Lupin Exh. 1019
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`Lupin Exh. 1019
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`

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`(cid:3) (cid:55)(cid:75)(cid:76)(cid:86)(cid:3)(cid:80)(cid:68)(cid:87)(cid:72)(cid:85)(cid:76)(cid:68)(cid:79)(cid:3)(cid:80)(cid:68)(cid:92)(cid:3)(cid:69)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:87)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:79)(cid:68)(cid:90)(cid:3)(cid:11)(cid:55)(cid:76)(cid:87)(cid:79)(cid:72)(cid:3)(cid:20)(cid:26)(cid:3)(cid:56)(cid:17)(cid:54)(cid:17)(cid:3)(cid:38)(cid:82)(cid:71)(cid:72)(cid:12)(cid:3)
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`GASTROENTEROLOGY 2000;118:S9-531
`
`Acid Suppression: Optimizing Therapy for Gastroduodenal
`Ulcer Healing, Gastroesophageal Reflux Disease, and
`Stress-Related Erosive Syndrome
`
`M. MICHAEL WOLFE* and GEORGE SACHSI
`*Section of Gastroenterology. Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts; and 1‘Division of
`Gastroenterology, UCLA School of Medicine and West Los Angeles VA Medical Center, Los Angeles, California
`
`ne of the hallmarks of the mammalian stomach is its
`
`Oability to secrete large quantities of concentrated
`
`(0.16 mol/L) hydrochloric acid (HCl).1 Although it is
`generally assmned 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} 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 rnucosal 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 H+ ions is mediated by 3 pathways:
`neurocrine, paracrine, and endocrine (Figure 1). The
`principal neurocrine transmitter is acetylcholine, which
`
`is released by vagal postganglionjc neurons and appears to
`stimulate H+ 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 5'5’-cyclic monophosphate
`(CAMP) levels and subsequent generation of H+ ions. The
`secretion of gastrin from antral G cells comprises the
`endocrine pathway and stimulates H+ ion generation
`both directlyand indirectly, the latter by stimulating
`histamine secretion from enterochrornaffin-like (ECL)
`
`cells of the corpus and fundus.
`
`Interactions among
`
`neurocrine, paracrine, and endocrine pathways are coordi-
`nated to promote or inhibit H"' ion generation. Hista-
`
`mine appears to represent the dominant route, because
`gastrin stimulates acid secretion principally by promot-
`ing histamine release from ECL Ce-lls.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-‘L6 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 releaseof sorI1atosta-
`tin from antral D cells, possibly through the activation of
`calcitonin gene—related peptide (CGRP) neurons.” So-
`matostatin then appears to act via a paracrine mechanism
`to inhibit
`further release of gastrin from G cel_ls.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.”
`
`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, entere-
`chromaffln-like; GERD, gastroesophageal reflux disease; GI, gastro-
`intestinal; GU, gastric ulcer; NCCP, noncardiac chest pain; PPI,
`proton pump inhibitor; PUD, peptic ulcer disease.
`© 2000 by the American Gastroenterological Association
`0016-5085/00/$10.00