Abstract
Nonsteroidal anti-inflammatory drugs are widely used for the treatment of chronic arthropathies, but their gastrointestinal damage remains a significant limitation to their use. In this review, the pathogenic mechanisms through which these drugs are believed to cause gastrointestinal damage are outlined. A better understanding of the pathogenesis of gastric and intestinal injury has resulted in novel strategies that are being employed to develop nonsteroidal anti-inflammatory drugs that do not have significant adverse effects on the gastrointestinal tract.
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Blower PR. Nonsteroidal anti-inflammatory drugs. Br J Rheumatol 1993;32(Suppl 4):35–38.
Baum C, Kennedy DL, Forbes MB. Utilization of nonsteroidal antiinflammatory drugs. Arth Rheum 1985;28:686–692.
Epstein AM, Read JL, Winickoff R. Physician beliefs, attitudes, and prescribing behavior for anti-inflammatory drugs. Am J Med 1984;77:313–318.
Wilkens RF. The selection of a nonsteroidal antiinflammatory drug. Is there a difference? J Rheumatol 1992;19(Suppl 36):9–12.
Myers ABR. Salicin in acute rheumatism. Lancet 1876;II:676–677.
Fries JF. NSAID gastropathy: Epidemiology. J Musculoskeletal Med 1991;8:21–28.
Rainsford KD. Introduction and historical aspects of the side-effects of anti-inflammatory analgesic drugs. In: Rainsford KD, Velo JP (eds) Side effects of anti-inflammatory drugs. Part 1: Clinical and epidemiological aspects. Lancaster: MTP Press, 1987;3–26.
Rampton DS. Non-steroidal anti-inflammatory drugs and the lower gastrointestinal tract. Scand J Gastoenterol 1987;22:1–4.
Silvoso G, Ivey KJ, Butt J. Incidence of gastric lesions in patients with rheumatic disease on chronic aspirin therapy. Ann Intern Med 1979;91:517–520.
Upadhyay R, Torley HI, McKinley AW, et al. Iron deficiency anemia in patients with rheumatic disease receiving non-steroidal anti-inflammatory drugs: The role of upper gastrointestinal lesions. Ann Rheum Dis 1990;26:359–362.
Madok R, Mackenzie JA, Lee FD, et al. Small bowel ulceration in patients receiving NSAIDs for rheumatoid arthritis. Q J Med 1986;58:53–58.
Day TK. Intestinal perforation associated with osmotic slow release indomethacin capsules. BMJ 1983;287:1672–1672.
Going J, Canvin J, Sturrock R. Possible precursor of diaphragm disease in the small intestine. Lancet 1993;341:638–639.
Bjarnason I. Hayllar J, Macpherson AJ, et al. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine. Gastroenterology 1993;104:1832–1847.
Morris AJ, Wasson LA, Mackenzie JF. Small bowel enteroscopy in undiagnosed gastrointestinal blood loss. Gut 1992;33:887–889.
Bjarnason I, Zanelli G, Smith T, et al. Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans. Gastroenterology 1987;93:480–489.
Bjarnason I, Zanelli G, Prouse P, et al. Effect of non-steroidal anti-inflammatory drugs on the human small intestine. Drugs 1986;32:35–41.
Langman MJS, Morgan L, Worall A. Use of inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. BMJ 1985;290:347–349.
Allison MC, Howatson AG, Torrance CJ, et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992:327(11):751–756.
Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Col Rec 1995;38(12):1311–1321.
Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987;107:513–515.
Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971;231:232–235.
Whittle BJR, Vane JR. A biochemical basis for the gastrointestinal toxicity of non-steroid anti-rheumatoid drugs. Arch Toxicol 1984;7:315–322.
Vane JR. Mitchell JA, Appleton I, et al. Inducible isoforms of cyclooxygenase and nitric oxide synthetase in inflammation. Proc Natl Acad Sci USA 1994;91:2046–2050.
Kitahhora T, Guth PH. Effect of aspirin plus hydrochloric acid on the gastric microcirculation. Gastroenterology 1987;93:810–817.
Asako H, Kubes P, Wallace JL, et al. Indomethacin-induced leukocyte adherence in mesenteric venules: Role of lipoxygenase products. Am J Physiol 1992;262:G903-G908.
Kitahora T, Guth PH. Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology 1987;93:810–817.
Andrews FJ, Malcontenti-Wilson C, O'Brien PE. Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. Am J Physiol 1994;266:G657-G664.
Wallace JL, Keenan CM, Granger DN. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophildependent process. Am J Physiol 1990;259:G462-G467.
Lee M, Lee AK, Feldman M. Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats. Am J Physiol 1992;263:G290-G926.
Wallace JL, Arfors K-E, McKnight GW. A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in rabbits. Gastroenterology 1991;100:878–883.
Wallace JL, McKnight W, Miyasaka M, et al. Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury. Am J Physiol 1993;265:G993-G998.
Wallace JL, Granger DN, The pathogenesis of NSAI-Dgastropathy-are neutrophils the culprits? TIPS 1992;13:129–131.
Vaananen PM, Meddings JB, Wallace JL. Role of oxygen-derived free radicals in indomethacin-induced gastric injury. Am J Physiol 1991;261:G470-G475.
Gryglewski RJ, Szczeklik A, Wandzilak M. The effect of six prostaglandins, prostacyclin and iloprost on generation of superoxide anions by human polymorphonuclear leukocytes stimulated by zymosan or fromyl-methionyl-leucyl-phenyl-alanine. Biochem Pharmacol 1987;36:4209–4212.
Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunological inducible TNF/cachectin. Nature 1990:346:274–276.
Kunkel SL, Wiggins RC, Chensue SW, et al. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun 1986;137:404–410.
Santucci L, Fiorucci S, Giansanti M, et al. Pentoxifylline prevents indomethacin-induced acute mucosal damage in rats: Role of tumour necrosis factor alpha. Gut 1994;35:909–915.
Rothlein R, Czaijkowski M, Kishimoto TK. Intercellular adhesion molecule-1 in inflammatory response. Chem Immunol 1994;50:135–142.
Appleyard CB, McCafferty DM, Tigley AW, et al. Tumor necrosis factor mediation of NSAID-induced gastric damage: Role of leukocyte adherence. Am J Physiol 1996;269:G119-G125.
Wallace JL, Keenan CM, Mugridge KG, et al. Reduction of the severity of experimental gastric and duodenal ulceration by interleukin-1β. Eur J Pharmacol 1990;186:279–284.
Wallace JL, Keenan CM, Cucula M, et al. Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastrogathy. Gastroenterology 1992; 102:1176–1185.
Kubes P, Suzuki M, Granger DN. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651–4655.
Rubanyi GM, Ho EH, Cantor EH, et al. Cytoprotective function of nitric oxide: Inactivation of superoxide radicals produced by human leukocytes. Biochem Biophys Res Commun 1991; 181:1392–1397.
MacNaughton WK, Cirino G, Wallace JL. Endothelium-derived relaxation factor (nitric oxide) has protective acions in the stomach. Life Sci 1989;45:1869–1876.
Wallace JL, Reuter BK, Cirino G. Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: A novel approach for reducing gastrointestinal toxicity. J Gastroenterol Hepatol 1994;9:S40-S44.
Lopez-Belmonte J, Whittle BJR, Moncada S. The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa. Br J Pharmacol 1993;108:73–78.
Asako H, Kubes P, Wallace JL, et al. Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate. Gastroenterology 1992;103:146–152.
Tepperman BL, Whittle BJR. Endogenous nitric oxide and sensory neuropeptides interact in the modulation of the rat gastric microcirculation. Br J Pharmacol 1992;105:171–175.
Brody TM. The uncoupling of oxidative phosphorylation as a mechanism of drug action. Pharmacol Rev 1956;7:335–365.
Glaborg-Jorgensen T, Weis-Fogh US, Neilsen NH, et al. Salicylate and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of stomach. Scand J Lab Invest 1976;36:649–653.
Somasundarum S, Hayllar H, Rafi S, et al. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastrointestinal tract: A review and a hypothesis. Scand J Gastroenterol 1995;30:289–299.
Bjarnason I, Smethurst P. Macpherson A, et al. Glucose and citrate reduce the permeability changes caused by indomethacin in humans. Gastroenterology 1992;102:1546–1550.
Rainsford KD. Prevention of indomethacin-induced gastrointestinal ulceration in rats by glucose-citrate formulations: Role of ATP in mucosal defenses. Br J Rheumatol 1987;26(Suppl 2):81.
Hayllar J, Somasandarum S, Sarathchandra P, et al. The synthetic prostaglandins, a glucose and citrate formulation of indomethacin and other agents in preventing NSAID enteropathy in the rat (abstract). Gastroenterology 1991;100(Suppl 1):586.
Davies NM, Wright MR, Jamali F. Glucose/citrate (G/C) gastrointestinal cytoprotective effect: A physiochemical G/C-NSAIDs interaction (abstract). Pharm Res 1995;12(Suppl 357): 8122.
Wallace JL, Cirino G. The development of gastrointestinal sparing nonsteroidal anti-inflammatory drugs. TIPS 1994;15:405–406.
Whittle BJR. Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 1981;80:94–98.
Davies GR, Wilkie ME, Rampton DS. Effects of metronidazole and misoprostol on indomethacin-induced changes in intestinal permeability. Dig Dis Sci 1993;38:417–425.
Miura S, Suematsu M, Tanaka S. Microcirculatory disturbance in indomethacin-induced intestinal ulcer. Am J Physiol 1991;261: G213-G219.
Akamatsu H, Oguchi M, Nishijima S, et al. The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: A possible mechanism of action of metronidazole in rosacea and acne. Arch Dermatol Res 1991;282:449–454.
Bjarnason I, Hayllar J, Smethurst P, et al. Metronidazole reduces intestinal inflammation and blood loss in non-steroidal antiinflammatory drug-induced enteropathy. Gut 1992;33:1204–1208.
Yamada T, Deitch E, Specian RD, et al. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 1993;17:641–662.
Collins AJ, Reid J, Soper CJ, et al. Characteristics of ulcers of the small bowel induced by non-steroidal anti-inflammatory drugs in the rat: Implications for clinical practice. Br J Rheumatol 1995;34:727–731.
Robert A, Asano T. Resistance of germfree rats to indomethacininduced intestinal lesions. Prostaglandins 1977;14:333.
Melarange R, Moore G. Blower PR, et al. A comparison of indomethacin with ibuprofen on gastrointestinal mucosal integrity in conventional and germ-free rats. Aliment Pharmacol Ther 1992;6:67–77.
Kent TH, Cardelli RM, Stamler FW. Small intestinal ulcers and intestinal flora in rats given indomethacin. Am J Pathol 1969;54:237–245.
Satoh H, Guth PH, Grossman MI. Role of bacteria in gastric ulceration produced by indomethacin in the rat: Cytoprotective action of antibiotics. Gastroenterology 1983;84:483–489.
Wax J, Clinger A, Varner P. et al. Relationship of the enterohepatic cycle to ulcerogenesis in the rat small bowel with flufenamic acid. Gastroenterology 1970;58:772–779.
Bjarnason I, Williams, P, Smethurst P, et al. Effect of nonsteroidal anti-inflammatory drugs and prostaglandins on the permeability of the human small intestine. Gut 1986;27:1292–1297.
Davies NM, Wright MR, Jamali F. Antiinflammatory-induced intestinal permeability: Rat is a suitable model. Pharm Res1994;11:1652–1654.
Giercksky K-E, Huseby G, Rugstad H-E. Epidemiology of NSAID-related gastrointestinal side effects. Scand J Gastroenterol 1989;24(Suppl 163):3–8.
Committee on the Safety of Medicines. Non-steroidal antiinflammatory drugs and serious gastrointestinal adverse reactions-2. BMJ 1986;292:1190–1191.
Boyce S, Chan CC, Gordon R, et al. L-745,337: A selective inhibitor of cyclooxygenase-2 elicits antinociception but not gastric ulceration in rats. Neuropharmacology 1994;33:1609–1611.
Masferrer JL, Zweifel BS, Manning PT, et al. Selective inhibition of inducible cyclooxygenase in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci USA 1994;91:3228–3232.
Morham SG, Langenbach RL, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Cell 1995;83:473–482.
Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995;378:406–409.
Lagenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 1995;83:483–492.
Appleton I, Tomlinson A, Willoughby DA. Inducible cyclooxygenase (COX-2): A safer therapeutic target? Brit J Rheumatol 1994;33:410–411.
Reuter BK, Cirino G, Wallace JL. Markedly reduced intestinal toxicity of a diclofenac derivative. Life Sci 1994;55:1–8.
Wallace JL, Reuter B, Cicala C, et al. A diclofenac derivative without ulcerogenic properties. Eur J Pharm 1994;257:249–255.
Wallace JL, Reuter B, Cicala C, et al. Novel nonsteroidal antiinflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994;107:173–179.
Cuzzolin L, Conforti A, Adami A, et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen. Pharmacol Res 1995;31:61–65.
Wallace JL, McKnight W, Del Soldato P, et al. Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. J Clin Invest 1995;96:2711–2718.
Takeuchi K, Ohuchi T, Miyake H, et al. Endogenous nitric oxide in gastric alkaline response in the rat stomach after damage. Gastroenterology 1990;106:367–374.
Brown JF, Hanson PJ, Whittle BJR. Nitric oxide donors increase mucus gel thickness in rat stomach. Eur J Pharmacol 1992;223:10–104.
Brown JF, Keates AC, Hanson PJ, et al. Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am J Physiol 1993;265:G418-G422.
Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:109–141.
Elliot SN, McKnight W, Cirino G, et al. A nitric oxide-releasing NSAID accelerates gastric ulcer healing in rats. Gastroenterology 1995;109:524–530.
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Davies, N.M., Wallace, J.L. Nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: New insights into an old problem. J Gastroenterol 32, 127–133 (1997). https://doi.org/10.1007/BF01213310
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DOI: https://doi.org/10.1007/BF01213310