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.
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.
