The effect of inhaled thiorphan on allergen-induced airway responses in asthmatic subjects.
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: 2.5 mg). 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 = 0.76). Correspondingly, the changes in PC20 histamine were not different between the two treatments (P > 0.40).


CONCLUSIONS
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 allergen-induced airway responses, or that allergen challenge induces NEP-dysfunction in humans in vivo.
Diamant
Z
Z
Department of Pulmonology, Leiden University Hospital, The Netherlands.
Van der Veen
H
H
Kuijpers
E A
EA
Bakker
P F
PF
Sterk
P J
PJ
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens / Q000187:drug effects*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009479:Neuropeptides / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D012129:Respiratory Function Tests / Q000379:methods; D015244:Thiorphan / Q000008:administration & dosage* / Q000494:pharmacology*
D000485:Allergens; D009479:Neuropeptides; D011480:Protease Inhibitors; D015244:Thiorphan; D015260:Neprilysin