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Published ahead of print on December 14, 2006, doi:10.1164/rccm.200608-1186OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 450-457, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200608-1186OC

Original Article

Effect of an NK1/NK2 Receptor Antagonist on Airway Responses and Inflammation to Allergen in Asthma

Johan D. Boot1, Sanne de Haas1, Svetlana Tarasevych1, Christine Roy3, Lin Wang4, Dilip Amin4, Judith Cohen1, Peter J. Sterk2,3, Barry Miller4, Anne Paccaly4, Jacobus Burggraaf1, Adam F. Cohen1 and Zuzana Diamant1

1 Centre for Human Drug Research, Leiden, The Netherlands; 2 Leiden University Medical Center, Leiden, The Netherlands; 3 Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 4 Sanofi-Aventis Pharma Recherche-Developpement, Vitry sur Seine, France; and 5 Sanofi-Aventis US, Inc., Bridgewater, New Jersey

Correspondence and requests for reprints should be addressed to Diderik Boot, M.Sc., Centre for Human Drug Research, Zernikedreef 10 2333 CL, Leiden, The Netherlands. E-mail: dboot{at}chdr.nl

Rationale: 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 NK1/NK2 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 FEV1 until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV1, 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 FEV1, 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.

Key Words: tachykinins • neurokinin A bronchoprovocation test • allergen bronchoprovocation test • asthma • AVE5883


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
The tachykinins substance P and neurokinin A are implicated in the pathophysiology of asthma. There are no published studies on the efficacy of dual tachykinin NK1/NK2 receptor antagonists against allergen challenge or on their clinical efficacy in asthma.

What This Study Adds to the Field
A single inhaled dose of AVE5883 provided protection against neurokinin A–induced bronchoconstriction in patients with asthma, whereas 7 days' pretreatment with multiple daily doses failed to reduce allergen-induced airway responses and markers of airway hyperresponsiveness/inflammation.

 



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