Lung Delivery of Nebulized Tissue Plasminogen Activator

雾化组织纤溶酶原激活剂的肺部输送

基本信息

  • 批准号:
    6690953
  • 负责人:
  • 金额:
    $ 9.97万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-15 至 2004-09-14
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Acute respiratory distress syndrome (ARDS) afflicts tens of thousands of individuals annually in the United States and is associated with significant mortality. Presently, there is no effective treatment and little optimism exists for prospective therapies currently under investigation. A unique antiinflammatory agent (protein) that reduces neutrophil reactive oxygen species (ROS)-mediated injury in an animal model of lung inflammation has been identified and represents a potentially viable therapy for ARDS. Therefore, the broad, long-term objectives of this research and drug development program are to develop a unique, localized (lung-targeted) therapy that will be effective in reducing the mortality associated with ARDS. The purpose of this phase I application is to prove the principle of this strategy in man by developing a drug formulation that will sustain the nebulization process and distribute adequately into the human respiratory tract. To this end, the specific aims of this project are to: 1) formulate the agent to make it suitable for local pulmonary delivery via nebulization while retaining activity. Optimal formulation will be derived by the addition of varying concentrations of surfactant. The formulation activities will include an assessment of protein stability, aerodynamic particle size, and biological function. Protein stability will be measured by total protein recovery and structural integrity. Particle size will be determine using a cascade impactor and biological activity will be quantified by the ability of the agent to inhibit neutrophil ROS production; 2) characterize the respiratory deposition of a nebulized formulation of the agent in a human lung replica model. This aim is designed to generate additional supportive evidence to prove the principle of the formulation in man. To accomplish this aim, each viable formulation, as determined by the feasibility criteria of specific aim #1, will be nebulized into a human lung replica. A high-fidelity human lung replica reproduced from a master cast made from a human cadaver which includes five to nine generations of bronchi will be utilized. Deposition in the small airways and alveoli regions of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. The results of the work performed in both specific aims will determine the feasibility of the nebulized formulation of this new and novel agent as well as serve as the basis for a phase II application and the subsequent commercialization of the product
描述(由申请人提供):急性呼吸窘迫综合征(ARDS)在美国每年折磨数以万计的人,并与显著的死亡率相关。目前,没有有效的治疗方法,目前正在研究的前瞻性治疗方法也不太乐观。一种独特的抗炎剂(蛋白质)可以减少肺炎症动物模型中中性粒细胞活性氧(ROS)介导的损伤,这是一种潜在可行的治疗ARDS的方法。因此,这项研究和药物开发计划的广泛、长期目标是开发一种独特的、局部的(肺靶向的)治疗方法,有效降低与ARDS相关的死亡率。这个I期申请的目的是通过开发一种能够维持雾化过程并充分分布到人体呼吸道的药物配方来证明该策略在人体中的原理。为此,本课题的具体目的是:1)配制药剂,使其适合于局部肺雾化输送,同时保持活性。通过加入不同浓度的表面活性剂,可得出最佳配方。配方活动将包括蛋白质稳定性、空气动力学粒度和生物功能的评估。蛋白质稳定性将通过总蛋白质回收率和结构完整性来衡量。颗粒大小将使用级联冲击器确定,生物活性将通过药物抑制中性粒细胞ROS产生的能力来量化;2)表征该制剂雾化制剂在人肺复制模型中的呼吸沉积。这一目标旨在产生额外的支持性证据,以证明人体配方的原理。为了实现这一目标,根据具体目标1的可行性标准确定的每种可行配方将雾化到人体肺复制品中。一个高保真的人体肺复制品复制从主铸造从人类尸体,其中包括5至9代支气管将被利用。在铸件的小气道和肺泡区域的沉积是由通过上游气道的材料模拟的,并收集在泡沫过滤器上。在这两个具体目标中进行的工作的结果将确定这种新型制剂的雾化配方的可行性,并作为第二阶段应用和随后产品商业化的基础

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs.
  • DOI:
    10.1007/s11095-015-1763-6
  • 发表时间:
    2016-01
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Lin S;Racz J;Tai MF;Brooks KM;Rzeczycki P;Heath LJ;Newstead MW;Standiford TJ;Rosania GR;Stringer KA
  • 通讯作者:
    Stringer KA
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KATHLEEN A STRINGER其他文献

KATHLEEN A STRINGER的其他文献

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{{ truncateString('KATHLEEN A STRINGER', 18)}}的其他基金

Translational Metabolomics in Critical Care
重症监护中的转化代谢组学
  • 批准号:
    10116432
  • 财政年份:
    2020
  • 资助金额:
    $ 9.97万
  • 项目类别:
Translational Metabolomics in Critical Care
重症监护中的转化代谢组学
  • 批准号:
    10569560
  • 财政年份:
    2020
  • 资助金额:
    $ 9.97万
  • 项目类别:
Translational Metabolomics in Critical Care
重症监护中的转化代谢组学
  • 批准号:
    10592586
  • 财政年份:
    2020
  • 资助金额:
    $ 9.97万
  • 项目类别:
Translational Metabolomics in Critical Care
重症监护中的转化代谢组学
  • 批准号:
    10365995
  • 财政年份:
    2020
  • 资助金额:
    $ 9.97万
  • 项目类别:
IND119678 Phase II Safety & Efficacy of Inhaled Activase for Acute Plastic Bronchitis 12-10-14
IND119678 第二阶段安全
  • 批准号:
    9631306
  • 财政年份:
    2016
  • 资助金额:
    $ 9.97万
  • 项目类别:
L-Carnitine Pharmacometabolomics in Sepsis (CaPS)
脓毒症中的左旋肉碱药物代谢组学 (CaPS)
  • 批准号:
    9233165
  • 财政年份:
    2016
  • 资助金额:
    $ 9.97万
  • 项目类别:
Pulmonary Formulation of tPA for Plastic Bronchitis
用于治疗塑料性支气管炎的 tPA 肺部制剂
  • 批准号:
    7938229
  • 财政年份:
    2010
  • 资助金额:
    $ 9.97万
  • 项目类别:
Safety of Lung Delivered Tissue Plasminogen Activator
肺递送组织纤溶酶原激活剂的安全性
  • 批准号:
    6991733
  • 财政年份:
    2002
  • 资助金额:
    $ 9.97万
  • 项目类别:
Safety of Lung Delivered Tissue Plasminogen Activator
肺递送组织纤溶酶原激活剂的安全性
  • 批准号:
    7125049
  • 财政年份:
    2002
  • 资助金额:
    $ 9.97万
  • 项目类别:

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