Review Article
`
`Effects of Nonsteroidal Anti-inflammatory
`Drugs an En~agenous Gastrointestinal
`Prostaglandins and Therapeutic S#rategies
`for Prevention and `treatment of lVonsteraidal
`Anti-inflammatory Drug—Induced Damage
`
`Syron Cryer, MD, Mark Feldman, MD
`
`+ Although ~~onsteroidal anti-inflammatory drugs (NSAIC7s)
`ave effective far pain relief and treatment of arthritis, they
`can induce ga~t~ic and duodenal ulcers and life•threatening
`eamplications. The mechanisms of their anti-inflammatory
`action and their gastroduodeaal toxic effects are relaEed, in
`part, to inhibition of prostaglandin synthesis. ThEs review
`article discusses prostaglandms, their functions in the gas-
`frointestinal tract, anti-inflammatory actions of NSAIDs,
`and mechanisms by which NSAIUs produce gastroduod~nal
`ulcers. Also reviewed are risk factors associated with the
`developmenk of NSA{[7-related ulcers and pharmacalagic
`strategies for the prevention and treatment of NSAtC1-
`induced utters.
`(Arch Intern Med. 1992;152:7145-1155)
`
`N onsteroidal anti-inflammatory drugs (NSAIDs) are
`widely used for pain relief and for treatmeixt of
`arthritis (including rheumatoid arthritis, ankylosing
`spandyliNs, osteoarthritis, and gouty arthritis}. A partial
`list of NSA~Ds is shown in the Table. Although NSATDs
`are effective, as therapeutic agen#s, their major toxic effect
`is induction ~f gastroduodenal ~ilcers. Mechanisms for
`their anti-inflammatory action and their gastroduodenal
`twcic effects are probably related to a~ inhibition of pros-
`taglandin synthefiis. The purposes of this article are to re-
`view ttie effects of NSAlDs on the gastroduodenal rnu-
`cosa, including their effects ~n mucosal prastaglandins,
`and to review the effects of therapeutic agents that can be
`used to prevent and treat NSAID-induced gastroduode-
`nal damage.
`PROSTAGLANDINS AN17 RELATEb COMPOUNDS
`Prostaglandins (PGs) are a family of related fatty acids
`that are produced by nearly all of the body's c~lis. Pros-
`tagtanains participate in a variety of acfivities, including
`rnedia6on of inflammatory responses, protection of the
`
`^~~
`Accepts or pu ication Nov- emFie~ iG, 1997. ~~
`Frvm the Medical Service, pepartmerit of veterans Affairs Med-
`ical Center, and Department of Internal Medicine, University of
`Texas Southwestern Medical Center at Dalfas.
`Ke~rint requests to Dallas VA Medical Center (1~1?, 450D 5 !an-
`raster Rr1, Dallas, 7X 7~21b (Dr Feldman).
`Arch Intern Med—Vol 152, )une'1992
`
`gastrointestinal mu~osa against injury, and regulation of
`renal blood flow. "C`he general chenucal stractiire of PGs
`is an oxygenated, 20-carbon, unsakurater~ fatty acid (ei-
`cosanoid) composed of alive-carbon ring, with two ear-
`bun s9dechains, one composed of seven carbon molecules
`and the other composed of eight.' Narnenctatvre ixsed to
`describe individual PGs is based on hvo distinguishing
`fEatures. First, the letter designakian of, PGs (ie, theix
`family) is determined Uy the structure of the five-carUnn
`rind. For example, all PGEshave a daublP-bonded oxygen
`(= O) a# carbon 9 and a hydrox}~1 group ~ — OH) at carbon
`11, while all ~'GFs have a hydroxyl group at both carbon
`9 and carbon ~l.z Second, the T7umber of double bonds in
`the side chains determines PC classification as 1-, 2-, c~z
`3-series and as reflected by a subscript (eg, PGEz [2-series]
`Or 6-keto-PGF,4 j1-series]} {Figure).
`Praetaglandins are nUt stored within ce1L~ in an5~ sfgriif-
`icant quantities, but are stored as precuzsor molecules.
`Prostaglandins of the 2-series axe the most plentiful and
`biologically important and are derived from ar~chidonSc
`acid, a component of phosphalipids present in all cell
`membranes. Tn response to a rne~hanical or chemical per-
`turbatinn of the cell membrane, aracktidonic acid is
`released front membrane phosphnlipids into the cyto-
`plasrn of the cell through the action of a plasma
`membrane-bound enzyme, phospholipase A2. Once re-
`leased, ar2chidonic acid may be acted on by cyclo-
`oxygenase, amembrane-boixnd enzyme, resulting in
`synthesis of I'Gs; alternatively, it may be metabolized by
`another enzyme, 5-tipoxygenase, Co a group of closely re-
`lated compounds, the leukotrienes (LTs) (Figure). The
`activiCies of the cyclo•q~rygenase and
`relative
`5-lipoxygenase pathways, and thus the relat9ve amounts
`of eicasanoids produced, vary with cell type 3 In gastric
`and ciuc~denal mncosa, most arachidonicacid is converted
`into PGE7, PGFza, and PGI~.°~
`FUNCTtdN C7F P{t(7SfAGLAND11V5 iN IHE
`GASTROINTESTINAL TRACT
`A.lthou~h PGs were Hrst identified in the human body
`in the 1930s, it was not until the znid-Y960s that PGs were
`identified in the gastrointestinal tract.''9 The earliest. r~c-
`ognized effect ~E PGs ~n gastric mucusal function vas an
`Effects of NSAIDs on Prostaglandins—fryer &Feldman tt~l5
`
`ll~nr nlunileJ Frum; littp:i;atchinte.j:+nuwet~~~orl:.ce~rnl h~• a Reprints De9k [iser otl tt3120/201i
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`
`Partial List df
`Salitylates
`Aspirin'
`gifluriisal (Do(obidi'
`Salsalate (Pisalcid)'
`Indoles
`Indomethadn (indocinl"
`5WIlndac (C(inorip'
`Tolmetin (TolectiN"
`Zomepirac (Zomarc}
`Pyrazoles
`Apazone (Rheumy)
`Feprazone (Methrazone)
`Phenylbutazone (Butazolidin)"
`Fenarnates
`Fiufenamic acid (Meralen)
`Mefenamic add (F'onsteq"
`Medofanamate (Meclamen};
`Tolfenamic acid (Clotam)
`Proprionlc acid derivatives
`Carprofen (Rimadyq
`Fenbufen (Cinopal, lederfen)
`Fenoprofen (Na(fon, Fenopron)'
`Flurbiprofen (Ansa~d, hoben)"
`Ibuprofen (Motrin, Advil)"
`Ketoprofen (Orudis)•
`Naproxen (Naprosyn, Anaprox)"
`Pirprofen (Rengasil)
`Phenylacetic acid derivatives
`Diclofenac (Voltaren, Voltarol)'
`Fencfofenac fPien~t}
`
`Oxiwms
`Isoxicam (~blaxicam>
`Piroxicam (Feldene)'
`•Available in the United States in 1991.
`
`'
`
`inhibition uE gastric acid and pepsin secretion.'a" Tntra-
`venouslyadministered PGs of the E, F, and A classes and
`urall~r administered synthetic analogies of tktese com-
`pounds have potenk anHsecretory effects, ~'Gs cif the ~
`class being the most potent.'`~'-0
`In the 1976s, investigators began to demonstrate that
`I'Gs could protect the gastric mucasa from injury az~d ul-
`cer~tion against a wide variety of damaging agents, such
`as alcohol, bite salts, acid, hypertonic saline, 'boiling wa-
`tQr, skress, aspirin, and other NSAtI~s.Z'~~ Robert et aiz1
`performed the earliest of these experiments, in which
`they demonstrated that pretreatment with I'Gs could
`prevent mucosat damage from various noxious agents itt
`rats. Tt was demoxistrated that mucosal protection could
`be observed at doses of I'Gs that did nok inhibit acid se-
`creti~n.~ This protective property of PGs was called "cy-
`toprotection."~ Bven though pretreatment with PGs may
`protect against macroscopic injury, there is usually mi-
`crascopicevidence of mucosal injury to surface epithelial
`cells after exposure to alcahpl ar other noxious agenks."'
`Bec~euse of persistent surface cell damage despite PG pre-
`treatment, the term cyto~rotecfioir is noE e~tikirely accurate
`and has for the most part been replaced by mucosa! profec-
`tion. Nlacosal. pro~~cHon by prastaglandins has nit only
`been demonstrated in the stomach, but has been shown
`in the duodenurtt.'~''a Protection has been demonstrated
`with PGs ~f all classes and is separate from any effects the
`conripocinds may have on gastric acid secretion. In Eaet, in
`animals, mueosal protection has been demonstrated with
`PGs, such as 6-keta-PGFi~„ 4Y~at hav€~ rto demonstrated
`1t46 Arch 1~7tern ~~ted—~V~f :52, Lune 1992
`
`hhnmbrano Phospholipids
`
`I Phosphofipase Ay
`
`5-Lipozygenase
`
`Arachidonic Acid
`_~---.____~
`
`Cyclo-oxygenasa
`
`i•HNETE —+ 5•METC
`
`PC;GZ
`
`LTAy PG Hz
`fir,,_--~' 4 '` PGIy
`K'~!
`LTBp LTCG ~/!
`Thromboxane AZ
`
`LTDq ~
`
`W ~
`PGC1z PGEZ PGF2a
`
`LiG,; Thrombozane 62 6-Keto-PGF~a
`
`Leukotrienes
`
`Thromhoxanes
`
`Prostaglandins
`
`~~fetabolism of arachidonic acid after its re/ease from membrane
`phospholipids, HPE7f indicates hydroperoxyeicosetetraenoic acrd;
`NETS, hydroxyeicosatetraenolc acrd; PG, prostaglandin; and L7,
`leukotriene.
`
`effect on aczd seaeti~n.31 However, in humans, it is not
`ceztain that the protective effects of PGs aze due to mech-
`anisms separate from inhibition of gastric acid secretion,
`since PGs, at doses ernploped in human trials, have
`antisecretory effecks as well.
`Haw is mucosal protection by PGs mediated? Integrity
`of the gastroduodenal mucosa is maintained by a balance
`between aggressive factors, such as acid and pepsin, and
`prvtecHve factors, such as biearbanate and mucus.'~•'0
`When there is an imbalance between aggressive and pro-
`tective factors, such that the extent of mncosal protection
`is lowered in relation to the level of pffeztding agents,
`mncosal injury ensues. Persistence of this imbalance
`caulci lead to mucosal erosions and ulceration. Same of
`several putative mechanisms prn~osed through which
`PGs may provide their rnucasal prakective effects include
`the fallowing: stimulation of rnucosal bicarbonate secre-
`tion, mucus secrekion, inereasect blood kiaw, prevention
`of disruption of the gastric mucosal barrier, acceleration
`of cell proliferation, stiinulallon of celluEar ionic transport
`processes, stirnutation of cyclic adenosine monophas-
`phate pr~dixction, promotion of formation of surEaee-
`active phospholipids, maintenance of gastric mucosal
`sixlfhydryl compounds, stabilization of cellular lyso-
`somes, and stabilization of cell rnembran~s,z4~28~~'~"'~ 5oA
`et al's categorized varinus protective mechanisms accord-
`in~ to their location with respect to the sarface epithelial
`cells. They have been accordingly described as ptee~i-
`thelial (mucus aid bicarbonate secretion), epithelial {sur-
`face epithelia] cell continuity and migration), and postep-
`ithelial (mucosal blood flow),
`INFLAMMATION AND ANTI-INFLAMMATt7RY ACTt~NS
`OF NSAIDs
`Inflammatory cell recn~itmem is achieved throuSh the
`release of a number of chemical mediators, such as PGs,
`LTs, histamine, serotonin, kinins, complement factors,
`and other pepkides."-~` Evidence implicating PGs in this
`~racess w<~s nit obtained until 1971, when Vane" pro-
`Effects t~P NSAIDs on Pros(aglandins—fryer &Feldman
`
`IJonnlonJr<L l~rp m: li ttp:/l;ii~cl~iiitr.janu~uet~rork.coiYi/ br a liepci nts Declt C~ser ua t1312012U15
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`paced C'Gs as sixbstances that could elicit an inflammatory
`raspanse.:Prostaglandins were dempnstrated to be asso-
`ciated with inflammakinn in a varistq of expeztin~ezltal sit-
`uations. Far example, after subcutaneous PG adrninislra-
`tion, edema and ezythema as well as corns of the
`histologic changes of inflammation were observed.5° Af-
`ter administration of aspirin, biosynthesis of PGs de-
`creased in pragortion to the decrease in the amount of in-
`flammarion,19~~'~52 and then, if exogenous PGs were later
`administered, there wotYltl be a return of inflarnrnarion,'9
`Experimental administration of PGs caiiid induce £ever'
`and potenriate pain,' and subsequent adnunistratioi~ of
`an N5AID cautd decrease fever end pain while also
`de<zeasing T'G concentrations. Tt soon became clear that
`the anti-infl~rnmatary effects of such t~rugs as aspirin
`could he explained by their suppression of PG synthesis
`and that such icihiUition could also expEain the actiorts of
`these dnigs as analgesics and anripyretics.
`Aspirin, an acetylated salicylate, was one of the first
`N5A[Ds shown to be clinically effect9ve as az~ anti-
`inflammatory agent.5$ t~lthvugh many other I~SAIDs
`have since been introduced, aspirin remains one of the
`most effective anti-infl~mrnatory agents. It is through
`the inhibition of cyclo-oxygerrase that aspirin and other
`NSAII3s decrease PG synkhesis. By ~cetylation a~ cycla-
`oxygenase, aspirin inhibits this enzyme irreversibly,
`while other C~fSAIDs (flufenarnic acid, ibupraEeci, and
`sutindac, for example) inhibit cyclo-oxygenise in a re-
`versible, concentration-dependent manner.~•57 When
`cycle-oxygenise is irreversibly inhibited within a~~y par-
`ticular cell, the capacity for T'G synthesis does not return
`to normal until new enzyme can be synthesired.~ This
`may explain why aspirin, in camparisgn with other
`NSAIbs, remains one nE the most patent inhibitors of T'G
`synthesis. Ct is hypothesized that cyclo-oxygenise exists
`in multiple forms throughotyt the body and that each form
`has its own drug specificity, although this has not yet
`been verified by i~ierttificaHon o£ structural cyclo-
`oxygenase variants. Cyclo-a~cygenases obtaitted from dif-
`ferent rissues have different sensitivities to inhibition by
`a particular NSAID, and differec~t NSAIDs have variable
`abilities to inhibit a pazHcular cycla-oxygenase.57~'~ Par ex-
`ample, acetaminophen is as effective as aspirin in the in-
`hibition of brain cyclo-axygenase, buk is npt nearly as eE-
`fecrive as aspirin in the inhibiteon of cyCl~-axyg~nase fxom
`some peripheral sites. This may explain why acetami-
`nophen is an effective centrally acting antipyretic anti an-
`algesic but is not an effective peripherally acting anH-
`iz~#lammatory agenk 'T"his may also explain why
`acetaminophen does not cause gastrod~iodenal tonic eE-
`ferts.
`The LTs also play a significant role in the ini7ammat~ry
`response. They increase vascular permea}~ility, are
`chemotactic for neutrophils, vasaeonstrict arteries, srim-
`ulate bronchial wall constricfiion and mucus secretion,
`and vlcrease intesHnai inflammation.$9-60 Certain N5AIL7s,
`in addirion toinhibiting cyclo-oxygenise, also may inhibit
`5-lipoxygenase,~~°~ The I~lSAI[~s differ in their relative
`potencies to reduce inftammatian,62 and tl7eir anH-
`inflammatory effects cio not always correlate with their
`ability to reduce PG synthesis. These observations may
`possibly be explai~~ed by different capaciries of the various
`NSAIDs to inhibit cyclo-oxy~enase, on the one hand, and
`5-li~oxygenase, on the c!ther hand, An NSAID such as
`indomethacin is predonvnacttly 1 eVc(o-oxygenase inhib-
`Arch Intern Med—Vol 152, Lune 1992
`
`itor, while ether experimenkal NSAIUs of the fenamate
`class are effective inhibitors of both enzyntes.~' Whether
`e~ifferences in the relative amounts of cyclo-oxygenase/5-
`lipaxygenase inhibition by NSA1Ds is indeed related to
`differences in anti-inflammatory actions of NSAIDs is
`Ctsnently under investigation.
`Anti-inflarnmatary actions of NSAIDs are not only ex-
`piained by inhibition of ezcosanoid synthesis. For exam-
`ple, NSAIUs inhibit PG synthesis in vivo and in vitro at
`concenYratioc~s much lower than those required to achieve
`anti-inflammatory effzcts.~' :vloreover, some salicylates,
`including nonacetylated salicy~lates, are beneficial in in'
`flarnmatory disease~"~~'`~ even though they do not inhibit
`I'G SYI1t2iL'SIS.~'69 Inh►bition of neutropl~il function lYas
`been suggested as a second mechanism by which NSAIDs
`can exert their anH4iztfi~tmmakary effects.bz,'°."
`
`MECHANISMS OF GASTRODUODENAL MUCOSAL
`IN(URY BY NSAIDs
`The mechanisms by which aspirin cast cause gas-
`trointestina~ ntucosal damage can be grouped into hvo
`categories: those independent of and those dependent on
`cycln-oxygenise ixlhibiHon. Within a few minutes of
`aspirin ingestion, denudation of surface epikhelial cells
`end increased mucosal permeability to sodium (Na') and
`hydrogen (H'} ions can be observed,'= reflected experi-
`mentatly as a decrease in transYnucosal potential differ-
`ence.73~" 5alicvlic acid, the deacetylated metabolite of as-
`pirin, does not inhibit cyclo-oxygenise acrivity in the
`gastric mucosa,75 yet it reduces transmucosal potential
`difference as mach as aspirin does." -Thus, surface
`epithelial cell disruption and a decline in potential ditEer-
`ence are not dependent on cydo-axygenase inMbition,
`and epiYh~l~al cell disxvpNon is not prevented by pre-
`treatment with PGs.76
`Endascopic observation of the gasiric mucosa after 1 to
`2 weeks aE enteric-coated aspirin therapy"~'~ ar after 1
`week of enteric-coated naproxen therapy's revealed con-
`siderably less gastric mncUsal damage than with plain,
`non—enteric-coated formulations. Although gastric injury
`from a topical effect is decreased w9th enteric-coated for-
`rnulatinns, hheir use on a long-term basis will resuik in
`gastric ulcers (GUs},80 presumably the result aF a systemic
`rather than typical effect. Gastric ulcers can be produced
`experimentally after N5AIDs are administered intrave-
`nously$1 or by rectal suppository~Z and without a cheese
`in gastric transmuCosal pvtenkial difference.87~83 Tt is likely
`that the NSATDs were ulcerogenic because they reduced
`mucosal PG synthesis, Thzs is supported by riuo observa-
`tions: (1) small nonantisecretory doses of exogenous PGs
`prevent hSAtD-tnduced ulcers~',sa,zs and (2) deplerion of
`mucosal PGs by another mechanism, active or ~assive
`immunization with T'G antibodies, leads to GTJs.
`Although inhibition of PG synthesis contribukes to
`NSAID-induced mucosal injury, it is not settled whethex
`PG inhibition is the primary mechanism. Tn some studies,
`there has been poor correlation between gastric rnucosal
`injury and PG suppression after NSACDs."~''~ Other faa
`tors probably work in combination with PG suppression
`to increase the propensity for mucosal injury by NSAIDs.
`For example, after indomethacin administration, gastric
`acid secretion has been shown. to incxease,~' gasMc mix-
`cc~sal blond fEow to deerease,QO-91 and duodenal biearbon-
`ate output to c3ecrease.9- Nonsteroldal anri~inflammatory
`drugs can also potentially affect mucus secrerian, as
`Effects of NSAlC~s on Prostaglandivrs—fryer &Feldman X141
`
`llo~r~0ooided Frain: i~ttp:Nnrcliintr.j:~rnauetwo~'k.cor~sl b~~ a I2eprinrY Dt~:k f!srr on t131ZIY(2(li5
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`they have been shown to inhibit mucus synthesis, to
`reduce incorporation of radiolabeled precursaxs into
`mucus glycoprotein, and to alter thickness of tt7e mu-
`cus layer.2g~~
`It has been hypothesized that, as a cansegixence of
`cyclo-oxygenise inhibition, arachidonic acid metabolism
`could alternatively be shunted knward the lipoxygenase
`pathway, resulting in increased LT synthesis.~''~ The
`postulated mechanism by which increased activity of the
`5-lipoxygenase pathway could enhance mucosai injury is
`by LT-mediated vasoconstriction or by direct vascular in-
`jury by oxygen radicals produced in this pathway.~~~' `The
`relative imporkance of LTs in NSAID-induced gastric mu-
`cosal damage is still unclear.
`Since other pathogenetic mechanisms are potentially
`operative, one may ask whether significant NSA[D-
`related mucosal injury can occur in the absence of
`suppression of mucosal PGs, After administration of
`saisalate, a nunacetylated saLicylate fihat is anH-
`intlarnmatary, mucosal Injury has been far less than after
`other NSAIDs.160.L02 Salsalate does not significantly inhibit
`cyclo-rxygenase activity ar reduce mucosal T'G con-
`tent.69~t02 Thus, inhibition of PG synthesis is ps•obably
`necessary but not sufficient £or mucosal injury.
`
`Stit}RT-TERM VS Lf3NG-TERM NSAID ADMINISTRATION
`After shock-term adnunistration, avariety of types of
`injury develop, ranging from petechiat hemorrhages, daf-
`twse hemorrhages, superficial erosions, and, Less com-
`monty, ulceration.' On the basis pf such observaHans,
`many claims have been made as to the superiority of one
`NSA1D over another regarding the incide~~ce of mixcasal
`injury. Lanza12 reported the largest experience wikh en-
`dascopic rnucosaI ubservatio~s after 7 days of NSATD in-
`gesrion. I-~Igh doses of aspirin had the highest incridence
`cf acute gastric xnucos~l injury, while therncidence ~f ir7-
`jury induced by other nonaspirin NSAIDs was less but
`also dose dependent. Among the nonaspirin N5A1Ds, it
`was npt easy' to compaze incidences of gastric mucosal
`toxic effects because o£ difficulties iz~ determining equiv-
`alent doses. By compiling all of his NSA[l~ data, C,anza
`observed a 6.7°!o incidence of GU and a 1.4%a incidence of
`duodenal ulcer (DU}after 1 week of NSAID ingesrian, The
`largest numbers of GUs were produced by aspirin and the
`l~~vest numbers by lower anti-inflammatory doses of ibix-
`profen.
`The evolurion of mucosal injury over time after short-
`term NSAID therapy also has been an interest of investi-
`~ation. After a single dose of aspirin {650 mg), gastric in-
`tramucosal hernprrhages endoscopically visible as
`petechiae appear in as little as 15 minutes and gastric ero-
`sions in as litkle as 45 rninukes.10 Petechial lesions F~ecome
`most prano~Ynced by 1 to 2 hours10.114 and can occur in any
`location in the storna~h.t10~"~ After many repeated doses
`of aspirin, multiple erosions appear, mostly in the air
`Crum,~0•'0d~"o but potentially in any gaskc~ic tocat~on. Psndo-
`scopic gastric mucosal injury peaks within the first 3 days
`and then tends to decrease despite continued aspirin ad-
`ministraHon,10~13~"a de~ite the fact that mucosAl PG
`content remains low.eS•` Thys phenomenon has been re-
`ferred to as gastric adaptaHon.14 Increased epithelial celE
`regeneration and mitoses have been nbserved to occur in
`response to aspirin-induced injury."~"y
`
`"Re arences 77.79, d2, 85, 87, 88, 101-114.
`i148 Arch Intern Med—VoV ESL, )une 1992
`
`Mucpsal petechiae and erosions ark rornparaHvely triv-
`iai, transient lesions that have law risk for rnajpr wnta-
`ward effects.i'g Acute mucasal injury ran be repaired rap-
`idly through processes of restitution and gastric
`adaptaCinn, With continued and frequent aspirin. adrnin-
`istraHon, the rate of rnucosal injury may be greater than
`the rate of mucosal repair, ixltimately resulting in a
`persistent epithelial defect.10 Consequently, an erosion or
`an ulcer may develop, the distinction between the two
`being depth of damage.12' An ulcer, once formed, has the
`potential tv cause significant bleeding, luminal obstruc-
`tion, or gas~raintestinal perforation, all of which are
`viot uncommon complicarions of long-term TJSAIi~
`therapy.12''~e "Thus, the clinically important aspects of
`N5AIL7 mucosal damage axe primarily the consequences
`seen after long-term rather than short-term therapy.
`Although there may be considezable differences in in-
`cidences of injury iffier short-term administration ob-
`served between the various nonaspirin NSA[Ds, these
`ai£ferences cannot ~Se used to predict injury after longer-
`tercn administration. Drugs that produce slight acute
`mucosal injury Can still prpduce ttlCers when given on a
`long-term basis. For example, sulindac produces little
`mucosal damage when ,riven for a short term"' but is as-
`sociated with one of the highest rates of NSAID-related
`upper gastrointestinal ble~ding.~=~ Mo5t data on conse-
`gtFences of long-term NSAT17 therapy come from epide-
`mialogic studies or from prospective trials of patients
`taking these medicarions for therapy for chronic rheu-
`matic diseases.
`~tetrospective reviews of retards of hospital admissions
`#ar u~~er gastrointestinal bleeding have provided fixrther
`evidence that long-ternti aspirin use is associated with
`GUs.t23 With tY~e newer, nanaspirin NSAIDs, case-
`contralled studies also suggest that gastroinfiestinal bleed-
`ing from ulcers is strongly associated with NSAID
`~S~.tu,~za.»~ ~-iowever, the incidence ref serious ulcer corn-
`plications with r~conaspirin IVSAIDs is less than that with
`asparir~, PaKents presenting with bleeding ulcers are three
`to Eive times as litcely as controls to have taken an NSAID,
`and 13% to 64% have a recenk his#ory of NSAID
`cons~~mption.tz~''3' Among subjecks without a history of
`ulcer, patients taking [~tSAlt7s have 1.5 times the risk. of
`developing upper gastrointestinal bleeding than do con-
`trols nqt taking NSr1ID5.'zr Adose-response relationship
`between I~fSAID consumption and development of mu-
`cosal ulcers may also exist. Cameran'32 Found that a pat-
`tern of regular aspirin consumption (>15 aspirin tablets
`per week} had a signifi~azltly higher association with GCIs
`than patterns of occasional (14 oz less per week} or no as-
`pirin consumption. On the basis of the distribution of as-
`pirinuse arnongthese patients, it has been estimated that
`the relative risk of developing a GL rises dramatically
`above 15 to 20 aspirin tablets per week zt an aspirin dose
`of 325 mg.~~
`Data on long-term znucasal effects of NSAID consnmp-
`tioncome mostly fmm endoscopic studies of patients with
`rheumatoid arthritis or osteoarthritis.BD~"~~'~'~ McCar-
`thy,"~ by combining data from a!1 available point preva-
`lence studies, esHm~ted a GLJ pDint prevalence of 13%
`and a Dli point prevalence of 11% £or parienks with
`arthritis taking long-term NSAID therapy. Enteriacoated
`aspirin appears to be associated with fewer GUs than
`pl~rfxl aspirin," However, .incidences of DUs after use o~
`either aspirin. prepar<3tion are similar.`'`
`ENects of NS.41Ds an Prtutagland~ns--Ctyer &Feldman
`
`Du~srdoaded l•bunt:LHp:l7:trcl~i~itr.frmanehrnrl:.cnm/6ya lZepiints T)esk Usr~' un b31207~0ii
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`Prospective, point-prevalence triAls are limited. by the
`fact that they look at the mucosa at only one paint in time,
`after variable IengEhs of NSA[ use. Ik is not certain
`whether the observed ulcer is truly a direct consequence
`of the NSAIL? or whether it was presenk before NSA[D
`therapy began. To assess the risk of ulcer formation
`directly attributable to NSAIDs, a lesion-free mucasa
`needs to be observed at a zero time point, and the
`incidence of ulcers arising while the parient is taking
`NSAIDs as compared with placebo kreatment is #hen re-
`corded. Caruso and Bi2nchi-Parroz~' observed new gastric
`lesions in 31 °I~c of parients after 3 months of NSAIDs. The
`incidence of ulcers aman~ these "lesions" was not re-
`ported, and there was no placebo-treatEd group for cam-
`parisc~n. An alternative means to study the evolurion of
`niucaaal dttmage in long-term I~iSAID users is to use data
`from placebo-cat trolled trials of protective agents coad-
`ministexeci with I~ISA~C7s. T'a date, there have been four
`large (ie, >100 subjects each) kxials in which either a his-
`taminer (I-[2) blacker, a synthetic PG, or placebo was
`coadrninistered with one of various N5AIDs to patients
`with Arthritis who were without mucosaI abnarmaliNes at
`initial endoscopy."~-~~0 Again, there was no group of pa~
`tSe~tts with arthritis ~vho received placebo wikhaut
`NSAIDs. Nevertheless, it appears that, at least after 2
`znanths of NSATD therapy, a new GU may develop in a
`little greater than 10% of NSATD users, and a I7U will de•
`vetop in somewhere less than 10%. tt is likely that gastric
`and duoaenat ulceration with NSAID usage beyond 2 to
`3 months wzlt continue td accar, since NSATp-related trl-
`cer complications, such as bleeding or ~erforarion, occur
`frequently in long-term NSAID users.` •"`,'a'
`RISK FACTORS FOR NSAID-INOGCED llLCER5
`Dose
`As the prescribed dose ~f an CVSAID increases, the per-
`centage ofpatients pxesenHng wSth uppexgastrointestinal
`b(eedislg or hospitalized for ulcers intreases.tz'~'}' Griffin
`et al"' recently reported that the relative risk of utceraEion
`in alder subjects who have consumed h'SAIDs £ar less
`than 30 days is almost twice the risk for l~n~er periods of
`consumption. "' The authors stated that the estimated risk
`foc development of an ulcer among an elderly individual
`who has recently begun a high dose a£ an NSAIDzs 10
`times that of a nonuser."' Prospective data directly eval-
`uating dose-response or duration-response relationships
`between lon~~terrn N5.ATD use and ulcer developmentare
`lacking.
`
`Ulcer HisEory
`A history of idiopathic ixlcer disease may increase khe
`risk of ulceration during NSAID therapy. After 2 months
`of NSAID consumption, six of 11 patients with a hrstary
`of pepticulcers developed recurrent ulceration, compared
`with only 11 of 115 patients with no ulcer history.' More
`studies of this risk factor are required before previous ul-
`cer disease can be accepted as a definite risk factor,
`
`Age
`Age is one factor khat has been consistently associated
`with an increased risk for NSAID-related ulcer compliea-
`rions.12a,'~s.'ae,"' TNe risk ni perforated ulcers may be high
`in elderly N6A1D users, especially elderly wornen,t2~ and
`mprtality fiorn tiilcer compliratio~7s is also markedly Ele-
`vated in the aged.1=8 c7ne likely explanaNnn for this asso-
`Arch li,tern ~~led—Vrrl X52, 1W+~~ 1492
`
`~iaHon of greater age and risk of NSAID ulcerations is that
`N5AID use. increases with advancing age, especially in
`those over 6Q years old.1z~~''~ However, there may be akher
`factors that predispose the elderly to damage by NSAIDs.
`For example, our group and a group from Japan recently
`showed that both gastric'R~~'~l and duodenal142 mticosal PG
`concentrations decline with aging in humans. Thus, older
`patients, at baseline, may have an already compromised
`pokenHal for rnucosal protection, perhaps placing this
`group at high risk for the devetopmentof NSAID-induced
`ulcers.
`
`Smoking
`It is not known whether cigarette smoking influences
`the pntentiaffor NSAID-induced ulcerafion. The ability of
`the gastrcaduodenal muco~a to pcntect itself against injury
`znay be decreased in smokers, since smoking is associated
`wikh reduced mucosal PG coz~centraHons in humans."`-'a5
`Use of NSATI?s by smokers shpuld further reduce their
`already law mucosal i'G concentrations.
`
`PREVENTION OF NSAID•INDUCED ULCERS
`[nitial attempts to lac+rer gasfiroduodenal toxic effects
`seen with aspirin were directed toward development of
`altern~kive formulations. Newer NSAIDs, enteriacoated
`preparations, suppositories, and prodzugs disappoint-
`ingly co~rinue to be associated with signifiear~t ulcerakion.
`None has demonstrated conclusive superiority to khe
`others for decreased gastroduodenal toxic effects. Conse-
`quently, amajor research interest has arisen to investigate
`other drugs that, when coadministered with I~SATbs, will
`either protect against or prevent mucosal injury.
`Evaluation of the e#ficacy of a caadministerzd agent to
`prevent mucosal damage is strongly influenced by the
`type of scale used to measure injury, :~Iucosal protection
`mxy or may not be observed, defending on which pattern
`of injury has been most heavily weighted in the scnrin~
`system. In 'a study of prevention of naproxen-induced
`acute gastroduoaenal injuty, cimetidine vas deman-
`strated to be sixperior to placebo when a scale primarily
`reflective of mucosal hemorrhage was used, but cimeti-
`dinewas not different from placebo when a scale 9n which
`erosions were incorporated into the scoring system was
`used."~ Results of cotreatment trials are iriore reliably ap-
`plied toclinical practice when erosions and ulcers are used
`as end points to define response to therapy. Here again,
`findings of the short-term rriats rn~y i~ot be relevant to
`long-term administratron and, thus, the weight of our
`co~iclGisians should be based on results a£ trials o£ ex-
`tended cotlierapy in the long-term NSAID user.
`
`H2-Receptor Antagonists
`It has become common practice to prescribe H2-
`antaganists, such as cimetidizte {Tagamet), raniridine
`(Zantac}, farnotidic~e (Pepcid), and nizatidine (Aycid},
`along with NSAIDs for ulcer prophylaxis, even though
`sixpporYing evidence from clinical trials is sparse. I~ane-
`theless, coadministration o£ an antisecretory agent does,
`far the fallowing reasons, have some theoretical merit; (1)
`a#ter mucosal integrity has been interrupted by an
`NSAFq, further cellixlar damage can occur through the
`back diffusion of acid; (2) during NSAID therapp, acid se-
`cretion may inczease,~'~757 possibly because of decreased
`mucosal PG content; and (3) in animals, NSAID mncosal
`ciama~e in the presence of add is greater than when mu-
`£ffects of NSAIDs on Prostaglandins—fryer 3e feidman t14h
`
`llo~enloaded I~rom: http:IJa re~I~in te.jamatnetwiiE~i:.cmn! b~' n Reprints T3esk [i5gr ut10312Q12Q i~
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`Page 5 of 11
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`Patent Owner Ex. 2009
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`IPR201 5-01 71 8
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`Cosa is exposed to a higher pH. "~ On the other hand, the
`Eact that HZ-antagonists have r~o known effects on gastric
`m~icusal I'Gs theoretically argues a~ainst their pc~ssibte
`benefit in a PG-deficient mucosa.'*9~
`Coadministration of HZ-antagonists and aspirin, dosed
`far 7 days or less, to normal volunteers produced less
`gastric and dtiiodenal macosal injury than did adminis-
`tration of placebo.'s'.`s' Thus, in the sharE term, HZ-
`antaganists are effecriv€ fur prophylaxis against gastric
`and duodenal N$ATl7-indured injury. During longer pe-
`riods of NSATD administration, Hx-antagonists, such as
`ranitidine (150 nlg twice daily), are effective for I~;5AID-
`indixced ulcer prevention ii7 the duodenum but not the
`storne~ch.'~"-'~'
`There is limited information on ulcer prevention ~~tFter
`an NSAID-induced ulcer has been healed by an H~-
`antagonist, assuming that coadministration of an H,-
`antagonist and the NS?iID as continued.`~'1~ Available
`data suggest that recurrence rates during cotherapy are
`low.'' In these maintenance shidies,