Pulmonary Formulation of tPA for Plastic Bronchitis

描述（由申请人提供）：可塑性支气管炎（PB）是一种罕见的儿科疾病，其特征是气道中存在大的纤维蛋白或粘蛋白管型。这是一个严重的健康危害儿童与高死亡率（约50%）。目前，PB是用吸入性组织纤溶酶原激活剂（tPA）治疗的，没有安全性或有效性的证据。我们已经开发了一种tPA的肺部制剂（pf-tPA），它能承受喷射雾化，是目前使用的未改性制剂的更安全的替代品。尽管目前在实践中使用tPA，但尚未确定减少PB管型质量所需的pf-tPA浓度以及pf-tPA向儿科人群的呼吸递送。这些数据对于确保设计安全有效的pf-tPA剂量治疗PB至关重要。因此，本申请的总体目标是证明pf-tPA在PB治疗中具有实用性，并对儿科剂量进行合理估计。与恢复法有限竞争的目标一致：学术研究增强奖（R15），这项工作还将通过为药学专业学生参与有价值的研究提供支持，刺激NIH资助不足的教育机构的研究。将测试以下具体目标：1）通过确定减少铸件质量的浓度范围，证明pf-tPA在PB中的有效性。我们将从密歇根大学的儿科PB患者队列中获取模型。我们的假设是，可以在气道中安全达到的pf-tPA浓度将减少离体纤维蛋白而不是粘蛋白PB管型的管型质量。这得到了我们的初步数据的支持，这些数据显示了pf-tPA减少纤维蛋白铸型质量的能力; 2）通过获取空气动力学粒度数据来估计雾化pf-tPA的肺部分布和可吸入剂量，以证明儿科肺部递送。通过将pf-tPA雾化到粒度测定系统中采集数据，该系统包含指示儿科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尺寸将导致> 10%的可吸入剂量; 3）开发pf-tPA的肺清除模型。我们的初步数据表明pf-tPA在肺部蓄积，这可能在男性中发生更大程度。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先前建立的（例如，性别）变量影响pf-tPA肺清除率。我们的假设是性别将是影响pf-tPA肺清除率的独立变量。总的来说，这些实验的结果很有可能对该领域产生持续和强大的影响，因为它们将能够构建合理的pf-tPA给药方案。目前的临床实践中使用未改性的tPA配方，虽然假定有效，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，通过支持研究来纠正这种情况，这将导致PB患者安全有效的pf-tPA剂量。 塑料性支气管炎是一种罕见但对儿童健康有重大危害的疾病。不幸的是，我们没有任何治疗塑料支气管炎的方法，所以使用的药物未经测试。这使儿童面临药物不良反应的风险。这个项目题为“tPA的塑料支气管炎肺部制剂“将有助于确定适当和安全剂量的药物是交付到肺部治疗塑料支气管炎。我们从这个项目中获得的信息与公共卫生有关，因为它将改善重病儿童的健康和护理。

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.