f ARCHIVES
`
`OF
`
`Internal
`MedICIne
`
`JUNE 1992
`
`E;
`;
`_.
`.jj’;
`
`mg
`Cw;—
`‘5',"
`
`3E? Ji?
`;
`—.-. 11+”
`.~._JL. ——J
`
`4:57:39")
`3de L7
`":7". 1'4
`
`4' 3*?
`Tint
`
`Nonpharmacologic Intervention to Reduce Blood Pressure
`in Older Patients With Mild Hypertension
`W. B. Applegate, S. T. Miller, 1. T. Elam, W. C. Cushman,
`D. E! Dem/i, A. Brewer, M. ]. Graney
`
`Saturated Fats, Cholesterol, and Dietary Compliance
`Y. Henkin, D. W. Garber, L. C. Osterlund, B. E. Darnell
`
`
`Adherence to Cholesterol-Lowering Diets
`S. M. Grundy
`
`
`Improving Clinical Teaching: Evaluation of a
`National Dissemination Program
`K. M. Skeff, G. A. Stratos, I. Berman, M. R. Bergen
`
`
`Marital Aggression: Impact, Injury, and
`Health Correlates for Husbands and Wives
`
`M. Cascardi, J. Langhinrichsen, D. Vivian
`
`Volume 152, Number 6
`
`American Medical Association
`
`Physicians dedicated to the health of America
`
`Page 1 of 16
`
`Patent Owner Ex. 2013
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`Mylan v. Pozen
`lPR2017-01995
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`

`

`EDITORIAL BOARD
`
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`James E. Dalen, MD
`2601 N Campbell Ave, Suite 202
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`Jack M. Matloff, MD, Los Angeles, Calif
`Kevin M. McIntyre, MD, JD, Boston, Mass
`Steven Swiryn, MD, Evanston, III
`John G. Weg, MD, Ann Arbor, Mich
`
`Copyright © 1992 by the
`American Medical Association
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`\rch intern Med—Vol 152, June 1992
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`ARCH IVES
`
`
`
`OF
`
`Internal
`MedICIne
`
`Vol 152
`
`No. 6
`
`JUNE 1992
`
`
`EDITORIAL
`_
`Adherence to Cholesterol-Lowering Diets
`Scott M. Grundy, MD
`
`.1139
`
`\
`
`
`COMMENTARY
`
`Medical Futility: Who Decides?
`Nancy S. Jecker, PhD, Robert A. Pearlman, MD, MPH
`
`1140
`
`
`REVIEW ARTICLE
`
`Effects of Nonsteroidal Anti-inflammatory Drugs on
`Endogenous Gastrointestinal Prostaglandins and
`Therapeutic Strategies for Prevention and Treatment of
`Nonsteroidal Anti-inflammatory Drug—Induced Damage
`Byron Cryer, MD, Mark Feldman, MD
`
`1145
`
`
`SPECIAL ARTICLE
`
`Improving Clinical Teaching: Evaluation of
`a National Dissemination Program
`Kelley M. Skeff, MD, PhD; Georgette A. Stratos, PhD;
`Judith Berman, EdD; Merlynn R. Bergen, PhD
`
`1156
`
`
`ORIGINAL INVESTIGATIONS
`
`,-
`_, 1162;
`.
`I;
`,x/
`
`V"
`
`
`
`i
`
`Nonpharmacologic Intervention to Reduce Blood Pressure
`in Older Patients With Mild Hypertension
`William B. Applegate, MD; Stephen T. Miller, MD; Janet T. Elam;
`William C. Cushman, MD; Douaa El Derwi, MD;
`Amy Brewer, RD; Marshall J. Graney, PhD
`
`Continued on page 1111.
`
`1109
`
`Patent Owner Ex. 2013
`
`Mylan v. Pozen
`lPR2017-01995
`
`Page 2 of 16
`
`Patent Owner Ex. 2013
`Mylan v. Pozen
`IPR2017-01995
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`

`

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`Saturated Fats, Cholesterol, and Dietary Compliance
`Yaakov Henkin, MD; David W. Garber, PhD;
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`
`
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`
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`Marital Aggression: Impact, Injury, and
`Health Correlates for Husbands and Wives
`Michele Cascardi, MA; Jennifer Langhinrichsen, PhD;
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`rch Intern Med—Vol 152, June 1992
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`Page 3 of 16
`
`The Clonidine Suppression Test for Pheochromocytoma:
`A Review of Its Utility and Pitfalls
`Robert J. Sjoberg, MD; Kenneth J. Simcic, MD;
`Gerald S. Kidd, MD
`
`
`
`Randomized Controlled Study of a Retiree Health Promotion
`Program: The Bank of America Study
`J. Paul Leigh, PhD; Nancy Richardson, MD;
`Robert Beck; Clark Kerr, PhD; Harry Harrington;
`Charles L. Parcell; James F. Fries, MD
`
`
`
`1193
`
`1201
`
`Predicting Postoperative Pulmonary Complications:
`Is It a Real Problem?
`Pamela Williams-Russo, MD; Mary E. Charlson, MD;
`C. Ronald MacKenzie, MD; Jeffrey P. Gold, MD;
`G. Tom Shires, MD
`
`Medical Care and Cost Outcomes After Pentoxifylline
`Treatment for Peripheral Arterial Disease
`Andy Stergachis, PhD; Steven Sheingold, PhD; Bryan R. Luce, PhD;
`Bruce M. Psaty, MD, PhD; Dennis A. Revicki, PhD
`
`
`
`Proteinuria, Renal Impairment, Metabolic Control, and
`Blood Pressure in Type 2 Diabetes Mellitus:
`A 14-Year Follow-up Report on 195 Patients
`Mordchai Ravid, MD; Hilel Savin, MD;
`Ruth Lang, MD; ltzhak Jutrin, MD;
`Ludvinovsky Shoshana, MSC; Michael Lishner, MD
`
`
`
`Single-Dose Compared With 3-Day Norfloxacin Treatment of
`Uncomplicated Urinary Tract Infection in Women
`Raphael Saginur, MD; Lindsay E. Nicolle, MD;
`Canadian Infectious Diseases Society Clinical Trials Study Group
`
`1209
`
`1220
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`1225
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`1233
`
`Continued on page 1113.
`
`1111
`
`Patent Owner Ex. 2013
`
`Mylan v. Pozen
`lPR2017-01995
`
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`

`

`
`
`ARCHIVES
`
`
`
`Cardiovascular Effects of Pseudoephedrine in
`Medically Controlled Hypertensive Patients
`MAJ Richard A. Beck, MC, USA; CPT Donna L. Mercado, MC, USA;
`CPT Sharon M. Seguin, MC, USA; COL W.P. Andrade, MC, USA;
`LTC Howard M. Cushner, MC, USA
`
`
`
`1242
`
`The Natural Course of Multiple Endocrine
`Neoplasia Type IIb: A Study of 18 Cases
`Hans F. A. Vasen, MD; Machteld van der Feltz, MD;
`Friedhelm Raue, MD; Arie Nieuwenhuyzen Kruseman, MD;
`Hans P. F. Koppeschaar, MD; Gerlach Pieters, MD;
`Fritz J. Seif, MD; Werner F. Blum, MD; Cees J. M. Lips, MD
`
`
`
`Plague: A Clinical Review of 27 Cases
`Larry D. Crook, MD, Bruce Tempest, MD
`
`
`
`Body Mass Index and Body Girths as
`Predictors of Mortality in Black and White Women
`June Stevens, PhD; Julian E. Keil, DrPH; Philip F. Rust, PhD;
`H. A. Tyroler, MD; C. E. Davis, PhD; Peter C. Gazes, MD
`
`
`
`The Potential Role of Thrombolytic Therapy
`in Venous Thrombosis
`Arie Markel, MD; Richard A. Manzo, CCVT;
`D. Eugene Strandness, Jr, MD
`
`1250
`
`1253
`
`1257
`
`1265
`
`
`
`Fever in Pheochromocytoma
`Donald L. Gordon, MD; Susan D. Atamian, MD;
`Marion H. Brooks, MD; Paolo Gattuso, MD;
`Melanie J. Castelli, MD; Jonas Valaitis, MD;
`William Thomas, Jr, MD
`
`1269
`
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`Continued on page 1115.
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`‘ch Intern Med—Vol 152, June 1992
`
`Page 4 of 16
`
`1113
`
`Patent Owner Ex. 2013
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`Mylan v. Pozen
`lPR2017-01995
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`Page 4 of 16
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`The Clinical Impact of Culturing Central Venous Catheters:
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`The Use of Hepatobiliary Scintigraphy in Patients
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`\rch Intern Med—Vol 152, June 1992
`
`1115
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`Page 5 of 16
`
`Patent Owner Ex. 2013
`
`Mylan v. Pozen
`IPR2017-01995
`
`Page 5 of 16
`
`Patent Owner Ex. 2013
`Mylan v. Pozen
`IPR2017-01995
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`

`

`Effects of Nonsteroidal Anti-inflammatory
`Drugs on Endogenous Gastrointestinal
`Prostaglandins and Therapeutic Strategies
`for Prevention and Treatment of Nonsteroidal
`Anti-inflammatory Drug\p=m-\InducedDamage
`
`Byron Cryer, MD, Mark Feldman, MD
`
`Although nonsteroidal anti-inflammatory drugs (NSAIDs)
`are effective for pain relief and treatment of arthritis, they
`can induce gastric and duodenal ulcers and life-threatening
`complications. The mechanisms of their anti-inflammatory
`action and their gastroduodenal toxic effects are related, in
`part, to inhibition of prostaglandin synthesis. This review
`article discusses prostaglandins, their functions in the gas-
`trointestinal tract, anti-inflammatory actions of NSAIDs,
`and mechanisms by which NSAIDs produce gastroduodenal
`ulcers. Also reviewed are risk factors associated with the
`ulcers and pharmacologic
`development of NSAID-related
`strategies for the prevention and treatment of NSAID\x=req-\
`induced ulcers.
`(Arch Intern Med. 1992;152:1145-1155)
`Nonsteroidal anti-inflammatory drugs (NSAIDs) are
`widely used for pain relief and for treatment of
`arthritis (including rheumatoid arthritis, ankylosing
`spondylitis, osteoarthritis, and gouty arthritis). A partial
`list of NSAIDs is shown in the Table. Although NSAIDs
`are effective as therapeutic agents, their major toxic effect
`is induction of gastroduodenal ulcers. Mechanisms for
`their anti-inflammatory action and their gastroduodenal
`toxic effects are probably related to an inhibition of pros-
`taglandin synthesis. The purposes of this article are to re¬
`view the effects of NSAIDs on the gastroduodenal mu¬
`cosa, including their effects on mucosal prostaglandins,
`and to review the effects of therapeutic agents that can be
`used to prevent and treat NSAID-induced gastroduode¬
`nal damage.
`PROSTAGLANDINS AND RELATED COMPOUNDS
`Prostaglandins (PGs) are a family of related fatty acids
`that are produced by nearly all of the body's cells. Pros¬
`taglandins participate in a variety of activities, including
`mediation of inflammatory responses, protection of the
`
`Accepted for publication November 16, 1991.
`From the Medical Service, Department of Veterans Affairs Med-
`ical Center, and Department of Internal Medicine, University of
`Texas Southwestern Medical Center at Dallas.
`Reprint requests to Dallas VA Medical Center (111), 4500 S Lan-
`caster Rd, Dallas, TX 75216 (Dr Feldman).
`
`-
`
`gastrointestinal mucosa against injury, and regulation of
`renal blood flow. The general chemical structure of PGs
`is an oxygenated, 20-carbon, unsaturated fatty acid (ei-
`cosanoid) composed of a five-carbon ring, with two car¬
`bon side chains, one composed of seven carbon molecules
`and the other composed of eight.1 Nomenclature used to
`describe individual PGs is based on two distinguishing
`the letter designation of PGs (ie,
`features. First,
`their
`family) is determined by the structure of the five-carbon
`ring. For example, all PGEs have a double-bonded oxygen
`( = O) at carbon 9 and a hydroxyl group (
`OH) at carbon
`11, while all PGFs have a hydroxyl group at both carbon
`9 and carbon ll.2 Second, the number of double bonds in
`the side chains determines PG classification as 1-, 2-, or
`3-series and is reflected by a subscript (eg, PGE2 [2-series]
`or 6-keto-PGFia [1-series]) (Figure).
`Prostaglandins are not stored within cells in any signif¬
`icant quantities, but are stored as precursor molecules.
`Prostaglandins of the 2-series are the most plentiful and
`biologically important and are derived from arachidonic
`acid, a component of phospholipids present in all cell
`membranes. In response to a mechanical or chemical per¬
`turbation of the cell membrane, arachidonic acid is
`released from membrane phospholipids into the cyto¬
`through the action of a plasma
`plasm of
`the cell
`membrane-bound enzyme, phospholipase A2. Once re¬
`leased, arachidonic acid may be acted on by cyclo-
`resulting in
`oxygenase, a membrane-bound enzyme,
`synthesis of PGs; alternatively, it may be metabolized by
`another enzyme, 5-lipoxygenase, to a group of closely re¬
`lated compounds,
`the leukotrienes (LTs) (Figure). The
`cyclo-oxygenase
`activities
`relative
`of
`the
`and
`5-lipoxygenase pathways, and thus the relative amounts
`of eicosanoids produced, vary with cell type.3 In gastric
`and duodenal mucosa, most arachidonic acid is converted
`into PGE2, PGF2tI, and PGI2.W
`FUNCTION OF PROSTAGLANDINS IN THE
`GASTROINTESTINAL TRACT
`Although PGs were first identified in the human body
`in the 1930s, it was not until the mid-1960s that PGs were
`identified in the gastrointestinal tract.7"9 The earliest rec¬
`ognized effect of PGs on gastric mucosal function was an
`
`Page 6 of 16
`
`Patent Owner Ex. 2013
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Partial List of Nonsteroidal Anti-inflammatory Drugs
`Salicylates
`Aspirin*
`Diflunisal (Dolobid)*
`Salsalate (Disalcid)*
`índoles
`Indomethacin (Indocin)*
`Sulindac (Clinoril)*
`Tolmetin (Tolectin)*
`Zomepirac (Zomax)
`Pyrazoles
`Apazone (Rheumox)
`Feprazone (Methrazone)
`Phenylbutazone (Butazolidin)*
`Fenamates
`Flufenamic acid (Meralen)
`Mefenamic acid (Ponstel)*
`Meclofenamate (Meclomen)*
`Tolfenamic acid (Clotam)
`Proprionic acid derivatives
`Carprofen (Rimadyl)
`Fenbufen (Cinopal, Lederfen)
`Fenoprofen (Nalfon, Fenopron)*
`Flurbiprofen (Ansaid, Froben)*
`Ibuprofen (Motrin, Advil)*
`Ketoprofen (Orudis)*
`Naproxen (Naprosyn, Anaprox)*
`Pirprofen (Rengasil)
`Phenylacetic acid derivatives
`Diclofenac (Voltaren, Voltarol)*
`Fenclofenac (Flenac)
`Oxicams
`Isoxicam (Maxicam)
`Piroxicam (Feldene)*
`»Available in the United States in 1991.
`inhibition of gastric acid and pepsin secretion.10"13 Intra¬
`venously administered PGs of the E, F, and A classes and
`orally administered synthetic analogues of these com¬
`pounds have potent antisecretory effects, PGs of the E
`class being the most potent.14"20
`In the 1970s, investigators began to demonstrate that
`PGs could protect the gastric mucosa from injury and ul¬
`cération against a wide variety of damaging agents, such
`as alcohol, bile salts, acid, hypertonic saline, boiling wa¬
`ter, stress, aspirin, and other NSAIDs.2128 Robert et al21
`performed the earliest of these experiments,
`in which
`they demonstrated that pretreatment with PGs could
`prevent mucosal damage from various noxious agents in
`rats. It was demonstrated that mucosal protection could
`be observed at doses of PGs that did not inhibit acid se¬
`cretion.22 This protective property of PGs was called "cy-
`toprotection."29 Even though pretreatment with PGs may
`protect against macroscopic injury, there is usually mi¬
`croscopic evidence of mucosal injury to surface epithelial
`cells after exposure to alcohol or other noxious agents.30
`Because of persistent surface cell damage despite PG pre¬
`treatment, the term cytoprotection is not entirely accurate
`and has for the most part been replaced by mucosal protec¬
`tion. Mucosal protection by prostaglandins has not only
`been demonstrated in the stomach, but has been shown
`in the duodenum.3138 Protection has been demonstrated
`with PGs of all classes and is separate from any effects the
`compounds may have on gastric acid secretion. In fact, in
`animals, mucosal protection has been demonstrated with
`PGs, such as 6-keto-PGFla, that have no demonstrated
`
`Membrane Phospholipids
`Phospholipase A2
`Arachidonic Acid
`
`Cyclo-oxygenase
`
`5-Lipoxygenase
`
`5-HPETE — 5-HETE
`
`I
`LTA4
`
`PGG2
`
`LTB4 LTC4
`
`LTD4
`
`Tnromboxane A2
`
`PGD2
`
`PGE2
`
`PGF2a
`
`LTE4
`
`Thromboxane B2
`
`Leukotrienes
`
`Thromboxanes
`
`6-Keto-PGFla
`
`Prostaglandins
`
`Metabolism of arachidonic acid after its release from membrane
`phospholipids. HPETE indicates hydroperoxyeicosatetraenoic acid;
`HETE, hydroxyeicosatetraenoic acid; PC, prostaglandin; and LT,
`leukotriene.
`
`effect on acid secretion.31 However, in humans, it is not
`certain that the protective effects of PGs are due to mech¬
`anisms separate from inhibition of gastric acid secretion,
`since PGs, at doses employed in human trials, have
`antisecretory effects as well.
`How 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
`protective factors, such as bicarbonate and mucus.39,40
`When there is an imbalance between aggressive and pro¬
`tective factors, such that the extent of mucosal protection
`is lowered in relation to the level of offending agents,
`injury ensues. Persistence of
`mucosal
`this imbalance
`could lead to mucosal erosions and ulcération. Some of
`several putative mechanisms proposed through which
`PGs may provide their mucosal protective effects include
`the following: stimulation of mucosal bicarbonate secre¬
`tion, mucus secretion, increased blood flow, prevention
`of disruption of the gastric mucosal barrier, acceleration
`of cell proliferation, stimulation of cellular ionic transport
`processes, stimulation of cyclic adenosine monophos-
`phate production, promotion of formation of surface-
`active phospholipids, maintenance of gastric mucosal
`sulfhydryl compounds, stabilization of cellular
`lyso-
`somes, and stabilization of cell membranes.24,28'29'4W5 Soil
`et al46 categorized various protective mechanisms accord¬
`ing to their location with respect to the surface epithelial
`cells. They have been accordingly described as preepi-
`thelial (mucus and bicarbonate secretion), epithelial (sur¬
`face epithelial cell continuity and migration), and postep-
`ithelial (mucosal blood flow).
`INFLAMMATION AND ANTI-INFLAMMATORY ACTIONS
`OF NSAIDs
`Inflammatory cell recruitment is achieved through the
`release of a number of chemical mediators, such as PGs,
`LTs, histamine, serotonin, kinins, complement factors,
`and other peptides.47,48 Evidence implicating PGs in this
`process was not obtained until 1971, when Vane49 pro-
`
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`posed PGs as substances that could elicit an inflammatory
`response. Prostaglandins were demonstrated to be asso¬
`ciated with inflammation in a variety of experimental sit¬
`uations. For example, after subcutaneous PG administra¬
`tion, edema and erythema as well as some of
`the
`histologie changes of inflammation were observed.50 Af¬
`ter administration of aspirin, biosynthesis of PGs de¬
`creased in proportion to the decrease in the amount of in¬
`flammation,49'51-52 and then, if exogenous PGs were later
`administered, there would be a return of inflammation.49
`Experimental administration of PGs could induce fever53
`and potentiate pain,54 and subsequent administration of
`an NSAID could decrease fever and pain while also
`decreasing PG concentrations. It soon became clear that
`the anti-inflammatory effects of such drugs as aspirin
`could be explained by their suppression of PG synthesis
`and that such inhibition could also explain the actions of
`these drugs as analgesics and antipyretics.
`Aspirin, an acetylated salicylate, was one of the first
`NSAIDs shown to be clinically effective as an anti-
`inflammatory agent.55 Although many other NSAIDs
`have since been introduced, aspirin remains one of the
`most effective anti-inflammatory agents.55 It is through
`the inhibition of cyclo-oxygenase that aspirin and other
`NSAIDs decrease PG synthesis. By acetylation of cyclo-
`oxygenase, aspirin inhibits this enzyme irreversibly,
`ibuprofen, and
`while other NSAIDs (flufenamic acid,
`sulindac, for example) inhibit cyclo-oxygenase in a re¬
`versible, concentration-dependent manner.56-57 When
`cyclo-oxygenase is irreversibly inhibited within any par¬
`ticular cell, the capacity for PG synthesis does not return
`to normal until new enzyme can be synthesized.56 This
`may explain why aspirin,
`in comparison with other
`NSAIDs, remains one of the most potent inhibitors of PG
`synthesis. It is hypothesized that cyclo-oxygenase exists
`in multiple forms throughout the body and that each form
`has its own drug specificity,58 although this has not yet
`been verified by identification of structural cyclo-
`oxygenase variants. Cyclo-oxygenases obtained from dif¬
`ferent tissues have different sensitivities to inhibition by
`a particular NSAID, and different NSAIDs have variable
`abilities to inhibit a particular cyclo-oxygenase.57-58 For ex¬
`ample, acetaminophen is as effective as aspirin in the in¬
`hibition of brain cyclo-oxygenase, but is not nearly as ef¬
`fective as aspirin in the inhibition of cyclo-oxygenase from
`some peripheral sites.58 This may explain why acetami¬
`nophen is an effective centrally acting antipyretic and an¬
`algesic but is not an effective peripherally acting anti-
`inflammatory agent. This may also explain why
`acetaminophen does not cause gastroduodenal toxic ef¬
`fects.
`The LTs also play a significant role in the inflammatory
`response. They increase vascular permeability, are
`chemotactic for neutrophils, vasoconstrict arteries, stim¬
`ulate bronchial wall constriction and mucus secretion,
`and increase intestinal inflammation.59-60 Certain NSAIDs,
`in addition to inhibiting cyclo-oxygenase, also may inhibit
`5-lipoxygenase.56-61 The NSAIDs differ in their relative
`potencies to reduce inflammation,62 and their anti-
`inflammatory effects do not always correlate with their
`ability to reduce PG synthesis. These observations may
`possibly be explained by different capacities of the various
`NSAIDs to inhibit cyclo-oxygenase, on the one hand, and
`5-lipoxygenase, on the other hand. An NSAID such as
`indomethacin is predominantly a cyclo-oxygenase inhib-
`
`itor, while other experimental NSAIDs of the fenamate
`class are effective inhibitors of both enzymes.63 Whether
`differences in the relative amounts of cyclo-oxygenase/5-
`lipoxygenase inhibition by NSAIDs is indeed related to
`differences in anti-inflammatory actions of NSAIDs is
`currently under investigation.
`Anti-inflammatory actions of NSAIDs are not only ex¬
`plained by inhibition of eicosanoid synthesis. For exam¬
`ple, NSAIDs inhibit PG synthesis in vivo and in vitro at
`concentrations much lower than those required to achieve
`anti-inflammatory effects.64 Moreover, some salicylates,
`including nonacetylated salicylates, are beneficial in in¬
`flammatory disease54-65"68 even though they do not inhibit
`PG synthesis.66-69 Inhibition of neutrophil function has
`been suggested as a second mechanism by which NSAIDs
`can exert their anti-inflammatory effects.62-7071
`MECHANISMS OF GASTRODUODENAL MUCOSAL
`INJURY BY NSAIDs
`The mechanisms by which aspirin can cause gas¬
`trointestinal mucosal damage can be grouped into two
`categories: those independent of and those dependent on
`cyclo-oxygenase inhibition. Within a few minutes of
`aspirin ingestion, denudation of surface epithelial cells
`and increased mucosal permeability to sodium (Na+) and
`hydrogen (H+) ions can be observed,72 reflected experi¬
`mentally as a decrease in transmucosal potential differ¬
`ence.73-74 Salicylic acid, the deacetylated metabolite of as¬
`pirin, does not inhibit cyclo-oxygenase activity in the
`gastric mucosa,75 yet it reduces transmucosal potential
`difference as much as aspirin does.73 Thus, surface
`epithelial cell disruption and a decline in potential differ¬
`ence are not dependent on cyclo-oxygenase inhibition,
`and epithelial cell disruption is not prevented by pre¬
`treatment with PGs.76
`Endoscopie observation of the gastric mucosa after 1 to
`2 weeks of enteric-coated aspirin therapy77-78 or after 1
`week of enteric-coated naproxen therapy79 revealed con¬
`siderably less gastric mucosal damage than with plain,
`non-enteric-coated formulations. Although gastric injury
`from a topical effect is decreased with enteric-coated for¬
`mulations, their use on a long-term basis will result in
`gastric ulcers (GUs),80 presumably the result of a systemic
`rather than topical effect. Gastric ulcers can be produced
`experimentally after NSAIDs are administered intrave¬
`nously81 or by rectal suppository82 and without a change
`in gastric transmucosal potential difference.81-83 It is likely
`that the NSAIDs were ulcerogenic because they reduced
`mucosal PG synthesis. This is supported by two observa¬
`tions: (1) small nonantisecretory doses of exogenous PGs
`prevent NSAID-induced ulcers23-24-28 and (2) depletion of
`mucosal PGs by another mechanism, active or passive
`immunization with PG antibodies, leads to GUs.84
`Although inhibition of PG synthesis contributes to
`NSAID-induced mucosal injury, it is not settled whether
`PG inhibition is the primary mechanism. In some studies,
`there has been poor correlation between gastric mucosal
`injury and PG suppression after NSAIDs.85"89 Other fac¬
`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 increase,89 gastric mu¬
`cosal blood flow to decrease,90-91 and duodenal bicarbon¬
`ate output to decrease.92 Nonsteroidal anti-inflammatory
`drugs can also potentially affect mucus secretion, as
`
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`

`they have been shown to inhibit mucus synthesis,
`to
`reduce incorporation of
`radiolabeled precursors into
`mucus glycoprotein, and to alter thickness of the mu¬
`cus layer.28-93
`It has been hypothesized that, as a consequence of
`cyclo-oxygenase inhibition, arachidonic acid metabolism
`could alternatively be shunted toward the lipoxygenase
`pathway, resulting in increased LT synthesis.94"99 The
`postulated mechanism by which increased activity of the
`5-lipoxygenase pathway could enhance mucosal injury is
`by LT-mediated vasoconstriction or by direct vascular in¬
`jury by oxygen radicals produced in this pathway.98-99 The
`relative importance of LTs in NSAID-induced gastric mu¬
`cosal damage is still unclear.
`Since other pathogenetic mechanisms are potentially
`operative, one may ask whether significant NSAID-
`in the absence of
`injury can occur
`related mucosal
`suppression of mucosal PGs. After administration of
`a nonacetylated salicylate that
`salsalate,
`is anti-
`inflammatory, mucosal injury has been far less than after
`other NSAIDs.100"102 Salsalate does not significantly inhibit
`cyclo-oxygenase activity or reduce mucosal PG con¬
`inhibition of PG synthesis is probably
`tent.69102 Thus,
`necessary but not sufficient for mucosal injury.
`SHORT-TERM VS LONG-TERM NSAID ADMINISTRATION
`After short-term administration, a variety of types of
`injury develop, ranging from petechial hemorrhages, dif¬
`fuse hemorrhages, superficial erosions, and,
`less com¬
`monly, ulcération.*