Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients.
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 x mLP(-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 x mL(-1) at 1 h after DNK333 treatment and -6.8 log10 mol x 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.
Joos
G F
GF
Dept of Respiratory Diseases, Ghent University Hospital, Belgium. guy.joos@ugent.be
Vincken
W
W
Louis
R
R
Schelfhout
V J
VJ
Wang
J H
JH
Shaw
M J
MJ
Cioppa
G D
GD
Pauwels
R A
RA
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001372:Aza Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D015288:Neurokinin A / Q000008:administration & dosage / Q000009:adverse effects*; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*
D001372:Aza Compounds; D001549:Benzamides; C448383:DNK 333; D018039:Receptors, Tachykinin; D015288:Neurokinin A