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.
| Hanania, Nicola A; Dickey, Burton F; Bond, Richard A (2010) Clinical implications of the intrinsic efficacy of beta-adrenoceptor drugs in asthma: full, partial and inverse agonism. Curr Opin Pulm Med 16:1-5 |
| Hanania, N A; Mannava, B; Franklin, A E et al. (2010) Response to salbutamol in patients with mild asthma treated with nadolol. Eur Respir J 36:963-5 |
| Hanania, Nicola A; Singh, Supria; El-Wali, Rami et al. (2008) The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther 21:134-41 |
| Xian, Wujing; Janmey, Paul A (2002) Dissecting the gelsolin-polyphosphoinositide interaction and engineering of a polyphosphoinositide-sensitive gelsolin C-terminal half protein. J Mol Biol 322:755-71 |
