Pulmonary Formulation of tPA for Plastic Bronchitis

描述（由申请人提供）：塑料支气管炎（PB）是一种罕见的儿科疾病，其特征是气道中存在大量纤维蛋白或粘蛋白铸型。对儿童来说，这是一种严重的健康危害，死亡率高（约50%）。目前，坊间传闻用吸入组织型纤溶酶原激活剂（tPA）治疗PB，但没有安全性或有效性的证据。我们已经开发了一种肺部配方的tPA (pf-tPA)，它可以承受喷射雾化，并且比目前使用的未经修改的配方更安全。尽管目前在实践中使用tPA，但减少PB铸型质量所需的pf-tPA浓度以及儿科人群呼吸输送pf-tPA的浓度尚未确定。这些数据对于确保设计安全有效的pf-tPA治疗PB剂量至关重要。因此，本应用的总体目标是显示pf-tPA在治疗PB方面的效用，并对儿科剂量做出合理的估计。与恢复法案有限竞争：学术研究增强奖（R15）的目标一致，这项工作还将通过支持药学学生参与有价值的研究，刺激NIH资助不足的教育机构的研究。以下具体目标将被测试：1)通过确定一系列降低铸件质量的浓度来证明pf-tPA在PB中的有效性。我们将从密歇根大学儿童PB患者队列中获取模型。我们的假设是，在气道中可以安全达到的pf-tPA浓度将减少纤维蛋白的铸型质量，但不会减少黏液蛋白的体外铸型。我们的试点数据支持了这一点，该数据显示pf-tPA能够减少纤维蛋白铸块；2)通过获取空气动力学颗粒尺寸数据来估计雾化pf-tPA的肺部分布和可吸入剂量，从而证明儿童肺部分娩。数据将通过将pf-tPA雾化到颗粒分级系统中获得，该系统结合了儿科PB患者的呼吸周期和通气参数。我们的假设是，在这种情况下产生的颗粒大小将导致可吸入剂量为100 - 10%；3)建立pf-tPA肺清除率模型。我们的初步数据表明，pf-tPA在肺部积聚，这可能在男性中更大程度上发生。我们将在实验模型中估计pf-tPA肺清除率，并使用多元线性回归来确定哪些先前建立的变量（例如，性别）会影响pf-tPA肺清除率。我们的假设是，性别将是一个独立的变量，影响肺清除率的pf-tPA。总的来说，这些实验的结果极有可能对该领域产生持续而有力的影响，因为它们将使构建合理的pf-tPA给药方案成为可能。目前的临床实践使用未经修改的tPA配方，虽然被认为是有效的，但可能会使儿童面临严重药物不良事件的风险。这项申请的资助代表了一个重要的机会，通过支持将导致对PB患者安全有效地给药pf-tPA的研究来纠正这种情况。

DESCRIPTION (provided by applicant): Plastic bronchitis (PB) is a rare pediatric disease characterized by the presence of large fibrin or mucin casts in the airways. It is a significant health hazard in children associated with a high mortality rate (~50%). Presently, PB is anecdotally treated with inhaled tissue plasminogen activator (tPA) with no evidence for safety or efficacy. We have developed a pulmonary formulation of tPA (pf-tPA) that withstands jet nebulization and would be a safer alternative to the unmodified formulation currently being used. Despite the current use of tPA in practice, the pf-tPA concentrations needed to reduce the mass of PB casts, and respiratory delivery of pf- tPA to the pediatric population have not been established. These data are essential to ensure the design of safe and effective pf-tPA dosing for the treatment of PB. Therefore, the overall goals of this application are to show that pf-tPA has utility in the treatment of PB and to make a logical estimate of a pediatric dose. Consistent with the objectives of the Recovery Act Limited Competition: Academic Research Enhancement Award (R15), this work will also stimulate research at an educational institution underfunded by the NIH by providing support for the participation of pharmacy students in meritorious research. The following specific aims will be tested: 1) To prove pf-tPA effectiveness in PB by identifying a range of concentrations that reduce cast mass. We will acquire casts from a cohort of University of Michigan pediatric PB patients. Our hypothesis is that pf-tPA concentrations that can be safely achieved in the airways will reduce the cast mass of fibrin but not mucin PB casts ex vivo. This is supported by our pilot data which show the ability of pf-tPA to reduce fibrin cast mass; 2) To demonstrate pediatric pulmonary delivery by acquiring aerodynamic particle size data to estimate lung distribution and respirable dose of nebulized pf-tPA. Data will be acquired by nebulizing pf-tPA into a particle sizing system that incorporates the respiratory cycle and ventilation parameters indicative of the pediatric PB patient. Our hypothesis is that the particle sizes generated in this setting will result in a respirable dose of > 10%; 3) To develop a lung clearance model of pf-tPA. Our preliminary data suggest pf-tPA accumulates in the lungs and this may occur to a greater extent in males. We will estimate pf-tPA lung clearance in an experimental model and use multivariate linear regression to identify which of the previously established (e.g., gender) variables influence pf-tPA lung clearance. Our hypothesis is that gender will be an independent variable that influences the lung clearance of pf-tPA. Collectively, the results of these experiments have a high likelihood of exerting a sustained and powerful influence on the field because they will enable the construction of a rational dosing scheme for pf-tPA. The current clinical practice of using the unmodified formulation of tPA, although presumed effective, may be placing children at risk for serious adverse drug events. Funding of this application represents an important opportunity to remedy this situation by supporting research that will lead to the safe and effective dosing of pf-tPA for patients with PB. PUBLIC HEALTH RELEVANCE: Plastic bronchitis is a rare but significant hazard to the health of children. Unfortunately, we do not have any treatments for plastic bronchitis so medicines are used that have not been tested. This puts children at risk for adverse drug reactions. This project entitled "Pulmonary Formulation of tPA for Plastic Bronchitis " will help determine the proper and safe dose of a drug that is delivered to the lungs for the treatment plastic bronchitis. The information we acquire from this project is relevant to public health because it will improve the health and care of severely ill children.