GASTROENTEROLOGY 2000;118:S9–S31
`
`Acid Suppression: Optimizing Therapy for Gastroduodenal
`Ulcer Healing, Gastroesophageal Reflux Disease, and
`Stress-Related Erosive Syndrome
`
`M. MICHAEL WOLFE* and GEORGE SACHS ‡
`*Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts; and ‡Division of
`Gastroenterology, UCLA School of Medicine and West Los Angeles VA Medical Center, Los Angeles, California
`
`One of the hallmarks of the mammalian stomach is its
`
`ability to secrete large quantities of concentrated
`(0.16 mol/L) hydrochloric acid (HCl).1 Although it is
`generally assumed that gastric acid and the proteolytic
`enzyme pepsin are required to initiate digestion, achlor-
`hydric individuals generally do not develop malabsorp-
`tion unless small bowel bacterial overgrowth is present. It
`is thus likely that the ability of the stomach to secrete
`acid evolved primarily from a need to sustain a sterile
`intragastric milieu. Organisms that possessed the capac-
`ity to kill ingested bacteria and other microbes were able
`to avoid the development of enteric colonization, and
`thereby ensure both efficient absorption of nutrients and
`prevention of systemic infections.1 Nevertheless, when
`present, gastric acid does play a significant role in protein
`hydrolysis and other aspects of the digestive process, and
`under various conditions, acid may play an etiologic role
`in producing various forms of discomfort and inciting
`esophageal and gastroduodenal mucosal injury.
`The normal human stomach contains approximately 1
`billion parietal cells that secrete hydrogen ions into the
`gastric lumen in response to various physiological stimuli.
`The generation of H1 ions is mediated by 3 pathways:
`neurocrine, paracrine, and endocrine (Figure 1). The
`principal neurocrine transmitter is acetylcholine, which
`is released by vagal postganglionic neurons and appears to
`stimulate H1 ion generation directly via a parietal cell
`muscarinic M3 receptor. Histamine is the primary para-
`crine transmitter that binds to H2-specific receptors on
`parietal cells. Adenylate cyclase is then activated, leading
`to an increase in adenosine 38,58-cyclic monophosphate
`(cAMP) levels and subsequent generation of H1 ions. The
`secretion of gastrin from antral G cells comprises the
`endocrine pathway and stimulates H1 ion generation
`both directly and indirectly, the latter by stimulating
`histamine secretion from enterochromaffin-like (ECL)
`cells of the corpus and fundus. Interactions among
`neurocrine, paracrine, and endocrine pathways are coordi-
`nated to promote or inhibit H1 ion generation. Hista-
`
`mine appears to represent the dominant route, because
`gastrin stimulates acid secretion principally by promot-
`ing histamine release from ECL cells.2,3 Thus, ECL cells
`are often referred to as ‘‘controller’’ cells in the process of
`gastric acid secretion.
`A negative feedback loop governs both gastrin release
`and the return of acid secretion to basal level.1,4–6 This
`autoregulatory mechanism prevents postprandial acid
`hypersecretion. After ingestion of a meal, gastrin release
`stimulates secretion of gastric acid. The intraluminal pH
`begins to decrease, which stimulates release of somatosta-
`tin from antral D cells, possibly through the activation of
`calcitonin gene–related peptide (CGRP) neurons.5,7 So-
`matostatin then appears to act via a paracrine mechanism
`to inhibit further release of gastrin from G cells.8
`Somatostatin produced by D cells in the gastric corpus
`and fundus may also directly inhibit acid secretion from
`parietal cells and may suppress histamine release from
`ECL cells (Figure 1).6,9 Other recent observations indicate
`that several other neurotransmitters, including vasoactive
`intestinal peptide (VIP), galanin, and pituitary adenylate
`cyclase–activating peptide, may play important roles in
`regulating gastric acid secretion, both directly and
`indirectly, under physiological conditions.10
`Pathophysiology of Acid-Related
`Disorders
`Gastroduodenal (Peptic) Ulcer
`The treatment of duodenal ulcer (DU) has served
`as the basis (correctly or incorrectly) for the management
`of nearly all acid-related disorders. This supposition in all
`likelihood contributed to delays in the optimal manage-
`ment of other gastrointestinal (GI) disorders in which
`
`Abbreviations used in this paper: DU, duodenal ulcer; ECL, entero-
`chromaffin-like; GERD, gastroesophageal reflux disease; GI, gastro-
`intestinal; GU, gastric ulcer; NCCP, noncardiac chest pain; PPI,
`proton pump inhibitor; PUD, peptic ulcer disease.
`r 2000 by the American Gastroenterological Association
`0016-5085/00/$10.00
`
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`S10 WOLFE AND SACHS
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`GASTROENTEROLOGY Vol. 118, No. 2
`
`Figure 1. Schematic representa-
`tion of the factors influencing
`gastric acid secretion by the pa-
`rietal cell, depicting neurocrine
`(acetylcholine and other neuro-
`transmitters from vagal efferent
`neurons), paracrine (somatosta-
`tin from D cells and histamine
`from gastric ECL cells), and en-
`docrine (circulating gastrin) fac-
`tors. Dashedarrowsindicate po-
`tential sites of pharmacological
`inhibition of acid secretion, ei-
`ther via receptor antagonism or
`via inhibition of H1,K1-ATPase.
`A, acetylcholine and other neuro-
`transmitters; H, histamine; G,
`gastrin; L365,260, synthetic
`gastrin receptor antagonist; PG,
`prostaglandin; S, somatostatin.
`
`cells, which decreases the magnitude of the response to
`luminal acidification.12–14 Thus,
`in patients with H.
`infection limited to the antrum, the negative
`pylori
`feedback inhibition of gastrin release is attenuated,
`resulting in higher postprandial gastrin levels and hyper-
`secretion of acid.
`Despite the existence of meal-induced hyperchlorhy-
`dria in DU patients, the presence of food in the stomach
`has a buffering effect that may protect the gastroduodenal
`mucosa from acid-induced injury. However, at night and
`during other prolonged periods of fasting, acid bathes the
`‘‘bare’’ mucosa, and in DU patients, the increase in
`nocturnal acid secretion magnifies this effect. Duodenal
`bicarbonate secretion also appears to be impaired in
`patients with DU,15 as well as in those infected with
`H. pylori, making the mucosal exposure to acid even
`greater. These observations, as discussed below, form the
`rationale for single nocturnal dosing of H2-receptor
`antagonists in the treatment of DU, a mode of therapy
`that is at least as effective as multiple dosing regimens.
`Clearly, factors other than acid and pepsin are involved
`in the pathogenesis of peptic ulcer disease (PUD), because
`only 30% of patients with DUs and very few patients
`with GUs are hyperchlorhydric.1 The balance between
`aggressive factors that act to injure the gastroduodenal
`mucosa and defensive factors that normally protect
`against corrosive agents is also important. When this
`delicate balance is disrupted for any reason, mucosal
`injury may ensue.1 These defensive properties appear to
`be mediated to a large extent by endogenous prostaglan-
`dins, nitric oxide, and trefoil proteins, and when the
`
`acid plays an etiologic role in producing symptoms and
`causing mucosal injury, such as gastroesophageal reflux
`disease (GERD). Although patients with gastric ulcers
`(GUs) tend to have normal or reduced levels of acid
`secretion,1 the average DU patient is an acid hypersecre-
`tor. When compared with age-matched controls, DU
`patients secrete ,70% more acid during the day (meal-
`stimulated) and about 150% more acid at night (basal
`secretion) (Figure 2).11 Postprandial gastric acid secretion
`is regulated primarily by increases in gastrin expression,
`which is controlled by a negative feedback loop. Individu-
`als infected with Helicobacter pylori have been shown to
`have a diminished number of somatostatin-secreting D
`
`Figure 2. Gastric acid secretion during the day and night in patients
`with DU (n 5 8) and in age-matched controls (n 5 7). Acid secretion is
`expressed as the mean 6 SE in millimoles per 12 hours. *P, 0.05.
`Data from Feldman et al.11
`
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`February Supplement 2000
`
`ACID SUPPRESSION THERAPY S11
`
`synthesis of any or all are diminished, the ability of
`the gastroduodenal mucosa to resist injury is decreased.
`Thus, even normal rates of acid secretion may be
`sufficient to injure the mucosa and produce gastroduode-
`nal ulcers. Nevertheless, even in DU patients who are
`normal secretors of acid, a reduction in the rate of acid
`secretion is the most efficient means of healing ulcers.1
`Although a large number of gastroduodenal ulcers are
`associated with H. pylori
`infection, at least 60% of
`individuals with complicated ulcers (e.g., hemorrhage or
`perforation) report the use of nonsteroidal anti-inflamma-
`tory drugs (NSAIDs), including aspirin.16 Mucosal injury
`associated with NSAID use is initiated topically by the
`acidic nature of NSAIDs.17 Topical mucosal injury may
`also occur as a result of indirect mechanisms, mediated
`through the biliary excretion and subsequent duodenogas-
`tric reflux of active NSAID metabolites.18,19 Topical
`injury caused by NSAIDs certainly contributes signifi-
`cantly to the development of gastroduodenal mucosal
`injury, but the systemic effects of these agents appear to
`play the predominant role,17,20,21 largely through the
`decreased synthesis of mucosal prostaglandins.22 Avoid-
`ance of topical mucosal injury by enteric-coated aspirin
`preparations22 or by the parenteral23 or rectal24 adminis-
`tration of NSAIDs does not prevent the development of
`ulcer complications. Moreover, doses of aspirin as low as
`10 mg are sufficient to significantly suppress gastric
`mucosal prostaglandin synthesis.25 A decrease in the
`above protective mechanisms normally stimulated by
`prostaglandins enables endogenous gastric acid to incite
`mucosal injury.
`In recent years, it has become evident that the actual
`percentage of ulcers associated with H. pylori may not be
`90%–95% as often reported, but may be as low as 32% in
`non–referral-based populations.26 Furthermore, despite
`the inclination to ascribe the etiology of ulcers in such
`individuals to NSAIDs, the use of these agents clearly
`does not account for the balance of the cases. Finally, the
`vast majority of remaining individuals do not have the
`Zollinger–Ellison syndrome (ZES) or another unusual
`cause of gastroduodenal ulcer. Thus, while peptic ulcer-
`ation involves the participation of several factors, as first
`stated by Karl Schwarz27 in 1910: ‘‘Ohne sauren Magensaft,
`kein peptisches Geschwu¨r,’’ i.e., ‘‘No acid, no ulcer.’’ The
`erosive properties of acid continue to play a central role in
`the pathogenesis of gastroduodenal mucosal ulceration,
`and conversely, acid suppression therapy remains the
`cornerstone of therapy.
`
`GERD
`Although the principal aggressive factor involved
`in causing heartburn and the other clinical manifestations
`
`of GERD is the presence of acid in the esophagus, the
`disorder does not usually result from the hypersecretion
`of gastric acid.28 Rather, GERD occurs as a result of
`several abnormalities in motor function of the lower
`esophagus and the lower esophageal sphincter (LES).
`Despite the etiologic role played by these important
`motor abnormalities, the severity of symptoms, most
`notably heartburn, and esophageal mucosal injury can be
`correlated with the total time that the esophageal mucosa
`is exposed to acid. Gastric acid thus also constitutes a
`critical element in the pathogenesis of GERD, and acid
`suppression comprises
`the principal mechanism for
`therapy. However, the optimal timing and degree of acid
`suppression differ significantly in GERD patients com-
`pared with the treatment of gastroduodenal ulcer (see
`below).
`
`Stress-Related Erosive Syndrome
`Many terms have been used to describe this entity,
`including stress ulcer syndrome, stress gastritis, stress-
`related mucosal disease, and stress-related erosive syn-
`drome (SRES).29,30 The principal feature of SRES is its
`relationship to serious systemic disease, such as sepsis,
`massive burn injury, head injury associated with in-
`creased intracranial pressure, severe trauma, and multiple-
`system organ failure. A meta-analysis of 2252 patients by
`Cook et al.31 identified mechanical ventilation and
`coagulopathy as the 2 singlemost important risk factors.
`Although the pathophysiology is multifactorial and
`definitely includes a component of
`ischemia, which
`compromises gastric mucosal
`integrity,
`luminal acid
`plays a dominant role in producing the multiple erosive
`lesions characteristic of the entity. Fiddian-Green et al.32
`emphasized the importance of H1 ion back-diffusion by
`demonstrating a high correlation between the degree of
`intramural pH and the development of SRES. Further-
`more, most, but not all, methods for preventing massive
`hemorrhage-associated SRES include the alkalinization of
`gastric contents.33
`
`Pharmacology of Parietal Cell
`Receptors
`The parietal cell possesses a unique morphology
`that differs markedly between the resting and stimulated
`states.1 Mitochondria occupy 34% of its cell volume,
`indicative of the importance of adenosine triphosphate
`(ATP) synthesis as an energy source required for the active
`transport of H1 ions out of the cell against a 3,000,000:1
`ionic gradient. A large percentage of resting cell volume
`is also occupied by tubulovesicles, which are elongated
`tubes with smooth surface membranes, and by the
`
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`S12 WOLFE AND SACHS
`
`GASTROENTEROLOGY Vol. 118, No. 2
`
`Table 1. Comparison of the Histamine H2-Receptor
`Antagonists
`Cimetidine Ranitidine Famotidine Nizatidine
`80
`50
`40
`70
`1
`5–10
`32
`5–10
`1.5–2.3
`1.6–2.4
`2.5–4
`1.1–1.6
`6
`8
`12
`8
`
`Bioavailability (%)
`Relative potency
`Circulator y t1⁄2 (h)
`a (h)
`Biological t1⁄2
`Relative effect on
`cytochrome P450
`metabolism
`
`1
`
`0.1
`
`0
`
`0
`
`t1⁄2, half-life.
`aApproximate values.
`Adapted and reprinted with permission. 37
`
`safety record, and in 1995 became available for use in the
`United States without prescription.
`
`Muscarinic Receptor and Its Antagonists
`The central nervous system, particularly via the
`vagus nerve, plays a dominant role in regulating basal
`acid secretion, as well as the cephalic phase of meal-
`stimulated acid secretion. Extracts of belladonna were
`used to treat dyspepsia since the time of the Roman
`empire, and in the recent past, nonspecific antimuscarinic
`agents such as atropine and propantheline bromide were
`used as inhibitors of gastric acid secretion. These drugs
`were associated with many adverse effects, including
`drowsiness, dry mouth, blurry vision, and urinary reten-
`tion, and as a result are rarely used today. To date,
`however, 5 muscarinic receptors have been subtyped and
`cloned, and although all are G protein coupled, they
`signal different intracellular pathways. In vitro character-
`ization of gastric acid secretion has indicated that the
`parietal cell normally expresses the M3 subtype.38 Clini-
`cally, the M1 antagonists, pirenzepine and telenzepine,
`are effective inhibitors of acid secretion and probably
`
`secretory canaliculus, a small invaginated area of the
`apical membrane. Upon stimulation, which is generally
`accomplished by eating a meal, the tubulovesicles de-
`crease in number and become transformed into microvilli
`around the secretory canaliculus, which serves to greatly
`expand the surface area of the parietal cell in preparation
`for the secretion of large quantities of HCl. The parietal
`cell also possesses several different receptors for stimula-
`tory and inhibitory ligands on its basolateral membrane
`(Figure 1).
`Histamine H2 Receptor and Its Antagonists
`The histamine receptor belongs to a large family
`of G protein–linked receptors possessing 7 transmem-
`brane domains.34 Despite the recognition that histamine
`stimulates gastric acid secretion, it was not until 1966,
`when Ash and Schield35 described H1 and H2 receptors
`for histamine, that the possibility of inhibiting acid
`secretion with histamine antagonists was proposed. In
`1970, Black et al.36 described selective histamine H2-
`receptor inhibition and initiated the search for pharmaco-
`logical agents that could effectively suppress the secretion
`of acid. Within 10 years of the release of cimetidine in the
`United States in 1977, 3 additional H2-receptor antago-
`nists—ranitidine, famotidine, and nizatidine—became
`available for use throughout the world. All 4 drugs
`(Figure 3) suppress basal and meal-stimulated acid
`secretion, albeit to a lesser degree than proton pump
`inhibitors (PPIs) discussed below. Despite similar thera-
`peutic profiles, some differences do exist with regard to
`the agents’ pharmacokinetic properties (Table 1), most of
`which are clinically insignificant.37 The elimination of
`these drugs occurs by a combination of hepatic metabo-
`lism and urinary excretion, and although hepatic dysfunc-
`tion does not alter their pharmacokinetic properties, dose
`reductions are recommended for all individuals with
`varying degrees of renal impairment (Table 2).37 H2-
`receptor antagonists as a class possess an unsurpassed
`
`Drug
`Cimetidine
`
`Ranitidine
`
`Famotidine
`
`Nizatidine
`
`Table 2. Histamine H2-Receptor Antagonist Dosing
`Adjustments With Renal Insuf ficiency
`Creatinine clearance (mL/min)
`.30
`15–30
`,15
`.75
`30–75
`15–30
`,15
`.75
`30–75
`15–30
`,15
`.75
`30–75
`15–30
`,15
`
`Dose (mg/day)a
`800
`600
`400
`300
`225
`150
`75
`40
`30
`20
`10
`300
`225
`150
`75
`
`Figure 3. Structure of the 4 H2-receptor antagonists in use in the
`United States.
`
`aDosing for gastroduodenal ulcer.
`Adapted and reprinted with permission. 37
`
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`

`February Supplement 2000
`
`ACID SUPPRESSION THERAPY S13
`
`exert their effect by interaction with a postsynaptic
`neuronal M1 receptor.1 These 2 agents are available in
`other countries for the treatment of duodenal ulcer, but
`they have not been approved for use in the United States.
`
`Gastrin Receptor and Its Antagonists
`As stated above, gastrin stimulates acid secretion
`via an endocrine pathway and induces H1 ion generation
`both directly and indirectly. The precise location and
`density of the gastrin receptor have been subjects of
`debate and may be somewhat species dependent. Several
`studies in rats and other rodents have suggested that
`gastrin stimulates acid secretion by enhancing the release
`of histamine from ECL cells.39,40 Conversely, receptors for
`gastrin receptors on canine parietal cells have been
`demonstrated by Soll et al.41 by employing the analogue
`125I-[Leu15]gastrin, and by Kopin et al.,42 who cloned and
`expressed the gastrin receptor from a purified canine
`parietal cell complementary DNA library. Moreover,
`single-cell video imaging has provided direct evidence for
`a functional gastrin receptor on the parietal cells of rats
`and rabbits.43
`The gastrin receptor belongs to the above-mentioned
`family of G protein–linked receptors possessing 7 trans-
`membrane domains.42 It is closely related to the receptor
`for cholecystokinin (‘‘CCK-A’’ or ‘‘CCK-1’’) and is thus
`often referred to as the ‘‘CCK-B’’ or ‘‘CCK-2’’ receptor.
`Gastrin-specific receptor antagonists have been devel-
`oped, which include L365,260 and YM022.44 The former
`is a benzodiazepine derivative that was derived from the
`fungus Aspergillus alliaceus and has been demonstrated to
`effectively antagonize gastrin-stimulated gastric acid
`secretion.44 Despite this effect, these antagonists have not
`been used clinically as inhibitors of acid secretion.
`However, they may ultimately prove useful
`in the
`treatment of panic and anxiety disorders by virtue of
`binding to gastrin receptors in the brain.45
`
`Miscellaneous Receptors on the
`Parietal Cell
`Other receptors on the parietal cell basolateral
`membrane have been suggested by the ability of various
`agents to inhibit gastric acid secretion. For example,
`prostaglandins inhibit H1 ion generation by binding to
`their EP3 G protein–linked receptor on the parietal cell,
`which appears to inhibit adenylate cyclase, and thereby
`decrease intracellular cAMP generation when activated.46
`As discussed below, the acid-inhibitory properties of
`prostaglandin analogues such as misoprostol, while not
`potent, are nevertheless critical for exerting any beneficial
`clinical effects.16
`
`Parietal Cell H11,K11-Adenosine
`Triphosphatase
`The gastric enzyme H1,K1-adenosine triphospha-
`tase (ATPase) is a member of the family of ion-motive
`ATPases that includes F1, V, and P ATPases. The latter is
`divided conveniently into P1 or P2 types in 1 of 2 ways,
`either based on the number of transmembrane segments
`(8 in the case of the P1 and 10 in the case of the P2
`catalytic subunits) or based on transport of transition
`metals (P1) or small cations (P2).47 Within the P2 family,
`the gastric H1,K1- and Na1,K1-ATPase isoforms are
`coexpressed tightly bound to a b-subunit that is smaller
`than the catalytic or a-subunit, has most of its sequence
`presented outside, and is glycosylated to different extents
`depending on the isoform.48,49 These latter 2 enzymes are
`also unique in that they both serve as drug targets,
`digoxin for congestive heart failure in the case of the
`Na1,K1-ATPase and substituted pyridyl methylsulfinyl
`benzimidazoles for acid-related disorders in the case of
`the H1,K1-ATPase.50 H1,K1-ATPase consists of 8 trans-
`membrane segments for the catalytic a-subunit and 1
`transmembrane segment for the b-subunit (Figure 4).51,52
`
`Inhibition of Acid Secretion
`The recognition that the ATPase was the final step
`of acid secretion has resulted in the development of a class
`of drugs, the PPIs, that are targeted toward this enzyme.
`They all share a common structural motif (Figure 5), a
`substituted pyridylmethylsulfinyl benzimidazole, but vary
`in terms of their substitutions. They also share common
`inhibitory mechanisms and are all weak protonatable
`pyridines, with a pKa of ,4.0 for omeprazole, lansopra-
`zole, and pantoprazole, and ,5.0 for rabeprazole. They
`thus accumulate selectively in the acid space of the
`secreting parietal cell. Within that space or on the surface
`
`Figure 4. A model of the 2-dimensional arrangement of the gastric
`H1,K1-ATPase subunits. The core structure of this P2-type ATPase
`consists of the first 6 membrane segments, arranged as helices with
`the possible exception of the cytoplasmic end of M6. Cross-linking and
`column chromatography of tryptic fragments has shown an associa-
`tion between M5 and M7, and M6 and M9 (curvedarrows). The major
`high-affinity interaction with the b-subunit is with the beginning of M8.
`
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`S14 WOLFE AND SACHS
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`GASTROENTEROLOGY Vol. 118, No. 2
`
`Figure 5. Structure and reaction pathways of the 4 PPIs in use in the United States. All are ampholytic weak bases and accumulate as prodrugs in
`the secretor y canaliculus of the actively secreting parietal cell. They are all acid-catalyzed to a reactive thiophilic species whereby the pyridine N
`reacts with the 2C of the benzimidazole to form a sulfenic acid (below), which, while in solution, reacts further to form a sulfenamide (above). The
`respective sulfenamides then react with available cysteines on the luminal sur face of the enzyme; cys 813 is common to all the PPIs and crucial
`for enzyme inhibition. Cys 892 reacts with omeprazole,
`lansoprazole, and rabeprazole; cys 321 with lansoprazole; and cys 822 with
`pantoprazole. 54
`
`of the enzyme, they undergo an acid-catalyzed conversion
`to a reactive species, the thiophilic sulfenamide or
`sulfenic acid, which are permanent cations. The rate of
`conversion varies among the compounds and is a function
`of their pKa and other structural features: rabeprazole .
`omeprazole 5 lansoprazole . pantoprazole.53,54 The
`reactive species reacts with cysteine residues available
`from the external surface of the enzyme that faces the
`lumen of the secretory space of the parietal cell, resulting
`in covalent inhibition of the enzyme by disulfide bond
`formation. The cysteine residue that is critical
`for
`inhibition is cys 813 in the catalytic subunit of the
`H1,K1-ATPase, strategically located in the M5/M6
`sector of the enzyme, which is intimately involved in the
`transport process.
`Because all the PPIs require accumulation and acid
`activation, their onset of
`inhibition is delayed, and
`because they also form a covalent derivative, the restora-
`tion of acid secretion is likewise delayed, depending on
`the turnover of the pump protein and the biological
`reversibility of the disulfide bond. Therefore, 24–48
`hours are necessary for maximal acid secretory capacity to
`be restored. Different doses of these drugs are recom-
`mended, but at equivalent doses, these agents are remark-
`ably similar when used in the treatment of acid-related
`disorders (Table 3).55
`The PPIs are without question the most potent
`inhibitors of gastric acid secretion available. However,
`because they are most effective when the parietal cell is
`stimulated to secrete acid in response to a meal, these
`
`drugs should only be taken before or with a meal and
`should not be used in conjunction with H2-receptor
`antagonists, prostaglandins, or other antisecretory agents
`(Table 3). Animal studies have demonstrated that the
`concomitant administration of PPIs and other antisecre-
`tory agents will markedly reduce the acid-inhibitory
`effects of the PPI.56 Because acid secretion must be
`stimulated for maximum efficacy, PPIs are administered
`before the first meal of the day (Table 3). Moreover, in
`
`Table 3. Helpful Facts on the Use of PPIs
`PPIs are prodrugs that require activation to their active moiety (thio-
`philic sulfenamide)
`pKa of PPIs: ,4 for omeprazole, lansoprazole, and pantoprazole; ,5
`for rabeprazole
`All PPIs are activated when regional pH decreases below their respec-
`tive pKa
`Achieved almost exclusively in parietal cell secretor y canaliculus
`Achieved optimally when parietal cell is activated, i.e., after meals
`Most effective after a prolonged fast, when a large amount of inac-
`tive H1,K1-ATPase present is in secretor y canaliculus, i.e.,
`after breakfast
`Clinical use
`Steady state not achieved for several days
`Thus often helpful to administer twice daily for the first 2–3 days
`of therapy
`Also likely not to be consistently clinically effective when taken
`sporadically
`First dose should be taken before breakfast
`Second dose, if used, should be taken before evening meal
`Donotadminister concomitantly with H2-receptor antagonists or
`prostaglandins
`Safety: toxicity seems to be gastrin-related and is probably species
`specific
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`
`ACID SUPPRESSION THERAPY S15
`
`most individuals, once-daily dosing is sufficient to
`produce the desired level of acid inhibition. A second
`dose, if required, should be administered before the
`evening meal.
`During meals, however, neither all parietal cells nor all
`proton pumps are active. The initial dose of the PPI will
`thus inhibit only activated H1,K1-ATPase present in the
`canalicular membrane.56 As inactive enzyme is recruited
`into the secretory canaliculus, acid secretion will resume,
`albeit at a reduced level. After a second dose, more
`enzyme will have been recruited and subsequently inhib-
`ited, and after a third dose, additional recruitment and
`further acid inhibition may be expected. Once-daily PPI
`dosing results in 66% steady-state inhibition of maximal
`acid output after 5 days, and the initial use of twice-daily
`dosing (for the first 2–3 days) may thus be helpful in
`achieving more rapid inhibition of gastric acid secre-
`tion.55 Based on these pharmacokinetic properties, the
`occasional use of a PPI taken on an ‘‘as-needed’’ basis
`would not be expected to provide adequate acid inhibi-
`tion and would be unlikely to produce a consistent or
`satisfactory clinical response.
`
`Safety Issues
`The safety profile of the PPIs is similar to that of
`H2-receptor antagonists. Although headache and diarrhea
`are occasionally reported, serious adverse reactions to
`these agents are rare and generally not well documented.
`Initial concern was expressed when PPIs were introduced
`as a result of their ability to precipitate ECL cell
`hyperplasia and subsequent gastric carcinoid tumors in
`rats when given at high doses. This trophic effect occurs
`as a result of
`interruption of the negative feedback
`mechanism for acid secretion, which induces an increase
`in antral gastrin gene expression.1,4–6 However, these
`drugs have been used for nearly 15 years in Europe and for
`10 years in the United States with no discernible increase
`in the incidence of carcinoid tumors. The reasons for such
`interspecies differences are not entirely evident, but are
`probably related in part to a lower mucosal ECL cell
`density and a considerably less pronounced increase in
`circulating gastrin in humans compared with rodents in
`response to antisecretory medications. One area of theo-
`retical concern that has not been completely resolved is
`the possible effect of gastrin and its precursor prohor-
`mone on promoting the growth of colonic neoplasms.
`An area of controversy has been the need to monitor
`serum gastrin concentrations in persons on long-term
`PPI therapy. In general, laboratory and other testing
`should be performed only if the treatment plan will be
`dependent on their results. Long-term PPI treatment is
`used most commonly in patients with GERD, many of
`
`whom have significant symptoms and mucosal injury.
`The sequelae of GERD are serious and real, whereas the
`effects of hypergastrinemia, which occurs in only ,5% of
`individuals receiving long-term PPI therapy, are theoreti-
`cal. Therefore, in situations in which the hypothetical
`risk of the PPI is clearly outweighed by the benefits
`offered by potent acid suppression, serum gastrin measure-
`ments should not be performed.57
`
`Treatment of Acid-Related Disorders
`Acute Gastroduodenal Ulcer
`The treatment of ulcer disease has changed dra-
`matically since the discovery that the probability of ulcer
`recurrence decreases significantly after successful eradica-
`tion of H. pylori infection, compared with annual recur-
`rence rates of 50%–80% when antisecretory therapy
`alone is used.58,59 Thus, a determination of H. pylori
`infection in a patient with gastroduodenal ulcer is critical
`for the appropriate management of this disease. If a
`patient is not infected with H. pylori, an alternative
`etiology must be sought, such as NSAID use, hypersecre-
`tory states, or one of the other less common causes of ulcer
`disease, such as Crohn’s disease, vascular insufficiency,
`viral infection, radiation therapy, and cancer chemother-
`apy. Regardless of the etiology, however, the inhibition of
`gastric acid secretion continues to play a prominent role
`in the management of acute gastroduodenal ulcer.
`Some differences do exist between DUs and GUs
`proximal to the prepyloric region of the stomach. Most
`previous studies have assessed the effects of acid suppres-
`sion on duodenal and pyloric channel ulcers and antral
`ulcers within 2–3 cm of the pylorus, but few have
`actually evaluated the healing of more proximal GUs.
`Although gastric acid secretion is generally lower than
`normal in patients with more proximal disease,1 these
`latter ulcers usually do heal in response to acid suppres-
`sion, although the total duration of therapy is often
`prolonged.
`In general, a dynamic relationship exists between the
`healing of DU and the inhibition of intragastric acidity.
`Important parameters that determine the effect of antise-
`cretory therapy include the degree of suppression of
`intragastric acidity, the length of acid inhibition over a
`24-hour period, and the duration of antisecretory treat-
`ment. For example, Burget et al.60 showed that if
`intragastric pH is maintained above 3.0 for a period of
`18–20 hours per day, DU healing approximates 100% at
`4 weeks. As discussed below, the DU healing rate at 4
`weeks is also directly proportional to the degree of the
`reduction of nocturnal acidity.61
`
`DRL EXHIBIT 1014 PAGE 7
`
`

`

`S16 WOLFE AND SACHS
`
`GASTROENTEROLOGY Vol. 118, No. 2
`
`Table 4. Current Recommendations for Treatment of
`Gastroduodenal Ulcers
`Active ulcer
`H2-receptor antagonists
`Cimetidine 800 mg
`Ranitidine/nizatidine 300 mg
`Famotidine 40 mg
`All administer ed between the evening meal and bedtime
`PPIs
`Omeprazole 20 mg
`Lansoprazole 30 mg
`Rabeprazole 20 mg
`Pantoprazole 40 mg
`All administer ed daily before breakfast
`Maintenance therapy
`H2-receptor antagonists
`Cimetidine 400 mg
`Ranitidine/nizatidine 150 mg
`Famotidine 20 mg
`All administer ed between the evening meal and bedtime
`PPIs
`As above
`Prevention of NSAID-induced ulcers
`Misoprostol
`At least 200 µg 3 times/day
`PPIs
`As above
`
`NOTE. In general, duodenal ulcers should be treated for 4 weeks and
`gastric ulcers for 8 weeks.
`
`Antacids. In a landmark controlled, double-blind
`study in 1977, Peterson et al.62 showed that antacids were
`superior to placebo in healing DU, although (contrary to
`prevailing opinions) no difference in symptom relief was
`detected. However, because of the need to take these
`d