TIOTROPIUM BROMIDE (BA-679-BR), A NOVEL LONG-ACTING MUSCARINIC ANTAGONIST FOR THE TREATMENT OF OBSTRUCTIVE-AIRWAYS-DISEASE

Tiotropium bromide (Ba 679 BR) is a novel potent and long-lasting muscarinic antagonist that has been developed for the treatment of chronic obstructive airways disease (COPD). Binding studies with [H-3]tiotropium bromide in human lung have confirmed that this is a potent muscarinic antagonist with equal affinity for M(1)- M(2)- and M(3)-receptors and is approximately 10-fold more potent than ipratropium bromide. Tiotropium bromide dissociates very slowly from lung muscarinic receptors compared with ipratropium bromide. In vitro tiotropium bromide has a potent inhibitory effect against cholinergic nerve-induced contraction of guinea-pig and human airways, that has a slower onset than atropine or ipratropium bromide. After washout, however, tiotropium bromide dissociates extremely slowly compared with the dissociation of atropine and ipratropium bromide. Measurement of acetylcholine (ACh) release from guinea-pig trachea shows that tiotropium bromide, ipratropium bromide and atropine all increase ACh release on neural stimulation and that this effect is washed out equally quickly for the three antagonists. This confirms binding studies to transfected human muscarinic receptors which suggested that tiotropium bromide dissociates slowly from M(3)-receptors (on airway smooth muscle) but rapidly from M(2) autoreceptors (on cholinergic nerve terminals). Clinical studies with Inhaled tiotropium bromide confirm that it is a potent and long-lasting bronchodilator in COPD and asthma. Furthermore, it protects against cholinergic bronchoconstriction for >24 h. This suggests that tiotropium bromide will be a useful bronchodilator, particularly in patients with COPD, and may be suitable for daily dosing. The selectivity for M(3)- Over M(2)-receptors may also confer a clinical advantage.