Assessments of protective effects of tiotropium bromide against methacholine- and neurokinin A-induced bronchoconstriction in patients with asthma

Abstract

Rationale: Previous studies using short-acting anticholinergics have suggested a possible protective effect on bronchoconstriction induced by the sensory neuropeptide neurokinin A (NKA).

Aim: To assess the effect of tiotropium bromide, a longacting anticholinergic agent, on NKA-induced bronchoconstriction.

Methods: PC₂₀ NKA and PC₂₀ methacholine were investigated in asthmatic patients after 20 days of treatment with tiotropium bromide (18 μg/od) or placebo. PC₂₀ was expressed in log₂ doubling concentrations (DC). Values were reported as median with 25th-75th percentiles. Pairwise comparisons of the log₂ PC₂₀ values at screening and at the end of active and placebo treatments were performed.

Results: 16 patients with asthma (9 male; age: 24 (18-63) years) were included. PC₂₀ NKA was 0.18 (0.06 - 0.29) μmol/ml at screening, 0.34 (0.09 - 3.34) μmol/ml after placebo, and 0.77 (0.08 - 3.34) μmol/ml after tiotropium bromide. PC₂₀ methacholine was 0.5 (0.3 - 0.7) mg/ml at screening, 0.3 (0.2- 1.5) mg/ml after placebo, and 256.0 (11.7 – 256.0) mg/ml after tiotropium bromide. Differences between active treatment and screening log₂PC₂₀ were 2.4 (0.4 – 3.2) DC for NKA (p = 0.06) and 7.6 (4.8 – 9.0) DC for methacholine (p <0.0001). Differences between placebo treatment and screening for log₂PC₂₀ NKA and log₂PC₂₀ methacholine were not observed.

Conclusions: Inhaled tiotropium bromide protects against methacholine-induced bronchoconstriction, but not against bronchoconstriction induced by NKA, suggesting that cholinergic mechanisms are not involved in the contractile effects of NKA in patients with asthma.