Background Neuropeptides are likely to be implicated in the pathophysiology of allergen-induced airway responses. However, upon release in the airways, neuropeptides are potentially inactivated by neutral endopeptidase (NEP). Objective We hypothesized that NEP-inhibition by inhaled thiorphan (TH) would increase allergen-induced early (EAR) and late (LAR) asthmatic responses, and allergen-induced airway hyperresponsiveness to histamine in asthmatic subjects in vivo. The dose and dosing intervals of TH were derived from previous pharmacokinetic and dose-finding studies.
Methods Nine non-smoking, atopic, asthmatic men with dual asthmatic responses to inhaled house-dust mite extract participated in a double-blind, placebo-controlled, cross-over study. During each study period PC20 histamine was measured 24 h before, and 3 and 24 h post-allergen. TH (1.25 mg/mL, 0.5 mL) or placebo (P) were aerosolized pre-allergen, and three times at 2 h intervals post-allergen (total dose of TH: 2.5mg). Forced expiratory volume in one second (FEV1) was recorded and expressed as percentage fall from baseline. The EAR (0–3 h) and the LAR (3–8 h) were defined as maximum percentage fall from the pre-allergen baseline and as corresponding areas under the time-response curves (AUC).
Results As compared with P, TH failed to induce an acute effect on FEV1 at any of the timepoints (P > 0.08). There was no significant difference between P and TH in the EAR and the LAR: neither in terms of maximum percentage fall from baseline (mean± SEM: EAR: 22.3 ±4.7% (P) and 20.4±4.1% (TH). P=0.75; LAR: 25.2 ± 4.7% (P) and 26.4±5.8% (TH), P= 0.77) nor in terms of AUC (P = 0.16). Correspondingly, the changes in PC20 histamine were not different between the two treatments (F > 0.40).
Conclusion We conclude that four adequate doses of the inhaled NEP-inhibitor, thiorphan. failed to potentiate allergen-induced airway responses in asthma. These results suggest that either neuropeptides do not play a predominant role in allergeninduced airway responses, or that allergen challenge induces NEP-dysfunction in humans in vivo.