Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs

The two isoforms of cyclooxygenase (COX) catalyze the initial step in the formation of biologically important prostanoids, such as prostaglandin (PG) E2, and thromboxane (TX) A2, in a variety of pathophysiologic processes. These include modulation of the inflammatory reaction, gastrointestinal (GI) cytoprotection and ulceration, angiogenesis and cancer, hemostasis and thrombosis, renal hemodynamics, and progression of kidney disease. Thus, it is not surprising that drugs inhibiting the activity of COX isozymes may have desirable as well as untoward effects on a variety of human diseases. Low-dose aspirin provides a paradigm of COX-isozyme-selective and cell-specific inhibition, by virtue of its short half-life and its ability to inactivate COX irreversibly (1). Other nonsteroidal anti-inflammatory drugs (NSAIDs) lack these unique pharmacokinetic and pharmacodynamic features and do not usually achieve the same degree of persistent platelet COX-1 inhibition as is obtained with low-dose aspirin. The coxib drugs, such as rofecoxib and celecoxib, were developed to spare COX-1 activity in GI mucosa and platelets, and this is achieved more or less effectively depending upon the biochemical selectivity of the individual agents (2). There is no evidence that coxibs inhibit COX-2 at sites different from those normally inhibited by nonaspirin NSAIDs, although the functional consequences of COX-2 inhibition may vary in the face of unopposed COX-1 activity at sites of cell-cell interactions. Here, we discuss the beneficial and harmful consequences of selective COX-1 versus COX-2 inhibition and suggest a mechanistic interpretation of their major clinical read-outs. A leading theme is that the extent and persistence of platelet COX-1 inhibition represent a major determinant of the efficacy and safety of the currently available classes of COX inhibitors. It should be emphasized that the relationships between inhibition of COX-isozyme activity, reduced prostanoid formation, and changes in prostanoid-dependent cell function in vivo are not necessarily linear (3). When measuring clinically relevant outcomes of COX inhibition, one should consider the low incidence rate of these outcomes in the general population (Table ​(Table1).1). Moreover, only a fraction of these events are likely to be COX-dependent. Thus, the signal-to-noise ratio of the measurements made in clinical studies is often less than ideal to allow unequivocal mechanistic interpretations.