Response to Beta2-Agonists in Acute Severe Asthma

急性重度哮喘中 Beta2 激动剂的反应

• 批准号: 6960206
• 负责人: NICOLA A HANANIA
• 金额: $ 14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-06 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960206
• 关键词: albuterol; asthma; beta adrenergic agent; beta adrenergic receptor; bronchodilators; clinical research; clinical trials; diagnosis quality /standard; drug screening /evaluation; genetic polymorphism; human subject; human therapy evaluation; patient oriented research; respiratory airflow disorder; respiratory airflow measurement; respiratory airway volume; respiratory disorder chemotherapy; respiratory disorder diagnosis; respiratory pharmacology; spirometry

DESCRIPTION (provided by applicant): Dr. Nicola Hanania is an adult pulmonologist and Assistant Professor of Medicine at Baylor College of Medicine. The candidate's long-term goal is to develop an independent research career in asthma. The career development plan of the proposed K-23 award includes, advanced didactic training through the Clinical Scientist Training Program (K-30) leading to a Masters degree in Clinical Investigations, formal mentoring from a multidisciplinary scientific advisory committee and mentors and, independently conducting a prospective clinical study investigating the response to beta2-agonists in adults with acute severe asthma. The initial management of acute asthma traditionally includes the administration of repeated doses of the inhaled short-acting beta2-agonist, albuterol. However, more than 30% of patients with asthma exacerbation fail to show an initial response to albuterol. This poor response may result from the fact that albuterol is a "weak" agonist (has a low intrinsic efficacy (ability to activate the beta2-receptor). Based on laboratory studies on beta2-adrenergic receptors and on the candidate's pilot data, there may be a therapeutic advantage in using a "strong" beta2-agonist with high intrinsic efficacy in some situations. One such situation is acute severe asthma where the beta2-receptor is often desensitized by the patient's frequent use of rescue beta2-agonists prior to seeking medical help or may be functionally antagonized by the presence of inflammatory mediators released during an acute attack. The response to beta2-agonists in acute asthma is traditionally determined by the change in the forced expiratory volume in the first second (FEV1,) measured using a forced expiratory maneuver preceded by deep inhalation (DI). However, this DI maneuver can dampen the bronchodilator response in patients with moderate to severe airway obstruction. A more sensitive method of determining bronchodilator response may be the measurement of expiratory airflow at tidal breath avoiding the DI maneuver (partial expiratory flow). Patients with acute severe asthma are symptomatic because of limitation in their expiratory airflow during tidal breath. Thus, changes in partial expiratory flow, which reflect airflow at the level of tidal breath, may correlate better with symptom improvement in this situation than changes in FEV Therefore, the aims of the proposed study are to: (1) to evaluate the role of intrinsic efficacy of beta2- agonists in determining the bronchodilator and symptomatic responses to these medications, (2) to compare the FEV1 and partial expiratory flow responses to beta2-agonist and, (3) to determine whether changes in partial expiratory flow are better indicators of symptom improvement than changes in FEV1.

描述（由申请人提供）： 尼古拉·哈纳尼亚 (Nicola Hanania) 博士是贝勒医学院的成人肺科医生和医学助理教授。候选人的长期目标是发展哮喘领域的独立研究生涯。拟议的 K-23 奖项的职业发展计划包括：通过临床科学家培训计划 (K-30) 进行高级教学培训，获得临床研究硕士学位、多学科科学咨询委员会和导师的正式指导，以及独立开展一项前瞻性临床研究，调查成人急性重度哮喘患者对 β2 受体激动剂的反应。 传统上，急性哮喘的初始治疗包括重复剂量的吸入短效β2受体激动剂沙丁胺醇。 然而，超过 30% 的哮喘急性发作患者未能对沙丁胺醇表现出初步反应。这种不良反应可能是由于沙丁胺醇是一种“弱”激动剂（具有较低的内在功效（激活 β2 受体的能力）。根据对 β2 肾上腺素能受体的实验室研究和候选者的试验数据，在某些情况下使用具有高内在功效的“强”β2 激动剂可能具有治疗优势。其中一种情况是急性严重哮喘，其中 患者在寻求医疗帮助之前频繁使用救援性β2受体激动剂通常会使β2受体变得不敏感，或者可能会因急性发作期间释放的炎症介质而在功能上受到拮抗。 传统上，急性哮喘对 β2 受体激动剂的反应是通过第一秒用力呼气量 (FEV1) 的变化来确定的，该变化是使用用力呼气操作测量的，然后是 深吸气（DI）。 然而，这种 DI 操作可以抑制中度至重度气道阻塞患者的支气管扩张剂反应。 确定支气管扩张剂反应的更灵敏的方法可能是测量潮式呼吸时的呼出气流，避免 DI 操作（部分呼气流量）。 急性重度哮喘患者由于潮式呼吸时呼气气流受限而出现症状。 因此，反映潮式呼吸水平气流的部分呼气流量的变化可能比 FEV 的变化与这种情况下的症状改善相关性更好。因此，本研究的目的是：（1）评估 β2 激动剂的内在功效在确定支气管扩张剂和对这些药物的症状反应中的作用，（2）比较 FEV1 和部分呼气流量反应 β2 激动剂，(3) 确定呼气末流量的变化是否是比 FEV1 变化更好的症状改善指标。