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Nonsteroidal anti-inflammatory drug gastropathy

      Abstract

      By inhibiting prostaglandin synthesis, nonsteroidal anti-inflammatory drugs (NSAIDs) compromise gastroduodenal defense mechanism including blood flow and mucus/bicarbonate secretion. This has led to NSAIDs being the most widely reported drug cause of adverse events. While NSAIDs also cause dyspepsia, inhibition of prostaglandin synthesis may reduce this from even higher levels that would otherwise prevail and mask ulcer-related dyspepsia, making anticipatory management difficult. On average, the risk of ulcer complications increases 4-fold, resulting in 1.25 additional hospitalizations per 100 patient-years according to one estimate. Older patients, those with a past history, and those taking anticoagulants or corticosteroids are at higher risk. Risk is dose dependent and is lower with ibuprofen at low doses than with other NSAIDs. It is unlikely that Helicobacter pylori increases the risk, and under some circumstances it may be protective. Selective inhibitors of the inducible cyclooxygenase 2 spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Their place in therapy, compared with use of misoprostol or proton pump inhibitors, is currently emerging. Future competitors may include nitric oxide–donating, zwitterionic, or R-enantiomer NSAIDs.
      GASTROENTEROLOGY 2000;119:521-535

      Abbreviations:

      COX (cyclooxygenase), NO (nitric oxide)
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      References

        • Vane JR
        • Flower RJ
        • Botting RM.
        History of aspirin and its mechanism of action.
        Stroke. 1990; 21: 12-23
        • Vane JR.
        Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
        Nature. 1971; 231: 232-235
        • Ferreira SH.
        Prostaglandins, aspirin-like drugs and analgesia.
        Nat New Biol. 1972; 240: 200-203
        • Wallace JL
        • Bell CJ.
        Gastromucosal defense.
        Curr Opin Gastroenterol. 1996; 12: 503-511
        • Douthwaite AH
        • Lintott SAM.
        Gastroscopic observation of the effect of aspirin and certain other substances on the stomach.
        Lancet. 1938; 2: 1222-1225
        • Fries JF
        • Williams CA
        • Bloch DA
        • Michel BA.
        Non-steroidal anti-inflammatory drug–associated gastropathy: incidence and risk factor models.
        Am J Med. 1991; 61: 213-222
        • Smalley WE
        • Ray WA
        • Daugherty JR
        • Griffin MR.
        Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons.
        Am J Epidemiol. 1995; 141: 539-545
        • Olivero JJ
        • Graham DY.
        Gastric adaption to nonsteroidal anti-inflammatory drugs in man.
        Scand J Gastroenterol. 1992; 27: 53-58
        • Fischer H
        • Becker JC
        • Boknik P
        • Huber V
        • Luss H
        • Neumann J
        • Schmitz W
        • Domschke W
        • Konturek JW.
        Expression of endothelial cell–derived nitric oxide synthase (eNOS) is increased during gastric adaption to chronic aspirin intake in humans.
        Aliment Pharmacol Ther. 1999; 13: 507-514
        • Baumgartner A
        • Koelz HR
        • Halter F.
        Indomethacin and turnover of gastric mucosal cells in the rat.
        Am J Physiol. 1986; 250: G830-G835
        • Skeljo MV
        • Cook GA
        • Elliott SL
        • Giraud AS
        • Yeomans ND.
        Gastric mucosal adaptation to diclofenac injury.
        Dig Dis Sci. 1996; 41: 32-39
        • Schmassmann A
        • Peskar BM
        • Stettler C
        • Netzer P
        • Stroff T
        • Flogerzi B
        • Halter F.
        Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastrointestinal ulcer models in rats.
        Br J Pharmacol. 1998; 123: 795-804
        • Lancaster-Smith MJ
        • Jaderberg ME
        • Jackson DA.
        Ranitidine in the treatment of non-steroidal anti-inflammatory drug–associated gastric and duodenal ulcers.
        Gut. 1991; 32: 252-255
        • Hudson N
        • Balsitis M
        • Filipowicz B
        • Hawkey CJ.
        Effect of Helicobacter pylori colonization on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.
        Gut. 1993; 34: 748-751
        • Bjorkman D.
        Nonsteroidal anti-inflammatory drug–associated toxicity of the liver, lower gastrointestinal tract, and esophagus.
        Am J Med. 1998; 105: 17S-21S
        • Mason JC.
        NSAIDs and the oesophagus.
        Eur J Gastroenterol Hepatol. 1999; 11: 369-373
        • Whittle BJ.
        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
        • Bjarnason I
        • Hayllar J
        • MacPherson AJ
        • Russell AS.
        Side effects of non-steroidal anti-inflammatory drugs on the small and large intestine in humans.
        Gastroenterology. 1993; 104: 1832-1847
        • Allison MC
        • Howatson AG
        • Torrance CJ
        • Lee FD
        • Russell RI.
        Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs.
        N Engl J Med. 1992; 327: 749-754
        • Langman MJ
        • Morgan L
        • Worrall A.
        Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and hemorrhage.
        Br Med J Clin Res. 1985; 290: 347-349
        • Jenkins AP
        • Trew DR
        • Crump BJ
        • Nukajam WS
        • Foley JA
        • Menzies IS
        • Creamer B.
        Do non-steroidal anti-inflammatory drugs increase colonic permeability?.
        Gut. 1991; 32: 66-69
        • Rampton DS
        • McNeil NI
        • Sarner M.
        Analgesic ingestion and other factors preceding relapse in ulcerative colitis.
        Gut. 1983; 24: 187-189
        • Evans JM
        • McMahon AD
        • Murray FE
        • McDevitt DG
        • MacDonald TM.
        Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease.
        Gut. 1997; 40 ([see comments]): 619-622
        • Stamm C
        • Burkhalter E
        • Pearce W
        • Larsen B
        • Willis M
        • Kikendall JW
        • Moses F
        • Rosen H
        • Wong RKH.
        Benign colonic ulcers associated with nonsteroidal anti-inflammatory drugs ingestion.
        Am J Gastroenterol. 1994; 89: 2230-2233
        • Campbell K
        • Steele RJ.
        Use of anti-inflammatory drugs and complicated diverticular disease: a case-control study.
        Br J Surg. 1991; 78: 190-191
        • Sutherland LR
        • Verhoef M
        • Wallace JL
        • Van Rosendaal G
        • Crutcher R
        • Meddings JB.
        A Simple, non-invasive marker of gastric damage: sucrose permeability.
        Lancet. 1994; 343: 998-1000
        • Davenport HW.
        Gastric mucosal injury by fatty acid and acetylsalicylic acids.
        Gastroenterology. 1964; 93: 245-253
        • Whittle BJR
        • Espulgues JV.
        Induction of rat gastric damage by the endothelium-derived peptide, endothelin.
        Br J Pharmacol. 1988; 95: 1033-1101
        • Miller TA.
        Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms.
        Am J Physiol. 1983; 245: G601-G623
        • Garner A.
        Mechanisms of action of aspirin on the gastric mucosa of the guinea pig.
        Acta Physiol Scand Suppl. 1978; 103: 101-110
        • Smith MJH
        • Dawkins PD.
        Salicylates and enzymes.
        J Pharm Pharmacol. 1971; 23: 729-744
        • Jorgensen TG
        • Weis-Fogh US
        • Nielsen HH
        • Olesen HP.
        Salicylate and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of the stomach.
        Scand J Clin Lab Invest. 1976; 36: 649-654
        • Roediger WEW
        • Mollard S.
        Selective inhibition of fatty acid oxidation in colonocytes by ibuprofen: a cause of colitis?.
        Gut. 1995; 36: 55-59
        • Kelly JP
        • Kaufman DW
        • Jurgelon JM
        • Sheehan J
        • Koff RS
        • Shapiro S.
        Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product.
        Lancet. 1996; 348 ([see comments] Comment in: Lancet 1996;348:1394-1395): 1413-1416
        • Appleyard CB
        • McCafferty DM
        • Tigley AW
        • Swain MG
        • Wallace JL.
        Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence.
        Am J Physiol. 1996; 270: G42-G48
        • Wallace JL
        • McKnight W
        • Miyasaka M
        • Tamatani T
        • Paulson J
        • Anderson DC
        • Granger DN
        • Kubes P.
        Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury.
        Am J Physiol. 1993; 265: G993-G998
        • Levi S
        • Goodlad RA
        • Lee CY
        • Stamp G
        • Walport MG
        • Wright NA
        • Hodgson HJF.
        Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer bleeding.
        Lancet. 1990; 336: 841-843
        • Uribe A
        • Johansson C
        • Rubio C.
        Cell proliferation of the rate gastrointestinal mucosa after treatment with E2 prostaglandins and indomethacin.
        Digestion. 1987; 36: 238-245
        • Zhu GH
        • Yang XL
        • Lai KC
        • Ching CK
        • Wong BC
        • Yuen St
        • Ho J
        • Lam SK.
        Nonsteroidal anti-inflammatory drugs could reverse Helicobacter pylori–induced apoptosis and proliferation in gastric epithelial cells.
        Dig Dis Sci. 1998; 43: 1957-1963
        • Bassotti G
        • Bucaneve G
        • Furno P
        • Morelli A
        • Del Favero A.
        Double-blind, placebo-controlled study on effects of diclofenac sodium and indomethacin on postprandial gastric motility in man.
        Dig Dis Sci. 1998; 43: 1172-1176
        • Sun DCH
        • Roth SH
        • Mitchell CS
        • Englund DW.
        Upper gastroin-testinal disease in rheumatoid arthritis.
        Dig Dis. 1974; 19: 405-410
        • Day JP
        • Lanas A
        • Rustagi P
        • Hirschowitz GI.
        Reversible prolonged skin bleeding time in acute gastrointestinal bleeding presumed due to NSAIDs.
        J Clin Gastroenterol. 1996; 22: 96-103
        • Hawkey CJ
        • Hawthorne AB
        • Hudson N
        • Cole AT
        • Mahida YR
        • Daneshmend TK.
        Separation of aspirin's impairment of hemostasis from mucosal injury in the human stomach.
        Clin Sci. 1991; 81: 565-573
        • Stack WA
        • Hawkey GM
        • Atherton JC
        • Logan RF
        • Hawkey CJ.
        Interactions of risk factors for peptic ulcer bleeding.
        Gastroenterology. 1999; 116 (abstr): A97
        • Schmassmann A.
        Mechanisms of ulcer healing and effects of nonsteroidal anti-inflammatory drugs.
        Am J Med. 1998; 104: 43S-51S
        • Podolsky DK.
        Mucosal immunity and inflammation. V. Innate mechanisms of mucosal defense and repair: the best offense is a good defense.
        Am J Physiol. 1999; 277: G495-G499
        • Dignass AU
        • Becker A
        • Spiegler S
        • Goebell H.
        Adenine nucleotides modulate epithelial wound healing in vitro.
        Eur J Clin Invest. 1998; 28: 554-561
        • Beltinger J
        • McKaig BC
        • Makh S
        • Stack WA
        • Hawkey CJ
        • Mahida YR.
        Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response.
        Am J Physiol. 1999; 277: C271-C279
        • Horie-Sakata K
        • Shimada T
        • Hiraishi H
        • Terano A.
        Role of cyclooxygenase 2 in hepatocyte growth factor–mediated gastric epithelial restitution.
        J Clin Gastroenterol. 1998; 27: S40-S46
        • Blikslager AT
        • Roberts MC
        • Rhoads JM
        • Argenzio RA.
        Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum.
        J Clin Invest. 1997; 100: 1928-1933
        • Ruthig DJ
        • Meckling-Gill KA.
        Both (n-3) and (n-6) fatty acids stimulate wound healing in the rat intestinal epithelial cell line, IEC-6.
        J Nutr. 1999; 129: 1791-1798
        • Powell DW
        • Mifflin RC
        • Valentich JD
        • Crowe SE
        • Saada JI
        • West AB.
        Myofibroblasts. II. Intestinal subepithelial myofibroblasts.
        Am J Physiol. 1999; 277: C183-C201
        • Mizuno H
        • Sakamoto C
        • Matsuda K
        • Wada K
        • Uchida T
        • Noguchi H
        • Akamatsu T
        • Kasuga M.
        Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice.
        Gastroenterology. 1997; 112: 387-397
        • Jackson LM
        • Wu KC
        • Mahida YR
        • Jenkins D
        • Hawkey CJ.
        Cyclooxygenase (COX)-1 and -2 in normal, inflamed and ulcerated human gastric mucosa.
        Gut. 2000; (in press)
        • Hudson N
        • Balsitis M
        • Everitt S
        • Hawkey CJ.
        Angiogenesis in gastric ulcers; impaired in patients taking non-steroidal anti-inflammatory drugs.
        Gut. 1995; 37: 191-194
        • Hull MA
        • Brough JL
        • Hawkey CJ.
        Expression of cyclooxygenase-1 and -2 by human gastric endothelial cells.
        Gut. 1999; 45: 529-536
        • Jones MK
        • Wang H
        • Peskar BM
        • Levin E
        • Itani RM
        • Sarfeh IJ
        • Tarnawski AS.
        Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing.
        Nat Med. 1999; 5: 1418-1423
        • Hawkey CJ.
        Nonsteroidal anti-inflammatory drugs and peptic ulcers. Facts and figures multiply, but do they add up?.
        BMJ. 1990; 300: 278-284
        • Gabriel SE
        • Jaakkimainen L
        • Bombardier C.
        Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta-analysis.
        Ann Intern Med. 1991; 115: 787-796
        • Garcia Rodriguez LA
        • Jick H.
        Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.
        Lancet. 1994; 343: 769-772
        • Langman MJS
        • Weil J
        • Wainwright P
        • Lawson DH
        • Rawlins MD
        • Logan RF
        • Murphy M
        • Vessey MP
        • Colin-Jones DG.
        Risk of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.
        Lancet. 1994; 343: 1075-1078
        • Slattery J
        • Warlow CP
        • Shorrock CJ
        • Langman MJS.
        Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin–analysis of gastrointestinal bleeding during UK-TIA trial.
        Gut. 1995; 37: 509-511
        • Henry D
        • Lim LL-Y
        • Garcia Rodriquez LA
        • Gutthann SP
        • Carson JL
        • Griffin N
        • Savage R
        • Logan R
        • Moride Y
        • Hawkey C
        • Hill S
        • Fries JT.
        The ability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis.
        BMJ. 1996; 312: 1563-1566
        • Wolfe MM
        • Lichtenstein DR
        • Sing G.
        Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs.
        N Engl J Med. 1999; 340: 1888-1899
        • Weil J
        • Langman MJS
        • Wainwright P
        • Lawson DH
        • Rawlins M
        • Logan RFA
        • Brown TP
        • Vessey MP
        • Murphy M
        • Colin-Jones DG.
        Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs.
        Gut. 2000; 46: 27-31
        • Hawkey CJ
        • Karrasch JA
        • Szcepanski L
        • Walker DG
        • Barkun A
        • Swannell AJ
        • Yeomans ND
        • for the Omeprazole vs Misoprostol for NSAID-Induced Ulcer Management OMNIUM Study Group
        Omeprazole compared with misoprostol for ulcers associated with non steroidal anti inflammatory drugs.
        N Engl J Med. 1998; 338: 727-734
        • Hawkey CJ
        • Laine l
        • Simon T
        • Beaulieu A
        • Maldonado-Cocco J
        • Acevedo E
        • Cello JP
        • Shahane A
        • Quan H
        • Bolognese J
        • Mortensen E
        • for the Rofecoxib Osteoarthritis Endoscopy Multinational Study Group
        Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen and placebo on the gastroduodenal mucosa of patients with osteoarthritis.
        Arthritis Rheum. 2000; 43: 370-377
        • Shorr RI
        • Ray WA
        • Daugherty JR
        • Griffin MR.
        Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease.
        Arch Intern Med. 1993; 153: 1665-1670
        • Piper JM
        • Ray WA
        • Daugherty JR
        • Griffin MR.
        Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs.
        Ann Intern Med. 1991; 114: 735-740
        • Hochain P
        • Berkelmans I
        • Czernichow P
        • Duhamel C
        • Tranvouez JL
        • Lerebours E
        • Colin R.
        Which patients taking non-aspirin non-steroidal anti-inflammatory drugs bleed? A case-control study.
        Eur J Gastroenterol Hepatol. 1995; 7: 419-426
        • Holvoet J
        • Terriere L
        • Van Hee W
        • Verbist l
        • Fierens E
        • Hautekeete ML.
        Relation of upper gastrointestinal bleeding to non-steroidal anti-inflammatory drugs and aspirin: a case-control study.
        Gut. 1991; 32: 730-734
        • Johnson PC.
        Gastrointestinal consequences of treatment with drugs in elderly patients.
        J Am Geriatr Soc. 1982; 30: S52-S57
        • Moore JG
        • Bjorkman DJ
        • Mitchell MD
        • Avots-Avotins A.
        Age does not influence acute aspirin-induced gastric mucosal damage.
        Gastroenterology. 1991; 100: 1626-1629
        • Cryer B
        • Redfern JS
        • Goldschmiedt M
        • Lee E
        • Feldman M.
        Effect of aging on gastric and duodenal mucosal prostaglandin concentrations in humans.
        Gastroenterology. 1992; 102: 1118-1123
        • Amagase K
        • Okabe S.
        A new ulcer model, “unhealed gastric ulcers,” induced by chronic treatment with indomethacin in rats with acetic acid ulcers.
        J Physiol Pharmacol. 1999; 50: 169-181
        • Gotzsche PC.
        Review of dose-response studies of NSAIDs in rheumatoid arthritis.
        Dan Med Bull. 1989; 36: 395-399
        • Brooks PM
        • Day RO.
        Nonsteroidal anti-inflammatory drugs-differences and similarities.
        N Engl J Med. 1991; 324: 1716-1725
        • Huang JQ
        • Lad RJ
        • Sridhar S
        • Sumanac K
        • Hunt RH.
        H. pylori infection increases the risk of non-steroidal anti-inflammatory drug (NSAID)-induced gastroduodenal ulceration.
        Gastroenterology. 1999; 116 (abstr): A192
        • Cullen DJE
        • Hawkey GM
        • Greenwood DC
        • Humphries H
        • Shepherd V
        • Logan RFA
        • Hawkey CJ.
        Peptic ulcer bleeding: relative roles of Helicobacter pylori and non-steroidal and anti-inflammatory drugs.
        Gut. 1997; 41: 459-462
        • Pilotto A
        • Leandro G
        • Di Mario F
        • Franceschi M
        • Bozzola L
        • Valerio G.
        Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly: a case-control study.
        Dig Dis Sci. 1997; 42: 586-591
        • Aalykke C
        • Lauritsen JM
        • Hallas J
        • Reinholdt S
        • Krogfelt K
        • Lauritsen K.
        Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case control study.
        Gastroenterology. 1999; 116: 1305-1309
        • Wu CY
        • Poon SK
        • Chen GH
        • Chang CS
        • Yeh HZ.
        Interaction between Helicobacter pylori and non-steroidal anti-inflammatory drugs in peptic ulcer bleeding.
        Scand J Gastroenterol. 1999; 34: 234-237
        • Labenz J
        • Peitz U
        • Kohl H
        • Kaiser J
        • Malfertheiner P
        • Hackelsberger A
        • Borsch G.
        Helicobacter pylori increases the risk of peptic ulcer bleeding: a case-control study.
        Ital J Gastroenterol Hepatol. 1999; 31: 110-114
        • Santolaria S
        • Lanas A
        • Benito R
        • Perez-Aisa MA
        • Montoro M
        • Sainz R.
        Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users.
        Aliment Pharmacol Ther. 1999; 13: 1511-1518
        • Bianchi Porro G
        • Parente F
        • Imbesi V
        • Montrone F
        • Caruso I.
        Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in long-term NSAID users. Response to omeprazole dual therapy.
        Gut. 1996; 39: 22-27
        • Chan FKL
        • Sung JJY
        • Chung SCS
        • To KF
        • Yung MY
        • Leung VKS
        • Lee YT
        • Chan CSY
        • Li EKM
        • Woo J.
        Randomised trial of eradication of Helicobacter pyloribefore non-steroidal anti-inflammatory drug therapy to prevent peptic ulcer.
        Lancet. 1997; 350: 975-979
        • Hawkey CJ
        • Tulassay Z
        • Szczepanski L
        • van Rensburg CJ
        • Filipowicz-Sosnowska A
        • Lanas A
        • Wason CM
        • Peacock RA
        • Gillon KRW.
        Helicobacter pylori eradication in patients taking non-steroidal, anti-inflammatory drugs: The HELP NSAIDs Study.
        Lancet. 1998; 352: 1016-1021
        • Chan FK
        • Sung JJ
        • Chung SC
        • et al.
        Does eradication of Helicobacter pylori impair healing of non-steroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective randomized study.
        Aliment Pharmacol Ther. 1998; 12: 1201-1205
        • Chan FKL
        • Sung JY
        • Suen R
        • Lee YT
        • Leung WK
        • Leung VKS
        • Wy JCY
        • Chung SCS.
        Eradication of H. pylori versus maintenance acid suppression to prevent recurrent ulcer hemorrhage in high risk NSAID users: a prospective randomized study.
        Gastroenterology. 1998; 114 (abstr): A87
        • Hawkey CJ.
        Letter: response to Calvet and colleagues.
        Aliment Pharmacol Ther. 2000; 14: 499-500
        • Labenz J
        • Tillenburg B
        • Peitz U
        • Verdu E
        • Stolte M
        • Borsch G
        • Blum AL.
        Effect of curing Helicobacter pylori infection on intragastric acidity during treatment with ranitidine in patients with duodenal ulcer.
        Gut. 1997; 41: 33-36
        • Labenz J
        • Tillenburg B
        • Peitz U
        • Idstrom J-P
        • Verdu EF
        • Stolte M
        • Borsch G
        • Blum AL.
        Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer.
        Gastroenterology. 1996; 110: 725-732
        • Hawkey CJ
        • Swannell AJ
        • Naesdal J
        • Walan A
        • Yeomans ND.
        Men are from Mars, women are from Venus: sex-related differences in ulcer disease expression and the influence of Helicobacter pylori.
        Gut. 1994; 41 (suppl): A42
        • Simmons DY
        • Levy DB
        • Yannoni Y
        • Erikson RL.
        Identification of a phorbol ester-repressible v-src-inducible gene.
        Proc Natl Acad Sci U S A. 1989; 86: 1178-1182
        • Fu JY
        • Masferrer JL
        • Seibert K
        • Raz A
        • Needleman P.
        The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes.
        J Biol Chem. 1990; 265: 16737-16740
        • Kujubu DA
        • Fletcher BS
        • Varnum BC
        • Lim RW
        • Herschman HR.
        TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.
        J Biol Chem. 1991; 266: 12866-12872
        • Masferrer JL
        • Zweifel BS
        • Manning PT
        • Hauser SD
        • Leahy KM
        • Smith WG
        • Isakson PC
        • Seibert K.
        Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and nonulcerogenic.
        Proc Natl Acad Sci U S A. 1994; 91: 3228-3232
        • Hawkey CJ.
        COX-2 inhibitors.
        Lancet. 1999; 353: 307-314
        • Langenbach R
        • Morham SG
        • Tiano HF
        • Loftin CD
        • Ghanayem BI
        • Chulada PC.
        Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid–induced inflammation and indomethacin-induced gastric ulceration.
        Cell. 1995; 83: 483-492
        • Dinchuk JE
        • Car BD
        • Focht RJ
        • Johnston JJ
        • Jaffee BD
        • Covington MB
        • Contel NR
        • Eng VM
        • Collins RJ
        • Czerniak PM
        • Gorry SA
        • Trzaskos JM.
        Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II.
        Nature. 1995; 378: 406-409
        • Catella-Lawson F
        • McAdam B
        • Morrison BW
        • Kapoor S
        • Kujubu D
        • Antes L
        • Lasseter KC
        • Quan H
        • Gertz BJ
        • Fitzgerald GA.
        Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.
        J Pharmacol Exper Ther. 1999; 289: 735-741
        • Rossat J
        • Mailard M
        • Nussberger J
        • Brunner HR
        • Burnier M.
        Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects.
        Clin Pharmacol Ther. 1999; 66: 76-84
        • Kirtikara K
        • Morham SG
        • Raghow R
        • Laulederkind SJ
        • Kanekura T
        • Goorha S
        • Ballou LR.
        Compensatory prostaglandin E2 biosynthesis in cyclooxygenase 1 or 2 null cells.
        J Exp Med. 1998; 187: 517-523
        • Luong C
        • Miller A
        • Barnett J
        • Chow J
        • Ramesha C
        • Browner MF.
        Flexibility of the NSAID binding site in the structure of cyclooxygenase-2.
        Nat Struct Biol. 1996; 3: 927-933
        • Ouellet M
        • Percival DM.
        Effect of inhibitor time dependency on selectivity towards cyclooxygenase isoforms.
        J Biochem. 1995; 306: 247-251
        • Patrignani P
        • Panara MR
        • Sciulli MG
        • Santini G
        • Renda G
        • Patrono C.
        Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs.
        J Physiol Pharmacol. 1997; 48: 623-631
        • Riendeau D
        • Charleson S
        • Cromlish W
        • Mancini JA
        • Wong E
        • Guay J.
        Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors using sensitive microsomal and platelet essays.
        Can J Physiol Pharmacol. 1997; 75: 1088-1095
        • Warner TD
        • Giuliano F
        • Vojnovic I
        • Bukasa A
        • Mitchell JA
        • Vane JR.
        Non-steroidal drug selectivities for cyclooxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis.
        Proc Natl Acad Sci U S A. 1999; 96: 7563-7568
        • Scott LJ
        • Lamb HM.
        Rofecoxib.
        Drugs. 1999; 58: 499-505
        • Chan CC
        • Boyce S
        • Brideau C
        • Charleson W
        • Ethier D
        • Evans J
        • Ford-Hutchinson AW
        • Forrest MJ
        • Gauthier JY
        • Gordon R
        • Gresser M
        • Guay J
        • Kargman S
        • Kennedy B
        • Leblanc Y
        • Leger S
        • Mancini J
        • O'Neill GP
        • Ouellet M
        • Patrick D
        • Percival MD
        • Perrier H
        • Prasit P
        • Rodger I.
        Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles.
        J Pharmacol Exp Ther. 1999; 290: 551-560
      1. FDA Rofecoxib website.
        (Available at) (Accessed)
        • Boyce EG
        • Breen GA.
        Celecoxib: a COX-2 inhibitor for the treatment of osteoarthritis and rheumatoid arthritis.
        Hosp Formulatory. 1999; 34: 405-417
        • Goldenberg MM.
        Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis.
        Clin Ther. 1999; 21: 1497-1513
        • Simon LS
        • Lanza FL
        • Lipsky PE
        • Hubbard RC
        • Talwlker S
        • Schwartz
        • Isakson PC
        • Gies GS.
        Preliminary study of the safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects.
        Arthritis Rheum. 1998; 41: 1591-1602
        • Emery P
        • Zeidler H
        • Kvien TK
        • Guslandi M
        • Naudin R
        • Stead H
        • Verburg KM
        • Isakson PC
        • Hubbard RC
        • Geis GS.
        Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomized double-blind comparison.
        Lancet. 1999; 354: 2106-2111
      2. FDA celecoxib web site http://www.fda.gove/cder/foi/label/1998/20998lbl.pdf

        • Lanza FL
        • Rack MF
        • Simon TJ
        • Quan H
        • Bolognese JA
        • Hoover ME
        • Wilson FR
        • Harper SE.
        Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.
        Aliment Pharmacol Ther. 1999; 13: 761-767
        • Laine L
        • Harper S
        • Simon T
        • Bath R
        • Johanson J
        • Schwartz H
        • Stern S
        • Quan H
        • Bolognese J.
        A randomized trial comparing the effect of rofecoxib, a cyclooxygenase-2 specific inhibitor, with that or ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.
        Gastroenterology. 1999; 117: 776-783
        • Langman MJ
        • Jensen DM
        • Watson DJ
        • Harper SE
        • Xhao P-L
        • Quan H.
        Incidence of upper gastrointestinal perforations, symptomatic ulcers and bleeding (PUBS). Rofecoxib compared to NSAIDs.
        JAMA. 1999; 282: 1929-1933
        • Goldstein JL
        • Agrawal NM
        • Silverstein F
        • Kaiser J
        • Burr AM
        • Verburg KM
        • Hubbard RC
        • Zhao W
        • Geis GS.
        Celecoxib is associated with a significantly lower incidence of clinically significant upper gastrointestinal (UGI) events in osteoarthritis (OS) and rheumatoid arthritis (RA) patients as compared to NSAIDs.
        Gastroenterology. 1999; 116 (abstr): A174
        • Wight NJ
        • Garlick N
        • Calder N
        • Dallob A
        • Gottesdiener K
        • Hawkey CJ.
        Evidence that the COX-2 specific inhibitor rofecoxib at 50 mg spares gastric mucosal prostaglandin synthesis in humans.
        Gut. 1999; 45: 30.03
        • McAdam BF
        • Catella-Lawson F
        • Mardini IA
        • Kapoor S
        • Lawson JA
        • FitzGerald GA.
        Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.
        Proc Natl Acad Sci U S A. 1999; 96 ([published erratum appears in Proc Natl Acad Sci U S A 1999;11:96:5890]): 272-277
        • Walan A
        • Bader JP
        • Classen M
        • Lamers CB
        • Piper DW
        • Rutgersson K
        • Eriksson S.
        Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer.
        N Engl J Med. 1989; 320: 69-75
        • Wallace JL
        • Reuter B
        • Cicala C
        • McKnight W
        • Grisham MB
        • Cirino G.
        Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat.
        Gastroenterology. 1994; 107: 173-179
        • Elliot SN
        • McKnight W
        • Cirino G
        • Wallace JL
        • et al.
        A nitric oxide-releasing non-steroidal anti-inflammatory drug accelerates gastric ulcer healing in rats.
        Gastroenterology. 1995; 109: 524-530
        • Hawkey CJ.
        Future treatments for arthritis–new NSAIDs, NONSAIDs or no NSAIDs.
        Gastroenterology. 1995; 109 (editorial)?: 614-616
        • Davies NM
        • Roseth AG
        • Appleyard CB
        • McKnight W
        • Del Soldato P
        • Calignano A
        • Cirino G
        • Wallace JL.
        NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects.
        Aliment Pharmacol Ther. 1997; 11: 69-79
        • Donnelly MT
        • Stack WA
        • Courtauld EM
        • Garlick N
        • Del Soldato P
        • Hawkey CJ.
        Nitric oxide donating flurbiprofen (HCT 1026) causes less endoscopic damage in healthy volunteers than flurbiprofen.
        Gastroenterology. 1998; 114 (abstr): A107
        • Lichtenberger LM
        • Wang ZM
        • Romero JJ
        • Ulloa C
        • Perez JC
        • Giraud MN
        • Barreto JC.
        Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.
        Nat Med. 1995; 1: 154-158
        • Wright MR
        • Davies NM
        • Jamali F.
        Rationale for the development of stereochemically pure enantiomers: are the R enantiomers of chiral nonsteroidal anti-inflammatory drugs inactive?.
        J Pharm Sci. 1994; 83: 911-912
        • Koch M
        • Capurso L
        • Dezi A
        • Ferrario F
        • Scarpignato C.
        Prevention of NSAID-induced gastroduodenal mucosal injury: meta-analysis of clinical trials with misoprostol and H2-receptor antagonists.
        Dig Dis. 1995; 1: 62-74
        • Wight NJ
        • Hawkey CJ.
        Peptic ulcer disease: NSAID related. Evidence based gastroenterology.
        in: A framework for clinical practice.2000 (in press)
        • Raskin JB
        • White RH
        • Jaszewski R
        • Korsten MA
        • Schubert TT
        • Fort JG.
        Misoprostol and ranitidine in the prevention of NSAID-induced ulcers: a prospective, double-blind, multicenter study.
        Am J Gastroenterol. 1996; 91: 223-227
        • Verdickt W
        • Moran C
        • Hantzschel H
        • Fraga AM
        • Stead H
        • Geis GS.
        A double-blind comparison of the gastroduodenal safety and efficacy of diclofenac and a fixed dose combination of diclofenac and misoprostol in the treatment of rheumatoid arthritis.
        Scand J Rheumatol. 1992; 21: 95-191
        • Silverstein FE
        • Graham DY
        • Senior JR
        • Davies HW
        • Struthers BJ
        • Bittman RM
        • Geis GS.
        Misoprostol reduces serious gastrointestinal complications in patients with arthritis receiving non steroidal anti-inflammatory drugs–a randomized double blind placebo controlled study.
        Ann Intern Med. 1995; 123: 241-249
        • Ekstrom P
        • Carling L
        • Wetterhus S
        • Wingren PE
        • Anker-Hansen O
        • Lundergardh G.
        Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study.
        Scand J Gastroenterol. 1996; 31: 753-758
        • Cullen D
        • Bardhan DK
        • Eisner M
        • Kogut DG
        • Peacock RA
        • Thomas JM
        • Hawkey CJ.
        Primary gastroduodenal prophylaxis with omeprazole for non-steroidal anti-inflammatory drug users.
        Aliment Pharmacol Ther. 1998; 12: 135-140
        • Yeomans ND
        • Tulassay Z
        • Juhasz L
        • Racz I
        • Howard JM
        • van Rensburg CJ
        • Swannell AJ
        • Hawkey CJ
        • for the ASTRONAUT Study Group
        A comparison of omeprazole and ranitidine for treating and preventing ulcers associated with non-steroidal anti-inflammatory drugs.
        N Engl J Med. 1998; 338: 719-726
        • Agrawal N
        • Safdi M
        • Wruble L
        • Karvois D
        • Greski-Rose P
        • Huang B.
        Effectiveness of lansoprazole in the healing of NSAID-induced gastric ulcer in patients continuing to take NSAIDs.
        Gastroenterology. 1998; 114 (abstr): A52
        • Rose P
        • Huang B
        • Lukasik N
        • Collis C.
        Evidence that lansoprazole is effective in preventing NSAID induced ulcers.
        Gastroenterology. 1999; 116 (abstr): A295
        • Taha AS
        • Hudson N
        • Hawkey CJ
        • Swannell AJ
        • Trye P
        • Cottrell J.
        Famotidine for the prevention of gastric and duodenal ulcers caused by non-steroidal anti-inflammatory drugs.
        N Engl J Med. 1996; 334: 1435-1439
        • Singh G
        • Ramey DR
        • Morfeld D
        • Shi H
        • Hatoum HT
        • Fries JF.
        Gastrointestinal tract complications of non-steroidal anti-inflammatory drug treatment in rheumatoid arthritis: a prospective observational cohort study.
        Arch Intern Med. 1996; 156: 1530-1536
        • Garcia Rodriguez LA
        • Ruigomez A.
        Secondary prevention of upper gastrointestinal bleeding associated with maintenance acid-suppressing treatment in patients with peptic ulcer bleed.
        Epidemiology. 1999; 10: 228-232