THE EFFECT OF INHALED FK224, A TACHYKININ NK-1 AND NK-2 RECEPTOR ANTAGONIST, ON NEUROKININ A-INDUCED BRONCHOCONSTRICTION IN ASTHMATICS

The tachykinins substance P and neurokinin A (NKA) are present in sens ory airway nerves and have been implicated in the pathogenesis of asth ma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway respons es 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 FK 224 on NKA-induced bronchoconstriction in 10 patients with stable asth ma. On Day 1 baseline lung function and PC20 methacholine were determi ned. 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 FEV(1). 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 befo re NKA challenge in a double-blind, crossover manner. The study medica tion was well tolerated. FK224 had no significant effect on baseline l ung function. After P and FK224, NKA caused a comparable concentration -dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mo l/ml) was -6.04 +/- 0.18 after 9 and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function a nd offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.