Lack of short-term effect of the thromboxane synthetase inhibitor UK-38,485 on airway reactivity to methacholine in asthmatic subjects

Abstract

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.