THE ROLE OF PLATELET-ACTIVATING-FACTOR (PAF) AND THE EFFICACY OF ABT-491, A HIGHLY POTENT AND SELECTIVE PAF ANTAGONIST, IN EXPERIMENTAL ALLERGIC RHINITIS

Platelet-activating factor (PAF) may be an important mediator of aller gic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig mod els of allergic rhinitis. PAF, when perfused through the nasal passage s of anesthetized Brown Norway rats, provoked an acute increase, measu red as dye leakage, in nasal vascular permeability evident within 15 m in after exposure to PAF. ABT-491, given orally 1 hr before PAF challe nge, inhibited the response in a dose-related manner (ED50 = 0.3 mg/kg ). Intranasal perfusion with ovalbumin in rats sensitized to the antig en 18 to 21 days before challenge also induced an increase in vascular permeability. The antigen-induced leakage was inhibited a maximum of 74% (P less than or equal to .001) by pretreatment with ABT-491 (3 mg/ kg p.o.). An antihistamine (mepyramine, 10 mg/kg i.p.), a serotonin an tagonist (methysergide) and a 5-lipoxygenase inhibitor (A-79175) also exhibited efficacy in this model (56%, 87% and 65% inhibition, respect ively). Nearly complete inhibition (93%, P less than or equal to .001) of the response was achieved by coadministration of ABT-491 and methy sergide. In guinea pigs intranasal administration of PAF resulted in i ncreased airway resistance that was inhibited in a dose-dependent mann er by oral administration of ABT-491 (ED50 = 1 mg/kg). Antigen-induced nasal airway resistance, triggered by exposure of sensitized animals to aerosolized ovalbumin, was also inhibited by ABT-491 (maximum inhib ition 64%, P less than or equal to .05, 10 mg/kg p.o.). The effectiven ess of the antagonist was increased to 80% protection by coadministrat ion with either an antihistamine or a 5-lipoxygenase inhibitor, agents which were separately insignificant in blocking the response to antig en. These results suggest a therapeutic utility for ABT-491, perhaps i n combination with other anti-inflammatory agents, in the treatment of allergic rhinitis.