Cyclooxygenase-2 inhibitors: a new approach to the therapy of ocular inflammation

Prostaglandins (PGs) can be synthesized through the activities of two cyclooxygenase (COX) isoforms. COX-1 is constitutively expressed in most tissues and its activity provides for the relative small amounts of PGs required for the mediation and modulation of normal physiological functions. In inflammatory conditions, COX-2 is rapidly induced by cytokines, growth factors and bacterial endotoxin, and its enzymatic activity accounts for the large amounts of PGs produced during inflammation. The currently used nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective inhibitors of both COX isoforms. Inhibition of COX-2 leads to the therapeutically desired inhibition of the synthesis of pro-inflammatory PGs, but at the same time produces side effects associated with inhibition of COX-1 and the consequent suppression of the production of PGs necessary for normal cellular functions. Selective inhibition of COX-2 expression explains, at least in part, the potent anti-inflammatory activity of corticosteroids. However, the systemic and ocular side effects of these steroids have greatly limited their use, especially their long-term use for the management of chronic inflammatory conditions. The current effort to develop highly selective nonsteroidal COX-2 inhibitors for the treatment of arthritis and other inflammatory diseases can also be expected to yield a new approach to the treatment of uveitis and other ocular inflammatory conditions. This new class of NSAIDs will provide anti-inflammatory and analgesic activity while circumventing the most serious side effects of the current available NSAIDs, resulting from their inhibition of the physiologically required COX-1 activity.