Indacaterol + Glycopyrronium + Mometasone Furoate

Indacaterol is a long-acting beta 2-adrenergic agonist, taken once a day. Beta 2-adrenoceptor agonists, indacaterol included, work at least in part by stimulating adenyl cyclase inside the cell. This is the enzyme that converts adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). When cyclic AMP levels rise, the smooth muscle of the bronchi relaxes. In vitro studies show that indacaterol is a weak partial agonist at beta 1-receptors, and its potency is more than 24-fold greater at beta 2-receptors than at beta 1-receptors. It is a full agonist at beta 3-receptors, with a potency 20-fold greater at beta 2-receptors than at beta 3-receptors. When inhaled, indacaterol acts locally in the lung as a bronchodilator. It is a nearly full agonist at the human beta 2-adrenergic receptor, with nanomolar potency. In isolated human bronchus, it starts working quickly and keeps working for a long time. Beta 2-adrenergic receptors are the main adrenergic receptors in bronchial smooth muscle, while beta 1-receptors are the main ones in the human heart. But the heart also has beta 2-adrenergic receptors, which make up 10% to 50% of its total adrenergic receptors. Nobody knows exactly what they do there, but their presence means even highly selective beta 2-adrenergic agonists may have effects on the heart.

Glycopyrronium is an inhaled long-acting muscarinic receptor antagonist (anti-cholinergic). It blocks the broncho-constrictor action of acetylcholine on airway smooth muscle cells, and this opens up the airways. Of the five known muscarinic receptor subtypes (M1-5), only M1-3 have a defined physiological function in the human lung. Glycopyrronium binds to all three of these with high affinity and blocks them. In competition binding studies it showed 4- to 5-fold selectivity for the human M3 and M1 receptors over the human M2 receptor. Its onset of action is rapid, as the receptor association/dissociation kinetic parameters and the onset seen after inhalation in clinical studies both show. The long duration of action is partly due to drug concentrations that stay high in the lungs. This shows in the prolonged terminal elimination half-life of glycopyrronium after inhalation via the inhaler, compared with the half-life after intravenous administration.

Mometasone furoate is a synthetic corticosteroid. It has high affinity for glucocorticoid receptors and local anti-inflammatory properties. Studies in asthmatic patients have shown that inhaled mometasone furoate gives a favorable ratio of pulmonary to systemic activity. Much of its effect is likely to come from its ability to inhibit the release of mediators of the inflammatory cascade. In vitro, it inhibits the release of leukotrienes (LT) from leukocytes of allergic patients. In cell culture, mometasone furoate was highly potent in inhibiting the synthesis and release of IL-1, IL-5, IL-6 and TNF-alpha. It is also a potent inhibitor of LT production, and an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.