Anti-inflammatory and antiallergic eVects of ketorolac tromethamine in the conjunctival provocation model

Aim—To study the eVect of the topical anti-inflammatory drug, ketorolac, on (1) the clinical allergic reaction induced by the conjunctival provocation test (CPT); (2) the release of tryptase in tears; and (3) the expression of adhesion molecules on the conjunctival epithelium. Methods—10 allergic but non-active patients were challenged in both eyes with increasing doses of specific allergen to obtain a positive bilateral reaction and rechallenged, after 1 week, to confirm the allergic threshold dose response. After 2 weeks, a third CPT was then performed bilaterally 30 minutes after topical application of ketorolac in one eye and placebo in the contralateral eye in a double blind fashion. Clinical symptoms and signs were registered 5, 10, 15, and 20 minutes after challenge. The following objective tests were performed: tear tryptase measurement; tear cytology; and conjunctival impression cytology for immunohistochemical expression of ICAM-1 on epithelial cells. Results—Compared with placebo, ketorolac significantly reduced the total clinical score and the itching score in the 20 minutes after challenge (p<0.0005). Tear levels of tryptase were significantly reduced in the ketorolac pretreated eyes compared with placebo (p<0.03). Eosinophils, neutrophils, and lymphocytes in tear cytology were significantly lower in ketorolac treated eyes compared with placebo. A significant diVerence in the epithelial expression of ICAM-1 was observed between placebo and ketorolac treated eyes (p<0.05). Conclusion—Ketorolac proved to be eVective in reducing mast cell degranulation, as indicated by significantly decreased tryptase tear levels, as well as the clinical and cytological allergic reaction. (Br J Ophthalmol 2000;84:1228–1232) Seasonal allergic conjunctivitis is a very common disease with symptoms such as itchy and tearing eyes, conjunctival redness, and chemosis and eyelid swelling. Ocular allergic inflammation is a consequence of single or repeated natural challenges to environmental allergens that induce IgE specific mast cell activation and the subsequent cascade of inflammatory mediators and cellular infiltration. The allergic reaction induced by the specific conjunctival provocation test (CPT) reproduces exactly the signs and symptoms of the acute seasonal allergic reaction. In this model, a single episode is induced in a standardised manner allowing for a homogeneous baseline for all allergic patients in the study independent of the allergen used for challenge. The CPT reproduces both the immediate and late allergic ocular response. The early phase of this reaction is characterised by mast cell activation and the release of preformed and newly formed mediators such as histamine, tryptase, prostaglandins, and leukotrienes. Mast cell degranulation also induces activation of vascular endothelial cells and the expression of chemokines and adhesion molecules, such as ICAM-1/CD54. These factors lead to a latent recruitment phase that ushers in the inflammatory late phase reaction characterised by cellular infiltration of the conjunctival mucosa. The conjunctival reaction induced by allergen challenge can be monitored in various ways, by scoring the clinical symptoms and signs, evaluating conjunctival or tear cytology, and/or measuring inflammatory mediators in the tear film. 8 Ketorolac tromethamine 0.5% ophthalmic solution is a highly potent non-steroidal anti-inflammatory agent that decreases the synthesis of prostaglandins by inhibiting the enzyme, cyclo-oxygenase. The pharmacological activity of prostaglandins (PGs) accounts for many of the signs, symptoms, and events associated with experimental and clinical allergic conjunctivitis. In recent studies, the clinical eYcacy of ketorolac in the treatment of seasonal allergic conjunctivitis has been evaluated. 11 The present study was performed to determine the protective eVect of ketorolac on allergic conjunctival inflammation induced by allergen challenge. In addition to a clinical evaluation, the objective variables of tryptase tear levels, tear cytology, and ICAM-1 immunohistochemical expression were considered to better evaluate the anti-inflammatory eVects of this drug. Materials and methods