Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma.
BACKGROUND
The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma.


OBJECTIVE
We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies.


METHODS
The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9.


RESULTS
AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883.


CONCLUSIONS
Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.
Boot
Johan D
JD
Centre for Human Drug Research, Zernikedreef 10 2333 CL, Leiden, The Netherlands. dboot@chdr.nl
de Haas
Sanne
S
Tarasevych
Svetlana
S
Roy
Christine
C
Wang
Lin
L
Amin
Dilip
D
Cohen
Judith
J
Sterk
Peter J
PJ
Miller
Barry
B
Paccaly
Anne
A
Burggraaf
Jacobus
J
Cohen
Adam F
AF
Diamant
Zuzana
Z
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens / Q000008:administration & dosage*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005540:Forced Expiratory Flow Rates / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013183:Sputum / Q000166:cytology / Q000378:metabolism; D016896:Treatment Outcome
D000485:Allergens; D018927:Anti-Asthmatic Agents; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2