Although they remain less effective than inhaled corticosteroids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLT1 receptor for leukotrienes (zafirlukast, montelukast, and pranlukast; see Chapter 20) are used clinically in mild to moderate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applications of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and the molecular target (5-LOX versus FLAP). Human genetic studies demonstrate a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, and indicate an interaction between the 5-LOX and COX-2 pathways, in some populations.
NSAIDs usually do not inhibit lipoxygenase activity at concentrations attained clinically that inhibit COX activity. In fact, by preventing arachidonic acid conversion via the COX pathway, NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways, leading to an increased formation of the inflammatory and proliferative leukotrienes. Even among the COX-dependent pathways, inhibiting the synthesis of one derivative may increase the synthesis of an enzymatically related product. Therefore, drugs that inhibit both COX and lipoxygenase are being developed. One such drug, the COX-2/5-LOX inhibitor darbufelone, has shown promise in studies of cancer cells and in
Dinoprostone Epoprostenol (prostaglandin E2, PGE2) (prostacyclin, PGI2)
FIGURE 18–5 Chemical structures of some prostaglandins and prostaglandin analogs currently in clinical use.
mouse tumor models. These mechanistic studies, paired with the observed up-regulation of both COX-2 and 5-LOX in multiple human tumors, including pancreatic cancer, suggest that this may be an important avenue for further investigations.
Several approaches have been used in the clinical application of eicosanoids. First, stable oral or parenteral long-acting analogs of the naturally occurring prostaglandins have been developed (Figure 18–5). Second, enzyme inhibitors and receptor antagonists have been developed to interfere with the synthesis or effects of the eicosanoids. The discovery of COX-2 as a major source of inflammatory prostanoids led to the development of selective COX-2 inhibitors in an effort to preserve the gastrointestinal and renal functions directed through COX-1, thereby reducing toxicity. However, it is apparent that the marked decrease in biosynthesis of PGI2 that follows COX-2 inhibition occurring without a concurrent inhibition of platelet COX-1-derived TXA2 removes a protective constraint on endogenous mediators of cardiovascular dysfunction and leads to an increase in cardiovascular events in patients taking selective COX-2 inhibitors. Third, efforts at dietary manipulation—to change the polyunsaturated fatty acid precursors in the cell membrane phospholipids and so change eicosanoid synthesis—is used extensively in over-the-counter products and in diets emphasizing increased consumption of cold-water fish.
Studies with knockout mice have confirmed a role for prostaglandins in reproduction and parturition. COX-1-derived PGF2α appears important for luteolysis, consistent with delayed parturition in COX-1-deficient mice. A complex interplay between PGF2α and oxytocin is critical to the onset of labor. EP2 receptor-deficient mice demonstrate a preimplantation defect, which underlies some of the breeding difficulties seen in COX-2 knockouts. PGI2 production leads to maturation of uterine smooth muscle cell prior to labor.
A. Abortion