A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: Effects of new topical ocular drugs

Two important realizations about pathophysiological mechanisms involved in allergic conjunctivitis have led to novel drug discovery efforts and new to pical ocular medications for prevention and treatment of this prevalent all ergic disease. The first of these, interspecies and intraspecies mast cell heterogeneity, was established in the mid-1980's by investigators working i n the field of asthma. It is now appreciated that secretory responses as we ll as effects of pharmacological agents differ depending upon the mast cell population studied. Two types of human mast cells, the tryptase containing (T) and the tryptase/chymase containing (TC) mast cells, have been charact erized in a variety of tissues Significantly, Irani et al. (1) demonstrated by immunohistochemical staining that the mast cells present in conjunctiva l tissues from patients with allergic conjunctivitis were 100% TC. Function al responses of human conjunctival mast cells to a variety of secretagogues (2) were consistent with their classification as TC or connective tissue t ype mast cells. Importantly, the studies by Miller et al. mentioned above a llowed the harvesting and preparation of human conjunctival mast cells for use in drug screening studies. Utilization of these cells has led to the id entification of Patanol(R), the most effective human conjunctival mast cell stabilizer available for topical use in allergic conjunctivitis (3). These same studies demonstrated the lack of mast cell stabilizing activity for c romolyn and nedocromil in these connective tissue type, TC containing, huma n conjunctival mast cells. Similar lack of effect was noted with these drug s on human skin mast cell degranulation (4). The second important discovery in the area of allergic conjunctivitis has been the demonstration that con junctival epithelial cells may contribute to the perpetuation of the allerg ic response. A report from Gamache et al. (5) identified cytokines produced by human conjunctival epithelial cells following treatment with a number o f stimuli. Significantly, Sharif et al. (6) subsequently identified functio nal histamine I-Il receptors on these same cell types. Recently, Weimer et al. (7) have shown that exposure of human conjunctival epithelial cells to histamine leads to the production of pro-inflammatory cytokines IL-6 and IL -8. Importantly, treatment of the epithelial cells with drugs that possess histamine H-1 antagonist properties prevents cytokine production. It is not eworthy that first generation anti-histamines antazoline and pheniramine ar e not potent inhibitors of histamine-stimulated cytokine synthesis in intac t epithelial cells, while newer anti-histamines Emadine(TM) and levocabasti ne are more potent. Surprisingly, Patanol(R) was more potent as an inhibito r of histamine-stimulated cytokine production by the epithelial cells than would be predicted from its histamine H-1 antagonist affinity, These inhibi tory effects on conjunctival epithelial cell production of pro-inflammatory cytokines may contribute to enhanced clinical activity noted with these re cently approved drugs.