Yanni J M, Miller S T, Gamache D A, Spellman J M, Xu S, Sharif N A
Ophthalmic Products Research, Alcon Laboratories, Inc., Fort Worth, Texas, USA.
Ann Allergy Asthma Immunol. 1997 Dec;79(6):541-5. doi: 10.1016/S1081-1206(10)63063-3.
The concept of mast cell heterogeneity is well established. Recent data indicate that human conjunctival tissue mast cells and human connective tissue mast cells respond to various secretagogues in similar fashion. It is now recognized that different mast cell populations respond differently to anti-allergic drugs.
The purpose of the study is to compare the effects of three new ocular anti-allergic drugs (nedocromil, olopatadine, and pemirolast) on mediator release from the target human conjunctival mast cell population with those of cromolyn sodium. The affinity of the compounds for the histamine H1 receptor was also compared.
A monodispersed suspension of partially purified human conjunctival mast cells was prepared from cadaver conjunctival tissue. Mast cells (5 x 10(3)) were challenged with anti-human IgE in the presence or absence of test drugs, and histamine content of the cell supernatants was determined using a specific radioimmunoassay. H1 receptor binding activity was assessed using a radioligand binding assay.
Cromolyn and pemirolast (100 nM to 1 mM) failed to significantly inhibit histamine release from human conjunctival mast cells using exposure times of 1 and 15 minutes prior to challenge. Using identical nedocromil concentrations and exposure times, statistically significant (P < .05) inhibition (28%) of histamine release was observed at only the 100 microM concentration and 1-minute exposure time. In contrast, olopatadine inhibited histamine release in a concentration-dependent fashion (r = 0.891, n = 59, IC50 = 653 microM). Only olopatadine exhibited significant H1 receptor binding activity at relevant concentrations (Ki = 36 nM, n = 13).
These data indicate that olopatadine possesses anti-allergic activity in the appropriate targets for topical ocular anti-allergic drug therapy, human conjunctival mast cells. Coupled with the compound's antihistaminic activity, this suggests that olopatadine will have efficacy advantages in allergic conjunctivitis patients over the other drugs tested.
肥大细胞异质性的概念已得到充分确立。近期数据表明，人类结膜组织肥大细胞和人类结缔组织肥大细胞对各种促分泌素的反应方式相似。现在人们认识到，不同的肥大细胞群体对抗过敏药物的反应不同。
本研究的目的是比较三种新型眼部抗过敏药物（奈多罗米、奥洛他定和吡嘧司特）与色甘酸钠对目标人类结膜肥大细胞群体介质释放的影响。还比较了这些化合物对组胺H1受体的亲和力。
从尸体结膜组织制备部分纯化的人类结膜肥大细胞单分散悬液。肥大细胞（5×10³）在有或无受试药物的情况下用抗人IgE刺激，使用特异性放射免疫测定法测定细胞上清液中的组胺含量。使用放射性配体结合测定法评估H1受体结合活性。
色甘酸钠和吡嘧司特（100 nM至1 mM）在刺激前1分钟和15分钟的暴露时间内，未能显著抑制人类结膜肥大细胞释放组胺。使用相同的奈多罗米浓度和暴露时间，仅在100 microM浓度和1分钟暴露时间时观察到组胺释放有统计学意义（P <.05）的抑制（28%）。相比之下，奥洛他定以浓度依赖方式抑制组胺释放（r = 0.891，n = 59，IC50 = 653 microM）。只有奥洛他定在相关浓度下表现出显著的H1受体结合活性（Ki = 36 nM，n = 13）。
这些数据表明，奥洛他定在局部眼部抗过敏药物治疗的合适靶点即人类结膜肥大细胞中具有抗过敏活性。结合该化合物的抗组胺活性，这表明奥洛他定在过敏性结膜炎患者中比其他受试药物具有疗效优势。
