tiotropium-bromide and Bronchial-Spasm

Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat(®) Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat(®) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV(1)) of ≥15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long-term treatment with tiotropium 5 or 10 μg via Respimat(®) SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low.

Topics: Administration, Inhalation; Aged; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Clinical Trials, Phase III as Topic; Female; Forced Expiratory Volume; Humans; Logistic Models; Lung; Male; Middle Aged; Multicenter Studies as Topic; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome; Vital Capacity

The novel quaternary ammonium salt (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino]carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407) showed subnanomolar affinities for human muscarinic M1 (hM1), M2 (hM2), and M3 (hM3) receptors and dissociated very slowly from hM3 receptors (t(½) = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32 h from radioligand washout. In contrast, [(3)H]CHF5407 dissociated quickly from hM2 receptors (t(½) = 31 min), whereas [(3)H]tiotropium dissociated slowly from both hM3 (t(½) = 163 min) and hM2 receptor (t(½) = 297 min). In the guinea pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC(50) = 9.0-9.6) and long-lasting (up to 24 h) inhibition of M3 receptor-mediated contractile responses to carbachol. In the guinea pig electrically driven left atrium, the M2 receptor-mediated inhibitory response to carbachol was recovered more quickly in CHF5407-pretreated than in tiotropium-pretreated preparations. CHF5407, administered intratracheally to anesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED(50) value of 0.15 nmol/kg. The effect was sustained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmol/kg. In conscious guinea pigs, inhaled CHF5407 inhibited Ach-induced bronchoconstriction for at least 24 h as did tiotropium at similar dosages. Cardiovascular parameters in anesthetized guinea pigs were not significantly changed by CHF5407, up to 100 nmol/kg i.v. and up to 1000 nmol/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, caused by a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behavior not shared by tiotropium.

Topics: Acetylcholine; Aged; Anesthesia; Animals; Blood Pressure; Bronchi; Bronchial Spasm; Bronchoconstriction; Bronchoconstrictor Agents; Bronchodilator Agents; Carbachol; Carbamates; CHO Cells; Cricetinae; Cricetulus; Diamines; Guinea Pigs; Heart Atria; Heart Rate; Humans; Kinetics; Male; Middle Aged; Molecular Structure; Muscarinic Antagonists; Myocardial Contraction; Quinuclidines; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Scopolamine Derivatives; Tiotropium Bromide; Trachea; Transfection; Ventricular Function, Left

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Topics: Administration, Inhalation; Animals; Bronchial Spasm; CHO Cells; Cricetinae; Cricetulus; Drug Stability; Esters; Guinea Pigs; Humans; Male; Mice; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quaternary Ammonium Compounds; Quinuclidines; Radioligand Assay; Receptor, Muscarinic M3; Stereoisomerism; Structure-Activity Relationship; Tropanes

The use of anticholinergics in antiobstructive therapy is well established in pulmonary medicine. We sought to improve the duration of action of inhaled antimuscarinics. A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range. Assessment of the dissociation rate of complexes of labelled Ba 679 and human muscarinic receptors revealed very slow dissociation in comparison to ipratropium. The half-lives in hours were: Ba 679-Hm3: 34.7, -Hm1: 14.6, -Hm2: 3.6; ipratropium-Hm3: 0.26, -Hm1: 0.11, -Hm2: 0.035. The duration of action in vivo was determined by means of acetylcholine-induced bronchospasms in dogs following inhalation of the drugs. Ba 679 demonstrated a significantly longer duration of protection than an equipotent dose of ipratropium. The plasma levels following inhalation in dogs declined rapidly and are unlikely to reflect the duration of the pharmacological activity. In summary, Ba 679 represents a novel type of antimuscarinic bronchodilator with a long duration of action, most likely due to its slow dissociation from Hm3-receptors. In addition, the drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.

Topics: Animals; Bronchial Spasm; Bronchoconstriction; Bronchodilator Agents; CHO Cells; Cricetinae; Dogs; Female; Guinea Pigs; Half-Life; Humans; Lung; Male; Parasympatholytics; Receptors, Muscarinic; Scopolamine Derivatives; Tiotropium Bromide; Trachea