differences between torsemide and furosemide on the ultimate target of diuretic therapy- volume status? We will address this by evaluating changes in gold standard body fluid space measurements (plasma volume, extra cellular water, total body water). 2) Are there clinically relevant pleiotropic anti-aldosterone effects of torsemide? We will address this with functional and structural readouts of tissue level aldosterone activity; potassium excretion and urinary exosomal levels of the aldosterone regulated protein γENaC. 3) Does torsemide, with its long half-life, result in adverse structural remodeling of the kidney and redistribution of intra- renal sodium handling? We will address this by evaluating structural changes with urinary exosomal levels of the distal tubular transporter NCC and functionally by evaluating changes in endogenous lithium clearance, a well-established in vivo metric of regional tubular sodium handling.

尽管袢利尿剂是心力衰竭 (HF) 去充血治疗的基石，但它却存在矛盾之处心力衰竭药物研究最少的类别之一，并且成员之间存在显着差异与呋塞米相比，托拉塞米具有 1) 优越的生物利用度和吸收，2) 显着。更长的半衰期和3）潜在的广谱“抗醛固酮”作用这些理论上的优点。托拉塞米在一定程度上推动了 NIH 资助的 6000 名参与者 TRANSFORM-HF 研究，该研究最终将乍一看，上述差异意味着托拉塞米对硬结果的价值。托拉塞米的明显优越性然而，也已知严重的剂量内利尿抵抗。事实上，动物研究已经证明，健康受试者在其较长的半衰期期间服用了托拉塞米；长期接触袢利尿剂会导致远端肾小管发生大规模不良结构重塑。最近证明，远端肾小管代偿实际上是袢利尿剂的主要机制人类心力衰竭的耐药性与药代动力学缺陷也有一定的关系，但也有一定的作用。可能是体外抗醛固酮作用，尚不清楚这是否会转化为心力衰竭的临床相关作用最后，呋塞米还具有独特的特性，例如混杂。亨利环近端和远端钠通道的拮抗作用以及自相矛盾的改善因此，根据目前可用的数据，从生物学角度来看，其与进行性肾功能障碍的相对效力。可以提出托拉塞米的优越性或劣势的合理理由该提案的总体目标。是严格描述托拉塞米可能影响结果的候选机制 TRANSFORM-HF 人群为了实现这一目标，我们提出了一个三中心、150 名患者的机制。 TRANSFORM-HF 的子研究将随机查询一组详细的机械参数 30 天后再次回答以下问题： 1) 已知和未知的净效应是什么托拉塞米和呋塞米在利尿治疗的最终目标——容量状态上的区别？将通过评估金标准体液空间测量值（血浆体积、 2) 是否存在临床相关的多效性抗醛固酮作用我们将通过组织水平醛固酮活性的功能和结构读数来解决这个问题；醛固酮调节蛋白 γENaC 的钾排泄和尿外泌体水平 3) 是否。托拉塞米半衰期长，会导致肾脏的不良结构重塑和体内肾素的重新分配。肾脏钠处理？我们将通过评估尿外泌体水平的结构变化来解决这个问题通过评估内源性锂清除率的变化来评估远端管状转运蛋白 NCC 的功能，区域肾小管钠处理的完善的体内指标。