Speaking of Pharmacology

Clearing up Inflammation: COX-2 Is Essential

See the communicated article on page 199.

Tissue damage, resulting from a wide range of injurious events, elicits a series of biochemical responses that function to limit the damage, prepare the reversibly injured tissue for replication, and replace irreversibly injured cells. Since the early 1990s, Dr. Derek Gilroy and colleagues have devoted their efforts towards enhancing our understanding of the interdependent mechanisms referred to as acute inflammatory resolution. The inflammatory response to tissue injury, if uncontrolled, leads to chronic inflammation, resulting in tissue destruction and scarring. In their review article in this issue of MI, Rajakariar, Yaqoob, and Gilroy focus on the mechanism(s) intrinsic to successful resolution of the inflammatory event and the role of arachidonic acid metabolites and other fatty acid precursors. Contrary to the popular notion that the primary actions of cyclo-oxygenase-derived metabolites are exclusively pro-inflammatory, the authors provide new insights into the essential role of eicosanoids and the lipoxins in the resolution of the inflammatory response. Recent data elucidate new functions for COX-2, indicating that the enzyme mediates not only the early phases of the inflammatory response, but also the termination of inflammatory activities and initiation of the healing phase. We are thus reminded to think of inflammation not as a disease state, but as part of a reparative process in response to injury. This widened understanding of the underlying mechanisms should assist in the development of selective therapeutic agents designed to prevent chronic inflammatory conditions without potentially dangerous side effects.

Genotyping for Drug Responsiveness: Learning from Warfarin

See the communicated article on page 223.

Warfarin is perhaps the best example of a therapeutically important drug with an almost dangerously narrow therapeutic index. The clinical benefits for patients with atrial fibrillation, prosthetic heart valves, and other conditions that predispose to thrombosis and embolism can be tremendous; warfarin significantly reduces risk of stroke, pulmonary embolism, and other life-threatening conditions. At the same time, warfarin toxicity may entail excessive anticoagulation, with potentially life-threatening bleeding.

It has been recognized for some time that S-warfarin, the pharmacologically more active enantiomer of this racemic drug, is metabolically inactivated by cytochrome P-450 (CYP) 2C9. The activity of this enzyme is polymorphically distributed, as described in the review article by Rettie and Tai in this issue. Initially, there was enthusiasm for CYP2C9 genotyping to identify individuals likely to require warfarin at particularly low doses. Unfortunately, a number of attempts to test the hypothesis that such genotyping would improve clinical warfarin therapy were not very satisfying, and it became clear that a substantial proportion of the variability seen in the clinic could not be explained by variability in the gene that encodes CYP2C9. In a hallmark study [reference (9) in the article by Rettie and Tai in this issue], however, investigators demonstrated that VKORC1, the gene that encodeds vitamin K epoxide reductase complex 1, the pharmacodynamic target of warfarin, contains regulatory polymorphisms that are highly associated with warfarin dose requirements. By coupling the genetic variants of CYP2C9 and VKORC1, a substantial proportion of the variability in clinical response to warfarin is explained. The clinical importance of using combined genotyping to predict appropriate clinical warfarin dose is now being studied. Moreover, these studies suggest that the genetics of pharmacodynamic effector(s) as well as the genetics of drug metabolism should be considered in concert for other drugs for which a “pharmacogenomic” approach is considered. At present, it is fair to say that the concept of “personalized medicine” has not been realized; however, Rettie and colleagues have in many ways reframed the discussion along positive lines.