Improving Drug Delivery In Individuals With Cystic Fibrosis Using Exercise

 描述(申请人提供)：本申请的目的是确定在运动期间雾化吸入沙丁胺醇是否可以改善沙丁胺醇的释放和生理反应，沙丁胺醇是一种支气管扩张剂，用于囊性纤维化(CF)患者。该项目将提供优秀的智力和技术培训机会，以支持申请者 为了实现她成为一名研究转化性心肺生理学的独立研究员的目标。具体目标1将检验这样一种假设，即与沙丁胺醇或单独运动相比，运动和沙丁胺醇联合使用时，健康个体和慢性阻塞性肺疾病患者的支气管扩张程度最大。我们将评估三种治疗方法的支气管扩张[1秒用力呼气量(FEV1)的变化，以及用力肺活量(FEF25-75)的25-75%的用力呼气流量]：1)运动，2)沙丁胺醇雾化吸入，3)运动联合沙丁胺醇吸入。在特定的目标2中，我们将检验这样的假设，即运动后支气管扩张的持续时间最短，而运动与沙丁胺醇联合使用时，支气管扩张的持续时间将显著增加。我们将在每次治疗后评估6小时的支气管扩张，如果在中等有氧运动期间服用沙丁胺醇的支气管扩张曲线下面积最大(FEV1和FEF25-75)超过6小时，我们将接受我们的假设。具体目标3将检验这样一个假设，即在运动中雾化吸入沙丁胺醇将改善药物输送。我们将在6小时内测量沙丁胺醇在三种情况下的血浆浓度，并进行药代动力学分析。我们预测，与标准的沙丁胺醇雾化疗法相比，运动期间雾化沙丁胺醇的释放将具有更好的药代动力学曲线(最大浓度和曲线下面积)。在运动期间使用吸入性支气管扩张剂可能会导致药物更好地传递和分布，这可能会增强或延长运动或沙丁胺醇单独使用的支气管扩张和药代动力学效应。这项研究将证明运动与雾化给药相结合可以改善药物输送，这将有益于其他吸入疗法在CF中的应用。此外，在锻炼期间定期服用沙丁胺醇将取代 每天久坐不动的活动，这可以帮助CF患者获得定期运动的许多好处，允许同时使用两种治疗方法(运动和吸入药物)，同时可能获得协同治疗效果。我们提出了一项新的、高影响的转译研究，调查运动期间雾化吸入沙丁胺醇的药代动力学和支气管扩张效应。研究团队与梅奥诊所的广泛资源相结合，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.