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.