Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 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

Seasonal allergic conjunctivitis is rarely associated with permanent vision impairment; however, it is a relatively common condition that may compromise the quality of life. It may, in extreme cases, impair daily activities, including work. Numerous treatment options have become available for the relief of acute symptoms. Avoidance should always be the first line in therapy but, in most cases, is not practical, especially with pollen allergies. The use of saline eyedrops is simple and nontoxic, and it is effective in up to 30% to 35% of cases. It can and should be added to all other remedies to reduce adverse effects and cost by decreasing the need for other therapeutic options. Antihistamines and decongestants are useful treatment choices for the majority of cases. Ketorolac tromethamine may be helpful in relieving pruritus, but it offers little advantage over topical antihistamines. Corticosteroids may be used for severe cases for a limited time. If topical corticosteroids are being considered, an ophthalmologist should be consulted. Cromolyn sodium and lodoxamide ophthalmic solution may be helpful in the prophylaxis of symptoms during the allergy season, but these agents require frequent dosing. Olopatadine hydrochloride is a mast cell stabilizer and antihistamine that can be dosed twice a day. Immunotherapy is effective and should be offered to those who are intolerant or have allergic conjunctivitis refractory to medications.
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PMID:Seasonal allergic conjunctivitis: overview and treatment update. 1047 15

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

Olopatadine hydrochloride (olopatadine) is an anti-allergic drug that functions as a histamine H(1) antagonist and inhibits both mast cell degranulation and the release of arachidonic acid metabolites in various types of cells. In this study, we examined the ability of olopatadine to inhibit the expression of cytokine genes in vitro via high-affinity receptors for immunoglobulin E in mast cells, using a rat basophilic leukemia (RBL-2H3) cell line and an in vivo mouse model. Levels of gene expression in RBL-2H3 cells were determined by semi-quantitative RT-PCR, and serum interleukin-4 (IL-4) level in mice was quantified by ELISA. Olopatadine inhibited significantly the induction of IL-4 expression by mast cells both in vivo and in vitro. Olopatadine inhibited Ca(2+) influx through receptor-operated channels (ROC) without affecting Ca(2+) release from intracellular stores. Comparative analysis of olopatadine with other anti-allergic drugs and the ROC blocker SKF-96365 demonstrated that the potency of inhibition of Ca(2+) influx correlated with the degree of suppression of degranulation and arachidonic acid release. Inhibition of Ca(2+) influx decreased phosphorylation of p38 mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase, which participate in regulation of cytokine (e.g. IL-4) gene expression. However, the rank order of inhibition of Ca(2+) influx did not correspond to reduction of IL-4 expression, suggesting that an unknown mechanism(s) of action, in addition to inhibition of Ca(2+) influx, is involved in the expression of cytokines in mast cells.
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PMID:Differential regulation of IL-4 expression and degranulation by anti-allergic olopatadine in rat basophilic leukemia (RBL-2H3) cells. 1501 47

Ocular allergy affects > 20% of the general population and many therapeutic preparations are available to individuals experiencing the most common forms--seasonal and perennial allergic conjunctivitis. 0.1% Olopatadine topical ophthalmic solution is currently approved for the treatment of allergic signs and symptoms in patients > or = 3 years of age. Olopatadine is available in Europe as Opatanol) and in > 30 other countries as Patanol. It inhibits mast cell degranulation and antagonises histamine receptors to manage the itching, redness, chemosis, tearing and lid swelling of the ocular allergic reaction, and its mast cell stabilising ability has been demonstrated both in vitro (using human conjunctival mast cells) and in vivo (human clinical experience). This article reviews both the laboratory and clinical information available on olopatadine, prefaced by a discussion of the current understanding of the ocular allergic reaction and followed by the future implications for this compound. Both laboratory and clinical studies have established the efficacy, safety and comfort of olopatadine in several study design models and comparisons to other antiallergy medications. The application of olopatadine, specifically in the management of lid swelling, an allergic sign recalcitrant to therapy and nasal allergic symptoms has also been established. In the future, a new formulation containing 0.2% olopatadine exhibits a duration of action up to 24 h, supporting once-daily dosing.
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PMID:A review of olopatadine for the treatment of ocular allergy. 1533 Jul 35

Olopatadine 0.1% (Patanol) and olopatadine 0.2% (Pataday) ophthalmic solutions are topical ocular anti-allergic agents with antihistaminic and mast cell stabilizing properties. The efficacy of two doses of olopatadine 0.1% was compared to one dose of olopatadine 0.2% in the prevention of ocular itching associated with allergic conjunctivitis over 24 hours. This double-masked conjunctival allergen challenge (CAC) study found no significant difference in the mean itching scores between two drops of olopatadine 0.1% and one drop of olopatadine 0.2%. Both showed significant activity at the 24-hour time point and were statistically superior to placebo. No adverse events occurred while on drug therapy.
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PMID:Efficacy of once-daily olopatadine 0.2% ophthalmic solution compared to twice-daily olopatadine 0.1% ophthalmic solution for the treatment of ocular itching induced by conjunctival allergen challenge. 1808 65

Olopatadine is a tricyclic compound with antihistaminic, mast cell-stabilizing, and anti-inflammatory properties. In the United States olopatadine is approved as a b.i.d. ophthalmic solution, Patanol (Alcon Laboratories, Inc., Fort Worth, TX) to treat all signs and symptoms of allergic conjunctivitis and as a q.d. formulation, Pataday (Alcon Laboratories, Inc.), to treat itching associated with allergic conjunctivitis. A nasal spray, Patanase (Alcon Laboratories, Inc.), was approved in 2008 for treatment of the symptoms of seasonal allergic rhinitis. The available data on olopatadine was assessed with regard to future uses through a comprehensive literature review and a Roundtable Discussion held at the 2009 meeting of the American Academy of Allergy Asthma and Immunology. The unique mechanisms of action of olopatadine still under study include mast cell stabilization, potent H(1)-anthistaminic activity, and anti-inflammatory effects. Data support consideration of nasal olopatadine for as-needed use for episodic symptoms of allergic rhinitis, for treatment of nonallergic rhinitis, and for use in combination with topical steroids for patients with moderate-to-severe allergy symptoms.
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PMID:Comprehensive review of olopatadine: the molecule and its clinical entities. 2040 93