title: The role of platelet-activating factor (PAF) and the efficacy of ABT-491, a highly potent and selective PAF antagonist, in experimental allergic rhinitis.
abstract: Platelet-activating factor (PAF) may be an important mediator of allergic rhinitis. In the present study we evaluated the effectiveness of a recently described PAF antagonist (ABT-491) in rat and guinea pig models of allergic rhinitis. PAF, when perfused through the nasal passages of anesthetized Brown Norway rats, provoked an acute increase, measured as dye leakage, in nasal vascular permeability evident within 15 min after exposure to PAF. ABT-491, given orally 1 hr before PAF challenge, inhibited the response in a dose-related manner (ED50 = 0.3 mg/kg). Intranasal perfusion with ovalbumin in rats sensitized to the antigen 18 to 21 days before challenge also induced an increase in vascular permeability. The antigen-induced leakage was inhibited a maximum of 74% (P < or = .001) by pretreatment with ABT-491 (3 mg/kg p.o.). An antihistamine (mepyramine, 10 mg/kg i.p.), a serotonin antagonist (methysergide) and a 5-lipoxygenase inhibitor (A-79175) also exhibited efficacy in this model (56%, 87% and 65% inhibition, respectively). Nearly complete inhibition (93%, P < or = .001) of the response was achieved by coadministration of ABT-491 and methysergide. In guinea pigs intranasal administration of PAF resulted in increased airway resistance that was inhibited in a dose-dependent manner 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 inhibition 64%, P < or = .05, 10 mg/kg p.o.). The effectiveness of the antagonist was increased to 80% protection by coadministration with either an antihistamine or a 5-lipoxygenase inhibitor, agents which were separately insignificant in blocking the response to antigen. These results suggest a therapeutic utility for ABT-491, perhaps in combination with other anti-inflammatory agents, in the treatment of allergic rhinitis.
authors.affiliation: Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Albert
authors.forename: P E
authors.initials: PE
authors.lastname: Malo
authors.forename: P
authors.initials: P
authors.lastname: Tapang
authors.forename: T K
authors.initials: TK
authors.lastname: Shaughnessy
authors.forename: D W
authors.initials: DW
authors.lastname: Morgan
authors.forename: C D
authors.initials: CD
authors.lastname: Wegner
authors.forename: M L
authors.initials: ML
authors.lastname: Curtin
authors.forename: G S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: S K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: J B
authors.initials: JB
authors.lastname: Summers
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D012220:Rhinitis / Q000188:drug therapy*
chemical_list: D007093:Imidazoles; D007211:Indoles; D010972:Platelet Activating Factor; C107116:ABT 491