Regulation of the Immune Response by Eicosanoids: Pharmacology and Clinical Effects of Prostaglandin E in Aspirin-Sensitive Syndromes.

Abstract

Immunomodulatory effects of prostaglandin E(2) (PGE(2)) have been documented both in vitro and in vivo. Our previous studies have examined the effects of intravenously administered PGE(2) in mast-cell-mediated diseases, including aspirin-sensitive asthma and systemic mast-cell-activation syndrome. The basis for investigations of these particular diseases has been the hypothesis that the inhibition of cyclooxygenase removes one of its products, PGE(2), that provides a critical restraint on the activation of the mast cell. Based on the beneficial effects of PGE(2) found in these studies, we have extended our investigations to an evaluation of misoprostol, the orally available analog of PGE(1). Our preliminary studies with this drug are consistent with an inhibition of mast cell activation by misoprostol, an effect observed at doses higher than currently recommended for gastric protection. The findings from these initial trials have led to the development of ex vivo whole-blood assays that assess the pharmacodynamics of misoprostol's immunomodulatory actions, which support the concept of employing higher doses to obtain sustained systemic effects. To extend these results, we have undertaken double-blinded, placebo-controlled clinical investigations to examine the effects of the higher doses of misoprostol (300--600 &mgr;g QID) given chronically in aspirin-sensitive asthma and systemic mast cell activation. Although still ongoing, our studies have confirmed by a variety of clinical evaluations that the higher doses of misoprostol can be tolerated by many patients and appear to be safe. Based on our findings and those of others, further investigation of the therapeutic usefulness of this drug or other PGE analogs in allergic and immunologic diseases appears warranted.