Improving Drug Delivery In Individuals With Cystic Fibrosis Using Exercise

 描述（由申请人提供）：本申请的目的是确定在运动期间雾化沙丁胺醇给药是否可以改善囊性纤维化（CF）患者中沙丁胺醇（一种支气管扩张剂）的输送和生理反应。这个项目将提供优秀的智力和强大的技术培训机会，以支持申请人 在实现她的目标，成为一个独立的研究者研究转化心肺生理学。具体目标1将检验以下假设：与沙丁胺醇或单独运动相比，在健康个体和CF患者中，运动和沙丁胺醇联合使用时支气管扩张程度最大。我们将评估支气管扩张[1秒用力呼气量（FEV 1）和25-75%用力肺活量（FEF 25 -75）的用力呼气流量的变化]对三种治疗的反应：1）运动，2）雾化沙丁胺醇给药，3）运动联合沙丁胺醇给药。在特定目标2中，我们将检验以下假设：运动后支气管扩张的持续时间最短，运动联合沙丁胺醇时支气管扩张的持续时间显著增加。我们将在每次治疗后评估6小时的支气管扩张，如果在中度有氧运动期间沙丁胺醇给药在6小时内具有最大的支气管扩张曲线下面积（FEV 1和FEF 25 -75），则接受我们的假设。具体目标3将检验在运动期间给予沙丁胺醇雾化剂将改善药物递送的假设。我们将在6小时内测量三种情况下的沙丁胺醇血浆浓度，并进行药代动力学分析。我们预测，与标准雾化沙丁胺醇治疗相比，运动期间雾化沙丁胺醇的递送将具有改善的药代动力学特征（最大浓度和曲线下面积）。在运动期间给予吸入性支气管扩张剂可能导致药物更好的递送和分布，这可能增强或延长运动或沙丁胺醇单独的支气管扩张和药代动力学作用。这项研究将作为概念证明，运动与雾化药物给药相结合可以改善药物输送，这将有利于CF的其他吸入治疗。此外，在运动期间定期输送沙丁胺醇将取代 这可以帮助CF患者获得定期锻炼的许多好处，允许同时使用两种疗法（运动和吸入药物），同时可能获得协同治疗效果。我们提出了一个新的，高影响力，和翻译研究，调查运动期间提供雾化沙丁胺醇的药代动力学和支气管扩张作用。研究团队结合马约诊所的广泛资源，为完成这一领域的研究提供了最佳的培训环境。

 DESCRIPTION (provided by applicant): The goal of this application is to determine if the administration of nebulized albuterol during exercise can improve the delivery and physiological responses of albuterol, a bronchodilator, in individuals with cystic fibrosis (CF). This project wil provide excellent intellectual and robust technical training opportunities to support the applicant in achieving her goal of becoming an independent investigator studying translational cardiopulmonary physiology. Specific Aim 1 will test the hypothesis that the degree of bronchodilation will be greatest when exercise and albuterol are combined in healthy individuals and in those with CF, compared to albuterol or exercise alone. We will assess bronchodilation [change in forced expiratory volume in 1 second (FEV1), and forced expiratory flow for 25-75% of the forced vital capacity (FEF25-75)] in response to three treatments: 1) exercise, 2) nebulized albuterol administration, and 3) exercise combined with albuterol administration. In Specific Aim 2, we will test the hypothesis that the duration of bronchodilation will be lowest after exercise, and will significantly increase when exercise is combined with albuterol. We will assess bronchodilation for 6 hours after each treatment and will accept our hypothesis if albuterol administration during moderate aerobic exercise has the largest area under the curve for bronchodilation (FEV1 and FEF25-75) over 6 hours. Specific Aim 3 will test the hypothesis that giving nebulized albuterol during exercise will improve drug delivery. We will measure plasma albuterol concentrations for 6 hours in response to each of the three conditions and run pharmacokinetic analyses. We predict that the delivery of nebulized albuterol during exercise will have an improved pharmacokinetic profile (maximum concentration and area under the curve) as compared to standard nebulized albuterol therapy. Administration of an inhaled bronchodilator during exercise may lead to better delivery and distribution of the drug, which could augment or prolong the bronchodilatory and pharmacokinetic effect of exercise or albuterol alone. This study will serve as proof of concept that combining exercise with aerosolized drug administration can improve drug delivery, which would be beneficial for other inhaled therapies in CF. In addition, regular delivery of albuterol during exercise would replace a daily sedentary activity with an active one, which could help CF patients reap the many benefits of regular exercise by allowing two therapies (exercise and inhaled medications) to be utilized at the same time while potentially receiving synergistic treatment effects. We propose a novel, high-impact, and translational study investigating the pharmacokinetic and bronchodilatory effects of delivering nebulized albuterol during exercise. The research team, combined with the extensive resources at the Mayo Clinic, provides the optimal training environment to complete studies in this area.