Effect of the hetrazepinoic platelet-activating factor antagonist Bepafant (WEB 2170) in models of active and passive anaphylaxis in mice and guinea pigs.

The selective hetrazepinoic platelet-activating factor (PAF) antagonist WEB 2170 (Bepafant) was used to study the pathophysiological role of PAF in several models of anaphylaxis in mice and guinea pigs. In actively sensitized mice, the PAF antagonist WEB 2170 (1.0-10 mg/kg p.o.) protected mice from anaphylactic death in a dose-dependent manner when the anaphylactic response was potentiated by the beta-receptor antagonist propranolol. When active anaphylaxis in guinea pigs was induced intravenously by 100 mg/kg ovalbumin (OA) in the presence of small doses of the antihistamine mepyramine, additional treatment with oral or intravenous WEB 2170 protected the guinea pigs from anaphylactic death. Also, the remaining anaphylactic bronchoconstriction and blood pressure changes (including anaphylactic hypotension) were attenuated. When guinea pigs were passively sensitized with a heterologous antibody via the tracheal route and then challenged by ovalbumin (100 mg/kg i.v.) 24 hr after sensitization in the presence of 0.003 mg/kg i.v. mepyramine, additional treatment with tracheal WEB 2170 at 0.1-1 mg/kg protected the guinea pigs dose-dependently not only from anaphylactic death but also from a further decrease of respiratory flow and changes of blood pressure. Increased levels of PAF-like activity (20-50 ng PAF/whole lung) were detected in lungs removed from antigen-challenged animals. The results suggest a causative role for PAF in active and passive anaphylaxis.