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Gastroduodenal Mucosal Damage with Salsalate Versus Aspirin: Results of Experimental Models and Endoscopic Studies in Humans

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Gastroduodenal Mucosal Damage with Salsalate Versus Aspirin: Results of Experimental Models and Endoscopic Studies in Humans Gastroduodenal Mucosal Damage With Salsalate Versus Aspirin: Results of Experimental Models and Endoscopic Studies in Humans By James M. Scheiman and Grace H. Elta Animal models have identified multiple mecha- NSAID-induced GI toxicity may represent the nisms of aspirin toxicity. Aspirin inhibits cycloox- most frequent drug side effect in the US.’ This ygenase in the gastroduodenal mucosa leading situation has generated interest in the develop- to a decrease in endogenous prostaglandins. ment of strategies designed to limit gastroduode- Prostaglandin mediated mucus and bicarbonate nal injury caused by chronic NSAID use. Con- secretion, epithelial hydrophobicity, blood flow, comitant use of conventional antiulcer therapy and cellular proliferation are all decreased. for both prevention of upper GI tract ulceration Salicylates may cause direct cellular toxicity via and treatment of NSAID-induced damage while inhibition of energy metabolism and membrane transport properties. Salicylate preparations the NSAID is continued, has shown mixed and have been designed to decrease gastroduode- largely disappointing results.3 Recently it has nal absorption. Endoscopic studies in humans been suggested that oral prostaglandins may have confirmed that buffering of aspirin does have a role in the prophylaxis of gastroduodenal not ameliorate damage, but enteric coating damage caused by NSAIDS.~ Unfortunately, does. Salicylsalicylic acid (salsalate) is an effec- they are costly and have significant side effects. tive antirheumatic drug that bypasses gastric An alternative to the administration of an absorption and also avoids cyclooxygenase inhi- additional drug, such as a prostaglandin, is to bition. In a randomized, single-blind, endoscopic utilize an NSAID which spares the upper GI comparison of salsalate versus enteric-coated tract. Salicylsalicylic acid (salsalate), a salicy- aspirin, significantly less gastroduodenal dam- late ester of salicylic acid, was originally devel- age was observed in volunteers after salsalate administration compared to enteric-coated as- oped as a safer, nonacetylated alternative to pirin. An endoscopic study in rheumatoid arthrit- aspirin (acetylsalicylic acid).5 In this review we its also confirmed the ability of salsalate to will discuss the mechanisms of salicylate-induced spare gastroduodenal mucosa when compared gastroduodenal damage in animal models and to naproxen administration. Salsalate may cause the results of endoscopic studies in humans that less gastroduodenal damage than enteric- suggest salsalate has potential as a gastroduode- coated aspirin based on the results of animal nal sparing agent. models and endoscopic studies in humans. @ 1990 by W.B. Saunders Company. MUCOSAL INJURY BY SALICYLATES IN ANIMAL MODELS INDEX WORDS: Salicylates; gastroduodenal damage: animal models: endoscopic studies. Aspirin is absorbed passively in the upper GI tract. This absorption is dependent on its concen- ALICYLATES and other nonsteroidal anti- tration and its lipid solubility at acid pH (the S inflammatory drugs (NSAIDs) are some of pKa of aspirin is 3.5). The compound is more the most commonly used drugs in clinical prac- tice. Epidemiological studies have estimated that they are prescribed in quantities sufficient to From the Department of Internal Medicine, Division of treat three million people on a daily basis, suggest- Gastroenterology. University of Michigan Medical School, ing as many as 1.2% of the United States and Veterans Administration Medical Center, Ann Arbor. MI. population may use these agents daily. In 1983, James M. Scheiman, MD: Instructor in Internal Medicine; over half the physician visits for arthritis involved University of Michigan Medical School; Grace H. Elta; MD: prescriptions for NSAIDs.’ Assistant Professor of Internal Medicine, University of While these agents are very effective in the Michigan Medical School. care of patients with painful musculoskeletal Address reprint requests to James M. Scheiman, MD, GI Section (1 IID), V.4 Medical Center, 2215 Fuller Rd. Ann disorders, their gastrointestinal (GI) side effects Arbor, MI 48105. remain a vexing clinical problem. Given the large 0 1990 by W.B. Saunders Company. number of patients exposed to these drugs, 0049-0172/90/2002-0007$5.00/O Seminars in Arthritis and Rheumatism, Vol 20. No 2 (October). 1990: pp 12 l-127 121 122 SCHEIMAN AND ELTA than 50% nonionized in gastric or duodenal fluid onstrated that sodium salicylate administration with a pH below 3.5 and rapid absorption occurs. fails to injure gastric mucosa.6’10 Investigators Once absorbed across the cell membrane, the have inferred from these data that cyclooxygen- higher intracellular pH favors dissociation to the ase inhibition is the most important mechanism ionized form, leading to accumulation and high of gastrointestinal injury by salicylates. Recent local cellular concentrations of the drug. When in vitro studies suggest that salicylic acid and the aspirin is completely absorbed, it is hydro- aspirin can damage mucosa equally, but only lyzed to salicylic acid by the action of intestinal, after the gastric luminal pH has been lowered to hepatic, and plasma esterases. The toxicity of 1 .0 . ‘L’~ These damaging effects occur with either acetylsalicylic acid depends upon both a local oral or parenteral administration. Because paren- toxic effect and the systemic effect of the drug. teral salicylic acid inhibits acid secretion to a Animal models have offered insight into the much greater extent than acetylsalicylic acid, the mechanisms of aspirin induced-toxicity. Depend- lack of gastric damage produced by salicylic acid ing upon the model studied, and the criterion to in previous studies may have been caused by measure damage, some animal models show insufficient luminal acidification. When luminal greater toxicity with aspirin than salicylic acid. pH is decreased, salicylate appears to accumu- late in the epithelium and diminish mucosal Cyclooxygenase Independent Mechanisms resistance to proton flux. To further elucidate the role of cyclooxygenase inhibition in the genesis of Acetylsalicylic acid inhibits mucosal cyclooxy- mucosal toxicity, investigators attempt to reverse genase, thereby decreasing levels of endogenous or prevent damage by exogenous administration prostaglandins. In contrast, salicylate is a weak of prostaglandins. Partial amelioration of the inhibitor of the enzyme.6 In addition to this aspirin injury was observed after administration prostaglandin mediated effect, salicylates can of prostaglandin E, (PGE,) but no effect on the have direct cellular toxicity independent of cy- salicylate injury was seen.12 The partial pro- clooxygenase inhibition. tective effect of PGE, points to the complex Pioneering work by Davenport demonstrated mechanisms of aspirin injury and suggests that that the gastric mucosal barrier, the unique additional mechanisms of damage related to ability of the gastric surface epithelium to sur- cyclooxygenase inhibition may be important in vive in the hostile acidic milieu of the stomach, is the intact animal. An understanding of the ef- lost after exposure to either aspirin or salicylic fects of cyclooxygenase inhibition on the compo- acid.’ Both drugs increase proton flux into the nents of gastroduodenal defense is required for mucosa and cause a drop in potential difference, further understanding of the mechanisms of a sensitive measure of epithelial integrity. Other aspirin toxicity. investigators have confirmed this decrease in mucosal potential difference, with increased cat- Cyclooxygenase Dependent Mechanisms ion flux after exposure to both aspirin and sali- cylic acid, yet only aspirin caused a dramatic Robert first described the ability of prostaglan- reduction in mucosal prostaglandin content.8 The dins, independent of their inhibition of acid back diffusion of protons leads to cellular acidifi- secretion, to protect the gastric mucosa against a cation and altered cellular metabolism. variety of noxious agents that produce tissue An additional mechanism of salicylate in- damage and cellular necrosis.13 This was called duced damage independent of cyclooxygenase “cytoprotection.” This observation prompted inhibition is the uncoupling of oxidative phospho- many investigations into the role of endogenous rylation by intracellular salicylates. This results prostaglandins in the maintenance of upper GI in depletion of cellular adenosine triphosphate mucosal integrity. The major prostaglandins syn- (ATP) levels and inhibition of active ion trans- thesized by the action of cyclooxygenase on port essential to maintain cellular integrity. This membrane arachidonic acid within gastrointesti- effect on energy metabolism is a major direct nal mucosa include PGE,, PGI,, PGD,, and toxic effect of salicylate.’ PGF,cu. To investigate the physiological role of Although salicylate has direct toxic effects on endogenous prostaglandins, most studies have gastric epithelia, a number of studies have dem- examined the effect of aspirin or other NSAID GASTRODUODENAL DAMAGE WITH SALSALATE V ASPIRIN 123 cyclooxygenase inhibitors on a parameter impor- dins on mucin synthesis, while others suggest tant in mucosal defense. that aspirin can qualitatively alter mucus, such Recently, Redfern and Feldman demonstrated as inhibition of sulfate incorporation.22 Salicylic that active immunization of rabbits, with the acid exposure appears to have a much weaker principal endogenous prostaglandins of gas- effect.22 Another qualitative deficiency of gastric
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