Clinical relevance of the relaxant effects of roflumilast on human bronchus: potentiation by a long-acting beta-2-agonist

Abstract

Roflumilast is an oral, add-on option for treating patients with severe COPD and frequent exacerbations despite optimal therapy with inhaled drugs. The present study focused on whether this phosphodiesterase 4 inhibitor and its active metabolite roflumilast N-oxide affect the tone of human bronchial rings. We also investigated the interactions between roflumilast, roflumilast N-oxide and the long-acting β₂ -agonist formoterol with regard to the relaxation of isolated human bronchial rings at basal tone or pre-contracted with histamine. Our results demonstrated for the first time that at a clinically relevant concentration (1 nm), roflumilast N-oxide and roflumilast induce a weak relaxation of the isolated human bronchus either at resting tone (22% and 16%, respectively) or even weaker on pre-contracted bronchus with histamine (7% and 5%, respectively). In addition, the combination of formoterol with roflumilast or roflumilast N-oxide is more potent than each component alone for relaxing pre-contracted isolated bronchi - the apparent pD2 of formoterol was significantly reduced for the threshold concentration of 1 nm of the phosphodiesterase 4 inhibitors by a factor of 2.4 for roflumilast N-oxide and 1.9 for roflumilast. The full inhibition of phosphodiesterase 4 activity is achieved at 100 nm but this high concentration only caused partial relaxations of the human bronchi. At a clinically relevant concentration, these oral phosphodiesterase 4 inhibitors are not effective direct bronchodilators but could enhance the efficacy of inhaled long-acting β2-agonists.

Keywords: beta-2-adrenoceptor agonist; human bronchus; relaxation; roflumilast.