Positive Interaction Of The Novel Beta(2)-Agonist Carmoterol And Tiotropium Bromide In The Control Of Airway Changes Induced By Different Challenges In Guinea-Pigs

This study evaluated the bronchodilating activity of the beta(2)-agonist carmoterol and the muscarinic M-3-antagonist tiotropium, given intratracheally alone or in combination in anaesthetized artificially ventilated normal and actively sensitized guinea-pigs. Carmoterol (0.3-100 pmol) and tiotropium (10-1000 pmol) were superfused (0.01 ml/min) for 5 min before challenges with acetylcholine (20 mu g/kg i.v.), histamine (10 mu g/kg i.v.) or ovalbumin (5 mg/kg i.v.).Both compounds given alone were markedly active against all the challenges. Tiotropium resulted more effective towards cholinergic challenge and carmoterol was very potent against histamine and ovalbumin-induced reaction, being effective already at 1 pmol. In the presence of tiotropium, the bronchodilating activity of carmoterol was significantly augmented. The ED50 value of carmoterol on the acetylcholine challenge was reduced by about 10 and 28 times (0.1 and 0.3 pmol of tiotropium), that on the histamine one by 4.5 and 13 times (1 and 3 pmol of tiotropium) and that on the ovalbumin-induced one by 8 and 25 times (10 and 30 pmol of tiotropium).A positive interaction was also evident when other parameters were evaluated. The histamine-induced release of thromboxane B-2 was markedly reduced (56%, P < 0.001) by combining completely ineffective doses of the two drugs (0.3 and 3 pmol for carmoterol and tiotropium, respectively). In ovalbumin-challenged animals the time to death, amounting in control animals to 7.2 +/- 0.9 min, was dose-dependently prolonged up to achieve complete protection from death with combination of 1 and 30 pmol of carmoterol and tiotropium, respectively.The favorable interaction between carmoterol and tiotropium can represent a good option in the control of bronchopulmonary diseases marked by an increase of airway resistances. (c) 2006 Elsevier Ltd. All rights reserved.