l'l‘AL I GAS'T'ROEN’I‘EROL HEPATOL l999;31(SUPPL.l):S(i3-72
`
`Prevention and treatment of non-steroidal anti-inflammatory
`drug-induced gastro-duodenal damage:
`rationale for the use
`of antisecretory compounds
`
`C. Scarpignato, I. Pelosini‘
`
`Gastm-duodenal mucosa possesses an array of defensive
`mechanisms and non-stemidal anti-inflammatm'y drugs
`have a deleterious efi'ect on most of them. This results in a
`mucosa less able to cope with even a reduced acid load.
`The presence of acid appears to be a conditio sine qua non
`for non-steroidal anti—inflammatory drug-infill}; which is
`in fact phi-dependent. The acute damage induced by acid
`non—steroidal anti-inflammatory drugs. like aspirin. can be
`markedly reduced or even prevented by raising intragastric
`pH with antacids or anlisecretonv compounds. Animal,
`studies have clearly show-In that not only the-degree; but al-
`so the duration, of acid inhibition. is an importantfactorfor
`prevention of non-steroidal anti-inflammatory drug-in-
`duced mucosa} damage. As a consequence, proton pump in-
`hibitors (PPls) appear to be more efiective that Hz-recep—
`tor antagonists both in preventing and treating gastro-duo-
`denal lesions. While acid suppression seems to be theonly
`efi‘ective mechanism for ulcer healing, prevention of non—
`steroi-dal anti—inflammatory drug-injury might also rely on
`[he macro-sol pmtective"activity of these compounds. Clini-
`cal pharmacological studies. perforated in healthy volun-
`teers, have'shown that - as in laboratory animals - eleva-
`tion of intragastric pH by means of antacids or antisecre-
`tory compounds protects against acute NSAID—intluced
`damage. Unlike fig-blockers, PPls protect from non-
`steroidal anti—inflamnuttory drug—injury not only the duo-
`' demon, but ”also the stomach, where the majority of mucos-
`al [mimic-ate usually located. Although elevation of intra-
`gastric pH afiects non-steroidal anti-inflanmzatory drug
`pharmacokinetics and phartnacodynamics in laboratory
`animals. a. lack of drug-to-drug interaction between PPIs
`and some of these compounds has been reported in hu-
`mans. To summarize, clinical and experimental pharmacol-
`ogy support the use of PPls for the prevention and treat-
`tnent of non—steroidal anti-inflammatorv drug-induced gas-
`tto-duodenal damage. Acid suppression. could. however;
`represent only one of the many mechanisms by which these
`
`._._.
`
`.
`
`.__..
`
`-
`
`_._..__..
`
`From: Department ofInternal Medicine, School of Medicine A}:
`! Dentistry, University of Parma. Italy and ’ Department of
`! Gastroenterology and Hepatology, Faculty of Medicine.
`University of Nantes. France.
`‘
`
`: Address for correspondence: Profl C. Scarpignato. Laboratory
`, of Clinical Pharmacology, Department of Internal Medicine.
`i Maggiore University Hospital, 43100 Pam-ta. Italy.
`' Fax: +3.9-052l-903864. E—mail: scetpi®tin.it
`
`
`l
`
`i
`x
`
`L-
`
`
`
`“.__..“...Wamn-w._..........
`
`
`
`
`
`compounds protect gastro—duodenal mucosa. Further stud—
`ies are, therefitre. needed to better elucidate the respective.
`role of the various pharmacologicall actions in their mu—
`cosal protective. activity as well as to assess the clinical rel-
`evance of each of them.
`
`Ital J Gastrocnterol Hepatol 1999:3l(Suppl.l):Sfi3-72
`
`Key words: antacids: antisecretory drugs; mucosal damage;
`NSAIDs
`
`1‘
`
`
`
`
`
`
`Introduction
`
`Castro-duodenal mucosa possesses an array of deion-
`. sive mechanisms and non-steroidal anti—inflammato-
`
`
`
`
`1y drugs (NSAIDS) have a deleterious effect on most
`
`of them (for review see 1). Although much of the ex-
`
`perimental work has been done using salicylates, it is
`
`now well accepted that almost all the non—steroidal
`
`anti—inflammatory drugs (NSAIDS) are capable of
`
`causing mucosal injury 3 3. These compounds appear
`
`to cause gastro-duodenal damage, by two main mech-
`
`anisms: a physiochemical disruption of the gastric
`
`mucosal barrier and a systemic inhibition of gastric
`
`mucosal protection, through inhibition of cycle-oxy-
`
`genasc (COX) activity of gastrointestinal (GI) mn-
`
`cosa. A reduced synthesis and secretion of mucus and
`
`bicarbonate, an impairment of mucosal blood flow
`
`(MBF) and an increase of acid secretion represent the
`
`main consequences of NSAID—induced prostaglandin
`
`_
`(PG) deficiency. Additional mechanisms which may:
`
`add to the damage have been demonstrated. "amen—- _
`
`
`clude. uncoupling of oxidalivc phosphoryle,ti'on,:= ,_
`
`duccd mucosal cell proliferation, and DNA synthc '
`
`
`as well as neuthrophil activation.“ Recent We;
`
`demonstrated that, after administra on _ " NS
`
`d
`neutrophil adherence to the yvascu
`
`
`
`
`
`the GI tract yiafia.
`
`which 'thcy";excrtf_ the _
`
`
`this context, it'is_'v_ery 'drffi
`_
`.
`
`_.
`NSAID completely .dc'voi'd- o'szIj.s .
`
`
`
`P200096216
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`
`
`564
`
`Antisecrelury drugs and NSAID-injury
`
`Role of gastric acid in the pathogenesis of NSAID—
`injury
`
`Impairment of defensive mechanisms results in a mu-
`cosa less able to cope with even a reduced acid load.
`The presence of acid appears to be a comlilio sine qua
`non for NSAID-injury. Acid not only injures the mu—
`cosa by back diffusing from the lumen causing tissue
`acidosis and triggering a train of pathophysiological
`events leading to gross lesion formation 6, but also
`serves to increase NSAlD absorption.
`In the stomach, at acidic pH, NSAIDs with pKa values
`of 4—5 will be un-ionized 7. Entry of the drug into the
`gastric mucosa] cells in the non-ionized state will be
`enhanced, but cytoplasmic pH being neutral,
`these
`drugs then become ionized, less lipid soluble, unable
`to leave the cell and thus accumulate within the gastric
`mucosal cells (Fig. 1). This produces a biochemical
`“green—house” effect. This phenomenon, known as ion
`trapping, in turn leads to alterations in cell membrane
`permeability (the so-called “barrier—brealdng" eli‘ect)
`with back-diffusion of hydrogen ions from the lumen
`and subsequent mucosa] damage 8". The rate of ab—
`sorption of aspirin (ASA) is, indeed, dependent on in-
`tragastric pH ““2, and aspirin—induced mucosal injury
`is reduced in achlorhydric patients '3 ’4 and when gas— .
`tric juice is buffered at pH 6-7 7 3.
`.
`in contrast to the oral route, no significant alteration
`is detectable in human-gastric. mucosa after a single
`parenteral dose of aspirin ‘5 ‘6, Whereas repeated ad-
`ministration results in mucosal damage, probably due
`to the systemic effects of the drug. However. animal
`experiments ‘7 have shown that - after instillation of
`
`acid into the gastric pouch — both ASA and salicylic
`acid (SA), given intravenously (i.v.) .- are invariably
`able to produce gross mucosal
`lesions (i.e., red
`steaks). These results were recently confirmed with a
`different NSAID (namely indomethacin) in the ele-
`gant experiments performed by Elliot et al. ”3. After
`completely blocking endogenous acid secretion by
`omeprazole,
`they introduced buffers with different
`pHs into the gastric pouch and gave indomethacin in-
`traduodenally (id). As illustrated in Figure 2. the ex-
`tent of the damage was clearly pH-dependent:
`the
`lower the intragastric pH,
`the higher the mucosa]
`damage. Despite a lOO-fold reduction in H+ concen-
`tration between pH 2 and pH 4,
`indomethacin-in-
`duced injury was not significantly reduced until the
`gastric pl-l was greater than 4, suggesting that inacti-
`vation of pepsin, which takes place above pH 4.5 ‘9,
`may contribute to the observed reduction in mucosal
`damage. A similar pl-l-dependent pattern of mucosal
`injury (which paralleled a similar pH-dependent pat-
`tern of peptic activity) has been observed in experi-
`ments where acid-peptic oesophagitis was induced in
`cats 2°. These results suggest that acid and pepsin in-
`teract very significantly and that the reduction of ag-
`gressiveness of the acid-peptic juice which occurs
`with the elevation of pH is largely determined by the
`pH—dependent proteolytic activity of pepsin. Although
`gastric and duodenal mucosae are more resistant to
`noxious agents than the oesophageal, it is conceivable
`that the mechanisms by which gastric acid disrupts
`mucosa] integrity are similar.
`The topical damaging effect of NSAIDs seems to be
`particularly important during acute administration. A
`
`
`
`Haemorrhagic mucosa] area (%)
`
`E Saline
`I lndomethacin
`
`
`
`7
`5.5
`,
`Indomethacin (40 mg/kg) intraduodenally
`
`pH
`
`Fig. 2. Effect of luminal pH on gastric damage, expressed as per-
`centage of total mucosa] area, occurring either spontaneously (saline)
`‘_ or after indomethacin administration in pyloms—ligated rats ’3.
`
`hrmwwwmmmmwaw”'-"
`
`M"..mwm.</mw{.m¢qwsm
`
`
`
`
`Cellular
`membrane
`
`(ionized)
`
`Salicylic acid
`(non ionized)
`
`@330 j)
`
`Salicylic acid
`
`Fig. 1. Ion trapping of weak acids in acidic milieu. Proportion of
`non ionized form of weak acid ('e.g. salicylic acid) is higher in ex—
`tracellular acidic environment (right) than more neutral environ-
`ment, such that. within the cell (left). Since the non-ionized form of
`drug is less lipid-soluble, it is unable to cross cell membrane and
`thus accumulate within gastric mucosal cclls '.
`
`Page 2
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`P200096217
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`

`

`,animal,-
`
`C. Scarpignsto. l. Pelosini
`
`S65
`
`Time (min)
`
`O
`
`30 60 90 120150
`
`O
`
`30 6O 90 120150
`
`Time (min)
`
`
`
`Fig. 3. Effect. of intragastric administration of normal (left panel) or acidified (right panel) ASA (1.5 ml) on transmucosal PD in anaesthetized
`rats. A 1% solution in water or in 0.15 l-lCl was used, respectively. Each point represents mean values from 10 animals. Vertical are standard
`error. Note a more pronounced PD increase and a slower return to baseline after acidified ASA in comparison with aqueous solution of drug 33.
`
`few minutes after intragastric administration of ASA,
`electron scanning microscopy reveals a complete_di—s-
`organization of the surface epithelial cells showing a
`picture of the so~called . “.‘honeycombed” surface 2‘.
`From a functional point of View, the degree of damage
`correlates well with an immediate increase in trans-
`
`mucosal potential difference (PD), which is followed
`by a slow return to baseline 2‘ 23. Compared with regu-
`lar ASA, acidified ASA causes a more marked in-
`crease in mucosal PD, which is not f0110wed by a re-
`turn to baseline (Fig. 3)”.
`AS A-induced increase in transmucosal PD is paral-
`leled by a similar decrease in hydrophobicity (evalu-
`ated through measurement of the contact angle) of the
`gastric mucosa, an effect which proved to be pH-de—
`pendent 2“. Along with ASA, other NSAIDs have a re-
`markable ability to rapidly complex - in a pH—depen—
`dent manner — zwitterionic phospholipids, like, for in-
`stance, phosphatidylcholine, that precipitates out of
`solution 25. This chemical association between
`
`NSAIDs and gastric surface phospholipids may ex-
`plain the decline of mucosal hydrophobicity observed
`after exposure of the gastric mucosa to acidic deriva-
`tives.
`
`In summary, mechanisms by which gastric acid en-
`hances NSAID-induced mucosal damage include:
`1) enhancement of NSAID gastric absorption;
`2) amplification of mucosal injury, either direct or me—
`diated by endogenohs PG deficiency, and
`3) activation of pepsin,
`the proteolytic activity of
`which may add to damage.
`
`. Acid inhibition for prevention and treatment of
`NSAID-injury: lessons from animal models
`
`
`
`The acute damage induced by acid NSAIDs, like ASA,
`can be markedly reduced, or even prevented, raising in-
`tragastric pH by means of antacids 'or buffers 264“. Un—
`like regular ASA, Alka Seltzer® (where aspirin is com-
`bined with citric acid and sodium bicarbonate) does not
`increase mucosal PD 2‘. Indeed,
`in this preparation.
`sodium acetylsalicylate is completely ionized, does not
`reconvert to aspirin, is rapidly emptied from the stom-
`ach (95% in 20 min) and is virtually not absorbed
`(about 1%) by the gastric mucosa 7 '0. Two tablets of un-
`buffered ASA damage about 20% of the epithelial cells.
`When given with an amount of sodium bicarbonate suf-
`ficient. to neutralize gastric acid, damage is reduced to
`control (saline) level (i.e., 3-4%) 27 29. Furthermore, also
`ASA-induced gastric microbleeding can be prevented
`by gastric alkalinization 3°.Buffcring toward an alkaline
`pH is important since Leonards 3‘ has shown that— af—'
`ter oral ASA - the degree of faecal blood lossis related
`
`to the buffer capacity of the formulation: thegreater the _'
`._
`
`buffer capacity, the lower the blood loss
`_
`.. _-
`__
`While the reduction of gastric mucdSal1nju13robse
`
`when ASAlS ingested with soluble antauds O, _bu
`can be simply explained by a reducedin
`
`ity with consequent reductionin gastric-
`.
`_
`.
`
`gastric) ASA absorption and.- reduct
`113.0
`available for back diffmidn, thesarn ”doe
`true for other insoluble antaCid fbrmulations; Alumini-
`urn-containing antacidsdisplay, indeed, a .gastropro—
`
`_
`
`
`
`
`
`P200096218
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`Dr. Reddy‘s EXh. 1045
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`.....,......,_.......,,..........,.....,.,.._._.um.
`
`il
`
`E-r
`i1 '
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`15-..-
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`

`IWW va-'.Mw
`
`44;: .........i...............,,.“we;
`
`S66
`
`Antisccieiory drugs and NSAlD-injury
`
`
`
`tective activity, independent of their acid neutralizing
`capacity and connected with their ability to strengthen
`mucosal defence mechanisms through release of en-
`dogenous PCs for review see 32.
`Results obtained with antacids suggested that raising in-
`tragastn'c pH by means of antisecretory drugs would
`have been more effective in preventing NSAID—injury.
`Pharmacological and clinical investigations did show
`that
`is the case. Indeed, inhibition of acid secretion
`through the selective Ml-antagonist, pirenzepine 3’3 or the
`Hz-receptor antagonist, ranitidine 3“ proved to be an ef-
`fective means of preventing NSAID~injury in laboratory
`animals. A recent investigation 35 showed that -— of the
`various fig-blockers — the relative potency for preventing
`indomethacin—induced antral ulcers in the rat. paralleled
`that for inhibiting histamine~induced acid secretion
`(Table 1), thereby suggesting that mucosa] protection
`with these drugs is connected with their acid inhibitory
`properties. This study also showed that not only the de-
`gree but. also the duration of acid inhibition is an import—-
`tant .factor for the prevention of'NSArIDLinjury. As a
`matter of fact, the longer acting Hg-receptor antagonists,
`loxtidine and AH 22216 (whose EDsoS for mucosa] pro-
`tection and acid inhibition were virtually the same, see
`Table I) proved to be more effective gastroprotective
`compounds than the short-acting drugs, namely cimeti—
`dine and mnitidine.
`.
`
`It follows from the aboveresults that a marked and
`long-lasting acid inhibition like that observed after ad—
`ministration of proton pump inhibitors (PPls) should
`provide a better protection from NSAlD-injury.
`in—
`deed, animal studies have consistently demonstrated
`that omeprazole provides dose-related protection
`against muc‘osal damage induced by a variety of nox—
`ious agents 3", including NSAIDs like aspirin and in-
`domethac'in 37'4", an effect observed despite persistent
`inhibition of PG synthesis (Table II) 4“. In comparative
`studies, the antisecretory and gastroprotective effects
`of omeprazole were generally equal to, or exceeded,
`
`' Table I. Comparison of mm values for inhibition of in-
`domethacin—induced antral damage with those for inhibition
`of histamine—stimulated acid secretion in rat (Modified from
`Calyton NM et. 211.35).
`
`
`
`Hz-blocker
`
`Ranitidine
`Cimetidine
`l.oxtidine
`AH 22216
`
`Inhibition of
`antral damage
`(IDsu, mg/kg p.o.)
`
`Inhibition of
`acid secretion
`(IDso, rug/kg i.d.)
`
`26 (2.2—50)
`552
`0.3 (0.2—0.4)
`0.1“ (0.1-0.3)
`
`1.6 (0.9-2.9)
`3.9 (1 .0-21)
`0.39 (0.34—0.45)
`0.04 (0.0250033)
`
`p.o.: oral route; i.d.: inn'aduodenal route
`
`Table II. Omeprazole prevents indomethaein—induced gas-
`tric damage in rabbits despite persistent inhibition of PG
`synthesis (Modified from Lee M, et a1. 40).
`
`Treatment
`
`Vehicle
`lndomethacin
`(20 mgfkg bid)
`Indomethacin
`
`+ 0mcprazole
`(20 mg/kg bid)
`
`N. animals Mean lesion
`PGE;
`N.
`animals (pg-min/mg) with lesions area (mmz)
`10
`259:14
`0
`. 0
`7
`43$?
`7
`10. 113.3
`
`7
`
`461-12
`
`l
`
`0.310.3‘
`
`‘ p<0.05; PG: ptostaglandin.
`
`those of Hg-receptor antagonists in different experi-
`mental models of gastric injury 37. Similar results have
`been obtained with lansoprazole‘H and pantoprazole 43.
`Unlike Pig-receptor antagonists, such as ranitidinc, the
`mucosa] protective action of PPIs is not limited to
`NSAID—injury but extends to other noxious agents,
`such as acidified ASA and absolute ethanol 3" 43"", thus
`. suggesting these drugs are endowed with a “true” gas—
`troproteetive activity. According to Robert et 111.50,
`in—
`deed, the ability to prevent mucosal damage from both
`acid-dependent and acid—independent noxious agents
`clearly distinguishes between antisecretory (antiulcer)
`and cytoprotective drugs.
`Preliminary studies from our laboratory have shown
`that administration of either omeprazole or lansopra-
`zoles‘ in the rat gastric pouch is able to significantly
`reduce the ASA-induced increase in transmu'cosal PD
`
`(Fig. 4) without any change in intragastric pl-l. These
`
`PD (-inV)
`
`4O
`
`
`
`0
`
`30
`
`90
`60
`Time (min)
`
`120
`
`150
`
`Fig. 4. Effect of intragastric administration of omeprazole (20
`mgfkg) on ASA—induced increase of transmucosal PD in anaes—
`thetized rats. Oineprazole was given 30 min before ASA (1.5 mg).
`Each point. represents mean values from 8-12 animals. Vertical bars
`are standard error. lntragastric pH was simultaneously recorded and
`no significant changes were observed throughout experiment.
`
`
`
`Page 4
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`Dr. Reddy‘s EXh. 1045
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`P200096219
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`

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`
`......
`
`5-“
`
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`
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`
`vs». M
`
`..“ - - .
`
`-
`
`
`
`
`
`Ct. Scnmignauo. l. Pelosini
`
`
`
` 567.—.—~__
`
`ittt
`
`3.
`
`
`
` -
`
`'r1’
`:(
`I}
`
`.i'
`
`3.
`.~
`
`.--=.
`
`'
`
`neutrophils. Taking into account that oxygen free radi-
`cals play a pivotal role in the development of NSAID-
`induced mucosa] lesionsffis 6“ this pharmacological ac-
`tion could also contribute to the protective effect. of
`PPIs on gastro—duodenal mucosa.
`Besides preventing NSAID-induced gastro-duodenal
`ulcers, PPls are also effective in healing them 3“ 4' “2. It
`is well known that NSAle inhibit cell proliferation in
`the gastric mucosa at the ulcer margin both in rats and
`humans “7. This effect may account for the epidemio-
`logic findings of delayed ulcer healing in patients tak-
`ing long-term NSAIDs therapy 53. The mechanisms un—
`derlying the therapeutic effect of PPIs involve a de—
`creased acid—peptic attack at the ulcer base as well as a
`reduced degradation of acid unstable fibroblast growth
`factors (FGFS). Ulcer healing is indeed quite a com—
`plex process which is initiated by secretion of GFs in
`the ulcer base and margin. These factors promote pro—
`liferation of epithelial cells and their margination over
`the ulcer crater 69. During healing, granulation tissue
`undergoes continuous remodelling and is usually
`transformed into a thinner mature scar within 2 weeks.
`Stimulation of angiogenesis, which has the potential of
`supplying oxygen and nutrients to the granulation tis-
`sue, also represents a major mechanism of acceleration
`' of ulcer healing 7". Schmassmann ct 211.7n 7‘ recently
`showed, in rats, that NSAIDs like, for instance,
`in—
`domethacin, decrease angiogenesis and increase the
`thickness of the granulation tissue (Fig. 6). In their ex—
`
` 2000
`
`
`)/mm-
` Micmvcsscl density (n-l
`
`Granulation tissue (thickness . m)
`
`
`mucosal damage (%)
`
`
`
`
`60
`
`Adherent Mucus (%)
`
`
`
`
`
`Omepmzole. Ing/kg
`
`
`
`
`
`Fig.5.Dose--dependcnt reduction of ethanoll-lCl—induced gastric
`Inucosal damage (left panel) and stimulation of adherent mucus
`(right panel) by intraduodenal omeprazole in conscious rats. The
`PM was given 30 min before noxious agent and animals were sac-
`rificed 10 min later. Each column represents mean values from 6—9
`rats. Vertical bars are sIanIlnrd error“.
`'
`
`results strongly 'Suggest a gastroprotective effect of
`PPls. independent of Lhci ' antisecretory activity.
`The mucosal protective activity of PPIs has been thor-
`oughly investigated by Del Tacca's team 4" 52‘“ who
`demonstrated the ability of omeprazole 4“", lansopra-
`zoles2 and pantoprazole 5“ to increase mucus secretion
`(Fig. 5), via stimulation of endogenous PG. release and
`activation of mucosal sulphydryl radicals. Comparison
`' of the dose-response curves for prevention of ethanol-
`induced injury and stimulation of gastric adherent Inu-
`cus did show a close relationship, the EDsn for both
`pharmacological effects being very similar 5". These re-
`sults are in line with the findings that omeprazole is ca-
`pable of significantly reducing ASA—induced decrease
`in corpus andantral mucus glycoprotein content ‘5 and
`are consistent with the idea that enhancement of mu-
`
`cosa] defence is an additional mechanism by which
`PPIs exert their gastroprotective activity. A preliminary
`investigation 5‘; also showed changes in gastric mucus
`composition (which may affect its functional proper-
`ties) after short—term treatment with omeprazole in
`rats.
`_
`While studies performed in cats 57 found a reduction in
`gastric bicarbonate secretion, other studies in guinea—
`pigs 53 and dogs 5" failed to show any effect of omepra-
`2016 on gastric alkaline secretion.
`Studies concerning the effects of omeprazole on gas-
`tric mucosal blood flow (GMBF) have also provided
`conflicting results. Indeed, while no effect was report—
`ed in rats 6”, cats 57 or dogs 59, an increase in GMBF was
`observed in rats either after intravenous bolus injec—
`tion“ and topical application of the drug 5' 6:.
`Finally, some in vitrp experiments have shown that
`both omeprazole ‘3 and lansoprazole“ are able to in-
`hibit oxygen-derived free radical production by human
`
`
`
` l 500
`
`
`
`1000
`
`500
`
`
`
`PLACEBO ‘
`
`
`
`
`** p< 0.02 versus placebo
`
`INDo
`
`INDO+OM
`
`
`
`
`
`
`
`
`
`Fig. 6. Mictovcssel density (expressed as number of mic-roves
`scls/mm-) in ulcer base and thickness of granulation tissue. (
`sured at ulcer centre) in an experimental model of. chronic ga
`
`
`ulcer in Int. lndomethacin (0.5 mg twice daily 5.c_.) treatment. Sig
`nificantly decreased microvessel density and increased-
`tissue (quantitated 21 days after ulcer induction); Conco
`ministration of omeprazole (40 pmol/ltg s.cc.) completely reversed
`
`indomethacin—induced effects on angiogencsis, maturation ofgran—
`ulation tissue, and, consequently, on ulcer henling- rate 79.
`'
`-
`-
`>
`
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`P200096220
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`568
`
`Antisecretory drugs and NSAID-injury
`
`perimental model, omcprazole was found capable of
`counterbalancing the deleterious effects of
`in-
`domethacin on both these parameters.
`In summary, data from experimental pharmacology
`clearly show that acid suppression via omeprazole and
`other PPls is highly effective in preventing and healing
`NSAID-induced gastro-duodenal damage. While acid
`suppression seems to be the only effective mechanism
`for ulcer healing, prevention of NSAID-injury might
`also rely on the mucosa] protective activity of these
`compounds.
`
`Antisecretory drugs for prevention and treatment
`of NSAID-injury in humans
`
`Clinical pharmacological studies, performed in healthy
`volunteers, have shown that - as in laboratory animals
`-
`elevation of
`intragastric pH by means of
`antacids 1“ 27 1" 72 or antisecretory compounds 73"”- pro-
`tects against acute NSAID—injury. ‘
`'
`' "
`For both Hg-receptor antagonists 73 and H“, K+-ATPase
`inhibitors 75 77 early investigations did show a dose—re—
`lated gastric protection (Fig. 7) which paralleled anti—
`secretory activity, thus suggesting acid inhibition to be
`the major mechanism for mucosal protection also in
`human beings. However, unlike Pig-blockers, PPls pro-
`tect from NSAID-injury, not. only the duodenum but
`also the stomach (Fig. 8) 8” “2. where the majority of
`mucosal lesions are usually located 33..
`
`% subjects with Lanztll'gsfl score g 2
`
`
`
`Placebo
`
`20 mg
`
`40 mg
`
`60 mg
`
`[Omeprazole given od for 4 days]
`
`Fig. 7. Dose—dependent protection of gastric mucosa from acute
`ASA injury in healthy volunteers. Subjects were given either place-
`bo or omeprazole for 4 days in double-blind fashion. One hour af-
`ter last drug administration,
`1 g ASA was given and video en—
`doscopy carried out 2 hours later 7".
`
`% subjects with a score 51 (S 5 erosions)
`Duodenum
`
`Stomach
`
`p<0.01
`
`
`
`
`
`Placebo OM 40 mg
`
`Placebo CM 40 mg
`
`[ASA 650 mg qid (i omeprazole) OM for 14 days]
`
`Fig. 8. Protection by timeprazole of duodenal as well as gastric mu-
`cosa from ASA injury in healthy volunteers. Subjects were given
`ASA (650 mg qid) with either placebo or omeprazole(40 tug/daily)
`for 14 days in double-blind fashion. On 15th study day endoscopy
`was performed to assess mucosal damage 3°.
`
`Unfortunately, the few studies performed in humans
`have been unable — maybe due to methodological
`drawbacks -— to reveal the mucosal protective activity
`of PPIs observed in experimental settings. indeed, al-
`though capable of enhancing duodenal bicarbonate se-
`cretion 54, omeprazole failed to affect gastric bicarbon-
`ate production 3“ or GMBF 35. A reduction in the vis—
`cosity of the gastric mucus “6 and of its protective prop-
`erties ’37 was actually reported, most likely a conse—
`quence of the profound acid inhibition. As expected,
`low (non antisecretory) doses of omeprazole (5
`rug/day) are completely ineffective in preve'iiting ASA-
`induced gastro-duodenal damage 88, suggesting, once
`more, that the underlying mechanism for NSAID mu-
`cosal protection is profound acid inhibition.
`Results obtained in clinical pharmacological studies
`have been confirmed in clinical trials dealing with pre-
`vention and treatment of gastro-duodenal lesions in pa—
`tients receiving short— or long-term NSAID therapy
`(for review see 89). While acid inhibition with standard
`doses of Hz-fCCCPIOT antagonists protects only the duo-
`denum 9° 9’, acid suppression via PPI 3" prevents both
`NSAID-induced gastric and duodenal damage. Al—
`though a high dose (40 mg twice daily) of famotidine
`was reported to be effective in reducing the cumulative
`incidence both of gastric and duodenal ulcers in a UK
`study 93, a large US trial 93 found famotidine 20 mg bid
`and 40 mg bid to be no more effective than placebo in
`preventing gastric ulceration in patients with os-
`teoarthritis requiring NSAIDs. Furthermore, a 12-
`month study 9“ demonstrated that high—dose ranitidine
`(300 mg bid) is effective in the prevention of recurrent
`duodenal but not gastric ulcer in rheumatoid arthritis
`
`
`
`
`
`
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`was-(Na «x. was;
`
`C. Scarpignato, I. Pelosini
`
`S69
`
`couraging. Whether or not prophylaxis of long—term
`NSAID users with antisecretory compounds will prove
`to be cost—effective remains to be determined ”2 ”3.
`
`Key messages
`
`- Castro-duodenal mucosa possess an array of defensive
`mechanisms and NSAIDr have a deleterious qfii’cr‘ on most of g
`them.
`i
`0 The acute damage induced by acidic NS'AIDS. like ASA. can
`be strongly reduced oreven prevented mixing intragustriz: pH
`,
`by means of antacids or antisecre/oty compounds.
`0 Both experimental and clinical phannacological studies have i
`shown tlmt— unlike Hz-hlockers — PP]: pmrectfnom NSAID-
`:
`injury not only the duodenum but also the stomach. where zhe
`,
`majority of mucosa! lesiorLr are. usually located.
`i
`- Although elevation of intragastric pH affects NSAID phar-
`nmc‘okinelics and plzannacozlvnanzics in laboratory animals,
`a lack ofdmg-to—(lrug interaction between PPls and some of
`these compounds has been reported in. Iranians.
`- The available rlam, therefore, support the use of PPlsfar the
`prevention and treatment quSAID-inducerl gastro-duodenal
`damage.
`
`;
`t
`l
`i
`E
`i
`ll
`
`l |
`
`.
`i
`
`References
`
`’ Scarpignato C. Nonsteroidal anti-inflammatory drugs: how do
`they damage gastroduodenal mucosa:7 Dig Dis l995:13(Suppl
`l):9-39.
`
`Henry DA. Side-effects of non-steroidal anti-inflammatory
`drugs. Balliere’s Clin Rheumatol 1988;2:425—54.
`Pemberton RE, Strand Ll. A review of upper-gastrointestinal ef—
`fects of the newer nonsteroidal antiinflammatory agents. Dig Dis
`Sci 1979;24:53-64.
`" Wallace JL. Non-steroidal anti-inflammatory drug gastropathy
`and cytoprotection: pathogenesis and mechanisms rte-examined.
`ScandJ Gastroenterol 1992;27(Suppl 192):3-8.
`5 Wallace .IL. NSAID gastroenteropathy: Past, present and future.
`Can J Gastroenterol 1996;10:451-9.
`
`6 Davenport HW. Back diffusion of acid through the gastric mu-
`cosa and its physiological consequences. In: Glass GBJ, editor.
`Progress in Gastroenterology, vol 1. New York: Giune & Strat—
`ton: 1970. p. 42-56.
`7 Cooke AR, Hunt JN. Absorption of acetylsalicylic acid from un—
`buffered and buffered gastric contents. Am J Dig Dis
`1970;15:95-102.
`
`8 Ivey KI, Morrison S, Gray C. Effect of salicylates on the. gastric
`mucosal barrier in man. J Appl Physiol 1972;33:81-5.
`9 Schoen RT. Vender RJ. Mechanisms of nonsteroidal anti-inflam-
`matory drug—induced gastric damage. Am J Med 1989;86:449-523.
`'0 Dotevall G, Ekcnved G. The absorption of acetylsalicylic acid
`from the stomach in relation to inrragastricpH. Scand 1 Gas-
`:
`troenterol 1976;11:801-5.
`.
`.
`_
`-
`'
`_
`._
`'
`” Mason WD, Winer N. Kinetics of aspirin, salicylic, acid, -and.sal—-
`icluric acid following oral administration of aspirin-us a tablet
`and two buffered solutions. .i_ Pharm Sci 1981;703262-‘5,
`’
`‘2 Mason .WD. Kinetics of aspirin absorption following oraliadtr'iin-I'
`istration of six aqueous solutions withdifi'ereut buffer-Capacities
`J Pharm Sci 1984;73:1258-61.
`-
`’3 St. John DJB, McDermott FT. Influence of achlorhydria on'as-
`
`patients taking NSAle. There are some potential con-
`cerns regarding prophylaxis with antisecretory com—
`pounds. It has been emphasized 95"” that it is not possi—
`ble to predict the effects of Hz-blockers on the inci—
`dence of clinically relevant complications and that, al~
`though these drugs may suppress symptoms,
`they
`could actually increase the probability of a serious
`complication because the absence of symptoms may
`encourage the use of higher doses of NSAIDs for
`longer periods.
`In addition, Lichtenberger et a1. 95 recently reported
`that pre-treatment with omeprazole or ranitidine, while
`reducing the severity of NSAID-induced gastric dam-
`age in rats, significantly reduced drug efficacy in terms
`of analgesic and anti-inflammatory properties. The
`same'team 9" also showed a significant reduction in
`ASA absorption (with consequent attenuation of its in-
`hibitory effects on PG biosynthesis) after omeprazole
`pre-treatment in rats. Therefore, although prescribing
`NSAIDS together with antisecretory agents seems to
`be a safe strategy, the drug combination could become
`less effective for its primary intention. Higher doses of
`NSAID would be necessary to guarantee a therapeutic
`effect, butthen risks are double 10°. It must be empha—
`sized, however, that in clinical pharmacological studies
`no effect of PPIs on NSAID pharmacokinetics. has
`been reported ‘0‘ ‘02.
`_
`"
`Finally, long-term use of marked acid suppression in
`NSAJD users infectedwnh H. pylori ”3405 may induce
`hypergastrinaemia large enough to stimulate cell pro-
`liferation in the gastric antral mucosa 105107.
`
`Conclusions and future perspective
`
`the key for preventing
`that
`There is "little doubt
`NSAID-associated gastro—duodenal damage lies in a
`better understanding of the underlying mechanisms for
`their GI toxicity. Although in the past some drugs were
`claimed to spare the GI tract, their promises have been
`mostly fulfilled. Recently, several approaches to the ra-
`tional design of Gl-sparing NSAle have shown
`promise in experimental studies (for review see "’8 '09)
`and phase II clinical data are now available showing
`that selective COX-2 inhibitors (e.g. celecoxib and ro-
`fecoxib) could be effective and safe alternatives to ex-
`isting NSAle in the treatment of inflammatory con-
`ditions “0 ”1. While waiting for their availability in
`clinical practice, we must rely on a better prescribing
`policy for the general population ”2 and on prophylac-
`tic co—therapy in patients at risk. Experimental and
`clinical pharmacology clearly shows that acid suppres-
`sion (but not acid inhibition) re