Abstract
The tachykinins substance P (SP) and neurokinin A (NKA) possess bronchoconstrictor and pro-inflammatory properties and are implicated in the pathophysiology of asthma. These effects are mediated by stimulation of NK1 (SP) and NK2 (NKA) receptors. Hence, NK1/NK2 receptor antagonists seem promising anti-asthma agents.
We tested the effect of AVE5883, a dual NK1/NK2 receptor antagonist, on NKA-induced bronchoconstriction in a double-blind, placebo (P)-controlled, cross-over study, consisting of 2 study days separated by a ≥1 wk washout. Twenty asthmatics (15F/5M; 19-47 y; FEV1 ≥75%; PC20MCh <8 mg/mL), inhaled AVE5883 (4.8 mg) or P from an MDI, 30 min before an NKA challenge. Serial NKA dilutions (3.9-1000 μg/mL) were inhaled by tidal breathing. The airway response was measured until a fall in FEV1 ≥20% from baseline.
Nineteen subjects completed the study. AVE5883 was well tolerated. Pre-NKA FEV1 was similar in both study periods (p= 0.36). Following AVE5883 inhalation, the least square mean ±SEM log10PC20NKA was -6.33±0.125 as compared to P -6.69±0.125. The mean treatment difference was 0.36±0.09 (p=0.001). Hence, AVE5883 shifted the mean concentration-response to NKA by 1.2 (90% CI: 0.68 to 1.74) doubling concentration equivalents.
AVE5883 produced a significant protection against inhaled NKA and may have therapeutic potential in the treatment of asthma.