Albert D H, Malo P E, Tapang P, Shaughnessy T K, Morgan D W, Wegner C D, Curtin M L, Sheppard G S, Xu L, Davidsen S K, Summers J B, Carter G W
Abbott Laboratories, Abbott Park, Illinois, USA.
J Pharmacol Exp Ther. 1998 Jan;284(1):83-8.
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.
血小板活化因子（PAF）可能是变应性鼻炎的重要介质。在本研究中，我们评估了一种最近描述的PAF拮抗剂（ABT - 491）在大鼠和豚鼠变应性鼻炎模型中的有效性。当通过麻醉的棕色挪威大鼠的鼻腔灌注PAF时，在暴露于PAF后15分钟内，以染料渗漏衡量的鼻血管通透性会急性增加。在PAF激发前1小时口服ABT - 491，以剂量相关方式抑制了该反应（半数有效剂量[ED50]=0.3毫克/千克）。在激发前18至21天对抗原致敏的大鼠中，经鼻内灌注卵清蛋白也诱导了血管通透性增加。用ABT - 491（3毫克/千克，口服）预处理可最大程度地抑制抗原诱导的渗漏达74%（P≤0.001）。一种抗组胺药（美吡拉敏，10毫克/千克，腹腔注射）、一种5 -羟色胺拮抗剂（甲基麦角新碱）和一种5 -脂氧合酶抑制剂（A - 79175）在该模型中也显示出疗效（分别抑制56%、87%和65%）。联合给予ABT - 491和甲基麦角新碱可实现对反应的几乎完全抑制（93%，P≤0.001）。在豚鼠中，经鼻内给予PAF导致气道阻力增加，口服ABT - 491以剂量依赖方式抑制了该增加（ED50 = 1毫克/千克）。致敏动物暴露于雾化卵清蛋白引发的抗原诱导的鼻气道阻力也被ABT - 491抑制（最大抑制64%，P≤0.05，10毫克/千克，口服）。通过与抗组胺药或5 -脂氧合酶抑制剂联合给药，拮抗剂的有效性提高到80%的保护作用，而这些药物单独使用时对阻断抗原反应无显著作用。这些结果表明ABT - 491可能具有治疗变应性鼻炎的效用，或许与其他抗炎药物联合使用。
