Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two important realizations about pathophysiological mechanisms involved in allergic conjunctivitis have led to novel drug discovery efforts and new topical ocular medications for prevention and treatment of this prevent allergic disease. The first of these, interspecies and intraspecies mast cell heterogeneity, was established in the mid-1980's by investigators working in the field of asthma. It is now appreciated that secretory responses as well 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 characterized in a variety of tissues. Significantly, Irani et al. (1) demonstrated by immunohistochemical staining that the mast cells present in conjunctival tissues from patients with allergic conjunctivitis were 100% TC. Functional responses of human conjunctival mast cells to a variety of secretagogues (2) were consistent with their classification as TC or connective tissue type mast cells. Importantly, the studies by Miller et al. mentioned above allowed the harvesting and preparation of human conjunctival mast cells for use in drug screening studies. Utilization of these cells has led to the identification of Patanol, 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 cromolyn and nedocromil in these connective tissue type, TC containing, human conjunctival mast cells. Similar lack of effect was noted with these drugs on human skin mast cell degranulation (4). The second important discovery in the area of allergic conjunctivitis has been the demonstration that conjunctival epithelial cells may contribute to the perpetuation of the allergic response. A report from Gamache et al. (5) identified cytokines produced by human conjunctival epithelial cells following treatment with a number of stimuli. Significantly, Sharif et al. (6) subsequently identified functional histamine H1 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 H1 antagonist properties prevents cytokine production. It is noteworthy that first generation anti-histamines antazoline and pheniramine are not potent inhibitors of histamine-stimulated cytokine synthesis in intact epithelial cells, while newer anti-histamines Emadine and levocabastine are more potent. Surprisingly, Patanol was more potent as an inhibitor of histamine-stimulated cytokine production by the epithelial cells than would be predicted from its histamine H1 antagonist affinity. These inhibitory effects on conjunctival epithelial cell production of pro-inflammatory cytokines may contribute to enhanced clinical activity noted with these recently approved drugs.
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PMID:A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs. 1033 30

Mast cells are involved in early and late-phase reactions by releasing vasoactive molecules, proteases, and cytokines. Azelastine and olopatadine are histamine 1 receptor (H-1R) antagonists with antiallergic effects present in the ophthalmic solutions Optivar and Patanol, respectively. Because it is difficult to obtain animal or human conjunctival tissue, we first investigated the effect of these compounds on histamine and tryptase release from cultured human mast cells (CHMCs) grown out of human umbilical cord blood-derived CD34+ cells. Sensitized CHMCs were pretreated with various concentrations of azelastine or olopatadine for 5 minutes. Then, CHMCs were challenged with anti-immunoglobulin E (IgE) and the released mediators were quantitated. The greatest inhibition of mediator release was seen when CHMCs were pretreated with 24 microM of azelastine or 133 microM of olopatadine (2% dilution of azelastine or 5% olopatadine original ophthalmic solutions, respectively). We then studied the drug concentrations that gave optimal results on skin vasodilation induced by the mast cell secretagogue compound 48/80. An intradermal injection of 48/80 in rats, to which Evan's blue had been administered via the tail vein, induced substantial dye extravasation. Pretreatment of the injection site for 5 minutes with either 24 microM of azelastine or 133 microM of olopatadine completely prevented extravasation; this effect was quantitated also by fluorometric assessment of Evan's blue extracted in formamide. Evaluation of skin mast cells from injected sites showed that mast cell degranulation was inhibited greatly. These results indicate that on an equimolar basis, azelastine was a more potent inhibitor than olopatadine of both CHMC and rat skin mast cells activation.
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PMID:Azelastine's inhibition of histamine and tryptase release from human umbilical cord blood-derived cultured mast cells as well as rat skin mast cell-induced vascular permeability: comparison with olopatadine. 1189 34