NSAIDs and Peptic Ulcer Disease

Abstract

In 1897 Felix Hoffman, a 29-year-old scientist working for the Bayer Company patented a chemical procedure that enabled the acetylation of salicylic acid with the enough purity to be used commercially (Wallace, 1997). The new product was evaluated by Dreser Heinrich, head of marketing at Bayer, who despite some initial misgivings gave his approval for marketing acetylsalicylic acid under the name "Aspirin" in 1899. The new compound was commercialized by Bayer as an effective therapy for fever and aches, one that, unlike its source molecule (salicylic acid), had no gastric side effects. For over six decades aspirin remained the mainstay of non-narcotic analgesic treatment and nonsteroidal antiinflammatory drug (NSAIDs) therapy. Beginning with the sale of indomethacin in 1963, used for the treatment of rheumatoid arthritis, at least twenty other NSAIDs with aspirinlike actions have been developed over the past half-century. Although aspirin's preeminence as an over-the-counter analgesic has been progressively displaced by new NSAIDs, new studies exploring its antiplatelet effect led to aspirin's development as a major antithrombotic agent (Patrono et al., 2005). Today, NSAIDs are popular because of their versatile effectiveness as analgesics, antipyretics, and as anti-inflammatory agents, and they remain among the most frequently prescribed medications worldwide. The long-standing confidence in the gastric safety of aspirin went unchallenged for 40 years until 1938 when two researchers at Guy's Hospital in London, Douthwaite and Lintott, showed unquestionably that it had a major gastro-erosive activity (Douthwaite & Lintott 1938). Unfortunately, most of the NSAIDs currently available on the market can injure the gastric and duodenal mucosa (Cryer & Feldman, 1992; Soll et al., 1991), much like aspirin, with considerable rates of morbidity and mortality. The standard evolution of peptic ulcers resulting from NSAIDs ranges from resolution without intervention to the development of complications, such as bleeding and perforation. To variable degrees aspirin and NSAIDs inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2, which synthesize the inflammatory mediators known as prostaglandins and thromboxane. Prostaglandin inhibition plays a critical role in the pathogenesis of NSAIDs-induced gastric injury. Beginning ten years ago new specific inhibitors of COX-2 became available, compounds that have significantly reduced gastrointestinal (GI) side effects compared with COX-1 inhibitors (Bombardier et al., 2000; Laine et al., 2007; Silverstein et al., 2000). Peptic ulcers are defects in the GI mucosa that extend throughout the muscularis mucosae, and which are often associated with Helicobacter pylori (H. pylori) infection or with