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

Abstract

Neurokinin A (NKA) causes bronchoconstriction in asthmatic patients. In vitro both NK 1 and NK 2 receptors can mediate airway contraction. Moreover in guinea pigs, NK 3 receptors facilitate cholinergic neurotransmission. Dual tachykinin NK 1/NK 2 receptor antagonism results in prevention of NKA-induced bronchoconstriction. We have now examined the effect of a single dose of the triple tachykinin receptor antagonist CS-003 on NKA-induced bronchoconstriction in asthmatics. A double blind, crossover, placebo-controlled trial in 16 mild asthmatics was performed. One single dose of CS-003 (200 mg, solution in distilled water) or matched placebo was given orally on the assessment days. NKA-provocation tests were performed pre-dose and 1, 8 and 24 h after dosing. There was a significant shift to the right of the dose–response curve at 1 and 8 h after intake of CS-003. PC 20 was not reached in 12/16 patients at 1 h post-dose and in 5/16 patients at 8 h post-dose. This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8 h post-dose in mild asthmatics.