Prostaglandins and Peptic Ulcer Therapy R . P. WALT Department of Medicine, Queen Elizabeth Hospital, Birmingham, U.K

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Walt RP. Prostaglandins and peptic ulcer therapy. Scand J Gastroenterol IYW, 25(~uppl174), 29-36 The expectation that prostaglandin analogues would improve the ulcer healing abilities of other agents by combining mucosal protection with decreased acid secretion has been proved unwarranted. The ulcer healing capabilities of these drugs reflect their antisecretory potency. A role for these drugs in ulcer healing is questionable but their use has been advocated most strongly to prevent ulceration developing during treatment with non-steroidal anti-inflammatory drugs. While some evidence supports this role, an important clinical benefit of reducing complication rates has yet to be demonstrated.

~

Key words: Acid secretory inhibition; cytoprotection; non-steroidal anti-inflammatory drugs; peptic ulcer

R. P. Walt, Senior Lecturer in Medicine, Queen Elizabeth Hospital, Birmiizgham BIS 2 TH . U . K

The simplistic view of peptic ulcer being the result of an imbalance of aggressive factors and defensive mechanisms remains our concept of peptic ulcer pathogenesis. Understanding of the hypothetic mechanisms involved has improved, but the exact pathogenetic process remains unknown. The therapeutic success of potent antisecretory drugs like omeprazole supports but does not confirm the hypothesis that without acid, ulcers do not deuelop. Clearly, acid plays a role (at least in healing), but whereas most patients with peptic ulcer have gastric secretory patterns similar to those of normals, it seems equally clear that other pathogenetic mechanisms must participate. The therapeutic choices include drugs that do not decrease gastric secretion (sucralfate, carbenoxolone, and colloidal bismuth). The actions of such agents are poorly understood, but a unifying mechanism might involve gastric prostaglandins (1). The development of prostaglandin analogues for clinical use in peptic ulceration has followed, but so far success has been limited. POTENTIAL ADVANTAGE OF PROSTAGLANDINS Many natural prostaglandins (particularly of the

E series) inhibit gastric acid secretion. The analogues of PGE, and PGEz which have been developed are potent inhibitors of acid secretion at a site close to or at the adenylate cyclase in the parietal cell (2). Over and above antisecretory activity, these drugs also share the property of ‘cytoprotection’. This term describes the relative protection from mucosal damage by prostaglandins used in doses that d o not decrease gastric secretion. Gastric secretory inhibition is in itself somewhat protective, so separation of these two effects is important. The analogues that have been tested in models of gastric damage are protective, and this combined with gastric secretory inhibition represents the greatest potential advantage of these agents. RESULTS OF THERAPEUTIC TRIALS WITH PROSTAGLANDIN ANALOGUES Several drugs have already come and gone; trimoprostil, arbaprostil, and nioprostil are amongst them. This section concentrates on results with the remaining two (misoprostol and enprostil), which have either become available in other parts of the world or are (we believe) awaiting licensing approval.

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R. P. Walt

Table I. Clinical trials comparing misoprostol with placebo in duodenal ulcer (all double-blind) Dose Reference Brand et al. (3)

50 Pi3 200 P

Sontag et al. (4)

100 v g

Bright-Asare et al. (5) (twice daily)

200 clg 400 P 200 M 300 Clg

P

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Healing at 4 weeks

(four times daily)

Lam et al. (6)

P

Confidence intervals

43/101 82/107 51/100 72/111 55/116

(43%) (77%) (51%) (65%) (47%)

33-53 67-84 41-61 55-74 38-47

55/104 53/81 38/90 47/77 54/76 27/76

(53%). (65%)' (42%)' (61%)' (71%)' (36%)'

43-63 54-76 32-53 49-72 59-81 25-48

' Numbers calculated as not given in paper. Significance testing repeated with calculation of 95% confidence intervals. All papers report significant improvement in healing compared with placebo (except 50 pg (3)).

Duodenal ulcer Misoprostol. Trials that have compared the effects of various doses of misoprostol with placebo in duodenal ulcer healing over 4-8 weeks are shown in Table I. These were generally multicentre and double-blind. Doses of misoprostol varied (one of the aims was to discern the most appropriate dose) from 50pg four times daily (ineffective) to 200 pg four times daily or 400 pg twice daily (effective). The results from these studies show that in adequate doses misoprostol accelerates duodenal healing. Enprostil. The results of two multi-centre double-blind trials comparing 35 pg or 70 pg enprostil twice daily with placebo are shown in Table 11. The trials are smaller, with enprostil making confidence intervals wide, but healing rates seem similar to those with misoprostol.

Comparisons with H2-receptor antagonists. Trials have not shown that prostaglandin analogues are more effective than cimetidine or ranitidine. Results are summarized in Table 111, which demonstrates that enprostil and misoprostol are about as effective as cimetidine, but that enprostil at least is significantly less effective than ranitidine. In one of these trials enprostil was given as a single dose at bedtime, which is possibly not the most suitable time for this drug. Gastric ulcer Misoprostol and enprostil (Table IV). Healing rates are lower than for duodenal ulcer, and a beneficial effect due to the prostaglandin analogues is less clear. In comparative studies with H2-receptor antagonists enprostil and misoprostol seem about as effective as cimetidine. An advan-

Table 11. Clinical trials comparing enprostil with placebo in duodenal ulcer (all double-blind) ~~

Reference Thomson et al. (7) Bright-Asare et al. (8)

Dose (twice daily)

Healing 4/52 n (%)

Confidence intervals

p i0.05

35 clg 70 P

26/40 (65) 28/36 (78) 5/36 (14)

48-80 60-9 1 5-31

E" v. P E"' v. P

23/33 (70) 18/37 (49)

51-85 32-66

p 35 P

from CI

Significance testing repeated with calculation of 95% confidence intervals. Both papers report significant improvement in healing compared with placebo.

Prostaglandins for Ulcers

31

Table 111. Clinical trials comparing enprostil or misoprostol with H2-antagonists in duodenal ulcer (all doubleblind) Drug dose

Healing at 4/52

Confidence intervals

Misop, 200 vg Misop, 50 CLg Cimet, 300 mg

1391224 (62%) 931217 (43%) 1581221 (72%)

55-68

Enpro, 35 clg Cimet, 400 mg

1241166 (75%) 124/ 161 (77%)

67-8 1

Enpro. 35 Pg Ranit, 150 mg

64/82 (74%) 77/87 (89%)

63-84

Enpro, 70 wg Ranit, 300 mg

2615 1 (52%) 39/51 (76%)

37-66

Reference

< 0.05 from CI

p

~~

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Nicholson (9) (four times daily)

Winters et al. (10) (twice daily)

Lauritsen et al. (1 1) (twice daily)

Walt et al. (12) (at night)

~

~~

M”’v. Msn 36-50 65-77

C v . MM

70-83

Rv.E 7%95

Rv.E 62-88

~~

~

~

Studies all double-blind and randomized. Winters et al. (10) data pooled from four separate studies to the same protocol. Significance testing has been repeated with calculation of 95% confidence intervals. Lauritsen (1 1) and Walt (12) report significant difference in favour of H2-antagonist. Nicholson (9) reports significant improvement with cimetidine and misoprostol, 200 pg, over misoprostol, 50 pg. Table IV. Clinical trial comparing enprostil or misoprostol with placebo in gastric ulcer (all double-blind) Reference

Dose

Agrawal et al. (13) (misoprostol four times daily)

25pg 100 pg

Navert et al. (14) (enprostil twice daily)

P 35 pg 70pg

P ~~

~

~

Healing n (%)

Confidence intervals

< 0.05 from CI

p

36/93 36/79 35/80

(39) (46) (44)

29-50 34-57 32-55

NS

22/41 21/40 12/34

(54) (53) (35)

38-70 36-69 20-54

NS ~

~~

Significance testing repeated with calculation of 95% confidence intervals. Both papers report significant improvement in healing compared with placebo (at 8 weeks only in Agrawal et al. (13)).

tage in favour of the prostaglandins has not emerged (Table V). SHOULD PROSTAGLANDIN ANALOGUES BE MORE EFFECTIVE THAN ANTISECRETORY TREATMENT? Replacement therapy It has been postulated that peptic ulcer is the result of a failure of synthesis or deficiency of local

endogenous prostaglandins. If this were true, and if the right prostaglandin could be delivered to the right place at the right time, then replacement therapy should be extremely effective. Unfortunately, evidence of prostaglandin deficiency is doubtful, and methodologic problems have hampered the formation of firm conclusions. Some have failed to show significant alterations in prostaglandin synthesis in peptic ulcer (18), and others have shown that gastritis may increase prostaglandin synthesis or secretion (19,20),

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R. P. Walt

Table V. Clinical trials comparing enprostil or misoprostol with H2-antagonistsin gastric ulcer (all double-blind) ~~

Healing

Confidence

p < 0.05

35-50

Mm’v. C NS

Cimet, 300 mg

701166 (42%) 1121208 (54%) 1261208 (61%)

Enpro, 35 Pg Ranit, 150 mg

25/43 (58%) 30146 (66%)

Reference Rachmilewitz et al. (15) (four times daily)

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Dammann et al. (16) (twice daily)

Drug Misop, 50 Pg 200 Pg

47-6 1

E v . RNS

42-73 50-79 ~~

Both trials show no significant difference between treatments with regard to valid statistics. Interim analysis of Rachmilewitz trial showed significant difference between the higher and lower misoprostol doses (17). Recruiting into latter group was therefore stopped.

Table VI. Healing of DU in smokers and non-smokers with prostaglandins

Trial Brand et al. (3) Nicholson (9) Vantrappen et al. (40) Walt et al. (12) Lauritsen et al. ( 1 1) Bright-Asare et al. (8) Lam et al. (6) Sontag et al. (4) Comparators Brand et al. (3) Vantrappen et al. (40) Sontag et al. (4) Bright-Asare et al. (8) Nicholson (9) Walt et al. (12) Lauritsen et al. (1 1)

Drug

Smokers

Non-smokers

M M A E E E M M

73 53 46 45 58 58 57

79 71 79 56 67 86 72 80

6 18 I5 10 22 28 14 23

(-12 to ( + 4 to ( - 14 to (-24 to (-5 to (-7 to (-3 to (-4 to

+23) +31) +42) +41) +48) +63) +31) +42)

43 27 46 49 63 71 60

65 65 51 50 74 81 82

22 38 5 1 11 10 22

(+0.2 to (+13 to (-2 to (-35 to (-1 to (-16 to (-8 to

+44) +62) +27) +40) +44) +38) +45)

P P

P P C R R

64

Difference (95% CI)

Percentage healing rates in smokers and non-smokers with confidence intervals of differences in comparative studies for which data are available. Overall, active treatment (irrespective of type) generally overcomes the detrimental effects of smoking, although a type-I1 error is likely. No particular advantage during prostaglandin treatment is apparent.

although this may be secondary t o inflammation. More studies have shown decreased gastric PG synthesis in gastric ulcer (21,22) than decreased duodenal prostaglandin synthesis in duodenal ulcer (23). Peptic ulcer is thus not clearly a disease characterized by prostaglandin deficiency per se, and replacement therapy might therefore not be expected to offer enormous hope.

Cytoprotection The experiments in animals which demonstrate cytoprotection generally consist of exposing previously normal mucosa to an injurious agent (bile acids, ethanol, aspirin) with or without additional exogenous prostaglandin. T h e experimental animal is then killed, and the number or extent of gastric lesions is counted or measured in some

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Prostaglandins for Ulcers

way. These experiments are far removed from human peptic ulcer, which is a chronic lesion and is not known to be preceded by s w h superficial ulceration. It is also clear that where healing is concerned, the damage has already been done, and what is needed is not protection but regeneration. That mucosal protection occurs in animals is accepted even when the doses of prostaglandins used have no effect on acid secretion. In humans, however, this evidence is less convincing. Studies have generally used doses of prostaglandins which are antisecretory, and any measured effect could be explained through this mechanism alone (24,25). In one endoscopic study 25 pg misoprostol was protective against 1300 mg aspirin-induced damage, although an antisecretory component to this cannot be excluded. Cytoprotection is vaguely dose-related, but so is gastric secretory inhibition, and with the lowest dose of misoprostol significant protection is questionable (26). The H2-receptor antagonists can protect similarly (27). The finding of mucosal protection in humans is not necessarily relevant. The methods used measure gastric mucosal blood loss from presumed ulceration (24) or assess endoscopic ‘lesions’ in a manner similar to the rodent experiments (25,28). The latter type is closest to the clinical setting, but it is not clear that the lesions seen are due to the same process as, or are definite precursors of, peptic ulcer. Two clinical trials demonstrate that cytoprotection is of no benefit in peptic ulcer healing. In one, 50 yg misoprostol four times daily, which is cytoprotective in acute experiments, made no impact on ulcer healing rates, whereas the larger antisecretory dose (200 pg) accelerated duodenal ulcer healing (3). In another trial cytoprotective doses of arbaprostil were not better than placebo in acute duodenal ulcer healing (29). It seems most likely that the ulcer healing potential of the prostaglandin analogues reflects their effect on acid secretion alone (30). Gastric acid secretion ‘Prostaglandin analogues are the most potent known antisecretory compounds in terms of doses required for significant activity’ (31). However,

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although microgram doses produce inhibition of basal, pentagastrin-, histamine-, and meal-stimulated gastric secretion, the effects over prolonged periods are limited. Ulcer healing with antisecretory drugs appears to correlate with their ability to decrease nocturnal and 24-h intagastric acidity. Enprostil, the analogue with greatest antisecretory potency and longest duration of effect, has been tested over 24 h and, in a comparison with 600mg cimetidine, was equieffective in a dose of 35 pg (32) at decreasing 24-h intragastric acidity. Two subsequent studies were non-comparative but show that the decrease of 24-h intragastric acidity after 35 yg enprostil twice daily is of the same order of magnitude as 400mg cimetidine twice daily, but a single nighttime dose of 70 pg is probably less effective than standard bedtime doses of H2 blockers (12,33). Disappointing healing rates presumably reflect the limited antisecretory of doses used clinically. PROSTAGLANDINS FOR SPECIAL CIRCUMSTANCES Smoking and peptic ulcer Cigarette smoking is an important factor predisposing duodenal ulcer patients to relapse after healing and probably to delayed healing (34,35). Cigarette smoking has multiple influences on the gastric mucosa, possibly including increased acid secretion (36) and increased bile reflux (37). Smoking also decreases mucosal prostaglandin synthesis (38). Drugs that inhibit gastric secretion are clinically less effective in smokers than in non-smokers, and it has been suggested that this differential response does not occur when prostaglandins are used (39). The facts, however, do not bear this out (Table VI). It appears that similar differential healing occurs in smokers and non-smokers with duodenal ulcer irrespective of treatment with H2receptor antagonist or prostaglandin. One study (41) suggests that sucralfate may also be particularly beneficial in smokers. This drug, which is not a prostaglandin, has actions that include stimulation of mucosal prostaglandin synthesis (42). This fact has been used to support the hypothesis that prostaglandins are particularly

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R. P . Walt

involved in ulcer healing in cigarette smokers, but other mechanisms like mucus stimulation (43) could explain any special effect of sucralfate, should it be confirmed. Thus, a particular role for prostaglandins or their synthesis is not proved in cigarette smokers.

but at what cost (53)? It is necessary to show that co-administration can decrease morbidity and, it is to be hoped, mortality before a role for prostaglandins here is concluded.

Non-steroidal anti-inflammatory agents The belief that any association between upper gastrointestinal ulceration and the NSAIDs is due to prostaglandin synthesis inhibition has led to the hypothesis that protection could be afforded by concomitant prescription. The financial implications of such practice to health services are considerable, as already over 20 million prescriptions for NSAIDs are issued each year in the U.K. The problem with NSAIDs, perceived as enormous by gastroenterologists (44,45),is one of bleeding or perforation of gastric and duodenal ulcer. The problem in real terms may be small (46,47),making co-administration difficult to justify. It is clear that ulceration in the form of erosions and submucosal reddening or haemorrhage follows the administration of NSAIDs to humans (48,49)and that co-administration of misoprostol limits this (but does not prevent it). The use of such data to support the argument in favour of co-administration of prostaglandins and NSAIDs must be viewed with suspicion. The correlation between the presence of these lesions and the extent of prostaglandin synthesis inhibition is poor (50). It is possible that the lesion whose prevention is sought with prostaglandins may have different aetiologiesy may not be the Same as chronic peptic ulcer, and may have little clinical importance. Two recent studies have shed some light, but the problem is not resolved. One of these studies showed that ranitidine could limit the development of ‘duodenal ulcers- in patients receiving NSAIDs but that the H2 antagonist was not effective at gastric ulcer prevention (51). Another trial has clearly shown that mi so pros to^ will protect from NSAID-induced gastric ulcer but will not alter duodenal ulcer prevalence (52). both duodenal ulceration and gastric ulceration are important causes of morbidity, effective prophylaxis will require the use of both agents,

The involvement of prostaglandins in peptic ulceration seems clear but is mostly related to prevention of ulceration rather than to its healing. Clinical evidence suggests that the prostaglandin analogues accelerate ulcer healing through inhibition of gastric secretion and does not support an added effect of cytoprotection. For uncomplicated peptic ulcer treatment other available drugs are as effective and have fewer side-effects. The evidence to support the use of prostaglandins to treat smokers or patients receiving non-steroidal anti-inflammatory drugs or to limit relapse of duodenal ulcer is unsatisfactory. A potential role in prevention of NSAID-induced ulcer requires further study.

CONCLUSIONS

ACKNOWLEDGEMENTS This article is adapted from and previously published in part in Topics in Gastroenterology 1989, 16,63-76,edited by D.P. Jewel1 and J. R. Lowes, and in Scand J Gastroenteroll988,23(suppl146), 40-49.

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Prostaglandinsfor Ulcers

5. Bright-Asare P, Sontag SJ, Gould RJ, Brand DL, Roufail WM. Efficacy of misoprostol (twice daily dosage) in acute healing of duodenal ulcer: a multicentre double blind controlled trial. Dig Dis Sci 1986, 3l(suppl 2), 63S-67S 6. Lam SK, Lau WY, Choi TC, et al. Prostaglandin E l (misoprostol) overcomes the adverse effect of chronic cigarette smoking on duodenal ulcer healing. Dig Dis Sci 1986, 3l(suppl 2), 68S-74s 7. Thomson ABR, Navert H, Halvorsen L, et al. Treatment of duodenal ulcer with enprostil, a prostaglandin E, analogue. Am J Med 1986, 8l(suppl 2a), 59-63 8. Bright-Asare P, Krejs GJ, Santangelo WC, et al. Treatment of duodenal ulcer with enprostil, a prostaglandin E, analogue. Am J Med 1986, 8l(suppl 2a), 64-68 9. Nicholson PA. A multicenter international controlled comparison of two dosage regimens of misoprostol and cimetidine in the treatment of duodenal ulcer in outpatients. Dig Dis Sci 1985,30(suppl Il), 171S-177s 10. Winters L, Wilcox R, Ligny G, et al. Comparison of enprostil and cimetidine in active duodenal ulcer disease. Summary of pooled European studies. Am J Med 186, 8l(suppl 2a), 69-74 11. Lauritsen K, Laursen LS, Havelund T, Bytzer P, Svendsen LB, Rask-Madsen J. Enprostil and ranitidine in duodenal ulcer healing: double blind comparative trial. Br Med J 1986, 292, 864-866 12. Walt RP, Pounder RE, Hawkey CJ, et al. Twentyfour hour intragastric acidity and clinical trial of bedtime enprostil 70 pg compared with ranitidine 300 mg in duodenal ulcer. Aliment Pharmacol Ther 1987, 1, 161-166 13. Agrawal NM, Saffouri DM, Kruss DM, Callison DA, Dajani EZ. Healing of benign gastric ulcer: a placebo controlled comparison of two dosage regimens of misoprostol, a synthetic analogue of prostaglandin E l . Dig Dis Sci 1985, 3O(suppl l l ) , 164% 170s 14. Navert H, Thomson ABR, Archambault A, et al. Treatment of gastric ulcer with enprostil. Am J Med 1986, 8l(suppl 2a), 75-79 15. Rachmilewitz D, Chapman JW, Nicholson PA, et al. A multicentre international controlled comparison of two dosage regimens of misoprostol with cimetidine in treatment of gastric ulcer in outpatients. Dig Dis Sci 1986, 3l(suppl 2), 75S-80s 16. Dammann HG, Huttemann W, Kalek HD, Rohner HG. Simon B. Comparative clinical trial of enprostil and ranitidine in the treatment of gastric ulcer. Am J Med 1986, 8l(suppl 2a), 80-84 17. Shield MJ. Interim results of a multicentre international comparison of misoprostol and cimetidine in the treatment of outpatient gastric ulcers. Dig Dis Sci 1985, 3O(suppl I I ) , 178s-184s 18. Alquist DA, Dozois RR, Zinsmeister AR, Malagelada J-R. Duodenal prostaglandin synthesis and acid load in health and in duodenal ulcer disease. Gastroenterology 1983, 85, 522-529 19. Hawkey CJ. Synthesis of prostaglandin E,, thromboxane-B2, and prostaglandin catabolism in gastritis and gastric ulcer. Gut 1986, 27, 1484-1492

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20. Schlegel W, Wenk K, Dollinger HC, Raptis S. Concentrations of prostaglandin A-, E-, and F- like substances in gastric mucosa of normal subjects and of patients with gastric diseases. Clin Sci Mol Med 1977, 52, 255-258 21. Konturek SJ. Actions of nonsteroid anti-inflammatory compounds on gastric mucosal integrity and prostaglandin formation in healthy subjects and peptic ulcer patients. Adv Inflamm Res 1984,6,2% 37 22. Wright JP, Young GO, Klaff LJ, Weerss LA, Price SK, Marks IN. Gastric mucosal prostaglandin E levels in patients with gastric ulcer disease and carcinoma. Gastroenterology 1982, 82, 263-267 23. Smith CL, Hillier K. Duodenal mucosa synthesis of prostaglandins in duodenal ulcer disease. Gut 1985, 26, 237-240 24. Hawkey CJ, Simpson G , Somerville KW. Reduction by enprostil of aspirin induced blood loss from human gastric mucosa. Am J Med 1986, 81(2A), 50-53 25. Dajani EZ, Nissen CH. Gastrointestinal cytoprotective effects of misoprostol: clinical efficacy overview. Dig Dis Sci 1985, 3O(suppl l l ) , 1 9 4 s 200s 26. Silverstein FE, Kinney MB, Saunders DR, Surawicz CM, Wilson RA, Silverman BA. Gastric protection by misoprostol against 1,300mg of aspirin. An endoscopic dose response study. Am J Med 1987, 83(1A), 32-36 27. MacKerchner PA, Ivey KJ, Baskin WN, Krause WJ. Protective effect of cimetidine on aspirin induced gastric mucosal damage. Ann Intern Med 1977, 87, 676679 28. Lanza FL. A double blind study of prophylactic effect of misoprostol on lesions of gastric and duodenal mucosa induced by oral administration of tolmetin in healthy subjects. Dig Dis Sci 1986, 3l(suppl 2), 131.9-136s 29. Euler AR, Tytgat G , Berenguer T. et al. Failure of a cytoprotective dose of arbaprostil to heal acute duodenal ulcers. Gastroenterology 1987, 92, 604607 30. Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987, 28, 1120-1127 31. Hawkey CJ, Rampton DS. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease or treatment? Gastroenterology 1985, 89, 1162-1188 32. Mahacai V, Walker K, Sevelius H, Thompson ABR. Antisecretory and serum gastrin lowering effect of enprostil in patients with duodenal ulcer disease. Gastroenterology 1985, 89, 555-561 33. Deakin M, Ramage J, Paul A , Gray SP, Billings J , Williams JG. Effect of enprostil, a synthetic prostaglandin E2on 24 hour intragastric acidity, nocturnal acid and pepsin secretion. Gut 1986.27, 1054-1057 34. Sontag SJ, Graham DY, Belsito A, et al. Cimetidine, cigarette smoking and recurrence of duodenal ulcer. N Engl J Med 1984, 311, 689-693 35. Korman MG. Hanskv J. Eaves ER. Schmidt GT. Influence of. cigarette smoking on healing and

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relapse in duodenal ulcer disease. Gastroenterology 1983, 85, 871-874 36. Massarrat S, Enschai F, Pittner PM. Increased gastric secretory capacity in smokers without gastrointestinal lesions. Gut 1986, 27, 43-39 37. Muller-Lissner SA, Fraass C. Bile reflux is increased in cigarette smokers. Gastroenterology 1986, 90, 1295-1209 38. Quimby GF, Bonnice CA, Burnstein SH, Eastwood GL. Active smoking depresses prostaglandin synthesis in human gastric mucosa. Ann Intern Med 1986, 104, 616-619 39. Lam SK. Prostaglandins smoking and duodenal ulcers [Letter]. Lancet 1987, I, 212-213 40. Vantrappen G, Jansens J, Popiela T , et al. Effect of 15(R)-15-methyl prostaglandin E, (arbaprostil) on the healing of duodenal ulcer. A double-blind multi-center study. Gastroenterology 1982,83,357363 41. Lam SK, Hui WM, Lau WY, et al. Sucralfate overcomes adverse effect of cigarette smoking on duodenal ulcer healing and prolongs subsequent remission. Gastroenterology 1987, 92, 1193-1201 42. Konturek SJ, Kwiecien N, Obtulowicz W, Kopp B, Oleksy J. Double blind controlled study of the effect of sucralfate on gastric prostaglandin formation and microbleeding in normal and aspirin treated man. Gut 1986, 27, 1450-1456 43. Shea-Donohue T , Steel L, Montcalm E, Dubois A. Gastric protection by sucralfate. Role of mucus and prostaglandins. Gastroenterology 1986,91,660-666 44. Somerville KW, Faulkner G, Langman MJS. Nonsteroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet 1986, 1, 462-464

45. Armstrong CP, Blower AL. Non-steroidal antiinflammatory drugs and life threatening complications of peptic ulceration. Gut 1987, 28, 527532 46. Inman WHW. Non-steroidal anti-inflammatory drugs. PEM News 1984, 2, 4-10 47. Jick SS, Perera DR, Walker AM, lick H. Nonsteroidal anti-inflammatory drugs and hospital admissions for perforated peptic ulcer. Lancet 1987, 2, 380-382 48. Lanza FL, Aspinall RL, Swabb EA, Davis RE, Rack MF, Rubin A. A double blind placebo controlled endoscopic comparison of the cytoprotective effects of misoprostol and cimetidine on tolmetin induced gastric mucosal injury. Gastroenterology 1987.92, 1491 49. Agrawal NM, Tulane U , Roth S, et al. Misoprostol coadministration heals aspirin-induced gastric lesions in rheumatoid arthritis patients. Gastroenterology 1987, 92, 1290 50. Redfern IS. Lee E, Feldman M. Effect of indomethacin on gastric mucosal prostaglandins in humans. Gastroenterology 1987, 92, 969-977 51. Ehsanullah RSB, Page MC, Tildedley G , Wood JR. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. Br Med J 1988. 297, 1017-1021 52. Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double blind, placebo-controlled trial. Lancet 1988, 2, 1277-1280 53. Anonymous. Misoprostol: ulcer prophylaxis at what cost? Lancet 1988, 2, 129S1294

Prostaglandins and peptic ulcer therapy.

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