Protection against allergen-induced airway hyperresponsiveness (AHR) by olodaterol in guinea pigs is synergistically enhanced by tiotropium

The ultra-long acting β 2 -agonist olodaterol has shown to be effective in asthma and COPD. Increased cholinergic tone, common to these diseases, may reduce β 2 -agonist responsiveness. In a guinea pig model of asthma, we investigated the protection of allergen (ovalbumin, OA)-induced AHR by olodaterol, alone and in combination with the long acting anticholinergic tiotropium. Airway responsiveness (PC 100 ) was assessed at baseline (24h before OA) and after the early (EAR, 6h after OA) and late (LAR, 24h after OA) asthmatic reactions. 1h before OA, animals were treated with PBS (control), 1 mM olodaterol and/or 0.1 mM tiotropium (nebulizer concentrations, 3 min). OA induced AHR to histamine after the EAR (4.9-fold decrease in PC 100 compared to baseline), which was fully protected by olodaterol (2.3-fold increase in PC 100 ) and tiotropium (1.3-fold increase ). When combined, a synergistic 4.8-fold increase in PC 100 was observed. After the LAR, AHR (2.8-fold decrease), was also protected by olodaterol, tiotropium and their combination (1.5-, 1.3- and 1.6-fold increase in PC 100 , respectively). OA-induced infiltration of inflammatory cells, measured by BAL after the LAR, was not affected by any treatment. In conclusion, in a guinea pig model of asthma olodaterol and tiotropium protect against allergen-induced AHR after the EAR and LAR, without affecting inflammatory cell influx. Synergism between the drugs was found after the EAR, indicating that acetylcholine reduces the effectiveness of the β 2 -agonist and that the combination of olodaterol and tiotropium may be beneficial in the treatment of allergic asthma. (supported by Boehringer Ingelheim Pharma).