REFERENCES:Aw, T., Haas, S., Liew, D., Krum, H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. American Medical Association. (2005). 165:490-496.Baker, Christopher S.R.; Hall, Roger J.C.; Evans, Thomas J.; Pomerance, Ariela; Maclouf, Jacques; Creminon, Christophe; Yacoub, Magdi H.; Polak, Julia M. Cyclooxygenase-2 Is Widely Expressed in Atherosclerotic Lesions Affecting Native and Transplanted Human Coronary Arteries and Colocalizes With Inducible Nitric Oxide Synthase and Nitrotyrosine Particularly in Macrophages. Arteriosclerosis, Thrombosis & Vascular Biology. (March 1999).19(3):646-655.Chang, Ingrid J.; Harris, Raymond C. Are All COX-2 Inhibitors Created Equal? Hypertension. (February 2005). 45(2):178-180.Chenevard, Remy; Hurlimann, David; Bechir, Markus; Enseleit, Frank; Spieker, Lukas ; Hermann, Matthias; Riesen, Walter; Gay, Steffen; Gay, Renate E.; Neidhart, Michel; Michel, Beat; Luscher, Thomas F; Noll, Georg; Ruschitzka, Frank, Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease. Circulation. (January 2003). 107(3):405-409.Crawford, A., White, J. Celecoxib-induced upper gastrointestinal hemorrhage and ulceration. Southern Medical Journal. (2002). 95:1444-1446.Ekenel, Meltem, Avsar, Erol, Imeryuz, Nese, Yuksel, Meral, Haklar, Goncagul, Kocakaya, Ozan, Tozun, Nurdan. Effects of selective COX-2 inhibitors on the gastric permeability of sucrose: a controlled study with placebo and ibuprofen. European Journal of Gastroenterology and Hepatology. (2003). 15:403-406.Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, et al. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet (1999). 354:2106-11.Is Celebrex as Detrimental to the GI Tract as Non-selective NSAIDs andIs There An Increased Risk of Cardiovascular Events With The Use ofCelebrex?An Argument Paper for Pfizer Pharmaceutical RepresentativesAkane Seki and Christine ErmakSpring 2005IssueThe recent controversy surrounding Vioxx has triggered many questions about thesafety of other COX-2 inhibitors such as Celebrex. Many studies have shown the statistical significance in which Vioxx demonstrated the increased risk of acute myocardial infarction (See Table 1). The incidence of stroke was greater with Vioxx than with other anti-inflammatory prescription medications as well. Celebrex is in the same COX-2 inhibitor class as Vioxx and is still being prescribed for similar purposes. Vioxx was thought to be the most effective COX-2 inhibitor, but because of its discontinuation many physicians have instead substituted Celebrex for Vioxx regimes. It is important to investigate the safety of Celebrex because it is a widely prescribed medication not only for arthritis patients, but for patients with severe migraines, dysmennorhea and to treat post-surgical procedures. Although Celebrex and Vioxx are in the same COX-2 class they have different functional groups within their chemical structures (see Figure 2). They also differ in their potency, specificity of COX-2inhibition, pharmacokinetics and metabolism. Thus, the question at hand is how much do 1these differences actually affect the physiological mechanisms in which risks of heart andgastrointestinal complications are increased? An understanding that the effectiveness of Celebrex is not what has caused so much controversy must be recognized. There were many studies reviewed by the FDA concerning Celebrex before it ever was put on the shelf, which showed it was just as effective as non-selective NSAIDs at decreasing inflammation (Crawford et al.2002 and Nachimuthu et al. 2001). The argument here is concerning the safety of the drug in termsof cardiovascular and gastrointestinal side effects. Despite studies that have inferred risksof Celebrex use, after sifting through a large portion of the current research that has been published about Celebrex, it is safe to say that this drug is gentler on the GI tract as well as safe for cardiovascular health than non-selective NSAIDs that are available on the market today. Table 1. Evidence that the issue is unresolvedCelebrex Safe interms ofCardiovascularrisksCelebrex unsafe interms ofCardiovascularsafetyCelebrexsafe on theGI tractCelebrex notany safer onthe GI tractthan non-selectiveNSAIDsChenevard et al.(2003)Levesque et al.(2005)Rabausch et al.(2005)Solomon et al.(2005)Simon et al.(1999)Silverstein etal. (2000)Mamdani etal. (2002)Crawford etal. (2002)Nachimuthuet al. (2001)Brief Overview of COX-2 InhibitorsCOX-2 inhibitors are manufactured with the specific purpose of gastrointestinal safety in mind. The COX-2 inhibiting drugs, such as Vioxx and Celebrex, have proved to be 2involved in directly alleviating inflammation with less gastrointestinal complications thannon-selective NSAIDs. Prostaglandin G/H synthase, the enzyme that catalyzes prostaglandins and thromboxanes which specify pain and platelet aggregation, is inhibited by both non-selective NSAIDs and COX-2 inhibitors. Inhibiting the COX-2 enzyme may be of therapeutic advantage, since this isoenzyme is almost certainly involved in prostaglandin production at the site of inflammation but not at other sites such as the gastrointestinal tract and kidney. Non-selective NSAIDs target the COX-1 enzyme activity in gastrointestinal mucosa and platelets as well as COX-2 enzyme activity. However, COX-2 inhibitors such as Celebrex do not interfere with the COX-1 receptor. COX-1 enzymes are responsible for producing the protective mucous lining in the GI tract as well as decreasing levels of HCl secretion in the stomach and stimulating intestinal motility. It also is the constitutive isoform found in the blood vessels, stomach and kidney. COX-2 enzymes on the other hand are induced in settings of inflammation bycytokines and inflammatory mediators. Consequently, this inhibition of both COX isoenzymes and prostaglandins has been related to gastrointestinal tract toxicity and the long-term use of non-selective NSAIDs is therefore limited by gastrointestinal effects such as abdominal pain, constipation, dyspepsia, nausea, vomiting and constipation (See Table 2). It is worth noting to hear that it is not the actual medication itself that is responsible for eating a hole through the mucosal lining of the stomach. Rather the COX-1 receptors are compromised with the use of the non-selective NSAID’s, which significantly decreases resilience of the mucosal