Yanni J M, Stephens D J, Miller S T, Weimer L K, Graff G, Parnell D, Lang L S, Spellman J M, Brady M T, Gamache D A
Alcon Laboratories, Inc., Fort Worth, Texas, USA.
J Ocul Pharmacol Ther. 1996 Winter;12(4):389-400. doi: 10.1089/jop.1996.12.389.
Olopatadine (AL-4943A; KW-4679) [(z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2 acetic acid hydrochloride] is an anti-allergic agent which inhibits mast cell mediator release and possesses histamine H1 receptor antagonist activity. Studies were conducted to characterize the in vitro and in vivo pharmacological profile of this drug relevant to its topical ocular use. AL-4943A inhibits histamine release in a concentration-dependent fashion (IC50 = 559 microM) from human conjunctival mast cell preparations in vitro. Histamine release was not stimulated by AL-4943A at concentrations as high as 10 mM. In contrast, ketotifen stimulated histamine release at concentrations slightly higher than effective inhibitory concentrations. AL-4943A did not display any in vitro cyclooxygenase or 5-lipoxygenase inhibition. Topical ocular application of AL-4943A effectively inhibits antigen- and histamine-stimulated conjunctivitis in guinea pigs. Passive anaphylaxis in guinea pig conjunctiva was attenuated by AL-4943A applied 30 min prior to intravenous or topical ocular antigen challenge (ED50 values 0.0067% and 0.0170%, w/v, respectively). Antihistaminic activity in vivo was demonstrated using a model of histamine-induced vascular permeability in guinea pig conjunctiva. AL-4943A applied topically from 5 min to 24 hrs prior to histamine challenge effectively and concentration-dependently inhibited the vascular permeability response, indicating the compound has an acceptable onset and a long duration of action. Drug concentrations 5-fold greater than those effective against histamine-stimulated conjunctival responses failed to inhibit vascular permeability responses induced with either serotonin or Platelet-Activating-Factor. These data indicate that the anti-histaminic effect observed with AL-4943A is specific. These anti-allergic/antihistaminic activities of AL-4943A observed in preclinical model systems have been confirmed in clinical trials in allergic patients.
奥洛他定（AL - 4943A；KW - 4679）[（Z）-11 - [3 - （二甲氨基）亚丙基]-6,11 - 二氢二苯并[b,e]氧杂䓬 - 2 - 乙酸盐酸盐]是一种抗过敏药物，它能抑制肥大细胞介质释放，并具有组胺H1受体拮抗剂活性。开展了多项研究以表征该药物与其局部眼部应用相关的体外和体内药理学特征。在体外，AL - 4943A以浓度依赖性方式抑制人结膜肥大细胞制剂中的组胺释放（IC50 = 559 microM）。在高达10 mM的浓度下，AL - 4943A不会刺激组胺释放。相比之下，酮替芬在略高于有效抑制浓度的情况下会刺激组胺释放。AL - 4943A在体外未表现出任何环氧合酶或5 - 脂氧合酶抑制作用。局部眼部应用AL - 4943A可有效抑制豚鼠体内抗原和组胺刺激引起的结膜炎。在静脉内或局部眼部抗原攻击前30分钟应用AL - 4943A可减轻豚鼠结膜的被动过敏反应（ED50值分别为0.0067%和0.0170%，w/v）。使用组胺诱导豚鼠结膜血管通透性的模型证明了其体内抗组胺活性。在组胺攻击前5分钟至24小时局部应用AL - 4943A可有效且浓度依赖性地抑制血管通透性反应，表明该化合物起效时间可接受且作用持续时间长。比有效对抗组胺刺激的结膜反应的药物浓度高5倍的药物浓度未能抑制由5 - 羟色胺或血小板活化因子诱导的血管通透性反应。这些数据表明，观察到的AL - 4943A的抗组胺作用具有特异性。在临床前模型系统中观察到的AL - 4943A的这些抗过敏/抗组胺活性已在过敏患者的临床试验中得到证实。
