Bronchodilator activity of a PGE2 analog in animals and in man

A C-11 substituted PGE2 analog, DHET-PGE2 [alpha-11-deoxy-11 alpha-(2-hydroxyethylthio)-PGE2 methyl ester], was demonstrated to exert potent bronchodilator activity in three in vivo models of augmented airway resistance: (1) acute bronchospasms, induced by 5-hydroxytryptamine, histamine and acetylcholine in the anesthetized guinea pig, (2) acute bronchospasm, induced by pilocarpine, in the anesthetized dog, and (3) chronic bronchospasm, induced by SO2 exposure, in the unanesthetized dog. In acute and 30-day toxicological studies in the dog, no cardiovascular, respiratory or gastrointestinal side effects were observed at aerosol doses at least 1,000 times those required for efficacy. In vitro, DHET-PGE2 effectively relaxed isolated preparations of dog bronchus that had been contracted with carbachol. In clinical studies, human asthmatics and bronchitics responded consistently to beta-agonist bronchodilators but variably to DHET-PGE2. Overall, increases in pulmonary resistance or decreases in FEV1 were observed with DHET-PGE2. Subsequent evaluation in isolated carbachol-contracted human bronchus revealed that, in contrast to the bronchodilator activity of PGE1 and beta-agonists, DHET-PGE2 and PGE2 induced contraction. Considered along with results from previous clinical studies on other PGs, these data underscore the difficulties in making extrapolations on this class of compounds from animal models to humans and suggest that human bronchial tissue may provide the only appropriate preclinical test system for predicting the clinical efficacy of PG bronchodilators.