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

Eur Respir J. 2004 Jan;23(1):76-81. doi: 10.1183/09031936.03.00101902.

Abstract

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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adolescent
  • Adult
  • Asthma / physiopathology*
  • Aza Compounds / administration & dosage
  • Aza Compounds / pharmacokinetics
  • Aza Compounds / pharmacology*
  • Benzamides / administration & dosage
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology*
  • Bronchoconstriction / drug effects*
  • Cross-Over Studies
  • Double-Blind Method
  • Humans
  • Middle Aged
  • Neurokinin A / administration & dosage
  • Neurokinin A / adverse effects*
  • Receptors, Tachykinin / antagonists & inhibitors*

Substances

  • Aza Compounds
  • Benzamides
  • DNK 333
  • Receptors, Tachykinin
  • Neurokinin A