Irylaumrurplrururm'nIu_gy_ Vol. 7. No. 3. pp 277—2lltr t I999)
`© VSP I999.
`
`Management of NSAID-related gastrointestinal
`
`mucosal injury
`
`ADAM F. BARRISON and M. MICHAEL WOLFE‘
`
`.$'e¢'Iimr ufGa.rtmr'nIrnrlu_r:_\'. Bmlun Urrirz-r\iI_\' .S'rIrunl ofMaIirim' um! Ilusmrr Illalirul ('¢'uIr'r:
`88 Em‘! N1-trtun Street. Ilmlmt. Mtt.\‘tru'Ittt.\'('ll.r MA 02I I-’l'-Z393. USA
`
`Received Ill August I999: accepted I8 August I999
`
`,\lvstraet—The three therapeutic goals in patients with NSAII)-induced gaxtroduodeuorxrthy are
`treatment ol' dyspeptic symptoms. mauagemettt oI' NSAID-related ulcers and their complications.
`and prophylaxis against recurrent gastrointestinal toxieity. Both H-_n-receptor antagonists and proton
`putup inhibitors tPPls) appear to be helpful in relieving the synptoms associated with NSAID use.
`while treatment of NSAID-indueed gastroduodenal ulcers. whether the NSAID is continued or not.
`is best achieved by the use of PPls However. heeautse symptoms do not often predict the presence
`of gastrodnodenal ulcers. the goal ol prevention has lweome pararnuunt in the treatment of patients
`with an increased likelihood ol gastrointestinal toxicity. The best pophylaxis against NSAID-related
`toxicity is the use ol an alternative agent .\'l.I.'ll as raalsalate or paracetamol (acetaminophen). However.
`il'an NSAID is to he used. prophylaxis is hest aceonplished with a PP! or misoprostol. a pmstaglandin
`El analogue. The use of misoprustol is limited by its frequent dosing. at least Ztltl n g three times a day.
`and its min gastmintestinal side effects. Future therapy will include NSAll)sthat maintain their anti-
`inllarntnatory el'l'u.1s. while possessing superior safety profiles. and include prel'erentiaI and highly
`selective COX-2 inhibitors and nitric oxide releasing compounds.
`
`Kr)‘ Il'0rtI.\Z (iastrointestinal: NSAlD.s: (‘OX-2: gastrointestinal
`hemorrhage: proton punp inhibitors: pnrstaglandim.
`
`tmicity: ulcers: gaslmittleslittztl
`
`I. IN'l'R()Dl'C'l'l()N
`
`Non—sleruida| anti—inl|ammatory drugs lNSA|Ds) have heeotne one of the most
`eomtnonly ttsed medications. Over 70 million NSAID prescriptions and 30 billion
`over-the-counter preparations are sold annually in the United States (Wolfe er al..
`I999). The majority of NS AID users tolerate these medications without untoward
`el'l'et:ts. hut adverse gastrointestinal effects are seen with relative lrequeney. In I984.
`the Center for l)i,-«ease Conlrol reported that
`l00.()(ll to 2llll.0()(l hospitalizations
`
`‘To whom eorrespondence should he addressed. E-mail: nu'r:ltael.wo|t'elt*lunc.org
`
`CFAD EXHIBIT 1025
`
`

`
`278
`
`A. If lhm1muumIM. M. Wnlfv
`
`and l().l)ll0 to 2(l.(Xl0 deaths occur annually in the United States due to the
`gastrointestinal side effect of these Inedications. Side effects range from dyspepsia
`to cotnplicated gastroduodenal ttlcers associated with hemorrhage or perforation.
`NSAIDs thus constitute a class of dntgs that can be best characterized as a 'dottble-
`edged sword‘. medication that
`is very elfcctive. yet carries a substantial
`l'l.\'l\
`potential.
`
`2. l'A'I'H()GI'INI".S'IS ()l-' GASTR()lN'l'l-'.S"l‘IN/\I. l)A.\lAGl*I
`
`Topical and systetnic effects contribute to the Inttcosal datnage associated with
`NSAID use. and although generally considered a primary cause of gastrodttode-
`nal ttlcers. NSAIDs are capable ofinducing widespread injury throughout the gas-
`trointestinal tract and liver. Lanas «I «L. I992 recently reported that approximately
`35% of NSAID-induced gastrointestinal bleeding occurred below the ligament of
`Treitz. with a spectrum of small intestinal and colonic injury ranging from a protein-
`and blood-losing enteropathy and colitis resembling inllammatory bowel disease to
`colonic perforation and bleeding.
`in the esophagus. injury induced by NSAIDs has been reported and is thought
`to result from local acidic injury to the esophageal mucosa. a condition tenned pill
`esophagitis (Minoch ¢*I¢tI.. I99! ).
`In the stomach and duodenum. topical injury
`results from both direct and indirect mechanisms. In the presence of highly acidic
`gastric contents. nonionizcd lipophilic NSAIDs are easily absorbed and migrate
`through gastric mucus to the surface epithelium. where NSAIDs are dissociated
`into the ionized fonn. resulting in H"' ion trapping (Somasundaram cl uI.. I995).
`In addition. NSAIDs reduce the hydrophobicity of gastric mucosa and rettder the
`surface epithelium sttsceptible to injury by gastric acid (Lichtenbergcr.
`I995).
`Indirectly. Inucosal erosion may resttlt from dutxlenogastric reflux of bile containing
`active NSAID melzbolites (Wolfe el uI.. I999).
`
`Although topical effects of NSAIDs are a signilicant cause of mucosal damage.
`the fact that NSAID-induced gastroduodenal injury occurs with equal frequency
`using ettteric-coated preparations and following either rectal or parenteral admin-
`istration suggests that the systemic effects of these compounds may play an even
`greater role. This contention is funher supponed by the tbservation that prodrugs
`such as sulindac. a compound whose effect is mediated by an active metabolite.
`have been associated with gastroduodettal ulceration.
`The Inucosal production of prostaglandins (PGs) appears to play an integral role
`in the stimulation of several mucosal components necessary for maintaining normal
`tnucosal
`integrity and possibly reducing gastric acid secretion (Table ll (Wolfe
`0! ul.. I999). PCs are derived from arachidonic acid by the action of cyclooxygenase
`(COX). Two related cyclooxygenase isoenzymes. COX-I attd COX-2. are expressed
`in mammalian cells. COX-I is exptessed constitutively in most tissues. including
`the gastric mucosa. and is thought to function as a ‘housekeeping’ en7.yIne. The
`expression of COX-2. especially in macrophages and synovial cells. is induced
`
`

`
`.4-Iuuugt-um)! uI'NSilIlJ-rrlulccl GI In.I'i1'iI_\’
`
`279
`
`Table I.
`
`Protective properties of the gastmduotlettal mucosa
`
`Mucus secretion
`Bicarbonate secrctiott
`Mucosal blood flow
`
`Intercellular tight junctions
`Mai ntcnancc of tissue acid hase status
`
`Epithelial restitution
`
`Table 2.
`
`Risk |'acttI's for dtvclopment ol'NS.~‘\|D related ulcers
`
`Delinite
`
`Advattccd age
`Prior history of ulcer
`('onu)mitant conicostcroid Ihcrap}
`(‘oncomitant anticnagnlation therapy
`I ligh doses of NS A|Ds
`Short duration of therap) t «/ two weeks)
`Serious systemic diseasm
`
`I’ossihle
`
`('oncomilant H. p_t‘lm'i inlectiott
`Smoking
`Alcohol
`
`it has heen hypothesized
`hy inflammation or mitogen stimulation. Therefore.
`that
`the anti-intlammatory action of NSAIDs are secondary to their inhibitory
`effect on COX-2. while their adverse properties are the result of the inhibition of
`(‘OX-I. Despite strong evidence that PGs play an itnportant mle in NSAID-induced
`gastrointestinal toxicity. recent studies perfonned in COX-I (
`I
`) Inice did not
`demonstrate spontaneous ulcer formation. suggesting that other mechanisms may
`he involved as well (Wolfe «I 141..
`l‘)‘)‘)).
`
`3. RISK I-7\C'l'()RS I-‘OR NSAI I)-REI..-\'I'El) (£:\b'I‘R()l)l|()l)EN:\I. 'l'()X l(.'l'I'Y
`
`Patients who use NSA|Ds develop gastrointestinal complications at a rate three
`times higher than those patients who avoid these medications. Unfortunately.
`the presence or absence of gastrointestinal symptoms dms not correlate with
`gastroduodenal pathology. and for this reason.
`it is important to identify patients
`at an increased risk of developing cotnplications (Table 2).
`
`Although corticosteroids alone do not appear to cause gastroduodenal ulcers.
`their cotnhination with NSAlDs is associated with a tnore than ten fold increase in
`
`gastrointestinal complications. Age also seems to play a signilicant role in NSAll)-
`associated complications. with data revealing a 5.6-lold increase in gastrointestinal
`complications in patients over the age of 70. A prior history of gastroduodenal
`ulcers is another imponant risk factor for the development of NSAID-related ulcers
`
`

`
`280
`
`A. F." Barrismt and M. M. llhlfc
`
`(Wolfe et ul.. I999). Whether a history of Helicnluu-tor pylm-i-related ulcers further
`increases this risk is ttot known. In a group of II. p_\'lm1' infected individuals. Chan
`(‘I uI..
`I997 recently reported a signilicant decrease itt naproxen-induced ulcers
`in ittdividttals whose H. p_\'luI'i infection was eradicated. Further investigation is
`needed to detennine whether screening for H. pylori infection prior to instituting
`NSAID therapy is indicated.
`In addition. the type. dose. and length of therapy appear to influence the rate of
`complications. Several studies have reported a greater risk of complications with
`pirosiczun and a relatively lower risk with the use of ibttprofen. While the risk of
`cotnplications is also proponional to the dose of the NSAID given. it appears to
`be inversely proportional to the duration of therapy (Wolfe et ul.. I999). Therefore.
`those patients at greatest risk for complications may be the elderly who require shon
`or intennittent courses of NSAIDs at high doses.
`
`4. TRFATIVIENT OF NSA ID-ASSOCIATI-ID D\’SI’El’SlA
`
`Dyspepsia is a broad tenn used to describe an array of upper abdotninal symptoms
`including pain. cramping. distention. nausea. anorexia and/or heanbum. At least
`5-2096 of patients taking NSAIDs in large epidemiological studies encountered
`dyspeptic symptoms (Wolfe et 141.. I999). Several studies have evaluated the effect
`
`of H3-receptor antagonists in treating NSAID-related gastrointestinal symptoms.
`Bijlsma et «I. (l 988) performed a prospective. double-blinded study evaluating the
`effectiveness of cimetidine in treating NSAID-related dyspeptic symptoms. They
`found that 72% of patients receiving citnetidine 400 mg BID reported resolution
`of their symptoms. while only 49% of those receiving placebo becatne symptom
`free. Taha (*1 111.. I996 examined famotidine 20 mg BID and 40 mg BID in patients
`with anhritis receiving NSAIDs and found that abdominal symptoms decreased
`by 36.6 % and 43.3%. respectively. These studies thus support
`the use of H3-
`antagonists in individuals with NSAID associated dyspepsia. As discussed below.
`proton pump inhibitors (PPls) also provide excellent symptomatic relief in addition
`to their capacity to decrease the incidence of NSAID-induced ulcers.
`
`5. 'I'REA'I'l\rlEN'I' 0|-‘ NSAII)-ASSOCIATED IJLCERS
`
`Since abdominal symptoms do not reliably predict the presence of NSAID-related
`gastroduodenal ulcers. patients with acute ulcers should have their NSAID therapy
`discontinued whenever possible or should have their current NSAID sulxstituted
`with a nontoxic analgesic such as acetatninophen or salsalale. a non-acetylaled
`salicylate that does not
`inhibit prostaglandin synthesis.
`If NSAID therapy is
`discontinued. treatment directed at healing the ulcer can be instituted with one of
`several agents discussed below. and at rates that cotnpare favorably to those patients
`with ‘idiopathic‘ peptic ulcers (Lancaster-Smith et ul.. I990).
`
`

`
`llrlunugeutml of NS/l ll)-I'('I(lI('tI (II In.\1'¢'i!_\'
`
`5. I. Sm'ru(I&m'
`
`Sucrallate. a basic aluminum salt ofsucrose oetasullate. is ell'ective in the treatment
`
`and prophylaxis olduodenal ulcers and appears to be as el'l'ective as H3-antagonists
`in the healing of gastric ulcers. In patients who remain on NSAlDs. sucrall'ate has
`been found to heal duodenal ulcers as effectively as H3-antagonists: however. its
`benelit in healing gastric ulcers in this selling has not been proven (Wolfe et ul..
`I999).
`
`5.2. H;-r¢'u-plnr unmguui.\1.\-
`
`l98lll and
`Several open. uncontrolled. non-randomized studies lCroker or uI..
`prospective.
`randomized studies (Davies H ul..
`I986) have demonstrated that
`treatment with conventional doses of H3-receptor antagonists for 6 to I2 weeks
`results in healing of approximately 75%. (S0-889!) of gastric ulcers and 87%
`(67— l(ll%l of duodenal ulcers despite the continued use of NSAIDs. When
`NSAlDs are continued. healing appears to he delayed and is largely dependent
`on the initial ulcer size with ulcers greater than 5 mm in diameter healing at a
`substantially lower rate than those less than 5 mm.
`
`5.3. I’m.rIu_g-Iumlius
`
`The role of PCs in the treatment of NSAID-associated ulcers is not well known. In
`
`I998. Hawkey 0! ul.. I998 published a double-blind study of 935 patients comparing
`the el'lieacy of misoprostol
`to ontepta/.ole in the healing of NSAID-associated
`gastroduodenal ulcers or erosions (greater than ll) erosions). The number of patients
`successfully treated after eight weeks was somewhat superior in those receiving
`omeprazole compared to those administered 2(X) [1 g QID of misoprostol. Healing
`of gastric ulcers occurred in 89%. 89%. and 77%. in those treated with 20 mg of
`omeprazole. 40 mg ofomcprazole. and tnisoprostol. respectively. while healing of
`duodenal ulcers was 80%. 87%. and 73%. respectively. in these groups. Of note.
`omepra/.ole was better tolerated than misoprostol.
`
`5.4. Pmlmt pump inltibilmzs
`
`suggests that PPls possess an improved capacity to heal NSAlD-
`Recent c
`related gastroduodenal ulcers independent of whether the NSAID is continued
`or not. A recent study comparing omeprazole to ranitidine in 5-ll patients with
`gastroduodenal ulcers demonstrated healing rates of 80% and 79% in patients
`treated with omeprazole 20 mg and 40 mg. respectively. while the healing rate with
`ranitidine was 63% l Veomans 0111].. I998). Agrawal et ul.. I998 compared the
`ellicacy ol' lansoprazole and ranitidine in the healing of gastric ulcers greater than
`()5 ctn in diameter in patients continuing NSAID therapy. After 8 weeks. ulcers
`were healed in 73% and 75% of those patients treated with lansoprazole IS mg and
`30 mg. respectively. while the healing rate in the individuals receiving ranitidine
`was 57% .
`
`

`
`283
`
`A. E Iiurrmou and M. M. Wall:
`
`6. PR! IPIIYIAXIS AGAINST NSAII)-INDUCI-II) G:\S'I'R()I)l|()I)EN:\l. lll.(.'|€RS
`
`Because of the potetttial risks associated with NSAID ttse. elforts have recently
`focttsed on the prevention ofmucosal injury. As mentioned earlier. prophylaxis is
`best accomplished by the avoidance of these medications in patients at increased
`risk frotn their toxicity. Alternative strategies to he considered include the co-
`adtnittistration of an agent with protective properties or the development of new
`anti-inllanunatory agents with improved safety profiles.
`
`6. I. Sm'mlIitl¢'
`
`The exact mechanism by which sucralfate protects gastroduodenal mucosa is not
`kttown. Sucralfate has beett shown by Caldwell 1'! ul.. I987 to reduce gastroduo-
`denal tnucosal injury associated with NSAlDs. However. Agrawal 1‘! ul.. l99I re-
`ported no signilicant beneficial effect of sucralfate in the prevention of gastric ulcers
`in osteoarthritis patients receiving NSAIDs.
`
`6.2. H3-rev:-plnr umugmti.\1.\-
`
`In two placebo-controlled. prospective studies investigating the protective effects of
`ranitidine itt atthtitis patients treated with NSAlDs. an eight-week cottrse of rani-
`tidine I50 mg BID was demonstrated to be elfective in presenting duodenal ulcers
`with rates of0% and l.S% in the treated patients. compared to 8% in the placebo-
`treated patients (Robinson 1‘! ul.. I989: Ehsanullah er uI.. I988). In contrast. raniti-
`dine was ineffective in preventing gastric ulcers in both studies. Furthermore. 'l'aha
`1'! ul.. I996) recently reported a benelicial effect of high does famotidine (40 mg
`BID) in preventing both gastric and duodenal ulcers in anhrilis patients receiving
`NSAIDs for 24 weeks. Although H;-receptor antagonists appear to be effective
`in teducittg NSAID-related ulcers and dyspeptic symptoms. Singh 1'! ul.. 1996 re-
`cently found that asymptomatic rheumatoid arthritis patients receiving H;-receptor
`antagonists had a significantly higher risk for developing GI complications than
`those not takittg these drttgs. Thus. the mulirw use of H3—receptor antagonists in the
`prevention of NSAID-associated ulcers cannot be recommended.
`
`6.3. ll1i.wpni.\IuI
`
`Graham ¢'IuI.. I988 examined the prevalence of gastric ulcers in patients with
`osteoarthtitis who had abdominal pain and were receiving NSAlDs. Patients were
`prescribed tnisoprostol I00 ug QID. tnisoprostol 200 [I g QID. or placebo. Ulcers
`
`In a subsequent stttdy of
`were detected in I.-‘PK’. 5.6%. and 2|.7%- respectively.
`638 patients with chronic anhritis. Graham «I ul.
`(I993) fttnher demonstrated
`that tnisoprostol signilicantly reduced the incidence of duodenal ulcers frotn -l.(i%
`in those taking placebo to 0.6% in those taking misoprostol. Despite these
`encouraging results. dyspeptic symptoms did not intpmve in these studies. and
`diarrhea developed in 39% of patients taking 200 pg of tnisoprostol.
`In a study
`
`

`
`.‘|iuIiug4‘nImI uI}‘VS.-\II)—I'ulu!a 1! (II tu.\iril_\‘
`
`283
`
`by Raskin (‘I «II. (I995) evaluating the prophylactic effect of misoprostol at doses
`of 200 [1 g BID. TID and QID. the authors found that lower doses of misoprostol
`were better tolerated. bttt that a signilicant pmtective etfect was only seen with
`the TH) and QID regitnens. Although the results of the above stttdies sttggest
`that Ittisoprostol is indeed effective in preventing NSAID-induced gastroduodenal
`ulcers. it is associated with signilicant side effects which include ttot only diarrhea
`attd abdotnittal pain. but also increased uterine contractility that cant
`lead to
`spontatteotts abortion. Misoprostol is thus contraindicated in women ofcltildbearing
`age who are sexually active.
`
`6.4. I’mImt pinup ill/tifiilurx
`
`Yeotnans ¢‘l uI.. I998 evaluated the pmphylactic effect of omeprazolc compared to
`that of ranitidine itt 432 patients who were randomly assigned tnaintenattce therapy
`
`with either 20 mg Ql) ofomeprazole or ISO mg BID of ranitiditte. After six months.
`l6.3‘A and 4.2% of those given ranilidine developed gastric and duodenal ulcers.
`respectively. but only 5.2% developed a gastric ulcer and 0.59! a duodenal ulcer in
`the omepr.t7.ole group (Fig. 1). Another study compared the etlicacy of onteprazole
`and tnisoprostol in the prevention of recurrettt ulcers itt 732 patients who contittued
`to receive NSAIl)s. Patients were randomly assigned either placebo. 20 mg QD
`
`of omeprazole. or 200 ug Bll) of misoproatol. At six months. duodenal ulcers
`were detected in I296 and |()‘% of those treated with placebo and misoprostol.
`respectively. while only NE of those treated with omeprazole developed a duodenal
`ulcer. Gastric ulcers recurred int 32%.
`l()%. and I3‘)? of the individuals receiving
`placebo. misoprostol. and omeprazole. respectively. These studies suggest that
`omeprazole is effective in preventing both initial ulcer fortnation as well as ttlcer
`recurrence in patients who continue NSAID use.
`
`3
`
`d cu
`
`6-MONTHRELAPSE($1.) 9on3
`
`
`
`
`
`I O4-nnpuuub 20 mo an,
`Rxnxtno 180 mg BID
`
`GU
`
`DU
`
`Figure I. Results of a randomized. double-blind. placehtseuntmlled trial that computed the ability
`of ranitidine I50 mg BID and omepra/ole 20 mg 0!) to prexent the development oI'NSAID~imluced
`gastroduodenal ulcers. Data adapted from Yeonuuts cl ul. (I908). ‘p c: tl.ll()l.
`
`

`
`A. If Iiurrimu and M. M. Wnllt
`
`N0|
`
`5-mmuocacswnl 3"8
`
`7 Placebo
`
`_l Rofecoxib 25 mg
`as Rohcnlm 50 mg
`. 2.4g
`
`12 Weeks
`
`24 Weeks
`
`Figure 2. Incidence ot‘ga.sn'odtuxlenal ulcers t > 5 mm in diameter). The placebo group «as ohsened
`t'or I2 weeks only. Data adapted from Laine «-1 ul. (in press). ‘,2 ~
`tl.tltl| eompmed to both duscs of
`rofecoxih
`
`6.5. l’mfi'renIiuI and .\'¢'I('('Iit'(’ (‘OX-2 iItItiIIiIm'.\'
`
`Attempts have been made to reduce NSAID toxicity through novel changes in their
`fonnulation. Recent surveillance and endoscopic studies have continued a lower
`incidence of gastroduodenal mucosal injury with the use of nabumetone. etodolac.
`and meloxicatn (Wolfe 1-I uI.. I999). These dntgs preferentially inhibit C()X—2. with
`less effect on C()X—I. which appears to accottnt for their imprtwed safety prolile.
`New highly selective C().‘\'-2 inhibitors. celecoxib and mfecuxib. recently entered
`the market and been shown to reduce the incidence of NSAID-related endoscopic
`ulcers (Fig. 2).
`
`7. l"ll'l‘URl-I DI-IVELOPM I-INT 0|" SAFER NS.-\II)S
`
`Several other compounds are in development with hopes of increasing NSAID
`safety. These include nitric oxide (NO) releasing NSAIDs and NSAIl)s preasso-
`ciated with zwitterionic phospholipids. Trefoil peptides and basic libroblast growth
`factor (bFGF) are also being examined for their potential clinical role in pmtecting
`against NSAID-induced mucosal injury.
`
`8. C()N(.'I.llSI()N
`
`that
`is important
`it
`Because of the pervasive use of NSAIDs in our society.
`physicians he able to identify and manage patients affected by NSAID-related
`gastrointestinal toxicity. Dyspepsia is a relatively common complication associated
`with NSAID use which is be best managed with either an H3-receptor antagonist or
`a PPl.Treatment of continued gastroduodenal ulcers should include withholding the
`NSAID when possible and providing a PPI. Once ulcer healing has been achieved.
`if NSAID therapy is to he re-institttted. prophylaxis against gastroduodenal toxicity
`
`

`
`.‘\lumt_g-mu-nl 4J'NS.~1lD-rrlulml GI Iu.u'«'itt‘
`
`Table 3.
`
`Recommendations for managcinatt of NSAID-associatecl g:|Sll‘ll(hl.ltI|¢I'l3l mut:o.~aI
`injtly
`
`Clinical presentation
`
`Rccnmmcttlatiun
`
`ll»_c-t-rpu.:
`
`Empirical "2 receptor antagonists (c.g. cimctidini‘. 4C0
`mg BID. ranitidinclnizatidine I50 mg BID. or fauna
`tidinc 20 mg BID) or proton pump inhibitor (c.g.
`omcpmzole 20 mg OD.
`lansopramlc 30 mg QD.
`rabeprazolc ‘.20 mg 0D. or pantuptazolc 40 mg OD)
`
`Active ulccr
`
`\SAIl) tiscnntinucd: l<l-_--rcccptnr antagnnist nr mitnn
`pump inhibitor
`
`NSAID cnntimtcd: prutnn pmtp inhibitor
`
`Maintcnancc therapy
`
`C0:It.h'ttlIi.\|t".tliIlt uf pmhttt pump inhibitnr
`
`C(V:I(lIIliI'ti\lI':Illt)l1tlffltlflfitttsltbl tat Icaxt 200 pg TID)
`
`COX-2 preferential agent tc.3. nabnmctonc. ctodolac.
`or mcloxicatn)
`
`C())(-2 .~.clct.1ivc agent tc.g. cclccuxih and rnfccuxilt)
`
`is best :—tct.'0ntp|i.s'I'tcd through the use ofa PPI. misoprtxstol (at least '_’I ll) [1 g TII) ). or
`an NSAID that prcfenentittlly or selectively inhibits COX-2 (Table 3).
`
`RI-IFI-IRI-ZNCI-IS
`
`Agranal. N. M.. Ruth. 8. H.. (‘tr-.tham. I). \".. at ul. tl99l ). Misnpmstnl cntnparcd with .sucr:tIt’atc
`itt thc prexcntiun ut‘ nun-.\'tcrnid:tI anti-intlammattry drug induct.-cl gastric ulccrz a rmtlntrtizctl
`ctmtrullcd trial. Ann- lnlrrlt. Med. H5. 91 I 3.
`
`Wruhlc. I... (-1 ul. t I998). l£ll'octivcncs.s nf lans-npr-.t7.nlc in the hcaling of
`Safadi.
`Agr-.t\\~.tl. N.
`NSAID ittdttccd g,'.l\'I|'lL' ttlccrs in patients continuing to talc NS.-\l[).\. (in.wmwI:~n:lag_t' I I4. A52.
`Caldwell. .l. R.. Roth. S. H.. Wu. W. C.. c-t ul. (I987). Sncralfatc trcattncnt nl' nun-stcrnidal anti-
`
`intlamm:Inr_\ thtg inthtcctl gastmintcstittal symptntm and tmtcmal damage. .-1m-oz 1. Hal. 83
`lsltppl 3B). 74 82.
`.I. J. Y.. Chung. S. C. S.. 4'! ul. (I997). Randnmi7.ctl trial til" cratlicatiun nf
`Cltattt. F. K. L. Sung.
`Ha-Iimlmt-n-r pyluri hcfnrc nnn-steroid anti-inllammatury drug Itcntp) tn prcutll pqnic ttlccr.\.
`I.uM‘('I350. 975 9.
`
`Crnkcr. J. R- Cnttcn. P. B.. Boyle. A C‘.. «-1 ul. tl9Kt)). Cimctitlinc fir peptic ulcer in patients with
`zrthritis. Ann. Rheum. Dis. 39. 275-8.
`
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