A Mechanistic Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

抑制 JAK 预防呼吸机引起的膈肌功能障碍的机制临床试验

• 批准号: 9803691
• 负责人: Leah M Backhus
• 金额: $ 39.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9803691
• 关键词: Air; Animal Model; Animals; Apoptosis; Atrophic; Autophagocytosis; Biochemical; Bioenergetics; Biological Process; Biopsy; Breathing; Cessation of life; Clinical; Clinical Trials; Complex; Dependence; Disease; Drug Targeting; Environmental air flow; Esophagectomy; Etiology; FDA approved; Failure; Fiber; Functional disorder; Funding; Goals; Hour; Human; Institution; Intensive Care Units; Lead; Lung; Measures; Mechanical ventilation; Mechanics; Mitochondria; Modeling; Molecular; Movement; Muscle; Muscle Fibers; Muscle Weakness; Outcome Measure; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Placebos; Prevention; Procedures; Process; Proteolysis; Randomized; Rattus; Respiratory Diaphragm; Role; STAT3 gene; Short Interspersed Nucleotide Elements; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Ventilator; Weaning; Work; base; care costs; cohort; cost; first-in-human; health economics; human model; human subject; inhibitor/antagonist; operation; prevent; transcription factor

The goal of this project is to identify a drug that could be administered to patients who require mechanical ventilation (MV) in our intensive care units – a drug which would reduce the time patients are required to be on the ventilator. It is known that MV leads to weakness of the diaphragm (ventilator-induced diaphragm dysfunction – “VIDD”). Since the diaphragm is the muscle that is primarily responsible for moving air into the lungs during breathing, if it becomes weak, then it becomes more difficult to separate patients from the ventilator. The resulting long-term dependence on the ventilator is associated with increased rates of complications and death. A drug that can be given at the initiation of MV and prevent weakness of the diaphragm will therefore reduce ventilator dependence and complications/deaths in intensive care unit (ICU) patients. Based upon work we have done previously, we know that inter-related molecules called “JAK” and “STAT3” are important in the etiology of VIDD in both animals and in humans. When we blocked the action of these molecules with a JAK inhibitor drug in mechanically ventilated animals, diaphragm weakness did not occur. We therefore believe that a JAK inhibitor holds promise as a drug to prevent VIDD in mechanically ventilated patients. We propose to study mechanically ventilated human subjects to determine if the FDA- approved JAK inhibitor, Tofacitinib, will prevent the activation of the biological processes that we know lead to VIDD and prevent VIDD itself. To achieve this, we will take 2 small diaphragm biopsies, 6 hours apart, in patients undergoing esophagectomy, and we will study the effects that MV and Tofacitinib have on the changes that occur in this tissue. Patients will be randomized to receiving Tofacitinib vs placebo prior to esophagectomy and diaphragm biopsies: Aim 1 –Study the biopsies to determine if JAK inhibition prevents the activation of JAK/STAT and known downstream effectors of VIDD in human diaphragm subjected to MV. Aim 2 –Study the biopsies to determine if JAK inhibition prevents the diaphragm weakness which defines VIDD in human diaphragm subjected to MV. This study will provide the required information to support a subsequent clinical trial in ICU patients, which we hope would establish that JAK inhibition will indeed reduce the duration of MV, complications, and deaths. It will also advance this field by allowing us to study pathways beyond JAK/STAT that may be important in causing VIDD in human diaphragm.

该项目的目的是识别可以给患者使用的药物 在我们的重症监护单元中需要机械通气（MV） - 一种可以减少您的药物 时间患者必须在呼吸机上。 众所周知，MV导致隔膜弱（呼吸机诱导的隔膜） 功能障碍 - “ vidd”）。 在呼吸过程中，将空气移入肺部，如果它变得虚弱，那么就变得更加困难 将患者与呼吸机分开。 与汇编和死亡率增加有关。 MV的启动和隔膜的预防弱点减少了呼吸机 重症监护病房（ICU）患者的依赖性和汇编/死亡。 基于我们以前所做的工作，我们知道相互关联的分子被升级 “ JAK”和“ STAT3”在动物和人类的Vidd的病因中很重要。 我们用JAK抑制剂药物在机械通风中阻止了这些分子的作用 动物，diaphragm弱点没有发生。 作为预防狂欢的通风患者的药物承诺。 我们建议研究机械通风的人类受试者，以确定FDA-是否是否 批准的JAK抑制剂Tofacitinib将产生生物学过程 知道导致VIDD并防止Vidd Iself实现这一目标。 活检，6小时的APAST，在接受食管的患者中，我们将研究这些作用 MV和Tofacitib在该组织中发生的变化中具有。 在食管切除术和隔膜活检之前，随机接受tofacitinib vs安慰剂： AIM 1-研究活检以确定JAK抑制是否阻止JAK/STAT的激活 并已知在人隔膜中的Vidden的已知下游效应子受到MV的影响。 AIM 2-研究活检以确定JAK抑制是否防止隔膜无力 它定义了受MV的人膜片中的VIDD。 这项研究将主要提供所需的信息，以支持随后的临床试验 ICU患者，我们希望这能确定JAK抑制确实会减少持续时间 MV，并发症和死亡。 超越JAK/STAT的途径可能在引起人体隔膜的VIDD可能很重要。