Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Acid and Barriers: Current Research and Future Developments for Peptic Ulcer Therapy J. W. Rademaker & R. H. Hunt To cite this article: J. W. Rademaker & R. H. Hunt (1990) Acid and Barriers: Current Research and Future Developments for Peptic Ulcer Therapy, Scandinavian Journal of Gastroenterology, 25:sup175, 19-26, DOI: 10.3109/00365529009093123 To link to this article: http://dx.doi.org/10.3109/00365529009093123
Published online: 08 Jul 2009.
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Date: 10 April 2016, At: 05:03
Acid and Barriers Current Research and Future Developments for Peptic Ulcer Therapy J . W. RADEMAKER & R. H. HUNT Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario, Canada
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Rademaker JW, Hunt RH. Acid and barriers. Current research and future developments for peptic ulcer therapy. Scand J Gastroenterol 1990,25(suppl 175), 19-26 Medical therapy for peptic ulcer disease has been targeted at inhibiting acid secretion based on the belief that ulcers occur due to an imbalance between aggressive and protective factors. New antisecretory agents are unlikely to show any dramatic improvement over the success and safety of histamine H 2 receptor antagonists or the recently introduced H'K' ATPase proton pump antagonist omeprazole. The development of specific muscarinic M3 and gastrin receptor antagonists will provide useful agents to suppress acid and pepsinogen secretion by alternative means and may prevent the associated hypergastrinaemia seen with anti-secretory therapy. Enhancement of mucosal defence by site protective agents will be based on a better understanding of the vascular and immune factors involved in maintaining mucosal integrity and the growth factors that regulate wound healing. Molecular techniques are likely to produce the 'model anti-ulcer' agent which will effectively inhibit acid secretion and also enhance wound healing thus providing a cure for this chronic disease. Key words: Current research; drug therapy; peptic ulcer Prof. Richard H . Hunt, FRCP, FRCPC, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main St. West, Hamilton, Ontario L8N 325, Canada
Despite the changing pattern of peptic ulcer disease and the advances in medical treatments seen during this century, ulcer disease remains a significant cause of morbidity and high cost to the health care systems of most countries. The introduction of the histamine Hz-receptor antagonist (H2RA) cimetidine in 1975 provided the first effective non-surgical therapy for duodenal and gastric ulcer. The rationale for the use of the H2RAs is based on the beliefs that ulcers occur as a result of an imbalance between luminal aggressive and mucosal defensive factors (1) and that by inhibiting acid-peptic activity, a more favourable environment for ulcer healing occurs. Despite their commercial success and safety, the H2RAs available today have not altered the natural history of the disease, although ulcer patients may be maintained free of symptoms and relapse by prolonged maintenance treatment (2). The past decade has seen dramatic devel-
opments in our understanding of the regulation of gastric secretion (3), especially at the cellular level (4).The identification of the H+,K+-ATPase proton pump led to the development of the highly specific H+,K+-ATPase antagonist omeprazole (9,which is the most potent and direct antisecretory agent available. The results of clinical trials with omeprazole have shown accelerated healing of duodenal and gastric ulcer and especial benefit in refractory duodenal ulcer ( 6 )and severe gastro-oesophageal reflux disease (7). Concern about the long-term safety of omeprazole continues following the result of animal toxicity studies (8), in which prolonged inhibition of gastric acid secretion at high doses was associated with hypergastrinaemia. Enterochromaffinlike cell (ECL) hyperplasia with micronodules occurs and may progress to frank carcinoids. However, antrectomized animals treated with omeprazole showed no such changes (9), sug-
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gesting that omeprazole has no direct toxic effect and that these changes are directly related to hypergastrinaemia. Omeprazole is currently advocated for short-term use, and surveillance of patients requiring long-term omeprazole has only demonstrated ECL hyperplasia (10). A better understanding of the mechanisms involved in acute injury (11) and the role of eicosanoids in regulating mucosal defence and acid secretion led to the introduction of the prostaglandin EI(PGE1) analogue misoprostol. In animal studies this drug demonstrated mucosal protective and inhibitory actions but has not lived up to its expectations in clinical trials of peptic ulcer healing (12). Healing rates which equate to other ulcer healing agents are only seen at antisecretory doses. However, a specific benefit has been seen in preventing the development of nonsteroidal anti-inflammatory drugs (NSA1D)associated gastric ulcer in high-risk patients (13). Non-antisecretory site protective agents such as bismuth compounds and sucralfate, which act by stimulating mucosal defence mechanisms rather than by a simple barrier effect, have not been universally accepted because of multiple and less convenient dosing and their mode of action not being fully understood. However, in clinical trials both tri-potassium dicitrato-bismuthate (14) and sucralfate (15) are as effective as the H2RAs in acute ulcer healing trials at 4 to 6 weeks. Particular interest in bismith followed reports of decreased recurrence after colloidal bismuth subcitrate (CBS) therapy (16) and the demonstration of both in vivo and in vitro bactericidal effect against Helicobacter pylori (17). Research and development of novel anti-ulcer agents that alter mucosal defence and wound healing still lags behind that of the market-dominated anti-secretory agents. This review will consider the development of future anti-ulcer drugs considering our present concept of ulcer pathophysiology occurring as an imbalance of luminal and mucosal factors. ACID SECRETION Understanding of the regulation of acid secretion at the cellular level has increased dramatically
and includes the identification of receptor subtypes and unravelling of the complex signal transduction pathways that activate the H+,K+ATPase pump. The sometimes confusing and differing results between studies can be largely accounted for by species variation, and experiments in isolated human glands have confirmed that histamine is the most potent secretagogue compared with acetylcholine and gastrin (18). Current concepts of receptor regulation of acid secretion involve stimulatory receptors for histamine and acetylcholine on the basolateral membrane of the parietal cell with gastrin probably acting indirectly via release of histamine from the ECL cells (4). Histamine signal transduction involves activation of membrane-bound adenylate cyclase to increase intracellular cyclic AMP, which then activates protein kinases (19). Muscarinic receptor stimulation results in the hydrolysis of membrane phospholipids to form inositol triphosphate (IP3) and diacylglycerol (20). IP3 releases calcium from intracellular stores, and diacylglycerol independently activates protein kinases. The location and function of the different protein kinase subtypes in regulating the H+,K+ATPase pump and acid secretion are not yet known. Non-specific protein kinase antagonists such as staurosporine inhibit pancreatic secretion in isolated rat acini (21) but have not yet been evaluated in parietal or chief cells. Further research will no doubt identify the genetic markers and specific function of these regulatory proteins, which may account for the genetic variation seen in acid secretion in patients with peptic ulcer disease. The development of specific protein kinase antagonists as therapeutic targets would appear to have no significant advantage over the already proven H+,K+-ATPasepump antagonists such as omeprazole or lansoprazole in the parietal cell. The development of omeprazole was associated with a rapid increase in our understanding of the structural and functional changes that occur in the parietal cell during acid secretion. Omeprazole and similar compounds can be considered ideal antisecretory agents, which are only activated by acid in the secretory canaliculus of the
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parietal cell to form an intermediate sulphenamide, which then binds irreversibly to the mercapto groups of the H+,K+-ATPase molecule to form the disulphide inhibitor complex (22). The central role of histamine in the stimulation of acid secretion has been based solely on the availability of pharmacologic antagonists, and the histamine H2 receptor itself has not yet been isolated. Evidence from animal studies proposes that a histamine H3 receptor exists in both central and peripheral nervous systems, and this appears to regulate pre-synaptic transmission and alter smooth-muscle tone (23). An H3 receptor antagonist may offer an alternative agent for reducing muscular hyperactivity and vasoconstriction. In the cat gastric fistula model, H3 receptor agonists also inhibit pentagastrin-stimulated acid secretion (24). Five subtypes of the muscarinic receptor have recently been identified by molecular cloning techniques (25). Experiments using the M3 antagonists hexahydrosiladifenidiol and silahexocyclium in rat parietal cells (26) have proposed an M3 receptor on the parietal cell which appears to inhibit acid secretion by acting on inositol phosphate pathways and intracellular calcium. This further characterization of the muscarinic receptor as M3 may explain the relatively weak antisecretory effects of the M1 receptor antagonists pirenzepine and telenzipine. The development of 3-benzoylamino and 3acyclamino benzodiazepine analogues as specific gastrin and cholecystokinin (CCK) antagonists, respectively, has shown a distinction between gastrin and CCK receptors in studies of amylase secretion from pig pancreatic acini and contraction of guinea pig stomach smooth muscle (27). These agents will help resolve the controversy that surrounds the location and function of the gastrin receptor on the parietal cell and provide potential agents for inhibiting acid secretion and preventing the hypergastrinaemia seen with H2RA and omeprazole. Inhibition of acid secretion at the cellular level occurs with prostaglandins of the E series and several hormones, including secretin, somatostatin, and neurotensin. A specific PGE receptor has been identified on canine parietal cells and
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appears to be linked to the histamine-adenyl cyclase receptor by a guanine nucleotide regulatory protein (28). Prostaglandin analogues, which also have mucosal protective properties in animal studies, have not achieved the expected clinical success and are associated with a measurable incidence of diarrhoea and abdominal pain (12). Continued research into the complex area of eicosanoids may provide a more specific analogue or novel compound that will fulfil the promise of a specific combined antisecretory and mucosal protective agent without significant side effects. Somatostatin, acting as a paracrine hormone, appears to have an important inhibitory role in regulating acid secretion by directly inhibiting parietal cell function (29) and regulating gastrin release via gastrin-releasing peptide nerves (30). The long-acting somatostatin analogues currently available must be given parenterally and are only of benefit for the complication of bleeding in peptic and stress ulcers (31). PEPSIN AND PEPSINOGEN The importance of pepsin as an aggressive factor in ulcer disease continues to receive little attention (32), although recent interest in the regulation of pepsinogen secretion and synthesis has been stimulated after the identification of pepsinogen isoenzymes. Recent animal experiments have clarified the regulatory mechanisms involved in the secretion and synthesis of pepsinogens (33). Despite species variation, pepsinogen secretion is stimulated via CCK and muscarinic M1 and M3 receptors (33), which act via both cyclic AMP and calcium signal transduction pathways to stimulate both secretion and synthesis of pepsinogen. Further studies with agents that inhibit pepsinogen secretion, especially in humans, may provide non-acid anti-secretory therapy, although it seems probable that such control is only likely to be achieved at the level of the regulatory genes. MUCOSAL DEFENCE The advances in our understanding of the different components of mucosal defence has fol-
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lowed a structural approach, and the importance and interaction between the mucosal immune and enteric nervous systems has only recently been recognized. Acid secretion can be considered the immediate mucosal protective response following exposure to foreign protein and antigen in the form of food and bacteria. Doubt now exists about the importance of the mucus-bicarbonate barrier and its ability to form an unbroken layer over the gastroduodenal mucosa (35). Rapid restitution by the active phospholipid layer has been confirmed, but its exact role in mucosal defence remains unclear (36). Rapid restitution by cell migration and regeneration are recognized as critical components of mucosal defence (37) and of wound healing, which will be discussed later. Damage to the network of mucosal blood vessels is critical in determining the degree and probably the depth of damage that occurs following exposure to luminal irritants (1 1). Maintenance of mucosal blood flow not only supplies oxygen and nutrients but also rapidly removes backdiffusing hydrogen ion and exogenous or endogenous toxins. As a result of the relationship of the blood vessels to the secretory glands, the bicarbonate ions produced during acid secretion are directed towards and maintain neutralization at the luminal surface (38). The mucosal immune and enteric nervous systems are also considered important regulators of mucosal blood flow. Morphologic studies of human gastric biopsy specimens have demonstrated that two populations of histamine-containing cells occur (39). Histamine-containing ECL cells are supplied by cholinergic nerve fibres and lie close to parietal cells, thus supporting the concept of an integrated relationship between central mechanisms and histamine as a secretagogue, A second population of histamine-containing cells is seen in the lamina propria adjacent to the origin of the mucosal capillary vessels. Histamine released from these separate populations of mast cells would result not only in acid secretion but also in local vasodilation and increased capillary permeability, which, if uncontrolled, would predispose the mucosa to damage. Animal studies have shown that the mast-cellstabilizing agent disodium chromoglycate reduces
ethanol-induced gastric damage (40) by preventing mast cell degranulation and release of histamine and other mediators of cell damage. Evidence exists to show that mucosal blood flow and the muscular activity of the muscularis mucosa are regulated by neural reflexes following luminal exposure to irritants. In animal studies ablation of mucosal neutrons by pre-treatment with capsaicin caused exacerbation of ethanolinduced injury (41), whereas stimulation prevented injury (42). The neutro-transmitter calcitonin gene-related peptide (CGRP) appears to be released from afferent neurons and enhances mucosal blood flow (43). Alterations in smoothmuscle activity are considered important in both experimental ulcer models (44) and duodenal ulcer patients ( 4 9 , but the mechanisms involved are not known. The anatomic relationship of the muscularis mucosa to the origin of the mucosal blood vessels may be important in maintaining mucosal integrity by the ability to constrict and reduce blood flow. Whether enteric neural pathways regulate mast cell and muscle activity in humans is not known, but a close association of neurons to mast cells of the small and large bowel has been reported in humans (46). This would suggest that a similar mechanism might exist in the stomach, but this remains to be confirmed, and the effect of any disease process on their regulatory function needs further investigation. Proposed mechanisms responsible for mucosal injury in acute haemorrhagic shock involve the formation of oxygen-derived free radicals following re-perfusion. These toxic oxygen metabolites result from the action of xanthine oxidase on accumulated hypoxanthines with oxygen (47). Free radicals produce direct damage by causing cell lysis and activation of lysosomal enzymes, which produce further damage and inflammation. The xanthine oxidase inhibitor allopurinol and free radical scavengers superoxide dismutase and dimethyl sulphoxide protect the gastric mucosa against haemorrhagic shock in animal models (48) and may be potential therapeutic agents for preventing stress ulceration. WOUND HEALING The gastrointestinal mucosa is a rapidly pro-
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liferating epithelium and is regulated by systemic hormones such as growth hormone, by thyroxine, and by local gut peptides, in particular gastrin and epidermal growth factor (EGF). EGF is a polypeptide present in secretions from salivary, duodenal Brunner’s glands, and the pancreas (49). EGF is not absorbed, is resistant to protease digestion, and appears to play an important role in mucosal defence and in wound healing. From the results of preliminary clinical trials (50) EGF not only increases cell turnover but also the release of prostaglandins, sulfhydryls, and somatostatin. Studies have also shown that parenteral EGF inhibits stimulated acid secretion in humans (51) and directly inhibits parietal cell activity via a guanine nucleotide inhibitory protein (52). Gastric and duodenal ulcer patients secrete less salivary EGF than healthy controls (53),and both smoking (49) and NSAIDs (54) are known to decrease salivary EGF secretion, which would impair wound healing in these groups. Recently, it has been suggested that the induction of an EGF-secreting cell line occurs following mucosal ulceration anywhere in the human gut (55). Biopsy specimens taken adjacent to the area of mucosal ulceration show that a small bud appears to form a new gland, which secretes EGF and hence stimulates ulcer healing. Fibroblast growth factor (FGF) stimulates the growth of fibroblasts and endothelium and has recently attracted considerable attention. An acid-stable FGF analogue ( m G F ) given orally accelerated the healing of cystamine-induced chronic duodenal ulcer in rats (56). Histology showed marked early angiogenesis followed by complete restoration of duodenal mucosal architecture in the FGF-treated group compared with controls. These results indicate that P G F stimulates regeneration, specifically angiogenesis, and produces a more rapid and complete wound healing without inhibition of acid secretion. The importance of the quality of wound healing in peptic ulcer disease has not been addressed except for a brief report that duodenal ulcer patients showed improved mucosal healing following treatment with bismuth when compared with cimetidine (57). The underlying mechanisms
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were not explained, and no long-term follow-up was reported. The cimetidine group with incomplete healing was felt to be more susceptible to luminal aggressive agents and ulcer recurrence. Clearly, good histologic studies of ulcer healing are necessary. FUTURE DEVELOPMENTS A considerable delay occurs between discovery and the introduction of a new drug, and any predictions concerning future therapeutic agents can only be made from compounds currently under development. The concept of a ‘model antiulcer drug’ remains difficult to predict in view of the basic lack of understanding of the aetiology and pathophysiology of peptic ulcer disease. The therapeutic target is shifting from inhibition of acid secretion to stimulation of mucosal defence and treatment of H.pylori infection but with only limited success. Treatments aimed at modifying wound healing would appear to provide the next major therapeutic opportunity for investigation. The importance of inhibiting acid secretion in healing peptic ulcer is well recognized, and a clear correlation between the degree of acid suppression and healing rates has been shown for duodenal ulcer (58). This relationship has been studied further, and the optimal degree of acid suppression defined as a threshold of pH 3 for 18-20 h daily, to achieve 100% duodenal ulcer healing at 4 weeks (59). The clinical requirements of acid inhibition are probably adequately fulfilled by the wide range of currently available antisecretory drugs. Development of more potent and longer-acting H2RA have not been successful, and all have been withdrawn after the development of various gastric tumours in long-term animal toxicology studies (60). The mechanism by which these lesions have developed remains unclear, although the hypergastrinaemia consequent upon prolonged acid suppression is generally accepted as the cause of ECL hyperplasia and carcinoid tumours, as seen with omeprazole (8). The proton pump antagonist clones (61,62) have already started to appear but must still face extensive animal toxicity testing and clinical trials before they become available for general use.
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The continued development of specific M3 muscarinic cholinergic antagonists may provide an alternative non-surgical form of vagotomy to inhibit not only acid but also pepsinogen secretion. These agents will need to be more potent than the currently available MI antagonists pirenzipine and telenzipine and to avoid the common and unwanted side effects of atropine. The benzodiazepine-related gastrin antagonists (27) will have considerable physioldgic and possible therapeutic applications. These agents may have a direct therapeutic role in controlling acid secretion but may also be used in combination with antisecretory agents to prevent the hypergastrinaemia felt to cause tolerance to therapy with HIRA (63) and carcinoids with more potent acid inhibition (8). Their application for the treatment ofgastric or colonic carcinoma to reduce the trophic effect of gastrin is of equal consideration and requires further study, since promising results have already been reported in isolated tumour cultures with these agents (64). The potential mucosal defence targets for therapeutic intervention must continue to be explored in view of the increasing use of NSAIDs, especially in the elderly, who are at increased risk of bleeding and perforation. The identification of mediators that produce vasospasm and contraction of non-vascular smooth muscle and the development of antagonists or inhibitors of these mediators or, alternatively, vasodilator substances could significantly alter the response to mucosal irritants in susceptible individuals. The relative lack of success of the PGE analogues should not discourage further research into development of new agents with a greater degree of specificity, and misoprostol has immunomodulatory effects. Mast cellstabilizing agents and selective immunomodulatory agents are attractive and novel approaches, but a more complete understanding of the integration of the immune system with the mucosal defence system is needed before these are likely to be developed. The study of growth factors has opened a whole new approach to healing ulcers, and human studies have already confirmed that oral EGF heals gastric ulcer (50) and parenteral E G F inhibits
stimulated acid secretion (51). The potential development for EGF analogues that inhibit acid secretion and increase the rate and quality of ulcer healing may provide a curative rather than palliative treatment. An alternative approach would be to combine the properties of the potent antisecretory agent omeprazole with the acidstable growth factor /3FGF to produce similar results. The pathogenic role of H. pylori remains controversial, and current regimens of bismuth and antibiotics have not proved able to eradicate the organism completely. Studies with furazolidone have shown both in vitro and in vivo activity against H. pylori (65) and may provide a specific and potentially less toxic anti-H. pylori agent than bismuth. Further clinical trials and discovery of newer anti-H. pylori agents are likely in the foreseeable future. The multifactorial nature of peptic ulcer disease and the importance of the brain-gut axis (66) and motility (45) must also be considered as potential targets. Animal studies have shown that the neurotransmitter thyrothropin-releasing hormone is ulcerogenic, whereas @endorphin, neutrotensin, and bombesin are protective (66). The possibility that ulcer disease may result from a neurochemical imbalance in the brain may help explain the association of stress with peptic ulcer disease. Studies that have demonstrated an association of altered gastroduodenal motility with ulcer models in animal (44) and duodenal ulcer patients (45) have proposed that a failure to clear acid from the duodenal bulb is as important as an increased acid load or decreased neutralizing capacity. Altering gastroduodenal motility with prokinetic drugs may benefit certain patients but much research is needed to identify further the duodenal receptors and specific neurotransmitters that regulate antropyloroduodenal function. Current technology and the development of molecular biologic techniques have provided powerful research tools in the form of highly specific genetic robes that have the potential to lead to new therapeutic agents such as the oligonucleotides, which regulate protein synthesis (67). The development of novel agents that modulate the mucosal defence mechanisms and wound
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healing by regulation of cellular protein synthesis could thus provide a cure by correcting the imbalance between the aggressive and protective factors in genetically predisposed individuals.
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REFERENCES 1. Schwarz K, Beitz Z. Ueber penetrierende magenund jejunalgeschwure. Klin Chir 1910, 67, 96-128 2. Freston JW. H,-receptor antagonists and duodenal ulcer recurrence: analysis of efficacy and commentary on safety, costs, and patient selections. Am J Gastrenterol 1987, 82, 1242-1249 3. Wolfe MM. Sol1 AM. The physiology of gastric acid secretion. NEJM 1988, 319, 1707-1715 4. Sachs G , Tache Y, Debas HT. et al. Control of gastric secretion. Am J Med 1987, 83, 307-327 5 . Fellenius E, Berglindh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+) ATPase. Nature 1981,159-l61 6 . Bardhan KD. Omeprazole in the management of refractory duodenal ulcer. Scand J Gastroenterol 1989, 24(suppI 166), 63-73 7. Dent J, Hetzel DJ, MacKinnon MA, et al. Evaluation of omeprazole in reflux oesophagitis. Scand J Gastroenterol 1989, 24(suppl 166), 76-82 8. Hakanson R, Sunder F. Gastric carcinoids and antisecretory drugs. TIPS 1986, 7, 386387 9. Lawsson H, Carlsson E, Mattsson H, et al. Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation. Gastroenterology 1986.96, 391-399 10. Solcia E, Rind G. Maru N , Elm G . Qualitative studies of gastric endocrine cells in patients treated long-term kith omeprazole. Scand j Gastroenterol 1989, 24(suppl 166), 129-137 11. Szabo S. Mechanisms of mucosal injury in the stomach and duodenum: Time-sequence analysis of morphologic, functional, biochemical and histochemical studies. Scand J Gastroenterol 1986, SUPPI PI 127), 21-28 12. Hawkey CJ, Walt RP. Prostaglandins for peptic ulcer: A promise unfulfilled. Lancet 1986, 2, 10841086 13. Graham DY, Agrawal N , Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, doubleblind, placebo-controlled trial. Lancet 1988, 2, 1277-1280 14. Miller JP. Colloidal bismuth in the treatment of duodenal ulceration: the benefit for the patient. Scand J Gastroenterol 1989. 2(suppl 157). I 6 2 0 15. Wagstaff AJ, Benfield P, Monk JP. Colloidal bismuth subsitrate. A review of its pharmacodynamics and pharmacokinetic properties, and its therapeutic used in peptic ulcer disease. Drugs 1988, 36, 132157 16. Marshall BJ, Goodwin CS. Warren JR, et al. Prospective doubleblind trial of duodenal relapse after eradication of Campylobacter pylori. Lancet 1988, 2, 1437-1442 17. Lambert JR, Hansky J, Davidson A, et al. Campylobacter like organisms (CL0)-in vivo and in
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vitro susceptibility to antimicrobial and antiulcer therapy. Gastroenterology 1985, 95, 1462 18. Hagland U, Elander 6,Fellenius E, et al. The effects of secretagogues on isolated human gastric glands. Scand J Gastroenterol 1982, 17, 455-460 19. Negutescu PA, Machen TE. lntracellular Ca regulations during secretagogue stimulation of the parietal cell. Am J Physiol 1988, 254, C1304140 20. ChibaT, Fisher SK, Park J, et al. Carbamoylcholine and gastrin induced inositol lipid turnover in canine gastric parietal cells. Am J Physiol 1988, 255, G99G I05 21, Verne TB, Verlarde RT, Cunningham RH, Hostman SR. Effects of staurosporine on protein kinase C and amylase secretion from pancreatic acini. Am J Physiol 1989, 257, G548-G553 22. Lindberg P, Brandstrom A, Wallmark B. Structureactivity relationships of omeprazole analogues and their mechanism of action. TiPS 1987, 8, 399-402 23, Van der Werf JF, Tipperman H. The histamine Hz receptor: A general presynaptic histaminergic regulatory system? TiPS 1989, 10, 159-162 24 Hervatin F, Dubrasquet M. Lewin MJM. Histamine H3 receptors in the regulation of gastrin stimulated gastric acid secretion in conscious cat. Gastroenterology 1989, 96, A207 25 Buckley NJ, Bonner T, Buckley CM, Brann MR. Antagonist binding properties of five cloned muscarinic receptors expressed in CKO-KI cells. Mol Pharmacol 1989, 35, 469-76 26 Pfeiffer, A, Rochlitz H, Noelke B, et al. Muscarinic receptors mediating acid secretion in isolated rat gastric parietal cells are of M3 type. Gastroenterology 1990, 98, 218-222 27 Huang SC, Zhang L, Chiang HCV, et al. Benzodiazepine analogues L365,260 and L364,718 as gastrin and pancreatic CCK receptor antagonists. Am J Physiol 1989, 257, G I 6 9 4 1 7 4 28. Chen MCY, Amirian DA, Toomey M, et al. Prostamoid inhibition of canine parietal cells: mediation by the inhibitory guanosine triphosphatebinding protein of adenylate cyclase. Gastroenterology 1988, 94, 1121-1 129 29. Park J, Chiba T, Yokolni K, et al. Somatostatin receptors on canine fundus D cells: Evidence for autocrine regulation of gastric somatostatin. Am J Physiol 1989, 257, G235-G241 30. Schubert ML, Hightower J. Inhibition of acid secretion by conversion is partly mediated by release of fundic somatostatin. Gastroenterology 1989, 97, 561-567 31. Tulassay Z , Gupta R, Pappa J , Bodna A. Somatostatin versus cimetidine in the treatment of actively bleeding duodenal ulcer: A prospective, randomized, controlled trial. Am J Gastroenterol 1989, 84, 6-9 32. Samloff IM. Peptic ulcer: The many proteinasse of aggression. Gastroenterology 1989, 96, 586595 33. Defize J, Hunt RH. Control of pepsinogen synthesis and secretion in chief cell monolayers. Dig Dis Sci 1988, 33, 1588-1589 34. Muller MJ, Hunt RH. Functional evidence for M, and M3 receptors on canine and guinea pig gastric
Downloaded by [Monash University Library] at 05:03 10 April 2016
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chief cells respectively. Gastroenterology 1989, 96, A353 35. Wallace JL. Gastric resistance to acid: is the ‘mucus bicarbonate barrier’ functionally redundant? Am J Physiol 1989, 256, G31-G38 36. Spychal RT, Marrero JM, Saverymuttu SH, et al. Measurement of the surface hydrophobicity of human gastrointestinal tract. Gastroenterology 1989, 97, lob111 37. Lacey ER. Epithelial restitution in the gastrointestinal tract. J Clin gastroenterol 1988, lO(supp1 l), S72-S77 38. Gannon B, Browning B, Browning J , et al. Mucosal microvascular architecture of the fundus and body of the human stomach. Gastroenterology 1984, 86. 866-875 39. Hui WM, Liu HC, Lam SK. Enterochromaffinlike cells of the human stomachdemonstration of histamine content and cholinergic nerve supply. Cell Mol Biol 1988, 34, 303-9 40. Beck PI, Morris GP. Ethanol-induced vascular permeability changes in the jejunal mucosa of the dog. Gastroenterology 1986, 90, 1162 41. Holzer P, Sametz W. Gastric mucosal protection against ulcerogenic factor in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 1986, 91, 975-981 42. Holzer P, Pasbst MA, Lippe IT. lntragastric capsaicin protects against aspirin-induced lesion formations and bleeding in the rat gastric mucosa. Gastroenterology 1989, 96, 1425-1433 43. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 1988, 24, 739-768 44. Takeuchi K, Ueki S, Okabe S. Importance of gastric motility in the pathogenesis of indomethacininduced gastric lesions in rats. Dig Dis Sci 1986,31, 1114-1122 45. Kerrigan DD, Read NW, Taylor ME, et al. Duodenal bulb acidity and the natural history of duodenal ulceration. Lancet 1989, 2, 61-63 46. Stead RH, Dixon MF, Brummell NH, et al. Mast cells are closely opposed to nerves in the human gastrointestinal mucosa. Gastroenterology 1989.97, 575-585 47. Itoh M, Guth PH. Rate of oxygen-derived free radicals in hemorrhagic-shock induced gastric lesions in the rat. Gastroenterology 1985.88, 11621167 48. Ogino K, Oka S, Okanzaki Y, Takemoto T. Gastric mucosal protection and superoxide dismutase. J Clin Gastroenterol 1988, lO(supp1 l), S129-S132 49. Konturek JW, Bielanski W, Konturek SJ, et al. Distribution and release of epidermal growth factor in man. Gut 1989, 30, 1199-1200 50. Itoh M, Joh T, Imai S, et al. Experimental and clinical studies on epidermal growth factor for gastric mucosal protection and healing of gastric ulcers. J Clin Gastroenterol 1988, lO(supp1 l), S7-Sl2 51. Konturek SJ, Bielanski W, Konturek JW, et al. Release and action of epidermal growth factor on
gastric secretion in humans. Scand J Gastroenterol 1989, 24, 485-492 52. Yakabi K, Masoaka I, Kakamura T. The mechanism for direct inhibition of canine gastric parietal cells by epidermal growth factor. Gastroenterology 1990, 98, A150 53. Olimura E, Emoto NM, Tsushima T, et al. Salivary immunoreactive human epidermal growth factors (IR-hEGF) in patients with peptic ulcer disease. Hepatogastroenterology 1987, 34, 160-163 54. Gilchrist W, Maydonovitch CL, Andrada F, et al. Indomethacin inhibits salivary epidermal growth factor in humans. Gastroenterology 1989,96, A171 55. Wright NA, Pike C, Elia G . Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 1990, 343, 82-85 56. Szabo S, Vatty P, Morales RE, et al. Oral administration of bFGF mutein: effect on healing of chronic duodenal ulcers in rats. Dig Dis Sci 1989, 34, 1323 57. Moshal MB, Gregory MA, Pillay C, Spitaels JM, Does the duodenal cell every return to normal? A comparison between treatment with cimetidine and Denol. Scand J Gastroenterol 1979, 14, 48-51 58. Jones DB, Howden CW. Burget DW, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretorv, drues. Gut 1987, i8, 1120-1127 59. Bureet DW. Chiverton SG. Hunt RH. Is there an o p t h a l degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 1990, 99, 345-351 60. Poynter D, Pick CR, Harcourt RA, et al. Association of longlasting unsurmountable histamine H2 blockade and gastric carcinoid tumors in the rat. Gut 1985, 26, 1284-1295 61. Simon B, Muller P, Bliesath H, et al. Gastrin as an autocrine growth factor for islet tumor cells. Gastroenterology 1989, 96, A473 62. Yamamoto 0, Tanaka H, Ueda F, Kimura K. Inhibition of H + , K+-ATPase by methyl(E)-2(3,4-dimethoxystyryl) - benzimidazole - 4 - carboxylate (ALE-36). Scand J Gastroenteroll989,24(suppl 162), 178-181 63. Wilder-Smith CH, Ernst T, Gennomi M, et al. Acute tolerance in H,-receptor agonists. Aliment Pharmacol Ther 1989, 3(suppl 1) (in press) 64. Watson SA, Durrant LG, Morris DL- Effect of L365,260, a potent gastrin receptor antagonist on the in vitro growth of animal and human gastrointestinal tumor cells. Gut 1989, 30, A1447 65. Coelho LGV, Queiroz DMM, Barbosa AJA, et al. Furazolidone vs cimetidine in duodenal ulcer C. pylori positive patients. Gastroenterology 1989, 96, A91 66. Hernandez DE, Neurobiology of brain-gut interactions: Implications for ulcer disease. Dig Dis Sci 1989, 34, 1809-1816 67. Cohen JS. Designing antisense oligonucleotides as pharmaceutical agents. TiPS 1989, 10, 435-437
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Acid and Barriers: Current Research and Future Developments for Peptic Ulcer Therapy J. W. Rademaker & R. H. Hunt To cite this article: J. W. Rademaker & R. H. Hunt (1990) Acid and Barriers: Current Research and Future Developments for Peptic Ulcer Therapy, Scandinavian Journal of Gastroenterology, 25:sup175, 19-26, DOI: 10.3109/00365529009093123 To link to this article: http://dx.doi.org/10.3109/00365529009093123
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Acid and Barriers Current Research and Future Developments for Peptic Ulcer Therapy J . W. RADEMAKER & R. H. HUNT Division of Gastroenterology, McMaster University Medical Centre, Hamilton, Ontario, Canada
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Rademaker JW, Hunt RH. Acid and barriers. Current research and future developments for peptic ulcer therapy. Scand J Gastroenterol 1990,25(suppl 175), 19-26 Medical therapy for peptic ulcer disease has been targeted at inhibiting acid secretion based on the belief that ulcers occur due to an imbalance between aggressive and protective factors. New antisecretory agents are unlikely to show any dramatic improvement over the success and safety of histamine H 2 receptor antagonists or the recently introduced H'K' ATPase proton pump antagonist omeprazole. The development of specific muscarinic M3 and gastrin receptor antagonists will provide useful agents to suppress acid and pepsinogen secretion by alternative means and may prevent the associated hypergastrinaemia seen with anti-secretory therapy. Enhancement of mucosal defence by site protective agents will be based on a better understanding of the vascular and immune factors involved in maintaining mucosal integrity and the growth factors that regulate wound healing. Molecular techniques are likely to produce the 'model anti-ulcer' agent which will effectively inhibit acid secretion and also enhance wound healing thus providing a cure for this chronic disease. Key words: Current research; drug therapy; peptic ulcer Prof. Richard H . Hunt, FRCP, FRCPC, Division of Gastroenterology, McMaster University Medical Centre, 1200 Main St. West, Hamilton, Ontario L8N 325, Canada
Despite the changing pattern of peptic ulcer disease and the advances in medical treatments seen during this century, ulcer disease remains a significant cause of morbidity and high cost to the health care systems of most countries. The introduction of the histamine Hz-receptor antagonist (H2RA) cimetidine in 1975 provided the first effective non-surgical therapy for duodenal and gastric ulcer. The rationale for the use of the H2RAs is based on the beliefs that ulcers occur as a result of an imbalance between luminal aggressive and mucosal defensive factors (1) and that by inhibiting acid-peptic activity, a more favourable environment for ulcer healing occurs. Despite their commercial success and safety, the H2RAs available today have not altered the natural history of the disease, although ulcer patients may be maintained free of symptoms and relapse by prolonged maintenance treatment (2). The past decade has seen dramatic devel-
opments in our understanding of the regulation of gastric secretion (3), especially at the cellular level (4).The identification of the H+,K+-ATPase proton pump led to the development of the highly specific H+,K+-ATPase antagonist omeprazole (9,which is the most potent and direct antisecretory agent available. The results of clinical trials with omeprazole have shown accelerated healing of duodenal and gastric ulcer and especial benefit in refractory duodenal ulcer ( 6 )and severe gastro-oesophageal reflux disease (7). Concern about the long-term safety of omeprazole continues following the result of animal toxicity studies (8), in which prolonged inhibition of gastric acid secretion at high doses was associated with hypergastrinaemia. Enterochromaffinlike cell (ECL) hyperplasia with micronodules occurs and may progress to frank carcinoids. However, antrectomized animals treated with omeprazole showed no such changes (9), sug-
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gesting that omeprazole has no direct toxic effect and that these changes are directly related to hypergastrinaemia. Omeprazole is currently advocated for short-term use, and surveillance of patients requiring long-term omeprazole has only demonstrated ECL hyperplasia (10). A better understanding of the mechanisms involved in acute injury (11) and the role of eicosanoids in regulating mucosal defence and acid secretion led to the introduction of the prostaglandin EI(PGE1) analogue misoprostol. In animal studies this drug demonstrated mucosal protective and inhibitory actions but has not lived up to its expectations in clinical trials of peptic ulcer healing (12). Healing rates which equate to other ulcer healing agents are only seen at antisecretory doses. However, a specific benefit has been seen in preventing the development of nonsteroidal anti-inflammatory drugs (NSA1D)associated gastric ulcer in high-risk patients (13). Non-antisecretory site protective agents such as bismuth compounds and sucralfate, which act by stimulating mucosal defence mechanisms rather than by a simple barrier effect, have not been universally accepted because of multiple and less convenient dosing and their mode of action not being fully understood. However, in clinical trials both tri-potassium dicitrato-bismuthate (14) and sucralfate (15) are as effective as the H2RAs in acute ulcer healing trials at 4 to 6 weeks. Particular interest in bismith followed reports of decreased recurrence after colloidal bismuth subcitrate (CBS) therapy (16) and the demonstration of both in vivo and in vitro bactericidal effect against Helicobacter pylori (17). Research and development of novel anti-ulcer agents that alter mucosal defence and wound healing still lags behind that of the market-dominated anti-secretory agents. This review will consider the development of future anti-ulcer drugs considering our present concept of ulcer pathophysiology occurring as an imbalance of luminal and mucosal factors. ACID SECRETION Understanding of the regulation of acid secretion at the cellular level has increased dramatically
and includes the identification of receptor subtypes and unravelling of the complex signal transduction pathways that activate the H+,K+ATPase pump. The sometimes confusing and differing results between studies can be largely accounted for by species variation, and experiments in isolated human glands have confirmed that histamine is the most potent secretagogue compared with acetylcholine and gastrin (18). Current concepts of receptor regulation of acid secretion involve stimulatory receptors for histamine and acetylcholine on the basolateral membrane of the parietal cell with gastrin probably acting indirectly via release of histamine from the ECL cells (4). Histamine signal transduction involves activation of membrane-bound adenylate cyclase to increase intracellular cyclic AMP, which then activates protein kinases (19). Muscarinic receptor stimulation results in the hydrolysis of membrane phospholipids to form inositol triphosphate (IP3) and diacylglycerol (20). IP3 releases calcium from intracellular stores, and diacylglycerol independently activates protein kinases. The location and function of the different protein kinase subtypes in regulating the H+,K+ATPase pump and acid secretion are not yet known. Non-specific protein kinase antagonists such as staurosporine inhibit pancreatic secretion in isolated rat acini (21) but have not yet been evaluated in parietal or chief cells. Further research will no doubt identify the genetic markers and specific function of these regulatory proteins, which may account for the genetic variation seen in acid secretion in patients with peptic ulcer disease. The development of specific protein kinase antagonists as therapeutic targets would appear to have no significant advantage over the already proven H+,K+-ATPasepump antagonists such as omeprazole or lansoprazole in the parietal cell. The development of omeprazole was associated with a rapid increase in our understanding of the structural and functional changes that occur in the parietal cell during acid secretion. Omeprazole and similar compounds can be considered ideal antisecretory agents, which are only activated by acid in the secretory canaliculus of the
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parietal cell to form an intermediate sulphenamide, which then binds irreversibly to the mercapto groups of the H+,K+-ATPase molecule to form the disulphide inhibitor complex (22). The central role of histamine in the stimulation of acid secretion has been based solely on the availability of pharmacologic antagonists, and the histamine H2 receptor itself has not yet been isolated. Evidence from animal studies proposes that a histamine H3 receptor exists in both central and peripheral nervous systems, and this appears to regulate pre-synaptic transmission and alter smooth-muscle tone (23). An H3 receptor antagonist may offer an alternative agent for reducing muscular hyperactivity and vasoconstriction. In the cat gastric fistula model, H3 receptor agonists also inhibit pentagastrin-stimulated acid secretion (24). Five subtypes of the muscarinic receptor have recently been identified by molecular cloning techniques (25). Experiments using the M3 antagonists hexahydrosiladifenidiol and silahexocyclium in rat parietal cells (26) have proposed an M3 receptor on the parietal cell which appears to inhibit acid secretion by acting on inositol phosphate pathways and intracellular calcium. This further characterization of the muscarinic receptor as M3 may explain the relatively weak antisecretory effects of the M1 receptor antagonists pirenzepine and telenzipine. The development of 3-benzoylamino and 3acyclamino benzodiazepine analogues as specific gastrin and cholecystokinin (CCK) antagonists, respectively, has shown a distinction between gastrin and CCK receptors in studies of amylase secretion from pig pancreatic acini and contraction of guinea pig stomach smooth muscle (27). These agents will help resolve the controversy that surrounds the location and function of the gastrin receptor on the parietal cell and provide potential agents for inhibiting acid secretion and preventing the hypergastrinaemia seen with H2RA and omeprazole. Inhibition of acid secretion at the cellular level occurs with prostaglandins of the E series and several hormones, including secretin, somatostatin, and neurotensin. A specific PGE receptor has been identified on canine parietal cells and
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appears to be linked to the histamine-adenyl cyclase receptor by a guanine nucleotide regulatory protein (28). Prostaglandin analogues, which also have mucosal protective properties in animal studies, have not achieved the expected clinical success and are associated with a measurable incidence of diarrhoea and abdominal pain (12). Continued research into the complex area of eicosanoids may provide a more specific analogue or novel compound that will fulfil the promise of a specific combined antisecretory and mucosal protective agent without significant side effects. Somatostatin, acting as a paracrine hormone, appears to have an important inhibitory role in regulating acid secretion by directly inhibiting parietal cell function (29) and regulating gastrin release via gastrin-releasing peptide nerves (30). The long-acting somatostatin analogues currently available must be given parenterally and are only of benefit for the complication of bleeding in peptic and stress ulcers (31). PEPSIN AND PEPSINOGEN The importance of pepsin as an aggressive factor in ulcer disease continues to receive little attention (32), although recent interest in the regulation of pepsinogen secretion and synthesis has been stimulated after the identification of pepsinogen isoenzymes. Recent animal experiments have clarified the regulatory mechanisms involved in the secretion and synthesis of pepsinogens (33). Despite species variation, pepsinogen secretion is stimulated via CCK and muscarinic M1 and M3 receptors (33), which act via both cyclic AMP and calcium signal transduction pathways to stimulate both secretion and synthesis of pepsinogen. Further studies with agents that inhibit pepsinogen secretion, especially in humans, may provide non-acid anti-secretory therapy, although it seems probable that such control is only likely to be achieved at the level of the regulatory genes. MUCOSAL DEFENCE The advances in our understanding of the different components of mucosal defence has fol-
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lowed a structural approach, and the importance and interaction between the mucosal immune and enteric nervous systems has only recently been recognized. Acid secretion can be considered the immediate mucosal protective response following exposure to foreign protein and antigen in the form of food and bacteria. Doubt now exists about the importance of the mucus-bicarbonate barrier and its ability to form an unbroken layer over the gastroduodenal mucosa (35). Rapid restitution by the active phospholipid layer has been confirmed, but its exact role in mucosal defence remains unclear (36). Rapid restitution by cell migration and regeneration are recognized as critical components of mucosal defence (37) and of wound healing, which will be discussed later. Damage to the network of mucosal blood vessels is critical in determining the degree and probably the depth of damage that occurs following exposure to luminal irritants (1 1). Maintenance of mucosal blood flow not only supplies oxygen and nutrients but also rapidly removes backdiffusing hydrogen ion and exogenous or endogenous toxins. As a result of the relationship of the blood vessels to the secretory glands, the bicarbonate ions produced during acid secretion are directed towards and maintain neutralization at the luminal surface (38). The mucosal immune and enteric nervous systems are also considered important regulators of mucosal blood flow. Morphologic studies of human gastric biopsy specimens have demonstrated that two populations of histamine-containing cells occur (39). Histamine-containing ECL cells are supplied by cholinergic nerve fibres and lie close to parietal cells, thus supporting the concept of an integrated relationship between central mechanisms and histamine as a secretagogue, A second population of histamine-containing cells is seen in the lamina propria adjacent to the origin of the mucosal capillary vessels. Histamine released from these separate populations of mast cells would result not only in acid secretion but also in local vasodilation and increased capillary permeability, which, if uncontrolled, would predispose the mucosa to damage. Animal studies have shown that the mast-cellstabilizing agent disodium chromoglycate reduces
ethanol-induced gastric damage (40) by preventing mast cell degranulation and release of histamine and other mediators of cell damage. Evidence exists to show that mucosal blood flow and the muscular activity of the muscularis mucosa are regulated by neural reflexes following luminal exposure to irritants. In animal studies ablation of mucosal neutrons by pre-treatment with capsaicin caused exacerbation of ethanolinduced injury (41), whereas stimulation prevented injury (42). The neutro-transmitter calcitonin gene-related peptide (CGRP) appears to be released from afferent neurons and enhances mucosal blood flow (43). Alterations in smoothmuscle activity are considered important in both experimental ulcer models (44) and duodenal ulcer patients ( 4 9 , but the mechanisms involved are not known. The anatomic relationship of the muscularis mucosa to the origin of the mucosal blood vessels may be important in maintaining mucosal integrity by the ability to constrict and reduce blood flow. Whether enteric neural pathways regulate mast cell and muscle activity in humans is not known, but a close association of neurons to mast cells of the small and large bowel has been reported in humans (46). This would suggest that a similar mechanism might exist in the stomach, but this remains to be confirmed, and the effect of any disease process on their regulatory function needs further investigation. Proposed mechanisms responsible for mucosal injury in acute haemorrhagic shock involve the formation of oxygen-derived free radicals following re-perfusion. These toxic oxygen metabolites result from the action of xanthine oxidase on accumulated hypoxanthines with oxygen (47). Free radicals produce direct damage by causing cell lysis and activation of lysosomal enzymes, which produce further damage and inflammation. The xanthine oxidase inhibitor allopurinol and free radical scavengers superoxide dismutase and dimethyl sulphoxide protect the gastric mucosa against haemorrhagic shock in animal models (48) and may be potential therapeutic agents for preventing stress ulceration. WOUND HEALING The gastrointestinal mucosa is a rapidly pro-
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liferating epithelium and is regulated by systemic hormones such as growth hormone, by thyroxine, and by local gut peptides, in particular gastrin and epidermal growth factor (EGF). EGF is a polypeptide present in secretions from salivary, duodenal Brunner’s glands, and the pancreas (49). EGF is not absorbed, is resistant to protease digestion, and appears to play an important role in mucosal defence and in wound healing. From the results of preliminary clinical trials (50) EGF not only increases cell turnover but also the release of prostaglandins, sulfhydryls, and somatostatin. Studies have also shown that parenteral EGF inhibits stimulated acid secretion in humans (51) and directly inhibits parietal cell activity via a guanine nucleotide inhibitory protein (52). Gastric and duodenal ulcer patients secrete less salivary EGF than healthy controls (53),and both smoking (49) and NSAIDs (54) are known to decrease salivary EGF secretion, which would impair wound healing in these groups. Recently, it has been suggested that the induction of an EGF-secreting cell line occurs following mucosal ulceration anywhere in the human gut (55). Biopsy specimens taken adjacent to the area of mucosal ulceration show that a small bud appears to form a new gland, which secretes EGF and hence stimulates ulcer healing. Fibroblast growth factor (FGF) stimulates the growth of fibroblasts and endothelium and has recently attracted considerable attention. An acid-stable FGF analogue ( m G F ) given orally accelerated the healing of cystamine-induced chronic duodenal ulcer in rats (56). Histology showed marked early angiogenesis followed by complete restoration of duodenal mucosal architecture in the FGF-treated group compared with controls. These results indicate that P G F stimulates regeneration, specifically angiogenesis, and produces a more rapid and complete wound healing without inhibition of acid secretion. The importance of the quality of wound healing in peptic ulcer disease has not been addressed except for a brief report that duodenal ulcer patients showed improved mucosal healing following treatment with bismuth when compared with cimetidine (57). The underlying mechanisms
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were not explained, and no long-term follow-up was reported. The cimetidine group with incomplete healing was felt to be more susceptible to luminal aggressive agents and ulcer recurrence. Clearly, good histologic studies of ulcer healing are necessary. FUTURE DEVELOPMENTS A considerable delay occurs between discovery and the introduction of a new drug, and any predictions concerning future therapeutic agents can only be made from compounds currently under development. The concept of a ‘model antiulcer drug’ remains difficult to predict in view of the basic lack of understanding of the aetiology and pathophysiology of peptic ulcer disease. The therapeutic target is shifting from inhibition of acid secretion to stimulation of mucosal defence and treatment of H.pylori infection but with only limited success. Treatments aimed at modifying wound healing would appear to provide the next major therapeutic opportunity for investigation. The importance of inhibiting acid secretion in healing peptic ulcer is well recognized, and a clear correlation between the degree of acid suppression and healing rates has been shown for duodenal ulcer (58). This relationship has been studied further, and the optimal degree of acid suppression defined as a threshold of pH 3 for 18-20 h daily, to achieve 100% duodenal ulcer healing at 4 weeks (59). The clinical requirements of acid inhibition are probably adequately fulfilled by the wide range of currently available antisecretory drugs. Development of more potent and longer-acting H2RA have not been successful, and all have been withdrawn after the development of various gastric tumours in long-term animal toxicology studies (60). The mechanism by which these lesions have developed remains unclear, although the hypergastrinaemia consequent upon prolonged acid suppression is generally accepted as the cause of ECL hyperplasia and carcinoid tumours, as seen with omeprazole (8). The proton pump antagonist clones (61,62) have already started to appear but must still face extensive animal toxicity testing and clinical trials before they become available for general use.
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The continued development of specific M3 muscarinic cholinergic antagonists may provide an alternative non-surgical form of vagotomy to inhibit not only acid but also pepsinogen secretion. These agents will need to be more potent than the currently available MI antagonists pirenzipine and telenzipine and to avoid the common and unwanted side effects of atropine. The benzodiazepine-related gastrin antagonists (27) will have considerable physioldgic and possible therapeutic applications. These agents may have a direct therapeutic role in controlling acid secretion but may also be used in combination with antisecretory agents to prevent the hypergastrinaemia felt to cause tolerance to therapy with HIRA (63) and carcinoids with more potent acid inhibition (8). Their application for the treatment ofgastric or colonic carcinoma to reduce the trophic effect of gastrin is of equal consideration and requires further study, since promising results have already been reported in isolated tumour cultures with these agents (64). The potential mucosal defence targets for therapeutic intervention must continue to be explored in view of the increasing use of NSAIDs, especially in the elderly, who are at increased risk of bleeding and perforation. The identification of mediators that produce vasospasm and contraction of non-vascular smooth muscle and the development of antagonists or inhibitors of these mediators or, alternatively, vasodilator substances could significantly alter the response to mucosal irritants in susceptible individuals. The relative lack of success of the PGE analogues should not discourage further research into development of new agents with a greater degree of specificity, and misoprostol has immunomodulatory effects. Mast cellstabilizing agents and selective immunomodulatory agents are attractive and novel approaches, but a more complete understanding of the integration of the immune system with the mucosal defence system is needed before these are likely to be developed. The study of growth factors has opened a whole new approach to healing ulcers, and human studies have already confirmed that oral EGF heals gastric ulcer (50) and parenteral E G F inhibits
stimulated acid secretion (51). The potential development for EGF analogues that inhibit acid secretion and increase the rate and quality of ulcer healing may provide a curative rather than palliative treatment. An alternative approach would be to combine the properties of the potent antisecretory agent omeprazole with the acidstable growth factor /3FGF to produce similar results. The pathogenic role of H. pylori remains controversial, and current regimens of bismuth and antibiotics have not proved able to eradicate the organism completely. Studies with furazolidone have shown both in vitro and in vivo activity against H. pylori (65) and may provide a specific and potentially less toxic anti-H. pylori agent than bismuth. Further clinical trials and discovery of newer anti-H. pylori agents are likely in the foreseeable future. The multifactorial nature of peptic ulcer disease and the importance of the brain-gut axis (66) and motility (45) must also be considered as potential targets. Animal studies have shown that the neurotransmitter thyrothropin-releasing hormone is ulcerogenic, whereas @endorphin, neutrotensin, and bombesin are protective (66). The possibility that ulcer disease may result from a neurochemical imbalance in the brain may help explain the association of stress with peptic ulcer disease. Studies that have demonstrated an association of altered gastroduodenal motility with ulcer models in animal (44) and duodenal ulcer patients (45) have proposed that a failure to clear acid from the duodenal bulb is as important as an increased acid load or decreased neutralizing capacity. Altering gastroduodenal motility with prokinetic drugs may benefit certain patients but much research is needed to identify further the duodenal receptors and specific neurotransmitters that regulate antropyloroduodenal function. Current technology and the development of molecular biologic techniques have provided powerful research tools in the form of highly specific genetic robes that have the potential to lead to new therapeutic agents such as the oligonucleotides, which regulate protein synthesis (67). The development of novel agents that modulate the mucosal defence mechanisms and wound
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healing by regulation of cellular protein synthesis could thus provide a cure by correcting the imbalance between the aggressive and protective factors in genetically predisposed individuals.
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REFERENCES 1. Schwarz K, Beitz Z. Ueber penetrierende magenund jejunalgeschwure. Klin Chir 1910, 67, 96-128 2. Freston JW. H,-receptor antagonists and duodenal ulcer recurrence: analysis of efficacy and commentary on safety, costs, and patient selections. Am J Gastrenterol 1987, 82, 1242-1249 3. Wolfe MM. Sol1 AM. The physiology of gastric acid secretion. NEJM 1988, 319, 1707-1715 4. Sachs G , Tache Y, Debas HT. et al. Control of gastric secretion. Am J Med 1987, 83, 307-327 5 . Fellenius E, Berglindh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+) ATPase. Nature 1981,159-l61 6 . Bardhan KD. Omeprazole in the management of refractory duodenal ulcer. Scand J Gastroenterol 1989, 24(suppI 166), 63-73 7. Dent J, Hetzel DJ, MacKinnon MA, et al. Evaluation of omeprazole in reflux oesophagitis. Scand J Gastroenterol 1989, 24(suppl 166), 76-82 8. Hakanson R, Sunder F. Gastric carcinoids and antisecretory drugs. TIPS 1986, 7, 386387 9. Lawsson H, Carlsson E, Mattsson H, et al. Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation. Gastroenterology 1986.96, 391-399 10. Solcia E, Rind G. Maru N , Elm G . Qualitative studies of gastric endocrine cells in patients treated long-term kith omeprazole. Scand j Gastroenterol 1989, 24(suppl 166), 129-137 11. Szabo S. Mechanisms of mucosal injury in the stomach and duodenum: Time-sequence analysis of morphologic, functional, biochemical and histochemical studies. Scand J Gastroenterol 1986, SUPPI PI 127), 21-28 12. Hawkey CJ, Walt RP. Prostaglandins for peptic ulcer: A promise unfulfilled. Lancet 1986, 2, 10841086 13. Graham DY, Agrawal N , Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, doubleblind, placebo-controlled trial. Lancet 1988, 2, 1277-1280 14. Miller JP. Colloidal bismuth in the treatment of duodenal ulceration: the benefit for the patient. Scand J Gastroenterol 1989. 2(suppl 157). I 6 2 0 15. Wagstaff AJ, Benfield P, Monk JP. Colloidal bismuth subsitrate. A review of its pharmacodynamics and pharmacokinetic properties, and its therapeutic used in peptic ulcer disease. Drugs 1988, 36, 132157 16. Marshall BJ, Goodwin CS. Warren JR, et al. Prospective doubleblind trial of duodenal relapse after eradication of Campylobacter pylori. Lancet 1988, 2, 1437-1442 17. Lambert JR, Hansky J, Davidson A, et al. Campylobacter like organisms (CL0)-in vivo and in
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vitro susceptibility to antimicrobial and antiulcer therapy. Gastroenterology 1985, 95, 1462 18. Hagland U, Elander 6,Fellenius E, et al. The effects of secretagogues on isolated human gastric glands. Scand J Gastroenterol 1982, 17, 455-460 19. Negutescu PA, Machen TE. lntracellular Ca regulations during secretagogue stimulation of the parietal cell. Am J Physiol 1988, 254, C1304140 20. ChibaT, Fisher SK, Park J, et al. Carbamoylcholine and gastrin induced inositol lipid turnover in canine gastric parietal cells. Am J Physiol 1988, 255, G99G I05 21, Verne TB, Verlarde RT, Cunningham RH, Hostman SR. Effects of staurosporine on protein kinase C and amylase secretion from pancreatic acini. Am J Physiol 1989, 257, G548-G553 22. Lindberg P, Brandstrom A, Wallmark B. Structureactivity relationships of omeprazole analogues and their mechanism of action. TiPS 1987, 8, 399-402 23, Van der Werf JF, Tipperman H. The histamine Hz receptor: A general presynaptic histaminergic regulatory system? TiPS 1989, 10, 159-162 24 Hervatin F, Dubrasquet M. Lewin MJM. Histamine H3 receptors in the regulation of gastrin stimulated gastric acid secretion in conscious cat. Gastroenterology 1989, 96, A207 25 Buckley NJ, Bonner T, Buckley CM, Brann MR. Antagonist binding properties of five cloned muscarinic receptors expressed in CKO-KI cells. Mol Pharmacol 1989, 35, 469-76 26 Pfeiffer, A, Rochlitz H, Noelke B, et al. Muscarinic receptors mediating acid secretion in isolated rat gastric parietal cells are of M3 type. Gastroenterology 1990, 98, 218-222 27 Huang SC, Zhang L, Chiang HCV, et al. Benzodiazepine analogues L365,260 and L364,718 as gastrin and pancreatic CCK receptor antagonists. Am J Physiol 1989, 257, G I 6 9 4 1 7 4 28. Chen MCY, Amirian DA, Toomey M, et al. Prostamoid inhibition of canine parietal cells: mediation by the inhibitory guanosine triphosphatebinding protein of adenylate cyclase. Gastroenterology 1988, 94, 1121-1 129 29. Park J, Chiba T, Yokolni K, et al. Somatostatin receptors on canine fundus D cells: Evidence for autocrine regulation of gastric somatostatin. Am J Physiol 1989, 257, G235-G241 30. Schubert ML, Hightower J. Inhibition of acid secretion by conversion is partly mediated by release of fundic somatostatin. Gastroenterology 1989, 97, 561-567 31. Tulassay Z , Gupta R, Pappa J , Bodna A. Somatostatin versus cimetidine in the treatment of actively bleeding duodenal ulcer: A prospective, randomized, controlled trial. Am J Gastroenterol 1989, 84, 6-9 32. Samloff IM. Peptic ulcer: The many proteinasse of aggression. Gastroenterology 1989, 96, 586595 33. Defize J, Hunt RH. Control of pepsinogen synthesis and secretion in chief cell monolayers. Dig Dis Sci 1988, 33, 1588-1589 34. Muller MJ, Hunt RH. Functional evidence for M, and M3 receptors on canine and guinea pig gastric
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J. W . Rademaker & R. H . Hunt
chief cells respectively. Gastroenterology 1989, 96, A353 35. Wallace JL. Gastric resistance to acid: is the ‘mucus bicarbonate barrier’ functionally redundant? Am J Physiol 1989, 256, G31-G38 36. Spychal RT, Marrero JM, Saverymuttu SH, et al. Measurement of the surface hydrophobicity of human gastrointestinal tract. Gastroenterology 1989, 97, lob111 37. Lacey ER. Epithelial restitution in the gastrointestinal tract. J Clin gastroenterol 1988, lO(supp1 l), S72-S77 38. Gannon B, Browning B, Browning J , et al. Mucosal microvascular architecture of the fundus and body of the human stomach. Gastroenterology 1984, 86. 866-875 39. Hui WM, Liu HC, Lam SK. Enterochromaffinlike cells of the human stomachdemonstration of histamine content and cholinergic nerve supply. Cell Mol Biol 1988, 34, 303-9 40. Beck PI, Morris GP. Ethanol-induced vascular permeability changes in the jejunal mucosa of the dog. Gastroenterology 1986, 90, 1162 41. Holzer P, Sametz W. Gastric mucosal protection against ulcerogenic factor in the rat mediated by capsaicin-sensitive afferent neurons. Gastroenterology 1986, 91, 975-981 42. Holzer P, Pasbst MA, Lippe IT. lntragastric capsaicin protects against aspirin-induced lesion formations and bleeding in the rat gastric mucosa. Gastroenterology 1989, 96, 1425-1433 43. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 1988, 24, 739-768 44. Takeuchi K, Ueki S, Okabe S. Importance of gastric motility in the pathogenesis of indomethacininduced gastric lesions in rats. Dig Dis Sci 1986,31, 1114-1122 45. Kerrigan DD, Read NW, Taylor ME, et al. Duodenal bulb acidity and the natural history of duodenal ulceration. Lancet 1989, 2, 61-63 46. Stead RH, Dixon MF, Brummell NH, et al. Mast cells are closely opposed to nerves in the human gastrointestinal mucosa. Gastroenterology 1989.97, 575-585 47. Itoh M, Guth PH. Rate of oxygen-derived free radicals in hemorrhagic-shock induced gastric lesions in the rat. Gastroenterology 1985.88, 11621167 48. Ogino K, Oka S, Okanzaki Y, Takemoto T. Gastric mucosal protection and superoxide dismutase. J Clin Gastroenterol 1988, lO(supp1 l), S129-S132 49. Konturek JW, Bielanski W, Konturek SJ, et al. Distribution and release of epidermal growth factor in man. Gut 1989, 30, 1199-1200 50. Itoh M, Joh T, Imai S, et al. Experimental and clinical studies on epidermal growth factor for gastric mucosal protection and healing of gastric ulcers. J Clin Gastroenterol 1988, lO(supp1 l), S7-Sl2 51. Konturek SJ, Bielanski W, Konturek JW, et al. Release and action of epidermal growth factor on
gastric secretion in humans. Scand J Gastroenterol 1989, 24, 485-492 52. Yakabi K, Masoaka I, Kakamura T. The mechanism for direct inhibition of canine gastric parietal cells by epidermal growth factor. Gastroenterology 1990, 98, A150 53. Olimura E, Emoto NM, Tsushima T, et al. Salivary immunoreactive human epidermal growth factors (IR-hEGF) in patients with peptic ulcer disease. Hepatogastroenterology 1987, 34, 160-163 54. Gilchrist W, Maydonovitch CL, Andrada F, et al. Indomethacin inhibits salivary epidermal growth factor in humans. Gastroenterology 1989,96, A171 55. Wright NA, Pike C, Elia G . Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 1990, 343, 82-85 56. Szabo S, Vatty P, Morales RE, et al. Oral administration of bFGF mutein: effect on healing of chronic duodenal ulcers in rats. Dig Dis Sci 1989, 34, 1323 57. Moshal MB, Gregory MA, Pillay C, Spitaels JM, Does the duodenal cell every return to normal? A comparison between treatment with cimetidine and Denol. Scand J Gastroenterol 1979, 14, 48-51 58. Jones DB, Howden CW. Burget DW, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretorv, drues. Gut 1987, i8, 1120-1127 59. Bureet DW. Chiverton SG. Hunt RH. Is there an o p t h a l degree of acid suppression for healing of duodenal ulcers? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 1990, 99, 345-351 60. Poynter D, Pick CR, Harcourt RA, et al. Association of longlasting unsurmountable histamine H2 blockade and gastric carcinoid tumors in the rat. Gut 1985, 26, 1284-1295 61. Simon B, Muller P, Bliesath H, et al. Gastrin as an autocrine growth factor for islet tumor cells. Gastroenterology 1989, 96, A473 62. Yamamoto 0, Tanaka H, Ueda F, Kimura K. Inhibition of H + , K+-ATPase by methyl(E)-2(3,4-dimethoxystyryl) - benzimidazole - 4 - carboxylate (ALE-36). Scand J Gastroenteroll989,24(suppl 162), 178-181 63. Wilder-Smith CH, Ernst T, Gennomi M, et al. Acute tolerance in H,-receptor agonists. Aliment Pharmacol Ther 1989, 3(suppl 1) (in press) 64. Watson SA, Durrant LG, Morris DL- Effect of L365,260, a potent gastrin receptor antagonist on the in vitro growth of animal and human gastrointestinal tumor cells. Gut 1989, 30, A1447 65. Coelho LGV, Queiroz DMM, Barbosa AJA, et al. Furazolidone vs cimetidine in duodenal ulcer C. pylori positive patients. Gastroenterology 1989, 96, A91 66. Hernandez DE, Neurobiology of brain-gut interactions: Implications for ulcer disease. Dig Dis Sci 1989, 34, 1809-1816 67. Cohen JS. Designing antisense oligonucleotides as pharmaceutical agents. TiPS 1989, 10, 435-437
