Bailffire's Clinical Gaattoenterofogy
`Vof. I4, No i, pp. I4y-f59, 2000
`doi: lO. l 053/bega.
`l 999.0065, available oniine at http://www.ideaiibrary.com
`
`on 18E+I,
`
`lr
`
`II
`i~a
`ll
`8 trial %1, II II
`
`I
`
`How do NSAlos cause ulcer
`
`diseases'ohn
`
`L. wallace Pho
`Pr ofessor
`Department of Pharmacology
`Alberta, Canada
`
`and Therapeutics,
`
`Faculty of Medicine, University of Calgary, Calgary,
`
`Gastroduodenal
`ulceration and bleeding are the major
`to the use of non-steroidal
`limitations
`drugs (NSAIDs). The development of safer NSAIDs or of effective therapies
`anti-inflammatory
`for the prevention of the adverse effects of existing NSAIDs requires a better understanding
`of the pathogenesis
`of NSAID-fnduced
`to the
`ulcer disease. NSAIDs
`can cause damage
`gastroduodenel mucosa via several mechanisms,
`ir ritant effect of these
`the topical
`including
`drugs on the epithelium,
`of the barrier properties of the mucosa, suppression of
`impairment
`gastric prostagfandin
`reduction of gastric mucosal blood flow and interference with
`synthesis,
`the repair of supetficfat
`injury. The presence of acid in the lumen of the stomach
`afso
`to the pathogenesis
`of NSAID-induced
`contributes
`ulcers
`the
`and bleeding,
`by impairing
`restitution
`process,
`interfering with haemostasis
`and inactivating
`several growth factors that
`are important
`In recent years, a fuller understanding
`in mucosaf defence and repair.
`of the
`of NSAID-induced
`ulcer disease
`pathogenesis
`facilitated
`soma new, very
`has
`promising
`to the development
`of stomach-sparing NSAiDs.
`'approaches
`
`Key words: ufcer; nonmeroidaf
`nitric oxicfe.
`
`anti-inflammatory
`
`drug;
`
`acid; neutrophifs;
`
`cycf~xygenase;
`
`The ability of non-steroidal
`(NSAIDs) to cause ulceration and
`anti-inflammatory
`drugs
`bleeding in the upper gastrointestinal
`tract was first documented
`by the endoscopic
`ln 1938.'n that study,
`study of Douthwaite
`and Lintott
`the investigators demonstrated
`the ability of aspirin to damage the stomach.
`In the years that followed, more potent
`NSAIDs, such as indornethacin,
`to
`and the fenarnates, were brought
`phenylbutazone
`market. Shortly thereafter, case reports of melaena associated with the use of aspirin
`and the newer NSAIDs began to appear
`in the literature,
`and in the l960s and 70s,
`began to document
`case-control
`studies
`the gastrointestinal
`toxicity of this class of
`In recent years,
`the upper gastrointestinal
`drug.
`tract damage caused by NSAIDs has
`to as an 'epidemic'y
`been referred
`a number of investigators.
`This
`is in part
`to the widespread
`attributable
`use of these drugs, particularly
`by patients with osteo-
`arthritis
`arthritis. The worid market
`and rheumatoid
`for NSAIDs is approximately
`$8
`billion. The cost of treating NSAID-related
`gastrointestinal
`effects almost
`adverse
`exceeds this amount
`certainly
`cost of treating NSAID gastropathy
`(the annual
`'in
`rheumatoid
`arthritis
`to
`in the USA,
`for example,
`patients
`been reported
`having
`exceed $4 billion).~
`Developing anti-inflammatory
`drugs that do not produce ulceration or bleeding in
`the gastrointestinal
`tract, or developing
`that
`therapies
`prophylactic
`substantially
`152l-69te/00/Of0147+ l3 $3500/00
`
`Q& 2000 Harcourt Publishers Ltd.
`
`Page 1
`
`Dr. Reddy's Exh. 1044
`
`

`

`I48
`
`1. L Waliate
`
`the
`clearly understanding
`reduce the toxicity of existing NSAIDs, depends
`upon
`the mechanisms
`by which
`In this chapter,
`ulceration.
`pathogenesis of NSAID-induced
`bleeding will be
`and promote
`interfere with repair
`the mucosa,
`NSAIDs damage
`the properties of NSAiDs that contribute to ulcerogenesis
`can be
`In general,
`reviewed.
`of pro-
`and (2) the suppression
`(I) topical
`into two categories:
`irritancy,
`divided
`the presence in the stomach and duodenum of
`In addition,
`activity.
`synthase
`staglandin
`(H. pylori), may contribute to the ability of
`in some cases; Helicobacter pylori
`acid and,
`NSAIDs to damage the mucosa.
`
`TQPICAL IRRITATIC) N GF THE NUCOSA
`
`the
`suggested that aspirin could directly damage
`in the 1960s by Davenport
`Studies
`the back-diffusion of acid
`gastric epithelium.s The breaking of the 'barrier'ermitted
`led to The rupture of mucosal blood vessels. These
`into the mucosa, which eventually
`found to be predorninantiy
`associated
`irritant properties were subsequently
`topical
`forms of these drugs
`with those NSAIDs with a carboxylic acid residue. The unionized
`cells in the stomach and duodenum. Once in the neutral
`intra-
`can enter epithelial
`the drugs are converted to an ionized state and cannot diffuse
`cellular environment,
`As the drug accumulates withtn the
`out. This has been referred to as 'ion trapping',
`in swelling of the
`into the cell results
`cell, the osmotic movement of water
`epithelial
`to the. point of lysis.
`cell, eventually
`epithelial
`epithel-
`the gastroduodenal
`Another mechanism by which NSAIDs could damage
`in the epithelial cells,"8 Various
`ium is via the uncoupling of oxidative phosphorylation
`to a
`to uncouple mitochondrial
`respiration7'8,
`leading
`NSAIDs have been shown
`depletion of ATP and therefore a reduced ability to regulate normal cellular
`functions,
`to uncouple
`pH. The ability of NSAIDs
`of intracellular
`such as the maintenance
`also appears to be related to some extent to acidic moieties
`oxidative phosphorylation
`at these sites interferes with the
`since substitution
`(such as carboxylic acid residues),
`to act as uncouplers.a
`ability of these compounds
`injury by virtue of their effects on mito-
`The theory that NSAIDs cause topical
`based on the observation that gastric
`has been challenged„mainly
`respiration
`chondrial
`and duodena! ulcers are observed following the parenteral or rectal administration
`of
`NSAIDs ' Erosions and ulcers can also be produced in experimental
`circumstances
`in
`to comprehend
`how
`It is also difficult
`parenterally."
`which NSAIDs are administered
`would occur in. gastrointestinal
`the uncoupling of oxidative phosphorylation
`epithelial
`other cells with which an'NSAID would have contact
`in the numerous
`cells but not
`bc
`the small
`to its absorption. Qn the other
`intestine would
`hand,
`subsequent
`exposed to NSAIDs that are excreted in bile and recycled enterohepa-
`repeatedly
`of oxidative
`the uncoupling
`is an
`phosphorylation
`that
`tically, so it
`is conceivable
`component of the pathogenesis
`of NSAID-induced
`enteropathy.
`important
`irritant properties of NSAIDs
`A third mechanism that could account for the topical
`in the stomach.
`is their ability to decrease the hydrophobicity
`of the mucus gel
`layer
`to
`is a primary barrier
`have propsed that
`and co-workers
`this layer
`Lichtenberger
`in the stomach. ~'hey demonstrated
`the surface of the
`that
`acid-induced
`damage
`can be reduced
`and that
`by various
`this hydrophobicity
`is hydrophobic
`stomach
`to associate with the
`agents, For example, NSAIDs were shown
`pharmacological
`its hydro-
`phospholipids within the mucus gel
`thereby reducing
`layer,
`surface-active
`the mucus
`phobic properties.'~'s
`that
`demonstrated
`further
`These
`investigators
`in the stomach of rats and mice gtven NSAIDs was
`from a
`ronverted
`layer
`gel
`
`Page 2
`
`Dr. Reddy's Exh. 1044
`
`

`

`Pathogenesis of NSAID ulceration
`
`i%9
`
`to a wettable state. This effect was found to persist for several weeks or
`non-wettable
`after the cessation of NSAID administration.
`months
`have been made to produce NSAIDs with reduced topical
`irritant effects.
`Attempts
`in slow-release or enteric coated tablets,
`as well as the
`These include
`formulations
`preparation of the drug as a pro-drug that requires hepatic metabolism in order to be
`the incidence of gastroduodenal
`ulceration with pro-
`active (e.g. suiindac}. However,
`to that seen with standard NSAIDs.'
`This is taken as evidence
`drugs is comparable
`irritant properties of NSAIDs are not paramount
`in terms of their
`the topical
`that
`ability to induce frank ulceration
`in the stomach. However, one cannot completely
`exclude this possibility. Most NSAiDs are excreted in bile. Even with parenteral
`a reflux of duodenal
`of the NSAID,
`into the
`contents
`therefore,
`administration
`in the topical exposure of the gastric mucosa to these drugs.
`stomach would result
`Efforts have recently been made to develop gastrointestinaily
`safe NSAIDs on the
`basis of a reduced ability to interfere with the surhce-active
`in the
`phospholipid
`layer
`et al proposed that pre-associating NSAIDs with
`gastrointestinal mucus. Lichtenberger
`to their administration
`should reduce the ability of
`xwitterionic
`prior
`phospholipids
`the NSAIDs to associate the phospholipids
`in the mucus gel, and should therefore
`this to be the case by pre-associating
`reduce their uicerogenicity.'~ They demonstrated
`aspirin and other NSAIDs with dipalmitoyl-phosphatidyichoiine
`(DPPC) and dernon-
`the complex produced
`in the gastrointestinal
`strating that
`less damage
`significantly
`the pre-association of aspirin with DPPC
`tract than did the parent drug.'4 Importantly,
`interfere with the effectiveness of the aspirin to reduce fever or inflam-
`did not
`mation.'~ Similar effects could be obtained with other NSAIDs.'~'~
`
`SUPPRESSIGN QF PROSTAGLANNN SYNTHESIS
`
`synthesiP Ied directly to
`Vane's discovery in I97I that NSAIDs inhibit prostaglandin
`the discovery of the ability of minute quantities of exogenous prostaglandins
`to protect
`and NSAIDs.~'his in
`tract from injury induced by topical
`the gastrointestinal
`irritants
`turn Ied to extensive
`research into the roles of prostaglandins
`in mucosal defence.
`the ability of an NSAID to cause gastric damage,
`There is substantial
`evidence that
`synthesis~ +; agents
`correlates well with its ability to suppress gastric prostaglandin
`that are weak inhibitors of gastric prostagiandin
`are less uicerogenic,~~+
`synthesis
`of suppres-
`There is also a good correlation between the time- and dose-dependency
`sion of gastric prostaglandin
`by NSAIDs and their ability to cause gastric
`synthesis
`lead to
`of gastric
`VAy does the suppression
`ulcers.
`prostaglandin
`synthesis
`it is now clear that prostagiandins
`play a central
`injury! As mentioned
`above,
`rnucosai
`in the
`role in modulating mucosal defence. Endogenous
`are involved
`prostaglandins
`regulation of mucus and bicarbonate secretion by the gastric and duodenal
`epithelium,
`blood flow, epithelial
`cell proliferation,
`mucosal
`restitution
`epithelial
`and rnucosal
`function.+ This is not to say that prostaglandins
`are the only endogenous
`immunocyte
`of mucosal
`these components
`substances
`nitric oxide
`defence;
`regulating
`indeed,
`appears to perform many of the same functions as the prostagiandins
`in this. respect.
`Thus, the inhibition of prostaglandin
`in the formation of
`synthesis alone may not, result
`gastric erosions or ulcers. For example, mice in which the gene for cycl~xygenase-I
`levels of gastric prostaglandin
`synthesis yet did not
`exhibited negligible
`was disrupted
`develop gastric erosions or ulcers.~~ Of course, one would,
`spontaneously
`in such a
`anticipate that adaptation of the stomach to the chronic absence of prosta-
`situation,
`(i.e. there might
`occur
`be an
`of other
`glandins would
`enhanced
`production
`
`Page 3
`
`Dr. Reddy's Exh. 1044
`
`

`

`substances). On the other hand,
`of mucosal
`the suppression
`gastroprotective
`pro-
`synthesis, while not necessarily resulting in ulcer formation, will reduce the
`staglandin
`ability of the gastric mucosa to defend itself against
`irritants. This has been
`luminal
`animals, Doses of NSAIOs that substantially
`demonstrated
`very clearly in experimental
`did not cause overt gastric injury but did
`reduced mucosai
`synthesis
`prostaglandin
`greatly increase the susceptibility of the gastric mucosa to damage induced by irritants
`(e,g, bile salts).~
`- In terms of the pathogenesis
`of ulcer disease,
`is there one component of mucosal
`to its
`defence
`is more
`that
`than others with
`important
`respect
`impairment
`by
`answered. The fact that gastric
`has not yet been completely
`NSAIDs& This question
`', and that
`ulcers can be induced
`by parentera! Iy administered NSAIDs~
`this damage
`of the presence of luminal
`that. the
`acidz~+, suggests
`can be produced
`independently
`impairment of mucus and/or bicarbonate secretion may be of lesser significance. While
`inhibitors of mast ceil degranulation3',
`are extremely
`potent
`prostaglandins
`and mast
`cells are capable of releasing a variety of mediators
`(e.g. Ieukotriene C& and platelet-
`injury "', the effects of NSAIDs on
`to mucosal
`activating factor) that can contribute
`mast cells do not seem to be crucial to the pathogenesis of mucosal
`injury. This latter
`conclusion is based on the observation that rats in which mucosat mast cells have been
`depleted by chemica! means, or mice that are genetically deficient of mast cells, exhibit
`to NSAID-induced
`gastric injury as do their respective controls.3~
`similar susceptibility
`has been shown to be reduced by NSAIDs and could
`The rate of epithelial
`turnover
`to the pathogenesis
`of ulcer disease.~s However,
`contribute
`that
`it
`this
`is unlikely
`leads to the development
`effect is the principal one that
`of an ulcer.
`The component of mucosal defence that appears
`to be most profoundly
`altered by
`to injury. When the mucosa
`the gastric mlcrocirculatory
`NSAIDs
`response
`is
`is
`exposed to an irritant, or when superficial
`injury occurs, rnucosai blood flow
`epithelial
`any toxins or
`increases. This is probably a response aimed at removing
`substantially
`that enter
`the lamina propria, neutralizing
`bacterial products
`acid and
`backdiffusing
`to the formation of a microenvironment
`at the surface of t:he mucosa that
`contributing
`to repair.36 As described
`is conducive
`in greater detail below NSAIDs can reduce
`alter the behaviour of neutrophiis
`gastric mucosal biood flow and profoundly
`flowing
`through the gastric microcirculation.
`
`EFFECTS QN THE HICROClRCULATION
`
`The ability of NSAIDs to reduce gastric mucosaf blood flow has been recognized for
`several decades. ~
`of the E and I series are potent vasodilators
`Prostaglandins
`that
`are continuously
`by the vascular
`so the inhibition
`of their
`produced
`endothelium,
`by an NSAID leads to a reduction in vascular
`tone. Several
`lines of evidence
`synthesis
`have suggested that damage to the vascular endothelium is an early event following the
`of NSAIDs to experimental
`animals.+~'ndathelial
`administration
`injury is also an
`in the pathogenesis of gasi:rointestinal
`early event
`damage associated with ischaemia-
`to play a critical
`reperfusion~z,
`in which neutrophits
`have been demonstrated
`role as
`led us to examine the possible role
`mediators of endotheiial
`injury.~3 This observation
`of the neutrophil
`in the pathogenesis of experimental NSAID gastropathy
`{Figure I),
`Our studies and those of others demonstrated
`to rats
`that NSAID administration
`resulted in a rapid and significant
`increase in the number of neutrophiis
`to
`adhering
`
`the vascular endothelium in both gastric and mesenteric venuies.+ ~This effect was
`
`typically seen within
`
`I 5-60 minutes after the administration
`
`of an NSAID, consistent
`
`Page 4
`
`Dr. Reddy's Exh. 1044
`
`

`

`pathogenesis of NSAID ulceration
`
`15i
`
`NSAlD
`
`Altered mediator production
`(decreased PG, Increased LT and TNF)
`
`adherence
`increased neutrophilwndotheiium
`(ICAM-I and CD11/t 8 up-regulation)
`
`Reduced rnucosel
`blood flow
`
`Free radical and
`'protease release
`
`Mucosal Ulceration
`
`Figure I. Role of changes
`in the pathogenesis of NSAID-induced
`uiceration.
`in the gastric microcirculation
`and cause an increase in the liberation of leukotriene
`(LT) B,
`(PG) synthesis,
`NSA1Ds suppress prostagiandin
`is an increase in ecpression of various adhesion moiecules,
`and tumour necmsis factor (TNF). The net result
`to the vascuiar endothelium,
`leading to neutrophil
`adherence
`
`of prostaglandin
`for the suppression
`with the period of time required
`synthesis
`by
`that this adherence was dependent on .
`these drugs.~ Subsequent
`studies demonstrated
`(CD I I/CD I aj on the neutrophil
`the expression of the P~-integrins
`and intercellular
`(ICAL-I) on the vascular endothelium.~
`Such adherence
`could
`adhesion molecule-I
`to occur in vitro using isolated human
`and endo-
`neutrophlls
`also be demonstrated
`of ICAN-I on
`umbilical vein.+ Furthermore,
`the upreguiation
`theiial celis from human
`the vascular endothelium in the gastric microcirculation was shown to occur within
`I 5-30 mmutes of the administration
`of an NSAIO to rats, and this could be prevented
`of'xogenous
`by the administration
`prostagiandlns.~9
`adhere to the vascular endothelium foliowing
`the fact that neutrophils
`Of course,
`to the
`these cells contribute
`does not necessarily mean that
`NSAID administration
`tissue injury that can be induced by NSAIDs. To test
`injury of the mumsal
`endotheiiai
`a number of studies were carried out. First, we demonstrated
`that
`this hypothesis,
`serum or
`in the rat, either with an anti-neutrophii
`neutrophils
`circulating
`depleting
`greatly reduced the severity of the gastric damage
`induced
`with methotrexate,
`by
`indornethacin or naproxen.~ Importantly,
`the induction of neutropenia
`also prevented
`
`Page 5
`
`Dr. Reddy's Exh. 1044
`
`

`

`I52 J. L. Wallace
`
`to the vascular
`by the NSAIDs.~ Second, we
`the damage
`endothelium
`induced
`treating rabbits or rats with monoclonai
`that
`that blocked
`antibodies
`demonstrated
`to the vascular
`also markedly
`adherence
`NSAID-induced
`neutrophil
`endothelium
`gastric damage.4'~ Third, we found
`the extent of NSAID-induced
`that
`reduced
`shown to prevent gastric injury
`of prostaglandins
`at doses previousgl
`administration
`leukocyte adherence.+ s
`prevented N SAID-induced
`for a link between
`evidence
`adherence
`Further
`and NSAID-induced
`neutrophil
`gastric injury carne from studies of arthritic rats.s'hese animals,
`like humans with
`to NSAID-induced
`arthritis,
`exhibit
`rheumatoid
`an increased
`gastric
`susceptibility
`these rats also exhibited an increased level of neutrophil
`adher-
`damage.
`Interestingly,
`ence to the vascular endothelium. This appeared to be due to an increase in expression
`of ICAM-I on the vascular endothelium of arthritic rats, since pre-treatment with an-
`to
`ICAM-l.reduced
`and the susceptibility
`adherence
`leukocyte
`against
`antibody
`gastric damage to levels seen in healthy controls.5l
`NSAID-induced
`in response to the suppression of prostaglandin
`These studies suggest
`that,
`synthesis
`there is a rapid upregulation
`of expression of ICAM-I on the vascular
`by NSAIDs,
`of P -integrin
`endothelium and possibly an upregulation
`on circulating
`expression
`to the endothelium.
`in an increased adherence of-neutrophils
`neutrophils,
`resulting
`This begs the question of whether
`the enhanced
`adhesion molecule
`expression
`is
`purely a consequence of the reduction of prostaglandin
`synthesis, or whether
`there ls
`to diminished
`another
`chemical
`in-response
`signal produced
`prostaglandin
`synthesis
`leading to neutrophil
`the events
`that
`adherence.
`triggers
`Santucci et al suggested
`factor-z {TNT) might be the keg
`that
`tumour
`necrosis
`2
`for NSAID-induced
`adherence within the gastric microcirculation.
`neutrophil
`signal
`The release of TNRx from macrophages
`and mast cells has been shown to be sup-
`and TNRx is a weil-characterized
`for adhesion
`pressed by prostaglandins3l~3,
`stimulus
`molecule expression.+ Santucci et al demonstrated
`the levels of TNRx in the
`that
`plasma of rats significantly
`increased following the administration
`of indomethacin,
`this
`of neutrophils
`accompanied
`the gastric
`by a parallel
`accumulation
`being
`within
`and the development of gastrIc injury.+ Furthermore,
`microcirculation
`pre-treatment
`with a TNT synthesis
`inhibitor, pentoxifyliine,
`dose-dependently
`reduced neutrophil
`z These results have
`in the gastric microcirculation
`accumulation.
`and gastric damage.
`et al using a number of structurally
`been confirmed
`and extended
`by Appleyard
`inhibitors of TNFu synthesis
`unrelated
`and an anti-TNFu antibody.~
`to the increase
`Another group of mediators
`that might contribute
`in neutrophil
`adherence
`is the leukotrienes.
`following NSAID administration
`Like prcetaglandins,
`are derived from arachidonic acid. They have been shown to be capable of
`leukotrienes
`altering the susceptibility of the gastric mucosa to injury~ s~, at least
`in part through
`effects on neutrophil
`to the vascular endothelium.+
`stimulatory
`adherence
`inhibitors
`of leukotriene
`have been shown to
`and leukotriene
`receptor
`synthesis
`antagonists
`exert
`some protective
`in experimental models of NSAID-induced
`effects
`gastric
`damage.s'
`There is also evidence of an eievated leukotriene B4 production foliowing
`to laboratory animals44 and man ~, and inhibitors of leukotriene
`NSAID administration
`and a ieukotriene
`to prevent
`84 receptor
`synthesis
`antagonist
`have been shown
`adherence to the vascular endothelium both in vivo44 and
`NSAID-induced
`neutrophil
`in vitro.4s
`for a role for neutrophils
`Evidence
`in the pathogenesis
`of gastric ulceration
`in
`recently been provided.~ Patients taking NSAID therapy who had signifi-
`humans.has
`cant numbers of neutrophils within the gastric mucosa were approximateiy
`six times
`more likely to develop an ulcer over the course of 24 weeks than were patients who
`
`Page 6
`
`Dr. Reddy's Exh. 1044
`
`

`

`Pathogeneais of NSA1D ulceration
`
`i 53
`
`in their gastric mucosa.
`is also
`It
`of neutrophils
`did not have significant
`numbers
`trial examining the potential benefit of famotidine for the
`in a clinical
`noteworthy that,
`ulcers, Taha et al observed
`of NSAID-related
`that
`an
`gastroduodena!
`prevention
`risk factor for ulcer develop-
`increased peripheral white cell count was a significant
`ment.6'hey suggested that this observation was consistent with the hypothesis
`that
`by neutrophils.
`at least partially,
`gastropathy was mediated,
`NSAID-induced
`to the vascular endothelium contribute to
`How would the adherence of neutmphils
`to the
`the adherence of neutrophils
`the Formation of gastroduodenaI
`ulcers! First,
`to the
`by an activation of these cells,
`leading
`vascular endothelium is accompanied
`free radicals
`and oxygenderived
`release of proteases {e.g. elastase and collagenase)
`anions). These substances may mediate much of the endothelial
`and
`{e.g.superoxide
`that the severity
`by observations
`injury caused by NSAIDs. This is supported
`epithelial
`that
`of NSAID-induced mucosal
`injury can be markedly
`by compounds
`diminished
`free radicals ~
`of neutrophil-derived
`by inhibitors
`oxygenMerived
`and
`scavenge
`adherence to the endothelium,
`and the subsequent
`proteases.~6s Second, neutrophil
`of other elements of blood (e.g. platelets), could produce an obstruction
`recruitment
`it
`of the capillaries,
`respect,
`blood flow.
`In this
`thereby
`reducing gastric mucosal
`ability of NSAIDs to reduce gastric blood
`the wellxharacterized
`should be noted that
`flow37 3s has been shown to occur subsequent
`to the appearance of 'white thrombi'n
`the gastric microcirculation.+
`
`INHIBITIC)N C3F RESTITUTIQN
`
`Damage to the gastric epithelium probably occurs on a daily basis but does not usually
`lead to deeper mucosal
`injury because of the ability of rapid (i.e, within minutes)
`repair to occur via the pr ocess of restitution. This process involves
`the rapid migration
`of healthy cells from the gastric pits to re-establish an intact epithelial barrier.@ The
`cells move along the denudecf basement membrane, which acts as a template and has
`to the restitution process.~s The basement. membrane
`been shown'o be crucial
`can
`leading to an inhibition of restitution
`of
`and the progression
`be damaged
`by acid,
`~ 'his does not, however, occur in normal
`necrosis to deeper
`layers of the mucosa.~
`because of the formation
`over sites of injury (i.e. exposed basement
`circumstances
`membrane) of a microenvironment
`in which the pH is maintained
`at near neutral,
`acid load in the lumen.
`even in the presence of a significant
`A 'mucoid
`of mucus,
`forms
`cellular debris
`and plasma proteins
`fibrin)
`(particularly
`seconds of gastric epithelial
`leaks from the
`the plasma
`that
`within
`trapping
`injury,
`for the near-neutral
`lt is this plasma which accounts
`underlying microcirculation.7
`the protective mucoid cap, since even a.very brief cessation of mucosal
`pH within
`blood flow results in a rapid decrease in the pH within the mucoid
`cap, which in turn
`in the formation of haemorrhagic
`results
`discussed above, NSAIDs can decrease mucosai blood Flow. Thus, NSAIDs can
`function of the mucoid cap and
`cause gastric injury by interfering with the appropriate
`therefore the process of restitution.
`following the systemic
`Indeed, we observed that,
`of an NSAID to an animal
`in which superficial
`injury had been
`administration
`epithelial
`the pH within the mucoid cap that had formed over the sites of epitheiial
`induced,
`began to decline in parallel with the inhibition of prostaglandin
`damage
`of haemorrhagic
`the formation
`thereafter,
`erosions was
`clearly
`minutes
`delivery of exogenous
`evident. This effect could be prevented
`the luminal
`through
`as could the formation of haemorrhagic
`erosions.4i
`prostaglandins,
`
`erosions."'s
`
`cap'onsisting
`
`synthesis.~'ithin
`
`Page 7
`
`Dr. Reddy's Exh. 1044
`
`

`

`IS4 J. L Vfallace
`
`REPAIR OF ULCERS
`
`to causing ulcer formation, NSAIDs can delay the healing of pre-existing
`in addition
`their bleeding.~~+ The effects on ulcer healing
`are probably
`and promote
`ulcers
`to the ability of NSAIDs to suppress
`related, once again,
`synthesis.
`prostaglandin
`In
`synthesis occurs mainly via the cycio~xygenase-I
`normal gastric mucosa, prostaglandin
`at a site of ulceration,
`the ulcer margin,
`isoform. However,
`around
`and particularly
`to be the primary
`to prostagtandm synthesis.
`contributor
`cyclo-oxygenase-2
`appears
`of cyclo-
`the marked
`demonstrated
`Studies
`in mice and rats
`upreguiation
`initially
`gastric tissue7~, and this has recently been confirmed
`oxygenase-2-in
`ulcerated
`in
`humans'oreover,
`the treatment of rats or mice with selective inhibitors of cyclo-
`in a significant delay of ulcer healing.~4 "s These observations,
`oxygenase-2 results
`and
`reports of selective cyclo-oxygenase-2
`exacerbating
`inhibitors
`inflammation
`intestinal
`that caution should be exercised in regarding the new cyclo-
`and uIceration+,
`suggest
`safe.
`as gastrointestinaily
`oxygenase-2 inhibitors
`to promote
`the bleeding of pre-existing
`The ability of NSAIDs
`ulcers
`is most
`'he inhibition
`probably related to their inhibitory effects on platelet aggregation;~
`of
`of platelet. aggregation
`by NSAIDs occurs as a consequence
`df the inhibition
`be noted
`unlike other NSAIDs,
`It should
`thromboxane
`that,
`synthesis.
`aspirin
`inhibition of thromboxane
`in the platelet. Thus,
`an irreversible
`produces
`synthesis
`even the Iow doses of aspirin used for the prophylaxis of'yocardial
`infarction
`and
`bleeding.~~
`increase the risk of gastrointestinal
`stroke can significantly
`
`ROLE OF ACID
`'as contributed
`
`The -observation
`that NSAID-induced
`can develop
`ulcers
`in achlorhydric
`individ-
`to a widely
`that acid ls not
`in the
`held belief
`uals
`involved
`of these lesions. Further
`-are several
`this hypothesis
`pathogenesis
`studies
`reinforcing
`treatment with histamine H -receptor antagonists
`that
`did not reduce
`demonstrating
`the incidence of NSAID-induced
`However, many of these types of
`ulceration;s
`that H2-antagonists
`studies
`have demonstrated
`inhibitors
`proton
`and
`can
`pump
`lesions, but not the formation of the clinically more
`prevent NSAID-induced'gastric
`however, Taha et ai
`as ulcer
`ulcers,
`significant
`as well
`complications.
`Recently,
`reported that a high dose of famotidine {40m~ twice daily) was effective in preventing
`and Hawkey et als
`uicerss',
`NSAID-induced
`demonstrated
`that omeprazole.could
`of NSAID-induced
`the
`reduce
`incidence
`significantly
`These
`ulceration.
`studies
`suggested that a profound suppression of acid secretion, as is produced, by omeprazole
`or by a high dose of famotidine, wm necessary in order to have a significant
`impact on
`the incidence of NSAID-induced
`ulcers.
`Acid may contribute to NSAID-induced
`ulcer for mation in several ways. First, acid
`can exacerbate damage to the gastric mucosa induced
`by other agents, For example,
`regions of ethanol-induced
`acid can convert
`in the mucosa to
`vascular
`congestion
`erosions.+ Second,
`to ulcer
`actively
`acid will contribute
`bleeding
`formation
`by
`for example,
`interfering with haemostasis. Platelet aggregation,
`at a pH of
`is inhibited
`less than 4.s~ Third,
`injury to deeper
`above, acid can convert
`as outlined
`superficiai
`by interfering with the process of restitution.
`necrosis
`mucosal
`Fourth,
`acid can
`inactivate several growth factors (e.g. fibroblast growth factor) that are important
`for
`of mucosal
`the maintenance
`integrity and for the repair of superficial
`since
`injury,
`these growth factors are acid-labile.+
`
`Page 8
`
`Dr. Reddy's Exh. 1044
`
`

`

`Pathogenesis of NSAID ulceration
`
`155
`
`to note that N SAiDs can increase gastric acid secretion, although
`jt is Important
`it is
`or healing.
`not clear whether
`such effects have
`any impact on ulcer
`formation
`cells ', so the inhibition
`exert
`of their
`effects on parietal
`inhibitory
`Prostagiandins
`in an increase in gastric acid secretion.92
`by NSAjDs can result
`synthesis
`
`SUMMARY
`
`A great deal has been learned about the pathogenesis
`of. NSAID-induced
`gastric injury
`two decades. As a result, several new NSAjDs, which will have greatly
`over the past
`toxicity relative to current drugs, are in the process of being
`reduced gastrointestinal
`introduced to the marketplace. For example, selective inhibitors of cycjo-oxygenase-2,
`spare the major
`in the gastrointestinai
`form of.cycjowxygenase
`which will
`tract,
`less injury to the stomach than do the current NSAlDs
`produce substantialiy
`that
`and -2.93 Whether or not these agents prove to be as
`inhibit both cycjo-oxygenase-i
`effective for the treatment
`range of inflammatory
`of the full
`conditions
`currently
`treated with NSAiDs remains to be seen, and some experimental
`that
`studies suggest
`this may not be the case.94+ Nitric oxide-releasing
`NSAIDs
`another
`represent
`to reducing the adverse effects of this cjass of drug.
`The design of these
`approach
`new NSAlDs would not have been possible had it not been for an increased under-
`, standing of the pathogenesis
`of.NSAlD-induced
`ulceration.
`
`Acknowledgements
`
`Dr Wallace is a Medical Research Council of Canada Senior Scientist and an Alberta Heritage
`for Nedical Research Senior Scientist.
`Foundation
`
`aspirin,
`
`and
`
`alcohoL
`
`druy affects gastric mucosal defenses? Clinical ond
`
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