tiotropium-bromide and Lung-Diseases

To compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan.. This double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged > or = 40 years, with a forced expiratory volume in 1 second (FEV1) < or = 65% of predicted and FEV1/forced vital capacity (FVC) < or = 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler) or two puffs of ipratropium 20 microg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation.. After 4 weeks, trough FEV1 had increased by 61.7 +/- 25.3 mL for tiotropium but decreased by 16.4 +/- 27.9 mL for ipratropium. The difference between groups was significant (p < 0.05; 95% CI, 10-146.1). The trough FVC also increased by 137.2 +/- 49.3 mL for tiotropium but was decreased by 84.5 +/- 54.5 mL for ipratropium (p < 0.001; 95% CI, 89.0-354.3). No major drug-related adverse events associated with tiotropium and ipratropium were observed.. Tiotropium 18 microg once daily using HandiHaler was significantly more effective than ipratropium 40 microg four times daily in improving trough FEV1 and FVC over a 4-week period. The safety profiles of both drugs are comparable.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Bronchodilator Agents; Cholinergic Antagonists; Double-Blind Method; Female; Humans; Ipratropium; Lung Diseases; Male; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Taiwan; Tiotropium Bromide; Treatment Outcome

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.

Topics: Administration, Inhalation; Animals; Calcium; Carbachol; CHO Cells; Cholinergic Antagonists; Cricetinae; Cricetulus; Guinea Pigs; Kinetics; Lung; Lung Diseases; Mice; Mice, Inbred BALB C; Muscarinic Agonists; Muscarinic Antagonists; Plethysmography; Quinuclidines; Receptor, Muscarinic M3; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide