The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics.

Abstract

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.

• Authors: G F Joos, J Van Schoor, J C Kips, R A Pauwels
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 153 Issue 6 Pt 1 Pg. 1781-4 (Jun 1996) ISSN: 1073-449X [Print] United States
• PMID: 8665034 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neurokinin-1 Receptor Antagonists
• Peptides, Cyclic
• Receptors, Neurokinin-2
• FK 224
• Neurokinin A

Topics

• Administration, Inhalation
• Asthma (drug therapy, physiopathology)
• Bronchoconstriction (drug effects)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Male
• Neurokinin A (antagonists & inhibitors)
• Neurokinin-1 Receptor Antagonists
• Peptides, Cyclic (pharmacology, therapeutic use)
• Receptors, Neurokinin-2 (antagonists & inhibitors)
• Respiratory Function Tests