The Truth About the Dangers of COX-2 Inhibitors

March 1 2005 David Seaman
The Truth About the Dangers of COX-2 Inhibitors
March 1 2005 David Seaman

AS MOST READERS ARE AWARE, VlOXX WAS RECALLED FROM THE marketplace in late September of 2004. It was discov­ered that a significant number of patients taking Vioxx suffered from heart attacks or strokes. A total of three COX-2 inhibitors have been in the market­place. These drugs are sometimes referred to as "coxibs;" celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). Celebrex and Bextra are still in use. COX is the acronym forcyclo-oxygenase. In 1990, research­ers discovered that there were two distinct COX enzymes, and referred to them as COX-1 and COX-2. More recently, it has been proposed that there is even a COX-3 enzyme. The difference between COX-1 and COX-2 is generally straightforward. COX-1 is a constitutively expressed enzyme; in other words, it is involved in normal homeostatic functions such as gastric protection, hemostasis, and normal renal func­tion.' In contrast, COX-2 is not normally expressed and not involved in tissue homeostasis; instead, its activity is induced after tissue injury.1 Confusion about regular NSAID's and COX-2 inhibitors A substantial area of confusion revolves around the notion that COX-2 is an inflammatory enzyme; it is not. COX-2 is an enzyme that is induced by tissue injury. The subsequent pro-or anti-inflammatory outcome depends on the pro- or anti-in­flammatory nature of the fatty acids in the cell membrane. COX-2 can act on three different cell membrane fatty acids, including arachidonic acid (AA), dihomo-gamma-linolenic acid (DGLA), and eicosapentaenoic acid (EPA). If COX-2 acts on AA, the outcome will be the synthesis of pro-inflammatory eicosanoids, known as prostaglandin E2 (PGE2) and thromboxane A2 (TXA2). PGE2 sensitizes nociceptors and promotes inflammation. TXA2 causes local vasoconstriction and platelet aggregation. Anti-inflammatory drugs like ibuprofen and Celebrex are taken to block the pro­duction of these pro-inflammatory eicosanoids. If COX-2 acts on DGLA, the outcome will be the synthesis of non-nociceptive/intlammatory PGEl and non-vasoconstricting/ aggregating TXA1. These non-inflammatory eicosanoids do not cause pain and inflammation. If COX-2 acts on EPA, the outcome will be the synthesis of non-nociceptive/inflammatory PGE3 and non-vasoconstricting/ aggregating TXA3. Again, the outcome of these non-inflam­matory eicosanoids will be a reduction of pain and inflamma­tion. Clearly, the inflammatory potential of our tissues depends on the inflammatory potential of the fatty acids in our cell mem­branes. Pharmacology articles' and pathology texts2 do not make this distinction, which is why many of us are led to be­lieve that COX-2 enzymes are inherently inflammatory. Cell membrane fatty acids and inflammation Almost all DCs learned about essential fatty acids (EFA's) in biochemistry or nutrition class while going to chiropractic col­lege. EFA's are the special fatty acids we must get from our diets, as we cannot synthesize them ourselves. The two EFA's include linoleic acid (LA), an omega-6 (n-6) fatty acid, and a-linolenic acid (ALA), an omega-3 (n-3) fatty acid. Linoleic acid is converted into DGLA and then into AA (also n-6), whereas, oc-linolenic acid is converted into EPA (also n-3). The ratio of LA: ALA, or our n-6:n-3 dietary ratio is supposed to be about 1:1; at least below 4:1 is the goal. With an LA:ALA ratio of 4:1 or less, the outcome will be the modulation and control of excessive immune responses and inflammation.3 This is because a dietary ratio of below 4:1 insures that there will be an even distribution of A A, DGLA, and EPA into cell membranes, which then leads to the synthesis of more anti-inflammatory eicosanoids com­pared to pro-inflammatory. Not surprisingly, the average American has a an n-6:n-3 ratio of 20:1 or greater, which means that we are eating 20 or more n-6 fatty acids for every single n-3 fatty acid. This leads to a significant increase in the syn­thesis of AA and its related pro-in­flammatory eicosanoids,' and is a main reason why Americans medicate with excessive amounts of ibuprofen, Celebrex and other anti-inflammatory drugs. We, literally, eat ourselves into a state of inflammation and pain, and then have to take medications as a counteractive measure. The excessive inflammation created by n6 fatty acids is also thought to be the driving force be­hind the development of cancer, heart disease, stroke, and other inflammatory diseases.3 Diet and supplements to increase cell membrane n-3 fatty acids An n6:n3 ratio of 4:1 or better is found in fruits, vegetables, grass fed animal products, wild game, and specially fed n-3 chicken eggs. Accordingly, these foods can be referred to as anti-inflammatory. In contrast, all grains have a ratio of 20:1 or greater and grain-fed animals have ratios above 4:1, and so should be referred to as pro-inflammatory foods. Most packaged goods are prepared with oils that have n-6:n-3 ratios greater than 4:1, such as saf-flower, sunflower, and corn oil. Margarine is almost purely an omega-6 fatty acid. Additionally, margarine has been chemi­cally altered by the partial hydrogenation process, which in­creases the inflammatory potential of margarine. At this point, it should be clear that the COX-2 is really not the problem; the issue is our excessive consumption of n-6 fatty acids, which increases the level of pro-inflammatory AA in cell membranes. The COX-2 enzyme merely acts on the pro-inflammatory fatty acids that we eat. Research suggests that most people would do well to take n-3 fatty acid supplements to get a boost in the anti-inflamma­tory direction. EPA/DHA is the most common n-3 fatty acid supplement. Patients should take 1 -3 grams per day, levels which are extremely safe for nearly everyone save for patients taking strong anti-coagulants, such as coumadin.| References 1. Gajraj NM. Cycloo.xysicnasi.--2 inhibitors. Anesih Analg 2003; 96:1720-38 2. Cotran RS. Kumar V. Collins T. Robhins Pathologic Basis of Disease. 6ih ed Phila­delphia: WB Saundcrs; 1999 3. Simopoulos AP. Essential fatty acids in health and chronic disease. Am J din Nuir 1999; 70(3 Suppl):S60S-S69S Dr. Seaman is the Clinical Chiropractic Consultant for Anabolic Laboratories, one of the first supplement manufacturers to service the chiropractic profession. He is on the /acuity of Palmer College of Chiropractic Florida and on the postgraduate faculties of sev­eral other chiropractic colleges, providing nutrition seminars that focus on the needs of the chiropractic patient. Dr. Seaman believes that chiropractors .should be thinking like chiropractors, while pro­viding nutritional recommendations. Doctors and patients who follow his programs report improved feelings oj well-being, weight loss, dramatic increases in energy, and significant pain reduction. Dr. Seaman can be reached by e-inail at docseaman@mac. com. Anti-inflammatory n6:n3 ratios 4:1 or better: fruits, vegetables Pro-inflammatory n6:n3 ratios 20:1 or greater: grains, grain-fed animals,