In contrast, by decreasing vasodilatory and antiaggregatory PGI2 production, COX-2 antagonists may tip the balance in favor of prothrombotic eicosanoids (thromboxane A2) and may lead to increased cardiovascular thrombotic events.[41] It was therefore not unexpected when within less than 1 year of their marketing, 4 cases of ischemic complications in patients receiving COX-2 inhibitors were reported.[42] Moreover, as predicted, urinary levels of a metabolite of thromboxane A2 were markedly elevated. NSAIDs are among the most commonly used medications in the world.[1] They act by inhibiting COX, a key enzyme in arachidonic acid metabolism. The COX enzyme catalyzes the initial actions in the conversion of arachidonic acid to numerous eicosanoids, including prostaglandins (PGs) and thromboxanes. A major factor limiting their use is usually GI toxicity, ranging from moderate dyspepsia to peptic ulcer to perforation and bleeding. This results from NSAID-induced disruption of the protective activities of PGE2 and prostacyclin created by COX in the gastric mucosa. In 1990, Fu and colleagues[2] detected a novel COX protein in monocytes stimulated by interleukin, and a 12 months later, Kujubu and colleagues[3] recognized a gene with considerable homology to COX-1. Further research demonstrated that this novel COX-2 protein Pimonidazole was an inducible enzyme with increased expression in inflammation. On the other hand, COX-1 was named a housekeeping enzyme because it was expressed constitutively, with relatively ubiquitous presence. It was also recognized as the main source of cytoprotective PGs in the gastric mucosa. Since the conventional NSAIDs inhibited both COX-1 and COX-2, it was Pimonidazole postulated that the efficacy of NSAIDs (attributable to COX-2 inhibition) could be achieved without GI toxicity (due to COX-1 inhibition). This realization rekindled the efforts of the pharmaceutical industry to produce a safe NSAID via selective inhibition of COX-2, and this class of agents (celecoxib and rofecoxib) was introduced in 1999.[4] By October 2000, celecoxib and rofecoxib had sales exceeding US$ 3 billion in the United States alone and a prescription volume in excess of 100 million for the 12-month period ending in July 2000.[5] Moreover, the sales of celecoxib alone Pimonidazole increased from US$ 2623 million in 2000 to US$ 3114 million in 2001.[6] Most of the credit for this more than 80% increase in sales could be attributed to a widely distributed study CLASS, published in in 2000.[7] The impact of the study can be gauged from the fact that about 30,000 reprints of CLASS were bought from the publisher, and it was cited more than 10 times as frequently as any other article published in the same issue.[8] No less influential was another trial, VIGOR, a double-blind trial conducted at 301 centers in 22 countries. Both of these trials concluded that COX-2 inhibitors were associated with significantly fewer adverse effects than the conventional NSAIDs. Were these conclusions justified? Are the COX-2 inhibitors really superior in safety profile to the older NSAIDs? The current review summarizes the adverse effect profile of COX-2 inhibitors as more adverse drug reactions (ADRs) are being attributed to COX-2 inhibitors with their growing use. Gastrointestinal Adverse Drug Reactions NSAID-associated serious upper GI adverse events result in 103,000 hospitalizations and 16,500 deaths per year in the United States alone.[9,10] NSAID-induced GI adverse effects may be the commonest cause of drug-related events leading to emergency visits, 43% in an earlier study by us.[11] In this light, the COX-2 hypothesis, proposing that at comparable inhibitory doses, selective COX-2 inhibitors would be as effective as traditional NSAIDs and would spare the GI mucosa, seemed not only attractive but also plausible. The decade of the 1990s saw Pimonidazole several in vitro and animal studies that seemed to prove this hypothesis being published, and this was the topic of several review articles as well.[12-14] Results of clinical trials[15-17] also supported the COX-2 Bmpr1b hypothesis.[18] However, the progress that we have made in science is because scientists tend to question everything, and not surprisingly, this hypothesis began to show cracks when in the late 1990s it was shown that within 40 minutes of oral challenge with acid, there was a marked upregulation of COX-2 in the rat stomach.[19] A subsequent study[20] demonstrated a crucial protective role for COX-2 in the so-called adaptive cytoprotection response of the stomach; that is, increase in resistance to injury observed following exposure to a mild irritant. A further functional role for COX-2 in mediating gastric epithelial proliferation was demonstrated.