Because cyclooxygenases are the main target of NSAID therapy, the role of cyclooxygenase-derived lipid mediators has been widely studied. Inhibition of cyclooxygenase leads to a decrease in the production of all prostaglandins and thromboxanes, and this accounts for the observed effects of NSAIDs as anti-inflammatory, antipyretic, analgesic, and antithrombotic agents. It also explains their gastrointestinal and renal side effects. Enormous effort has been expended to develop NSAIDs whose specificity of action will enhance the benefits of eicosanoid inhibition yet minimize the harmful effects on gastric mucosa and renal vasculature. The discovery of Cox-2 and its role in inflammation but not gastric protection led not only to the development of specific inhibitors of Cox-2, but also to studies examining the differential effects of existing NSAIDs upon the cyclooxygenase isoforms.
Aspirin is currently the only NSAID that covalently modifies cyclooxygenase. Aspirin has greater inhibitory activity against Cox-1 than against Cox-2, and this explains its antiplatelet and cardiovascular effects, as well as its tendency to produce ulceration of gastric mucosa. Cyclooxyge-nase blockade by the other known NSAIDs occurs as a result of reversible binding of the drug to the cyclooxygenase molecule. The kinetics of NSAID—cyclooxygenase interactions are quite complex, with both competitive and time-dependent elements. This, together with the complexity of prostaglandin biology in vivo, makes it difficult to compare the Cox-1/Cox-2 selectivity of different NSAIDs. Depending upon dosage, cell type, and assay conditions, every NSAID exhibits some degree of inhibition of both Cox-1 and Cox-2. In general, however, most NSAIDs, such as aspirin, indomethacin, and piroxicam, are relatively nonspecific. A few, such as meloxicam, have some degree of increased specificity for Cox-2. A new class of NSAIDs, the selective Cox-2 inhibitors, include NS398, celecoxib, and rofecoxib. These agents are strong inhibitors of Cox-2 with minimal effect on Cox-1.
Leukotrienes, through their ability to modulate leuko-cyte—endothelial cell interactions, are thought to mediate NSAID-associated gastric mucosal damage. Leukotrienes are also potent vasoconstrictors and inducers of bron-chospasm in susceptible individuals. The enzyme responsible for leukotriene synthesis, 5-LOX, is expressed only in a limited repertoire of cells, mostly leukocytes. Leukotriene receptors, however, are widely distributed among smooth muscle cells of the vasculature and respiratory tract. Leukotriene modifiers, such as zileuton and montelukast, are 5-LOX inhibitors used clinically for asthma therapy. For unknown reasons, these agents are particularly useful for exercise-induced and aspirin-intolerant asthma.
A promising therapeutic approach to minimize the gastric side effects of aspirin while providing antithrombotic therapy is to concurrently suppress the activities of both cyclooxygenase and 5-LOX enzymes. Based upon the activity profiles of cyclooxygenase and 5-LOX products, these agents would be clinically useful in a wide variety of diseases, including inflammatory states, cancer prevention, and cardiovascular disorders. Several of these dual inhibitors of prostaglandin and leukotriene synthesis have been developed. A few of these, including the agent licofelone, are under evaluation in Phase III clinical trials for the treatment of osteoarthritis.
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