Chapter 10. Agents for the Treatment of Peptic Ulcer Disease

Chapter 10. Agents for the Treatment of Peptic Ulcer Disease David E. Bays and Roger Stables, Glaxo Group Research Ltd., Ware, Hertfordshire, England

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General Reduction in gastric acid secretion by histamine H2-antagonists, anticholinoceptor drugs o r by compounds that affect specific enzymes within the parietal cell continues to be the main approach to therapy for peptic ulcers. Some good reviews on the mechanisms of acid production have appeared. l-3 A comprehensive book on the pharmacology of histamine receptors includes a chapter on structure activity relationships. The role of peptide hormones in the control of acid secretion,5i6 and the antisecretory and cytoprotective properties of prostaglandins,79 have been reviewed. Clinical experience with histamine H2-antagonists and other treatments for ulcers form the basis for many symp0sia.9,~~The options for treating peptic ulcers with drugs were discussed in an editorial The assessment of antisecretory dru s,l2l13 the role of endoscopy1$ in the clinic, and surgical approaches,$5 have been reviewed. Histamine H?-Antagonists- The discovery of cimetidine (1)and its clinical success have provided both the rationale and stimulus for the development of improved H2-antagonists. The pharmacology and clinical use of ranitidine (AH 19065 2 ) has been reviewed, and it has been the subject of numerous symposia.f7T18 Ranitidine is 4 to 10 times more potent than cimetidine in inhibiting stimulated gastric secretion in volunteers, and 150mg b.i.d. is clinically effective in healing gastric and duodenal ulcers over 4 to 6 weeks. Ranitidine is more selective than cimetidine in that it does not displace 3H-dihydrotestosterone from androgen binding sites ,I9 nor alter hepatic metabolism of drugs since it does not bind to cytochrome P450,20,21 and it does not augment the response of lymphocytes from patients to in vitro mitogenic stimulation.22 Although cholinomimetic effects of ranitidine have been seen in some gastrointestinal tissues in certain s ecies,23 they are of no clinical significance as they do not occur in man. 34,25 The parietal cells of patients treated with ranitidine for 1 year appeared normal on examination by light and electron microscopy.26 With cimetidine over 4 weeks the population of the parietal cells does not change.27 Further reviews on cimetidine have ap eared,28,29 including one on the effects of cimetidine on drug metabolism.fO In a recent clinical trial in 848 patients cimetidine b.i.d. (800% daily) was equivalent to q.i.d. ( lOOOmg daily) .31 The possibility that cimetidine treatment might raise intragastric nitrosamine levels and predispose to gastric cancer has been explored. In studies measuring intragastric bacterial counts and concentrations of nitrite and N-nitroso compounds during cimetidine treatment, no changes were detected during 24 hour sampling from normal v0lunteers,~2 but there were significant increases in these parameters in samples taken from peptic ulcer patients after an overnight fast.33 However, a survey of 9940 patients treated with cimetidine found no evidence of an increased incidence of gastric cancer.34 N-Nitrosocimetidine ( 3 ) was not carcinogenic in rats.35

ANNUAL REPORTS IN MEDICINAL CHEMISTRY- 18

Copyright 0 1983 by Academic Ress. Inc. All rights of reproducoan in any form reserved ISBN 0-12-Mo518-0

90

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- Pharmacodynamic Agents

Comer, Ed.

The pyrimidinone (SK&F 93479, 2) was more potent than cimetidine in the rat (xl0) and dog (x16) and had a longer duration of action than either cimetidine or ranitidine.36 In man it inhibited nocturnal gastric acid secretion at 0.6 and 0.9 mg/kg37 and 40~1g.3~ Trials were suspended following the discovery in the rat of some non-malignant changes in the mucosa at doses of 1000mg/kg/day .39 In man, oxmetidine (21,400mg b.i.d., reduced mean gastric acidit over 24 hr. by 59% and it had a similar duration of action to cimetidine.48 In a clinical trial, oxmetidine, 400mg b.i.d., was equivalent to cimetidine, Ig, in the treatment of duodenal ulcer.41 Unlike cimetidine, oxmetidine does not penetrate the cerebrospinal fluid after a single iv dose42 o r affect the mixed function oxidase in the l i ~ e r . ~ 3It does not raise serum prolactin levels after an i.v. bolus dose of 50 or 200mg,44 or alter basal levels of gonadotrophins in male patientsS45 It did not affect the parietal cell population.27 The background to the discovery of ranitidine, the guanidinothiazole tiotidine (61, and some of SK&F's work on H2-antagonists and histamine receptors, has been published.46 Introduction of a benzyl group into histamine did not give new H2-antagonists, and both HI- and H2-agonist activity was reduced.47 The guanidinothiazole famotidine (YM-11170, 7) lacks the usual NH in the chain. It is 40 and 50 times as potent as cimetidine in inhibiting acid secretion in the dog48 and pylorus-ligated rat respectively.49 Doses as low as 5-10mg reduced basal and tetragastrin-induced gastric secretion in man .5O It was more active than cimetidine in inhibiting gastric lesions in the rat induced by aspirin o r indomethacin, and it is not antiandr~genic.~g

Y

H

yF3a:)

c H 3 mCH2SCH2CH2NHN HNVN

5

(H2N12C=Ni&H2scH2~~NHR

X 6 CH2NH 7 CH2

-

Y

R1

NCN NS02NH2

CH3

H

One of the most significant developments in this field is the discovery of two new classes of H2-antagonists with a long duration of action, the thiadiazoles BL-6341A (8),51L-643441 (2),52 and the triazole lamtidine (AH 22216, 10) .53954 BL-6341A is described as a competitive antagonist on guinea pig atrium, 45 times as potent as cimetidine. In the pylorus-ligated rat, it is 116 times more potent than cimetidine. In the dog lumol/kg p.0. is significantly longer acting than an equieffective dose of cimetidine or ranitidine in that 9 hours after dosing inhibition of acid secretion is still >50%.5' L-643441 was 152 times as potent as cimetidine in

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the rat.52 The Merck group described L-643441 as an irreversible H2antagonist on guinea pig atrium.55 In the dog, it had a similar potency to ranitidine but had a longer duration of action, in that 24 hours after an oral dose of 15mg/kg secretion was reduced by 84% . 5 6 The two thiadiazoles (!,9) had significantly less affinity than cimetidine for andro en receptors and did not potentiate hexabarbital sleeping time in mice 3 2 The triazole (10)is an unsurmountable antagonist of histamine on the guinea pig a t r i ~ m . ~ T H o w e v e in r the dog, in vivo, it is a competitive antagonist, 4 to 10 times as potent as ranitidine against various secretagogues, and it has a prolonged duration of action. At O.lm /kg P.o., gastric secretion was still inhibited by 50% after 18 h0urs.~3,~'

Other Antisecretory Agents 1. Inhibitors of H+/K+zATPase. The benzimidazole omeprazole (H168/69,X), one of a series of compounds which act b inhibiting the parietal cell H+/K+ATPase,57 was reviewed at a s y m p ~ s i u m .Omeprazole ~~ inhibits acid secretion in the dog (ED50 0.3mg/kg) and at 0.6mg/kg 30-40% inhibition was present after 22-24 hours. Pentagastrin stimulated acid secretion in volunteers was inhibited by 65% at 40mg, and clinically 4Omg daily for 4 weeks is effective in the treatment of duodenal ulcer. It has also been used successfully in patients with Zollinger-Ellison syndrome.59

2. Tricyclic Compounds. Pirenzepine ( 2 1 , a selective antimuscarinic agent, has been the subject of another symposium.60 Clinically it is about as effective as cimetidine but side effects such as dry mouth have been reported. Pirenzepine and atropine have been compared with ranitidine and cimetidine in the anaesthetised dog.6 The anticholinoceptor agents reduced both gastric and salivary secretions, but the H2-antagonists selectively inhibited acid secretion. In another study62 in the rat, pirenzepine had less effect on pupil diameter than on salivary o r acid secretion; ED50 1.8, 0.5 and 0.7 mg/kg respectively.

A phenothiazine (LM24056, 13) inhibited gastrin, gastrin plus bethanacol but not histamine stimulated gastric secretion in the d0g.~3 The long duration of action (>20hours) in the dog at 2.5 mg/kg p.0. may i%eai;; be due to the formation of an active metabolite, desmethyl LM24056 vitro, this metabolite had a higher affinity f o r the muscarinic receptor than LM24056. In man at 100-300mg1 LM24056 inhibited nocturnal acid ~ecretion.~5 Dry mouth was a side effect at the highest dose. Desmethylimipramine (14) was compared with atropine in the rat.66 Both markedly inhibited acidsecretion, but unlike atropine the former did not substantially increase pupil size, cause urinary retention, or increase heart rate. Desmethylimipramine may act at central a*-adrenoceptors.66

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14

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Corner, Ed.

CH2CH2CH2NHCH3 I

3. Gut Peptides. A number of gut peptides can inhibit gastric acid secretion, but their therapeutic use is limited by their short half life and lack of selectivity.67 Intracranial administration of peptides such as bombesin, calcitonin, the opioid peptides and neurotensin decreased gastric acid secretion and protected against stress-induced ulcers in the rat.5 The opiate antagonist naloxone inhibited gastric secretion elicited by intravenous met-enkephalin68 o r sham feeding69 in man. The protective effect of somatostatin against ethanol induced astric damage in the rat may involve an interaction with sulfhydryl groups.$0 4. Other Structures. An imidazopyridine (SCH 28080, 15)inhibited histamine stimulated acid secretion in dogs (ED50 0.09 mg/kg i.v., 4.4 mg/kg p.0).7~ It is 4 to 10 times more potent than cimetidine in the pylorus ligated rat. It prevented aspirin induced gastric lesions in the rat and protected rats from necrosis induced by ethanol (ED50 4mg/kg p.0.). In man, doses of 50200mg inhibited gastric secretion by a mechanism not related to H2-blockade or an anticholinoceptor effect .T2 In the anaesthetised dog, the chromone (FPL 52694, 16) inhibited pentagastrin stimulated acid secretion by 70%.73 In conscious dogs with gastric fistulae it was more potent given intragastrically than by i.v. infusi0n.7~ A 32% reduction in pentagastrin stimulated acid secretion was seen in man.75 In man, the thioamide (RP 40749, 31, at 2mg/kg P.o., inhibited pentagastrin stimulated gastric secretion by an unknown me~hanism.7~ The amidine fenoctimine (2) inhibits acid secretion in rats and dogs.77 In the latter, given intragastrically, it resembles cimetidine but shows prolonged activity at a dose of 6mg/kg. It is not an anticholinergic, nor an H2-antagonist, but may act directly on parietal cells. It inhibits food and pentagastrin stimulated secretion in man and was active 8 hours after d0sing.7~

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CH2CN I

02Na dCH2Ph 15

%

CSNHCH3

17 -

C

Ph2CH-

NCH=N(CH2I7CH3 18 -

Prostaglandins - Prostaglandins have antisecretory and cytoprotective properties, and may have a physiological role in peptic ulcer disease. Mechanisms of mucosal damage and of cytoprotection have been reviewed.79 $7 An important defence against mucosal damage may be a "mucus-bicarbonate barrier" consisting of bicarbonate ions trapped below a mucus gel layer covering the gastroduodenal mucosa.80 A pH gradient across this layer, from a luminal pH of 2 to pH7 at the mucus/mucosa interface, has been measured in rat and human gastric mucosa.81,82 Aspirin treatment reduced this pH gradient by lowering the intra mucus pH, an effect prevented by 16,16-dimethyl P G E Z . ,a2 ~~ 16,16-Dimethyl PGE2 increased mucus synthesis by rat isolated mucus cells,83 and increased the mucus gel thickness in the rat.84 Gastric ulcer patients had gastric mucus with a weak structure.a5 Gastric bicarbonate secretion has been detected in man, and is stimulated by PGs. 86 3 87

Other mechanisms involved in cytoprotection could include direct effects of PGs on the mucosal cells. 16,16-Dimethyl PGE2 (lpg/ml) prevented ethanol induced increases in 5lCr release from rat isolated gastric mucosal cells.a8 A decrease in mucosal DNA levels following ethanol was prevented by 16,16-dimethyl PGE2 (lpg/kg s.c.) in the rat89 and by PGE2 (20pg/ml) in human rnuc0sa.9~ Proliferation of gastric mucosal cells resulted from chronic administration to rats of PGE2, (15R),15-methyl PGE2, (arbaprostil,2),and 16,16-dimethyl PGE2.g1,g2 Although 16,16-dimethyl PGE2 completely prevented formation of macroscopically visible necrotic lesions in rat gastric mucosa exposed to ethanol o r to indomethacin, microscopic analysis revealed that damage to the surface epithelial cells was unaffected o r only reduced by the pG.93394795 Endogenous prostanoids may have a cytoprotective function. Human gastrointestinal mucosa forms PGE2, P G F p and PGI2 from arachidonic acid ,g6 and PGE levels are low in gastric mucosal samples from gastric ulcer patients.97 Arachidonic acid protected rat gastric mucosa from ethanol damageg8 and inhibited gastric acid secretion in canine parietal cells,99 both effects being prevented by indomethacin. In the rat, paracetamol, sodium salicylate and mild irritants, such as 20% ethanol, increased mucosal PG generation and protected the mucosa from damage by 100% ethanol.' O 0 * l o l This effect was prevented by indomethacin. However in the dog, acfaptive cytoprotection to bile salt did not occur,lO2 and the importance of endogenous PGs to mucosal integrity in this species has been questioned.'03 In man there was no correlation between severity of mucosal damage and degree of reduction of mucosal PGE following 5 days treatment with acetyl salicylic acid. lo4

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Both PGE2 and (15R),15-methyl PGE2 reduced gastric damage caused by non-steroidal antiinflammatory compounds, and enhanced duodenal ulcer healing in man. Faecal blood loss following indomethacin in rheumatic disease patients was inhibited by oral PGE2, 0.33mg t.d.s., o r (15R),15-methyl PGE2, 0.05mg t d s ,105 and gastric bleedi;l(;binduced in volunteers by aspirin was inhibited by orai PGE2, 0.5mg q.d.s. Duodenal ulcer healing was enhanced by 4 weeks oral treatment with PGE2, 0.5mg t.d.s. plus lmg at night,l07 o r (15R),15-methyl PGE2 at O.lmg q.d.s.lo8 PGE2 does not inhibit gastric acid secretion at these dose levels. lo6,

...

16,16-Dimethyl PGE , at 0.1-l.Opg/kg P.o., inhibited gastric acid secretion in volunteers ,lo+lpg/kg t.d.s. , reducing acidity over 24 hours by 60%. lo Lower, non-antisecretory dose levels prevented the fall in gastric potential difference caused b aspirin,111 o r sodium taurocholate ,I12 but not that caused by ethanol.

111

ll-Methyl-16,16-dimethyl PGE2 (R021-6937, 0 )inhibited astric acid secretion in the dog at doses of 5pg/kg i .v. o r 30pg/kg p.0. ‘14 and also inhibited secretion induced by a test meal in man.l15 R021-6937 prevented chemically induced gastric o r duodenal ulcers in the guinea pig and rat, but was ineffective against gastric lesions caused by ethanol in the rat. It did not produce side effects such as hypotension o r diarrhea. l4 2-Decarboxy-1~-deoxy-16-hydroxy-2(hydroxyacetyl)-l6-methyl PGEl (CL 115,574, 1) prevented experimental ulcers in the rat at doses of 3-100pg/kg P.o., inhibited gastric acid secretion in the rat (100-1000pg/kg s.c.) and dog (5-100~/k i.g.1, and was free from behavioural effects in the dog at 500pg/kg.11 y 1 7 In volunteers CL 115,574 was well tolerated at doses of 500-1OOOpg P.o., reduced basal secretion by 85% and pentagastrin-stimulated secretion by 50%.

f 4

The thia PGE1 analogue (EMD 33290, 2) was a potent, but short acting inhibitor of basal acid output in man (ED50 20~g/kgp.0.). Doses of O.7pg/kg and 36pg/kg p.0. prevented the fall in gastric potential difference caused by aspirin and sodium taurocholate, respectively. l9 16-Methyl-16-methoxy PGEl methyl ester (DL646, 3)was cytoprotective in rats at doses of 0.02-O.lpg/kg P.o., inhibited gastric acid secretion at 15pg/kg i.g., and higher oral doses did not cause diarrhea in mice o r rats, o r hypotension in dogs.120 (15S), 15-Methyl PGE2 (4)infused subcutaneously at 0.015-0.03pg/ker/ min, (15S),15-methyl P G F p (carbaprost, 3)at l-2pg/kg/min s.c., and prostacyclin infused intravenously at 0.125-0.25pg/kg/ min all inhibited gastric acid secretion in the rhesus monkey, but stimulated a non-parietal secretion to differing degrees. l2 Prostacyclin reduced aspirin-induced gastric ulceration when infused intravenously in the cat.122 In the rat two stable prostacyclin analogues, nileprost (26) and ciloprost ( 3 )inhibited gastric secretion, reduced indomethacin lesions123,124 and neither induced diarrhea123 nor inhibited it. 124 Thus it is possible to obtain PGs in which cytoprotective and antisecretory properties are separated from side effects such as diarrhea.

Peptic Ulcer Disease

Chap. 10

0

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Bays, Stables

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Non-prostaglandin Mucosal Protectants - Other drugs that increase mucosal resistance include colloidal bismuth subcitrate (De-No11 and sucralfate, an aluminum salt of sucrose octasulphate. De-No1 and sucralfate form a protective coating on the surface of pe tic ulcers.125,126 Sucralfate also inhibits pepsin and binds bile a ~ i d s . ~ ~Both 7 drugs are as effective as cimetidine in the treatment of peptic ulceration and have been the subject of 129 Studies have su gested a lower relapse rate after recent symposia. treatment with De-Noll3O o r s~cralf'atel3~ than after cimetidine.

'

In Vitro Studies On Gastric Mucosa - The importance of histamine in the control of acid secretion was demonstrated in rabbit gastric gland132 and canine parietal cell preparations,l33 where potentiating interactions occur between histamine and other secretagogues. However, pepsin secretion by isolated rabbit g l a n d ~ I 3o~r rat chief cells135 is more responsive t o the muscarinic agonist , carbachol. PGE2 binding sites ,136 stimulation of mucus secretion83 and cytoprotective effects of PGs88990 have also been studied & vitro. References 1.

2. 3. 4.

5. 6.

7. 8.

9.

10. 11.

12. 13. 14. 15.

W.D.W. Rees and L.A. Turnberg, Clin. in Castroenterol., 2 , 5 2 1 (1981). T.K. Ray and D. Fromm, J.Surg.Res., 31, 496 ( 1981 1. B.I. Hirschowitz, Am.J.Gastroenterol., 281 (1982). ttPharmacologyof Histamine Receptors", C.R. Ganellin and M.E. Parsons, Ed., Wright PSG, Bristol, 1982. J.E. Morley, A.S. Levine and S . E . Silvis, Life Sci., 2 , 399 (1982). V . Mutt, Scand.J.Gastroenterol., Suppl 77, 133 (1982). 21 (1982). C. J o h n s o n and S. Bergstrom, Scand.J.Gastroenterol., Suppl "Physiology of the Gastrointestinal Tract", Ed. L.R. Johnson, p1407, A. Robert Raven Press, New York, 1981. W.A. Check, J.Am.Med.Assoc., 248, 1683 (1982). Scand.J.Gastroenterol., 11,Suppl. 78, (1982). Editorial, Lancet g,473 (1982). E.J.S. Boyd and K.G. Wormsley, Br.J.Clin.Pharmacol., 2,15 (1982). J.J.H. Chuong and H.M. Spiro, J.Clin.Gastroenterol., 4, 311 (1982). A.K. Grant and H.A.J. Harley, Br.Med.J., &, 868 (1982). J . B . Blalock, Am.J.Surg., K, 317 (1982).

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16. R.N. Brogden, A.A. Carmine, R.C. Heel, T.M. Speight and G.S. Avery, Drugs, 24, 67 (1982). 17. "The Clinical Use of Ranitidine", J.J. Misiewicz and K.G. Wormsley, Ed., Medicine Publishing Foundation Series 5, Oxford, 1982. 18. "Ranitidine", A.J. Riley and P.R. Salmon, Ed., Excerpta Medica, Amsterdam, 1982. 19. P. Pearce and J.W. Funder, Clin.Exp.Pharmaco1. Physiol., 1,442 (1980). 20. J.A. Bell, A.J. Cower, L.E. Martin, E.N. Clare-Mills and W.P. Smith, Biochem.Soc.Trans., 2, 113 (1981). 21. R . G . Knodell, J.L. Holtzman, D.L. Crankshaw, N.M. Steele and L.N. Stanley, Gastroenterology, 82, 84 (1982). 22. N.R. Peden, A.J. Robertson, E.J.S. Boyd, R.A. Brown, J.H. Gibbs, R.C. Potts, K.G. Wormsley and J. Swanson Beck, Gut 3.398 (1982). 23. G . Bertaccini and G. Coruzzi, Agents Actions, 12, 168 (1982). 24. T . Wallen, T. Madsen and S. Boesby, Gut, 4, 154 (1982). 25. G. Bertaccini, L. Lucchin, C. Bonoldi, M. Felder and G . Dobrilla, 1tal.J. Gastroenterol., l3, 253 (1981). 26. K . R . Hine, G.K.T. Holmes, J.P. Milnes, A. Phillips, D. Poynter and G. Ainge, Gastroenterology,82, 1085 (1982). 27. A. Emmanouilidis, P. Nicolopoulou-Stamati and 0. Manousos, J.Int.Med. Res., lo, 113 (1982). 28. J.W. Freston, Ann.Int.Med., 97, 573 and 728 (1982). 29. "Cimetidine in the ~ O ' S " , J.H. Baron, Ed., Churchill Livingstone, Edinburgh, 1981. 30. A. Somogyi and R . Gugler, Clin.Pharmacokinet., 1,23 (1982). 31 M. Delattre, A. Prinzie and D. Underwood, Clin.Trials J., 2 , 226 (1982). 32. G.J. Milton-Thompson, Z . Ahmet, N.F. Lightfoot, R.H. Hunt, J. Barnard, P.M.G. Bavin, R.W. Brimblecombe, D.W. Darkin, P.J. Moore and N. Viney, Lancet, 1, 1091 (1982). 33. R.W. Stockbrugger, P.B. Cotton, N. Eugenides, B.A. Bartholomew, M.J. Hill and C.L. Walters, Gut, 3,1048 (1982). 34. D.G. Colin-Jones, M.J.S. Langman, D.H. Lawson and M.P. Vessey, Br.Med.J., 9 , 1311 (1982). 35. M. Habs, G. Eisenbrand, H. Habs and D. Schmaehl, Proc.Am.Assoc. Cancer Res., 3, 73 Meet.104 (1982). 36. R.C. Blakemore, T.H. Brown, G.J. Durant, C.R. Ganellin, M.E. Parsons, A.C. Rasmussens and D.A. Rawlings, Br.J.Pharmacol., 2,ZOOP (1981). 37. H.G. Dammann and P. Mueller, Dtsch.Med.Wockenschr.,107, 194 (1982). 38. T. Gledhill, J.G. Mills, A. Clancy, M. Buck, R.H. Hunt and W.L. Burland, Gut, 23, A455 (1982). 39. Scrip, 686, 5 (1982). 40. J.G. Mills, P.L. Brunet, R. Griffiths, R.H. Hunt, D. Vincent, G.J. Milton-Thompson and W.L. Burland, Gut, 3,157 (1982). 41. G. Dobrilla, M.C. Bonoldi, F. Chilovi, G. Mazzacca and F. Sabbatini, Clin.Trials J., 3,308 (1982). 42. K-A. Jonsson, S-E. Eriksson, I . Kagevi, B. Norlander, G. Bodemar and A. Walan, Br.J.Clin.Pharmacol., 3, 815 (1982). 43. G. Mihaly, R . Hanson, R . Smallwood, J. Anderson and F. Vajda, Gastroenterology, 80, 1232 (1981). 411. P.C. Sharpe, M.A. Melvin, J.G. Mills, W.L. Burland and G.V. Groom, Acta Endocrinol., 95, 308 (1980). 45. A. Corinaldesi, A. Galassi, C. Borghi, R . Pasquali, M. Migioli, T. Sacco and L. Barbara, Hepato-gastroenterol., 2, 319 (1981). 46. "The Chemical Regulation of Biological Mechanisms", A.M. Creighton and S. Turner, Ed., Special Publication No. 42, The Royal Society of Chemistry, London, 1982, p . 1 . 47. J.C. Emmett, G.J. Durant, C.R. Ganellin, A.M. Roe and J.L. Turner, J.Med.Chem., 25, 1168 (1982). 118. T. Takagi, M. Takeda and H. Maeno, Arch.Int.Pharmacodyn., 256, 49 (1982). 49. M. Takeda, T. Takagi, Y. Yashima and H. Maeno, Arzneim.Forsch., 32, 734 (1982). 50. M. Miwa, I. Senque, T. Nomiyama, S. Suzuki, S. Harasawa, N. Tani and T. Miwa, Scand.J.Gastroenterol., l7, Suppl 78, 107 (1982). 51. A.A. Algieri, G.M. Luke, R.T. Standridge, M. Brown, R.A. Partyka and R . R . Crenshaw, J.Med.Chem., 5 , 210 (1982). 52. W.C. Lumma Jr., P.S. Anderson, J.J. Baldwin, W.A. Bolhofer, C.N. Habecker, J.M. Hirshfield, A.M. Pietruszkiewicz, W.C. Randall, M.L. Clineschmidt, G.H. Denny, R . Hirschmann, J.M. Hoffman, B.T. Phillips and K.B. Streeter, J.Med.Chem., 5 , 207 (1982). 53. R.T. Brittain, M.J. Daly, J.M. Humphray and R . Stables, Br.J.Pharmacol., 76, 195P (1982). 54. J.M. Humphray, M.J. Daly and R . Stables, Gut, 3,A899 (1982). 55. R . G . Pendleton, M.L. Torchiana, C.A. Hanson and B.V. Clineschmidt, Fed.Proc., 41, 7507 (1982). 56. M.L. Torchiana, P.G. Cook, S.R. Wiese, J.R. Stavorski, B.V. Clineschmidt and C.A. Stone, Fed.Proc.. 41, 7506 (1982). 57 E. Fellenius, B. E1andec.B. Wallmark, H.F. Helander and T. Berglindh, Am.J. Physiol., 3, G505 (1982).

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Peptic Ulcer Disease

Bays, Stables

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112.

36A (19621.

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_

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Sect. I1

- Pharmacodynamic Agents

Comer, Ed.

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