Dual tachykinin NK₁/NK₂antagonist DNK333 inhibits neurokinin A‐induced bronchoconstriction in asthma patients

Abstract

Inhalation of neurokinin A (NKA) causes bronchoconstriction in patients with asthma. In vitro both tachykinin NK 1 and NK 2 receptors can mediate airway contraction. In this study the authors examined the effects of a single dose of the dual tachykinin NK 1 /NK 2 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 (3.3610 -9 to 1.0610 -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 log 10 provocative concentration causing a 20% fall in forced expiratory volume in one second for NKA was -5.6 log 10 mol?mL -1 at 1 h after DNK333 treatment and -6.8 log 10 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. Eur Respir J 2004; 23: 76-81.

Neurogenic mechanisms in bronchial inflammatory diseases

“…Additionally, a further potent NK 1 -receptor antagonist (CP 99994) did not show any inhibitory effect on either hypertonic saline-induced bronchoconstriction or on cough (143). However, the administration of a dual tachykinin NK 1 /NK 2 -antagonist DNK333 was recently reported to inhibit neurokinin A-induced bronchoconstriction in asthma patients in a randomized, doubleblind, placebo-controlled, crossover trial (144). This reported difference of four doubling doses of NKA at 1 h was decreased to a difference of 0.9 doubling doses at 10 h post-treatment (144).…”

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

“…Neurokinin A (NKA, substance K) is a ten amino acid peptide translated from the pre-protachykinin gene with broncho-constrictive properties, in asthma (Joos et al 2004). NKA levels are considered to have utility in evaluating carcinoid heart disease and treatment responses (Dobson et al 2013).…”

The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma

“…DNK333 was the first dual NK 1 /NK 2 receptor antagonist which showed a clear inhibition of NKA-induced bronchoconstriction. The protective effect of DNK333 was shown at 1 h post-dose (protection in 15 out of 18 patients) but not at 10h post-dose [19].…”

“…Also in the trial with DNK 333, there was no relationship between the plasma drug concentration and the bronchoprotection [19]. This can be explained by a relatively low number of observations (16 patients) and a rather high inter-patient variability in provocative concentration of NKA.…”

“…DNK 333, a dual NK 1 /NK 2 receptor antagonist protected clearly against the NKA-induced bronchoconstriction in mild-tomoderate asthmatics. Although DNK 333 had a good activity in the NKA-provocation model, the duration of action of this compound was rather short [19]. Moreover, the tachykinin NK 3 receptor plays an important role in the pathogenesis of asthma, especially for cough and hyperresponsiveness [12].…”