Prostaglandins: Gastrointestinal Effects and Peptic Ulcer Disease

Symposium on Prostaglandins

Prostaglandi ns: Gastroi ntesti nal Effects and Peptic Ulcer Disease Donald E. Wilson, MD., * and Hulya Kaymakcalan, M.D. t

It is appropriate that the first specific description of the actions of prostaglandins by von Euler in 1935 include the smooth muscle-stimulating effects of these compounds. 1 Although prostaglandins are virtually ubiquitous, biologically active compounds, their actions on gastrointestinal motility and secretion and their recent emergence as potentially the most effective anti-ulcer compounds known, are particularly noteworthy. While prostaglandins are not hormones that circulate, there is ample evidence that these compounds may act physiologically as local regulators of cellular and tissue functions. This review will concentrate on effects of prostaglandins in the gastrointestinal tract that have or may have clinical relevance and, in the interests of brevity, will omit many other interesting gastrointestinal actions.

EFFECTS ON GASTROINTESTINAL MOTILITY Prostaglandins affect smooth muscle throughout the gastrointestinal tract. While in general longitudinal muscle is contraGted by both E and F prostaglandins and circular smooth muscle is relaxed by E and contracted by F prostaglandins, there is variation in these responses from tissue to tissue (Fig. 1). In addition, observations in vitro frequently differ from in vivo observations. The exact mechanism by which prostaglandins affect smooth muscle contraction is not precisely known. There are at least several prostaglandin receptors which may respond to different groups of prostaglandins and may respond differently in different tissues. Actions of prostaglandins at the receptor level are not blocked by atropine, methysergide, mepyramine, phenoxybenzamine, propranolol, or hexamethonium. 2 While prostaglandins do not appear to be neurotransmitters, they do modify synaptic function. 3 In 'Professor and Chairman, Department of Medicine. State University of New York, Downstate Medical Center, Brooklyn, New York t Assistant Professor, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York

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MOTILITY

Circular Muscle

E

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Longitudinal Muscle

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Figure 1. Variations in tissue response of circular and longitudinal muscle to prostaglandin E and prostaglandin F throughout the gastrointestinal tract.

many instances their actions have been associated with an effect on cAMP levels in tissues but there are other instances in which this association is apparently lacking. An association between prostaglandin activity and cation exchange across membranes, especially Ca++, has also been postulated.

Esophageal Motility The administration of exogenous E-type prostaglandins (PGEl> PGE 2) relaxed the lower esophageal sphincter (LES) in both animals and man, while administration of PGF contracts the LES. 4 -7 Prostaglandins do not appear to affect the contraction of the upper esophageal sphincter and either have no effect on motility of the body of the esophagus or cause a reduction of the amplitude of peristaltic contractions in the lower part of the esophagus. A number of studies have been performed to determine whether or not prostaglandins may have a physiologic role in the control of lower esophageal sphincter pressure and possibly gastroesophageal reflux. In man, the administration of indomethacin to inhibit prostaglandin synthesis results in an increase in LES pressure, suggesting an inhibitory role for prostaglandins. 7 , 8 The intra-arterial administration of arachidonic acid to promote endogenous prostaglandin synthesis causes a dose-related reduction in LES pressure in animals, again suggesting that the major effect of prostaglandins on LES

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pressure is an inhibitory one. 9 However, the observed effects of prostaglandins in vivo differ in many studies from those seen in vitro. While PGF 2" contracts LES circular muscle strips from animals, arachidonic acid also causes an increase in tension in LES strips.s Additionally, an analogue of the prostaglandin endoperoxide PGH 2 (U-46619) is reported to be 500 times as potent as PGE 2 in contracting LES circular muscle in vitro, suggesting that either the prostaglandin endoperoxide or a product of the endoperoxide other than prostaglandins such as thromboxane A2 may be more important in controlling LES pressure. This suggestion is supported by studies showing that imidazole at concentrations that should selectively inhibit thromboxane A2 synthesis diminished arachidonic acid-LES muscle contraction. 10 At present the reasons for the differences between in vivo and in vitro studies are not known. Recently it was reported that in radiation-induced esophagitis in opossums, the administration of indomethacin prevented the inflammatory changes while the administration exogenous prostaglandin increased the inflammatory response. l l It has been reported that indomethacin reduces LES hypotension observed in experimentally induced esophagitis in cats.12 Thus, the role of prostaglandins in the maintenance of LES tone, gastroesophageal reflux, and esophagitis as well as the potential therapeutic value of using inhibitors of prostaglandin synthesis remains to be determined.

Gastric Motility Prostaglandin actions on circular and longitudinal muscle in the stomach conform pretty much to the general responses previously described, although there are quantitative differences in the responses of fundic and antral longitudinal muscle. The in vivo effects of prostaglandins on gastric motility are potentially of importance with respect to gastric emptying and effects on the pyloric sphincter. Indirect evidence of relaxation of the pyloric sphincter by prostaglandins was reported by Horton et al. in 1968 when it was noted that the oral administration of PGE in man was associated with reflux of bile into the stomach. 13 We and others have observed increased bile in the gastric juice of human volunteers receiving antisecretory prostaglandins or prostaglandin analogs orally.14 The effects of prostaglandins on gastric emptying are less straightforward. The administration of 16,16-dimethyl PGE 2 has been reported to delay gastric emptying in the rat and in man. 15 . 16 The same group of investigators reported that while 15 (S)-15-methyl PGE 2 stimulated gastric emptying, prostacyclin (PGI 2) delayed gastric emptying in monkeys.17.18 Different experimental designs may account for some of the differences. However, it would appear that PGE administered orally to man does not have a marked effect on gastric emptying and that the observed effect appears to be independent of actions on [H+] secretion.

Intestinal Motility Horton and co-workers first reported in 1968 the occurrence of watery diarrhea following the oral administration of PGE 1 to manY Misiewicz later provided quantitative evidence of more rapid intestinal transit in man following the administration of PGE 1,t9 Although the diarrhea occurring after the administration of prostaglandin is the result not only of an effect upon

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intestinal motility but also of an effect upon water secretion by the intestine, action on motility plays a significant role in the occurrence of these sideeffects following the ingestion of prostaglandins. Additional studies in man indicated that the small intestine was the site of the described responses. 20 Although the results of in vitro studies differ from species to species and differ with respect to methodology, when isolated segments of ileum and colon are used, most investigators report stimulation of propulsion and circular muscle peristalsis following the administration of compounds to the serosal surface. The motility response to PGE compounds is more variable, particularly in the colon. Both PGE and PGF generally cause contraction of isolated longitudinal muscle from human colon. The facts that prostaglandins are present in the small and large intestine and their release is increased by muscle contraction, suggest a possible physiologic role for prostaglandins in intestinal motility. Further, the administration of nonsteroidal anti-inflammatory drugs to inhibit prostaglandin synthesis has been shown to diminish or result in the cessation of basal motility in the rabbit small intestine, suggesting a physiologic role for prostaglandins in maintaining intestinal tone. 2I The spontaneous activity of isolated colonic muscle is diminished both by indomethacin and by prostaglandin antagonists, an effect that is reversed by the addition of exogenous prostaglandins. 22 Moreover the stimulatory effect of both pentagastrin and cholecystokinin are also suppressed. Additional studies using other inhibitors of prostaglandin synthesis also support the concept that prostaglandins may play a physiologic role in the maintenance of intestinal motility, particularly in the colon. 23 Considering these findings it is also possible that prostaglandins may be important in the pathogenesis of a variety of intestinal disorders. Elevation of prostaglandin levels in the circulation of some patients with diarrhea and endocrine type tumors such as medullary carcinoma of the thyroid and carcinoid has been reported. 24 Prostaglandins may play a secondary role in the diarrhea observed in a variety of intestinal disorders such as inflammatory bowel disease and radiation enteritis or colitis (see below). Although the majority of patients with these disorders do not have elevated circulating levels of prostaglandins and although the mucosal administration of prostaglandins do not generally result in the motility changes observed following their serosal administration, the possibility that prostaglandins are locally synthesized, have an effect, and are then metabolized is consistent with our current knowledge. Finally, the successful administration of pros tag land ins to animals to reverse postoperative ileus may lead to the evaluation of these compounds in man for similar use clinically.25.26

EFFECTS ON SECRETION Effects on Gastric Secretion Prostaglandins Eh E 2, and Al have been shown to inhibit gastric acid secretion caused by a variety of secretory stimuli in animals and man. 64-68 The possible therapeutic use of prostaglandins as anti secretory compounds ap-

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peared unlikely at first because although they were effective when administered parenterally, these compounds were inactive by the oral route. 13 The ineffectiveness of naturally occuring prostaglandins administered orally is due both to metabolism by the gastrointestinal tract and inactivation by the lungs and liver following absorption. 69-7l Over the past several years analogs of PGE have been synthesized and have been found to be not only more potent than natural prostaglandins as inhibitors of gastric acid secretion but also effective when administered orally.72-75 Although 16, 16-dimethyl PGE 2 (DMPGE 2) and 15(R) 15-methyl-PGE 2 (15m-PGE 2) have received relatively extensive evaluation, a number of analogs of both PGE 2 and PGEl has been evaluated in man. In normal males DM-PGE 2 at a dose of 1.5 JLg/kg inhibited 2-hour basal and histamine-stimulated gastric acid secretion by 99 and 79 per cent, respectively; at a dose of 1.7 JLg/kg in subjects with duodenal ulcer disease it inhibited meal-stimulated secretion by 94 per cent. 76 . 77 At a fixed dose of 127 JLg administered in a gelatin capsule, DM-PGE 2 inhibited histamine-stimulated acid secretion in normal males by a mean of 60 per cent over 2 hours. 78 In healthy volunteers, 15m-PGE 2 is also a potent inhibitor of meal-stimulated secretion, causing a 67 per cent inhibition over 2 hours at a dose of 1.5 JLg/kg.79 In most studies both DM-PGE 2 and 15m-PGE 2 at dosages up to 2 JLg/kg cause no side-effects. Higher dosages may cause abdominal cramps and/or diarrhea in some subjects. Prostaglandins inhibit the volume of gastric secretion as well as total acid output, although the effect on acid output is generally somewhat greater than that on volume. The inhibitory effect of prostaglandins on total pepsin output parallels the changes in the volume of gastric secretion. 76 . 79 The mechanism(s) by which prostaglandins inhibit acid secretion is not precisely known. While prostaglandins are vasoactive substances that decrease gastric mucosal blood flow during the inhibition of gastric acid secretion, this change in blood flow is felt to be a secondary effect rather than a cause of the inhibition of acid secretion. BO • 81 Moreov~r, it is clear that prostaglandins act directly at the level of the parietal cell, since inhibition of [H+] secretion occurs in isolated gastric muco,sa that is devoid of a blood supply.82 As is the case is many tissues, there is a relationship between the action of prostaglandins and stimulation of the cyclic nucleotides. Exogenously administered cAMP or dibutyryl cAMP causes changes in gastric secretion similar to those observed after PGE administration in animals and man. 83 Moreoever, PGE increases gastric mucosal cAMP via stimulation of adenylate cyclase. SolI and co-workers in several studies have found that prostaglandins cause less stimulation of cAMP in parietal cell-enriched fractions of disbursed canine gastric mucosal cells than in non-enriched fractions, indicating that prostaglandin stimulation of cAMP in mucosa may be secondary to actions on cells other than parietal cells. 84 . 85 Concurrently, they have observed inhibition of histamine-induced stimulation of cAMP by prostaglandins, implying a stimulatory role for cAMP on gastric acid secretion in the dog. The fact that prostaglandins, known inhibitors of gastrin and cholinergically stimulated gastric acid secretion failed to inhibit gastrin or carbachol stimulation of parietal cell activity in these studies poses some difficulties. On the other hand, Wilson and co-workers reported in vivo stimulation of cAMP in the dog as well as in vitro stimulation of adenylate

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cyclase by PGE 2 and secretin, an inhibitor of gastrin-stimulated acid secretion; while both histamine and acetylcholine caused primarily an increase in mucosal cGMP.86 Recent studies in rats also suggest an inhibitory role, if any, for cAMP on gastric acid secretion, although the literature is replete with reports indicating both a stimulatory and an inhibitory effect for cAMP on acid secretion in various animal species. 87 Much additional information is needed with respect to specific receptors for prostaglandins and secretory stimulants, identification of the specific changes in the ATP transformation pathway, as well as hormonal interactions as they may relate both to gastric acid secretion and actions of prostaglandin.

Effects on Intestinal Secretion Numerous studies over the past 10 years have documented that PGE stimulates the secretion of water and electrolytes from the jejunum in both animals and man. 27 -30 These effects of prostaglandins are similar in many respects to those caused by cholera toxin. Both cholera toxin and prostaglandin E increase intestinal cyclic AMP by stimulating mucosal adenylate cyclase. 3l • 32 The similarity of observed effects of cholera toxin and prostaglandins caused a number of investigators to speculate that prostaglandins mediated the secretory effects of cholera toxin. 33 Indeed the use of prostaglandin synthesis inhibitors such as aspirin and indomethacin has been reported to decrease or inhibit the secretory effects of cholera toxin. 34-36 However, a number of recent studies shed doubt upon this hypothesis and suggest that the role of prostaglandins in cholera toxin-induced intestinal secretion is secondary rather than primaryP-40 The possibility that prostaglandins may yet be primarily involved in cholera toxin-induced secretion involving a mechanism other than activation of adenylate cyclase remains theoretically possible, but appears unlikely. Both in vivo and in vitro studies indicate that PGI 2 unlike PGE does not stimulate intestinal secretion, a finding probably related to the lack of a stimulatory effect for PGI 2 on mucosal adenylate cyclase activity.41-43 Intestinal secretion caused by both cholera toxin and prostaglandins as' well as cAMP-induced secretion is inhibited by ethacrynic acid, suggesting a common active secretory process. 44 Prostaglandins have been observed to increase luminal flow of protein in animals and man. 45 . 46 In studies in man these effects are rapidly reversible (within 60 minutes) suggesting the absence of structural changes. 44 However, in animal studies, mucosal structural damage upon ultrastructural analysis has been reported. 45 Changes in blood flow may also be important in mediating some of the prostaglandin actions. Prostaglandins have also been implicated in diarrheas associated with other toxin-producing bacteria as well as with some of the vasomotor changes associated with endotoxin shock. As was the case initially with cholera toxin-induced diarrhea, the finding that indomethacin reduced fluid secretion caused by salmonella and shigella enterotoxin suggested a possible primary role for prostaglandins. 36 Salmonella, shigella, and E. coli enterotoxin have also been shown to stimulate adenylate cyclase. 47 . 48 Endotoxin administered intravascularly has been shown to stimulate prostaglandin synthesis as determined both by analysis of isolated jejunal loops as well as measurement of portal blood levels of prostaglandins. 50.51 The

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extent to which hemodynamic changes observed in endotoxin shock are caused by prostaglandins, however, is questionable since inhibition of prostaglandins synthesis by drugs such as indomethacin does not prevent all of the hemodynamic changes. 51 Finally, several non-osmotic laxatives which increase water secretion in the colon also stimulate the release of PGE. However, inhibition of PGE synthesis by indomethacin does not abolish the secretory effects of these compounds, again indicating either a secondary role for prostaglandins or at least two separate mechanisms of action for these drugs. 52

Effects on Pancreas and Biliary Tract Secretions After many in vivo and in vitro studies, there is still confusion as to the specific actions of prostaglandins on exocrine pancreatic function. Prostaglandin El has been reported to inhibit fluid and electrolyte secretion while increasing the release of pancreatic enzymes both in vivo and in vitro. 53. 54 In vivo, PGE l augmented the effects of cholecystokinin-pancreozymin on enzyme secretion. 55 However, inhibition of enzyme secretion by prostaglandins has also been reported in vivo. 56 Recently, prostacyclin (PGI 2) has also been reproted to inhibit both fluid and protein secretion in vivoY The observed effects of prostaglandins in vivo may in fact be related to changes in pancreatic blood flow. At least one study using dispersed rat pancreatic acinar cells failed to observe any effects for prostaglandins or arachidonic acid on the secretory process and in fact found no evidence that acinar cell microsomes contained cyclo-oxygenase, suggesting the prostaglandins play no direct role in pancreatic secretion. 58 The difficulty in interpreting increased prostaglandin levels associated with pharmacologic or pathologic events is well illustrated by a previous report by Glazer and Bennett in which they observed elevated levels of PGE in experimentally induced hemorrhagic pancreatitis in dogs, suggesting that prostaglandins have a contributory role in this disorder. 59 However, recently a protective effect for PGE 2 against diet-induced acute pancreatitis in mice has been reported. 60 Prostaglandins Eland Al have previously b~en reported to stimulate bile flow in the dog; PGA 1 being more potent than PG El' 61 Prostaglandin F 2" is a potent choleretic compound producing bile rich in bicarbonate and chloride and bile containing increased levels of cAMP.62 Prostaglandin F 2 ", however, increased bile cAMP at high bile flow rates induced by the infusion of bile salts but not at low rates of bile flow. Prostaglandin F 2" stimulates bile salt-independent bile flow during choleresis without increasing bile cAMP, whereas an analogue of PGF 2" produced choleresis without affecting the bile salt-independent fraction. 63 Thus, the relationship between prostaglandin actions on cAMP and stimulation of bile flow is not clear.

CYTOPROTECTIVE EFFECTS A unique property of prostaglandins is their ability to protect the stomach and upper intestine against mucosal damage and ulceration caused by a variety of different insults, as well as by the depletion of endogenous prostaglandins. Robert first observed that prostaglandins prevented Shay

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ulcers in the rat. 88 Prostaglandins have since been shown to inhibit stress ulcers, as well as ulcers induced by acid, alcohol, caustic agents, boiling water, and corticosteroids, as well as a variety of other ulcerogenic agents. 89 Nonsteroidal anti-inflammatory drugs such as aspirin and indomethacin will induce ulcers in rats in the stomach as well as the jejunum and ileum. The administration of exogenous prostaglandins will prevent this damage. 9o Of particular significance is the fact that the protective action of prostaglandins can be totally separated from the anti secretory effects of prostaglandin on gastric acid. For example, not only are non-anti secretory prostaglandins such as PGF 2" protectors; anti secretory prostaglandins also exhibit this protective effect when administered at a fraction of the anti secretory dose. It should also be noted that the protective effect against some of the ulcer-inducing agents such as alcohol or boiling water can be demonstrated when prostaglandins are administered as little as 5 minutes prior to the ulcerogenic insult. Of particular clinical importance is the finding in two recent studies in man that PGE 2, 3 to 4 mg daily, prevented the increased blood loss caused by either aspirin, or indomethacin as measured by 51Cr labelled red cell studies. 91 , 92 As is the case with gastric acid secretion, the exact mechanism of prostaglandin cytoprotective effects is unknown. However, there are several interesting possibilities. Compounds such as aspirin are felt to damage the gastric mucosa primarily by "breaking" the "gastric mucosal barrier." The gastric mucosal barrier, a concept developed by Davenport,93 is an electrically measurable barrier which prevents the back-diffusion of [H+] into cells, once secreted into the lumen of the stomach. Traditionally, changes in the integrity of the gastric mucosal barrier have been determined by measuring changes in the negative electrical potential difference between the mucosal and serosal surfaces of the stomach, changes in electrical resistance, and changes in ionic fluxes. Compounds which damage the gastric mucosal barrier reduce the electrical potential difference and may as well affect net ionic fluxes. Theoretically, therefore, compounds which strengthen the integrity of the gastric mucosal barrier may have a protective effect upon the gastric mucosa. Studies by Chaudhury and Jacobson revealed that DM-PGE 2 increased both the negative electrical potential difference as well as net sodium flux, whereas indomethacin, an inhibitor of prostaglandin synthesis, had the opposite effects. 94 In addition compounds which increased intracellular cAMP such as theophylline and dibutyryl cAMP caused changes similar to those observed following the administration of DM-PGE 2 • An increase of mucosal cAMP was observed prior to the electrophysiologic changes occurring following the administration of DM-PGE 2• These studies suggest that one effect of prostaglandins is to strengthen the gastric mucosal barrier. In our early human antisecretory studies, we noted retrospectively that when receiving prostaglandins, subjects appeared to have more mucoid material in their gastric juice than when receiving placebo. Prostaglandins and prostaglandin analogs have previously been reported to stimulate mucus secretion in animals and man. 95-97 Recent studies from our laboratory indicate that the mucogenic properties observed after prostaglandin administration are also present following the administration of an analogue of the prostaglandin endoperoxide, PGH 2.98 We have also found that prostaglandins not only

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stimulate the release of mucus from the gastric mucosa but in in vitro studies stimulate the synthesis of mucus. 99 A consistent relationship exists in animals between the occurrence of stress ulcers and changes in mucus secretion. 1OHOI For example, drugs such as aspirin and phenylbutazone, which inhibit prostaglandin synthesis, and corticosteroids, which limit the availability of arachidonic acid, decrease both the quantity and carbohydrate content of mucus.102-106 It is likely, therefore, that the mucogenic properties of prostaglandins are important in the cytoprotective actions of these compounds. The stimulation of alkaline secretion by the gastric mucosa in response to prostaglandins has also been suggested as one of the possible mechanisms to explain prostaglandin cytoprotection. Garner and Heylings reported that PGF 2" as well as DM-PGE 2 stimulated alkaline secretion in the isolated amphibian gastric mucosa.I07 More recently Schiessel et aI., in repeating Garner's work, found no stimulation of alkaline secretion by DM-PGE 2 suggesting that the stimulatory effect previously reported was in fact an artifact related to methodology. lOB While we have not specifically measured alkaline secretion, in similar studies we have observed that certain doses of both PGE 2 and DM-PGE 2 can reduce acid concentration but increase the volume of secretion in the rat. 99 Finally, an effect upon gastric mucosal blood flow has been suggested as an additional possible mechanism for prostaglandin cytoprotection. Main and Whittle have observed that prostaglandins increase resting mucosal blood flow while indomethacin reduces gastric mucosal blood flow.lo9-llo Clearly other mechanisms must be involved since some ulcer-producing agents such as aspirin and ethanol increase mucosal blood flow. Moreoever indomethacin can damage the gastric mucosa in vitro where an intact blood supply no longer exists. 94 Thus it appears likely that multiple mechanisms come into play with respect to prostaglandin cytoprotection and that these mechanisms may differ depending upon the site of the involved gastrointestinal tract.

PROSTAGLANDINS AND INFLAMMATORY BOWEL DISEASE Over the past several years, interest in the possible role of prostaglandins in specific and nonspecific inflammatory disorders of the colon and small intestine has been stimulated by several case reports which suggested that patients with a variety of intestinal disorders such as radiation enteritis, irritable bowel syndrome, and food intolerance improved when inhibitors of prostaglandin synthesis such as aspIrIn or indomethacin were administered. 111- ll3 Additional preliminary reports indicated that prostaglandin levels measured either in stool or in blood were increased in patients with ulcerative colitis.1l4· 115 In 1978 Sharon et aI. measured PGE 2 levels in the rectal mucosa of patients with ulcerative colitis and found them to be higher than levels in normal rectal mucosaY6 Additionally, they found that azulfidine as well as its components, sulfapyridine, and 5-aminosalicylic acid, inhibited prostaglandin synthesis in incubated mucosal biopsies. The authors suggested that prostaglandins may therefore mediate the inflammatory response in ulcerative colitis. Other investigators have also documented in-

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creased PGE levels in patients with ulcerative colitis, observing higher levels of PGE during activity than during quiescence, and also documenting the inhibition of prostaglandin synthesis by azulfidine. 117- 12o Regrettably, the role of prostaglandins is not so simply assessed. Other investigators have failed to find a significant effect of azulfidine on prostaglandin synthesis but have instead noted major actions upon the metabolism of PGE 2 and PGF 2".1 21. 122 It should also be pointed out that at best azulfidine is a weak inhibitor of prostaglandin synthesis when compared to compounds such as indomethacin. At least one clinical study (as yet unpublished) has failed to show efficacy for indomethacin in the treatment of ulcerative colitis. A number of further considerations and studies are needed before one can accept the apparent paradox of prostaglandins being cytoprotective in the stomach and upper small intestine and pro-inflammatory in the colon, distal ileum, and esophagus. It must be remembered that prostaglandins are a normal by-product of the inflammatory response and the finding of elevated prostaglandin levels in inflammation does not necessarily indicate a pathogenetic role for prostaglandins. Studies assessing arachidonic acid metabolism in . normal colonic mucosa as well as in diseased mucosa, with specific pathway inhibitors, will be necessary in order to assess the role of prostaglandins in inflammatory bowel disease. Prospective studies in patients with inflammatory bowel disease to assess arachidonic acid metabolism in addition to well designed clinical trials utilizing inhibitors of prostaglandin synthesis may also be helpful.

PROSTAGLANDINS AND ULCER DISEASE As might be expected, prostaglandins have been implicated in the pathogenesis of peptic ulcer disease. Decreased levels of PGE in blood and gastric juice has been reported in patients with peptic ulcer disease when compared to normals. 123 In addition, a circadian rhythm of PGE noted in normals was found to be absent in subjects with peptic ulcer disease. 124 However, other investigators have not noted these differences. 125 Considering the anti secretory and cytoprotective actions of prostaglandins, these compounds are at least theoretically very likely to be effective in the treatment of peptic ulcer disease. Prostaglandin E2 as well as DM-PGE 2 and I5m-PGE 2 have been reported to accelerate the healing of both gastric and duodenal ulcers in randomized studies in man.126-130 In one study127 I5-methyl PGE 2 significantly improved the healing of both gastric and duodenal ulcers with 50 per cent healing after one week and 65 per cent healing after two weeks of treatment compared with 19 and 46 per cent for the placebo group at one and two weeks respectively. In this study gastric ulcers were more resistant to healing with I5-methyl PGE 2 than were duodenal ulcers. A significant number of individuals experienced diarrhea at the dose given, 1.5 jLg/kg; however, the diarrhea quickly subsided after discontinuation of the drug. Two observations noted in this study which require careful consideration in the future were the observations that both basal acid output and maximal acid output were significantly reduced ten days after discontinuation of prostaglandin therapy when compared to pretherapy levels and the finding of a number

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of recurrences of ulcer disease in the prostaglandin treated group within 6 months after discontinuation of the drug as compared to no recurrences seen in the placebo group after treatment with conventional antacid and/or anticholinergic therapy. At the present time several multi-center control studies are in progress evaluating the efficacy of several PGE analogues in the healing of gastric and duodenal ulcers in man. Should safety and efficacy be established prostaglandins would seem ideal compounds to prove effective in the treatment of clinical disorders such as erosive gastritis with and without bleeding, chronic gastritis, and gastritis secondary to bile reflux.

REFERENCES 1. von Euler, U. S.: Dber die spizifiche Blut drach senken de Substanz des Menschlichen. Prostats und Samenblasenseliretes. Klin. Wochenschr., 14:1182-1183,1935. 2. Horton, E. W.: Prostaglandins and smooth muscle. Br. Med. Bull., 35(3):295-300, 1979. 3. Horton, E. W.: Hypotheses on physiological roles of prostaglandins. Physiol. Rev., 49: 122-161, 1969. 4. Rattan, S., Hersh, T., and Goyal, R. K.: Effect of prostaglandin F '0 and gastrin pentapeptide on the lower esophageal sphincter. Proc. Soc. Exper. BioI. Med., 141 :573-575, 1972. 5. Goyal, R. K., and Rattan, S.: Mechanism of the lower esophageal sphincter relaxation. Action of prostaglandin El and theophylline. J. Clin. Invest., 52:337-341, 1973. 6. Goyal, R. K., and Rattan, S.: Comparison of the effects of pros tagland ins Eb E, and A, and of hypovolemic hypotension on lower esophageal sphincter. 7. Dilowar, J. B., Newman, A., Doles, J., et al.: Response of the human cardiac sphincter to circulating prostaglandins F '0 and E, and to anti-inflammatory drugs. Gut, 16:137-143, 1975. 8. Kruidinier, J., Tao, P., and Wilson, D. E.: The role of prostaglandins in lower esophageal spincter pressure in man. Clin. Res., 26:663A, 1978. 9. Rattan, S., and Goyal, R. K.: Role of prostaglandins in the regulation of lower esophageal sphincter. In: Christens en, J. C., ed.: Proceedings of the Seventh International Symposium on Gastrointestinal Motility. New York, Raven Press, 1980 (in press). 10. Daniel, E. E., Crankshaw, J., and Sarna, S.: Myogenic control of esophageal motor function. In Regulation of esophageal function. Second International Symposium on the Esophagus and Gastroesophageal Junction. Ixtapa, Mexico, March, 1978, pp. 14-19. 11. Northway, M. G., et al.: Radiation esophagitis in the opossum: radioprotection with Indomethacin. Gastroenterology, 78:883-892, 1980. 12. Brown, F., Beck, B., Fletcher, J.,pet al.: Evidence suggesting prostaglandins mediate lower esophageal sphincter (LES) incompetence associated with inflammation (abstr). Gastroenterology, 72:1033,1977. 13. Horton, E. W., Main, I., Thompson, C. J., et al.: Effects of orally administered prostaglandin El on gastric secretion and gastrointestinal motility in man. Gut, 9:655--658, 1968. 14. Dilawari, J. B., Newman, A., Poleo, J., et al.: Response of the human cardiac sphincter to circulating prostaglandins F,o and E, and to anti-inflammatory drugs. Gut, 16:137-143, 1975. 15. Robert, A., Nezamis, J. E., and Lancaster, C.: Effect of 16,16-dimethyl PGE, on gastric emptying. In Samuelsson, B., ed.: Advances in Prostaglandin and Thromboxane Research. New York, Raven Press, 1976, p. 946. 16. Wilson, D. E., Quertermus, J., Raiser, M., et al.: Inhibition of stimulated gastric secretion by an orally administered prostaglandin capsule: A study in normal men. Ann. Intern. Med., 84 :688--691, 1976. 17. Nompleggi, D., Myers, L., Castell, D. 0., et al.: Effect of a prostaglandin E2 analog on gastric emptying and secretion in rhesus monkeys. J. Pharmacol. Exp. Ther., 212:491-495, 1980. 18. Terez Shea-Donohue, P., Myers, L., Castell, D. 0., et al.: Effect of Prostacyclin on gastric emptying and secretion in rhesus monkeys. Gastroenterology, 78:1476--1479,1980. 19. Misiewicz, J. J., WaIler, S. L., Kiley, N., et al.: Effect of oral prostaglandin El on intestinal transit in man. Lancet, 1 :648-651, 1969. 20. Milton-Thompson, G. J., Cummings, J. H., Newman,]. A., et al.: Colonic and small intestinal response to intravenous prostaglandin F '0 and E, in man. Gut, 16:42-46, 1975. 21. Ferreira, S. H., Herman, A., and Vane, J. R.: Prostaglandin generation maintains the smooth muscle tone of the rabbit isolated jejunum. Br. J. Pharmac., 44:328, 1972. 22. Bruch, H. P., Schmidt, E., Laven, R., et aI.: The role of prostaglandins in peristalsis of the human colon. Acta Hepato-Gastroenterol., 25:303-307,1978.

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