CYCLOOXYGENASE-2 INHIBITORS - A NEW APPROACH TO THE THERAPY OF OCULARINFLAMMATION

Prostaglandins (PGs) can be synthesized through the activities of two cyclooxygenase (COX) isoforms. COX-1 is constitutively expressed in mo st 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 cy tokines, growth factors and bacterial endotoxin, and its enzymatic act ivity accounts for the large amounts of PGs produced during inflammati on. The currently used nonsteroidal anti-inflammatory drugs (NSAIDs) a re nonselective inhibitors of both COX isoforms. Inhibition of COX-2 l eads to the therapeutically desired inhibition of the synthesis of pro -inflammatory PGs, but at the same time produces side effects associat ed with inhibition of COX-1 and the consequent suppression of the prod uction of PGs necessary for normal cellular functions. Selective inhib ition of COX-2 expression explains, at least in part, the potent anti- inflammatory activity of corticosteroids. However, the systemic and oc ular side effects of these steroids have greatly limited their use, es pecially their long-term use for the management of chronic inflammator y conditions. The current effort to develop highly selective nonsteroi dal COX-2 inhibitors for the treatment of arthritis and other inflamma tory diseases can also be expected to yield a new approach to the trea tment of uveitis and other ocular inflammatory conditions. This new cl ass of NSAIDs will provide anti-inflammatory and analgesic activity wh ile circumventing the most serious side effects of the current availab le NSAIDs, resulting from their inhibition of the physiologically requ ired COX-1 activity.