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Eur Respir J 2004; 23:76-81
Copyright ©ERS Journals Ltd 2004

Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients

G.F. Joos1, W. Vincken2, R. Louis3, V.J. Schelfhout1, J.H. Wang4, M.J. Shaw4, G.D. Cioppa4 and R.A. Pauwels1

1 Dept of Respiratory Diseases, Ghent University Hospital, 2 Academic Hospital, University of Brussels, Brussels, and 3 CHU-Sart-Tilman, University of Liège, Belgium, 4 Novartis Horsham Research Center, Horsham, UK

CORRESPONDENCE: G. F. Joos, Dept of Respiratory Diseases, Ghent University Hospital, De Pintelaan 185, B-9000, Ghent, Belgium. Fax: 0032 92402 341. E-mail: guy.joos@ugent.be

Keywords: asthma, bronchoconstriction, DNK333, neurokinin A, substance P, tachykinins

Received: November 7, 2002
Accepted September 11, 2003

This project was supported by a grant from Novartis, Belgium. Part of this paper was presented at the American Thoracic Society International Conference in May 2001, San Francisco, California.

Inhalation of neurokinin A (NKA) causes bronchoconstriction in patients with asthma. In vitro both tachykinin NK1 and NK2 receptors can mediate airway contraction. In this study the authors examined the effects of a single dose of the dual tachykinin NK1/NK2 receptor antagonist, DNK333, on NKA-induced bronchoconstriction in asthma.

A total of 19 male adults with mild asthma completed a randomised, double-blind, placebo-controlled, crossover trial. Increasing concentrations of NKA (3.3x10–9 to 1.0x10–6 mol·mL–1) were inhaled at 1 and 10 h intervals after a single oral dosing with either DNK333 (100 mg) or a placebo.

It was observed that DNK333 did not affect baseline lung function but did protect against NKA-induced bronchoconstriction in those patients. The mean log10 provocative concentration causing a 20% fall in forced expiratory volume in one second for NKA was –5.6 log10 mol·mL–1 at 1 h after DNK333 treatment and –6.8 log10 mol·mL–1 after placebo. This was equivalent to a difference of 4.08 doubling doses, which decreased to a difference of 0.90 doubling doses 10 h after treatment.

The results shown in this report indicate that DNK333 blocks neurokinin A-induced bronchoconstriction in patients with asthma.




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J. D. Boot, S. de Haas, S. Tarasevych, C. Roy, L. Wang, D. Amin, J. Cohen, P. J. Sterk, B. Miller, A. Paccaly, et al.
Effect of an NK1/NK2 Receptor Antagonist on Airway Responses and Inflammation to Allergen in Asthma
Am. J. Respir. Crit. Care Med., March 1, 2007; 175(5): 450 - 457.
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