Rationale: Combination muscarinic antagonist (MA) − β2−adrenoceptor agonist (BA) bronchodilator therapy may provide additional clinical benefits in patients with COPD (van Noord, 2005). Combivent, a co−formulation of muscarinic antagonist (MA; ipratropium) and β2−adrenergic agonist (BA; albuterol), requires dosing every 6−8 h. Here, we characterized the in vivo bronchodilatory effect of a bifunctional MABA, TD−5959, in a guinea pig (GP) model of bronchoprotection. Methods: Conscious GPs were dosed by inhalation with nebulized aqueous solutions of vehicle or TD−5959 for 10 min. GPs were anesthetized, tracheotomized and ventilated before changes in ventilation pressure induced by either methacholine (MCh) ± propranolol (for MA or MABA activity, respectively) or histamine (HA) (for BA activity) were measured. Inhibition (%) of MCh or HA bronchoconstrictive response relative to the vehicle−treated groups were calculated. Results: Inhaled TD−5959 dose−dependently inhibited both MCh (± propranolol) and HA−induced bronchoconstriction. The onset of action was < 1.5 hr (the earliest time point tested) and the estimated bronchoprotective inhibitory potency (ID50) was 33.9 µg/mL for MA and 14.1 µg/mL for BA. Against HA challenge, bronchoprotection by TD−5959 (30 µg/mL) was completely blocked by propranolol confirming the BA mechanism. Dual pharmacology yielded bronchoprotection that was 2−5 fold more potent (MABA ID50 = 6.4 µg/mL) than either MA or BA alone. This MABA effect of TD−5959 was observed for up to 24 h after inhalation. Conclusion: TD−5959 is a novel bifunctional molecule that confers potent 24 h bronchoprotection in GPs through a dual mechanism involving antagonism of muscarinic receptors and agonism of β2−adrenoceptors. TD−5959 exemplifies a new class of bronchodilators with the potential to improve on the existing treatments for COPD. This abstract is funded by: Theravance, Inc. Am J Respir Crit Care Med 179;2009:A6195 Internet address: www.atsjournals.org Online Abstracts Issue

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