chiniofon and Airway-Obstruction

For improving effectiveness of chronic obstructive pulmonary disease (COPD) therapy is necessary to influence on pharmacologic receptors in the complementary way and to reduce the dose frequency. The once-daily dose administration is an important step which may allow to enhance of patients compliance. Novel long-acting bronchodilators--beta2-agonists or ultra long-acting beta2-agonists (LABAs) such as indacaterol and carmoterol--are under clinical application for the treatment of COPD patients. Moreover, some new long-acting antimuscarinic agents (LAMA) (aclidinium, glycopyrrolate) and dual-action ultra LABA+LAMA combination products are under development. The main target of therapeutic research is to produce a dimmer molecule known as M3 antagonist-beta2 agonist (MABA) bronchodilators which will open the door for a new range of combination products.

Topics: Airway Obstruction; Amphetamines; Bronchodilator Agents; Drug Administration Schedule; Drug Combinations; Humans; Hydroxyquinolines; Indans; Muscarinic Antagonists; Patient Compliance; Pulmonary Disease, Chronic Obstructive; Quinolones

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 (0.3-100pmol) and tiotropium (10-1000pmol) were superfused (0.01ml/min) for 5min before challenges with acetylcholine (20mug/kg i.v.), histamine (10mug/kg i.v.) or ovalbumin (5mg/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 1pmol. In the presence of tiotropium, the bronchodilating activity of carmoterol was significantly augmented. The ED(50) value of carmoterol on the acetylcholine challenge was reduced by about 10 and 28 times (0.1 and 0.3pmol of tiotropium), that on the histamine one by 4.5 and 13 times (1 and 3pmol of tiotropium) and that on the ovalbumin-induced one by 8 and 25 times (10 and 30pmol 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 3pmol for carmoterol and tiotropium, respectively). In ovalbumin-challenged animals the time to death, amounting in control animals to 7.2+/-0.9min, was dose-dependently prolonged up to achieve complete protection from death with combination of 1 and 30pmol 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.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Airway Obstruction; Airway Resistance; Amphetamines; Animals; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Histamine; Hydroxyquinolines; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Male; Ovalbumin; Quinolones; Scopolamine Derivatives; Survival Analysis; Thromboxane B2; Tiotropium Bromide; Treatment Outcome