THE EFFECT OF INHALED THIORPHAN ON ALLERGEN-INDUCED AIRWAY RESPONSES IN ASTHMATIC SUBJECTS

Background Neuropeptides are likely to be implicated in the pathophysi ology of allergen-induced airway responses. However, upon release in t he airways, neuropeptides are potentially inactivated by neutral endop eptidase (NEP). Objective We hypothesized that NEP-inhibition by inhal ed thiorphan (TH) would increase allergen-induced early (EAR) and late (LAR) asthmatic responses, and allergen-induced airway hyperresponsiv eness to histamine in asthmatic subjects in vivo. The dose and dosing intervals of TH were derived from previous pharmacokinetic and dose-fi nding studies. Methods Nine non-smoking, atopic, asthmatic men with du al 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 p ost-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 do se of TH: 2.5 mg). Forced expiratory volume in one second (FEV(1)) 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 t he pre-allergen baseline and as corresponding areas under the time-res ponse curves (AUC). Results As compared with P, TH failed to induce an acute effect on FEV(1) at any of the timepoints (P > 0.08). There was no significant difference between P and TH in the EAR and the LAR: ne ither 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 = 0.76). Correspondingly, the changes in PC20 histamine were not differe nt between the two treatments (P > 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 a llergen-induced airway responses, or that allergen challenge induces N EP-dysfunction in humans in vivo.