Effects of a thromboxane-receptor antagonist, BAY u 3405, on prostaglandin D2- and exercise-induced bronchoconstriction.
In the pathogenesis of exercise-induced bronchoconstriction (EIB), prostaglandin D2 (PGD2) may play a role as a newly generated, mast cell-derived mediator. As the bronchoconstrictor effects of PGD2 are predominantly mediated via stimulation of thromboxane receptors in the lung, we studied a novel, orally effective, thromboxane-receptor antagonist, BAY u 3405, on EIB in 12 male subjects with mild asthma. On 4 study days, we determined, in a randomized, double-blind, placebo-controlled, crossover fashion, the effects of 20 mg of BAY u 3405 administered orally 1 hour before PGD2 and exercise challenges, respectively. Increasing dosages of PGD2 were inhaled to establish dose-response curves that allowed determination of the provocative concentration necessary to decrease FEV1 by at least 20% (PC20) and to increase specific airway resistance (SR(aw)) by 100% (PC100). EIB was measured as a maximal fall/increase in postexertional FEV1/SR(aw) after bicycle exercise and cold-air breathing. Prechallenge lung-function values were similar on all four occasions. BAY u 3405 did not elicit any effect on resting bronchial tone. After placebo, the geometric means (SD) of PC20 and PC100 were 0.0380 (2.6) and 0.0266 (2.4) mg/ml, increasing to 0.554 (5.9) and 0.143 (8.1) mg/ml after BAY u 3405 (p = 0.0002). Mean (SD) maximal postexertional decrease in FEV1 and increase in SR(aw) after placebo was 29.4% (16.4%) and 280% (135%), and after BAY u 3405, 31.4% (18.1%) and 379% (281%) (not significant). No clinically relevant BAY u 3405-related side effects were observed. From these results we conclude that BAY u 3405 is highly effective in attenuating PGD2-induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
Magnussen
H
H
Krankenhaus Grosshansdorf, Center for Pneumology and Thoracic Surgery, Germany.
Boerger
S
S
Templin
K
K
Baunack
A R
AR
D000388:Air; D000403:Airway Resistance / Q000187:drug effects; D001250:Asthma, Exercise-Induced / Q000188:drug therapy* / Q000503:physiopathology; D001985:Bronchial Provocation Tests / Q000379:methods; D016084:Bronchoconstriction / Q000187:drug effects*; D002227:Carbazoles / Q000009:adverse effects / Q000627:therapeutic use*; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004341:Drug Evaluation; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D015230:Prostaglandin D2 / Q000008:administration & dosage* / Q000009:adverse effects; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*; D013997:Time Factors
D002227:Carbazoles; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; C063119:ramatroban; D015230:Prostaglandin D2