Gut, 1992, 33, 179-183

Bismuth subsalicylate in the treatment of H2 blockerresistant duodenal ulcers: role of Helicobacter pylori

S Wagner, M Gebel, K Haruma, W Bar, P Lange, J Freise, U Gladziwa, FW Schmidt

AbstractFifty nine patients with Helicobacter pylonpositive duodenal ulcers that failed to healafter a six week course of treatment with H2blockers were randomly assigned to one of thefollowing three regimens: (i) bismuth subsali-cylate, 600 mg three times daily (n=19), (ii)ranitidine, 300 mg at night (n=20), (iii) bismuthsubsalicylate plus ranitidine (n=20). Cumula-tive ulcer healing rates after four and eightweeks respectively were as follows: bismuthsubsalicylate 74% (14/19) and 95% (18/19),ranitidine 40% (8/20) and 65% (13/20), bismuthsubsalicylate plus ranitidine 80% (16/20) and95% (19/20). Bismuth subsalicylate treatmentwas better than ranitidine at both four and ateight weeks (p<0*05). The clearance rates forH pylon after four weeks were: bismuth sub-subsalicylate 58%, ranitidine 0%, bismuth sub-salicylate plus ranitidine 55%. After stoppingbismuth therapy bacterial recrudescence fre-quently occurred. After bismuth treatment86% (19/22) ofulcers had healed ifHpylori hadbeen cleared, whereas only 65% (11/17) hadhealed ifH pylon persisted (NS). This studyshows that bismuth subsalicylate is more effec-tive in the treatment of resistant duodenalulcers than standard dose ranitidine. It may bethat suppression ofH pylori by bismuth sub-salicylate promotes ulcer healing.

Departments ofGastroenterology andHepatology and ClinicalMicrobiology,MedizinischeHochschule Hannover,GermanyS WagnerM GebelW BarP LangeJ FreiseFW Schmidt

Department of Medicine,Rheinisch-WestfalischeTechnische HochschuleAachen, GermanyU Gladziwa

First Department ofInternal Medicine,Hiroshima UniversitySchool of Medicine,Hiroshima, JapanK HarumaCorrespondence to:Dr S Wagner, Department ofGastroenterology andHepatology, MedizinischeHochschule Hannover,D-3000 Hannover 61,Germany.Accepted for publication7 May 1991

Approximately 85-95% of duodenal ulcers healwithin six to eight weeks of treatment withstandard doses of H2 blockers.'2 The reasons fortreatment failure remain unclear but inadequatecontrol of acid secretion may be a crucialfactor.'3 Recently, the identification of Helico-bacter pyloni and its association with duodenalulcer disease led to the hypothesis that H pylonmight be involved in H2 blocker resistant ulcera-tion.2 The successful treatment of H2 blockerrefractory ulcers by colloidal bismuth subcitrate,which is able to eliminate H pylon, supports thistheory.4 5 Unfortunately, the role ofH pylon wasnot investigated in these therapeutic trials.Bismuth salts exert bactericidal effects onH pylon and have cytoprotective properties as

well, thus it is not clear whether the beneficialeffect of colloidal bismuth in refractory ulcers isdirectly related to the elimination ofH pylon.

This study aimed to investigate the efficacy ofbismuth subsalicylate in the treatment of refrac-tory duodenal ulcers and to elucidate the role ofH pylon.

Methods

PATIENTS AND STUDY DESIGN

Between September 1987 and May 1990 out-

patients with endoscopically proved H2 blockerresistant duodenal ulcers were recruited to thestudy. A resistant duodenal ulcer was defined asone that failed to heal after at least six weeks'continuous treatment with cimetidine 800 mgdaily or ranitidine 300 mg daily. The largestulcer diameter was not less than 5 mm. Thepatients did not have complications of pepticulcer disease, previous gastric surgery, concomi-tant treatment with ulcerogenic drugs, anti-coagulants, or antibiotics, or any serious chronicdisease. Only patients who had not had antibiotictreatment in the previous six months wereincluded.At initial endoscopy the ulcer size was assessed

and antral biopsy specimens were taken forhistological examination and H pylori screening.All patients were H pylori positive. Detailedinformation on duration and age of onset ofdyspeptic symptoms, previous drug therapy,previous ulcer complications, and social habitswere recorded.

After giving informed verbal consent, patientswere randomised by a nurse (to guarantee blind-ness of the investigators) using given regimensstratified for 63 subjects. Randomisation pro-cedure was accomplished by a computer pro-gram. Patients were allocated to receive one ofthe following three treatment regimens: (i)bismuth subsalicylate (Jatrox) 600 mg threetimes daily (two chewable tablets half an hourbefore the three meals); (ii) ranitidine (Zantac)300 mg at night; (iii) bismuth subsalicylate 600mg three times daily plus ranitidine 300 mg atnight. Treatment began within three days of theinitial endoscopy and was continued for fourweeks. If healing had occurred after four weeksthe treatment was stopped; if not the patientcontinued on the same regimen for another fourweeks. If at the end of eight weeks the ulcer hadnot healed the patient was withdrawn from thetrial and ranitidine 900 mg/day was given. Noother medications were allowed during the studyperiod.Compliance was ascertained by counting the

number of remaining tablets at the end of eachtreatment period. Clinical symptoms were asses-sed by recording the number and severity of painepisodes on a diary card. Endoscopy andHpylonscreening tests were repeated every four weeksduring the course of treatment and four weeksafter the end of the trial.

ENDOSCOPYEndoscopies were performed by PL, SW and JFwho were not aware of the clinical data, the bac-teriological findings, or the treatment regimen.At each endoscopy five biopsy specimens weretaken with sterilised biopsy forceps from antralmucosa 2 cm proximal to the pylorus. Two

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specimens were placed in 2 ml phosphatebuffered saline at 4°C for bacteriological exami-nation, two were fixed in 10% formalin forhistopathology, and one specimen was used for arapid urease detecting test (CLO-test, DeltaWest Ltd, Australia). In addition, smears ofbiopsy specimens were made for cytologicalexamination using Giemsa staining.

H PYLORI SCREENINGH pylon status was assessed by bacterial culture,a modified Giemsa stain, and the CLO-test asdescribed previously.6 Two biopsy specimenswere cultured under microaerobic conditions inblood agar base containing 5% horse blood andSkirrow selective supplement for seven days.Cultures were considered positive forH pylori ifGram negative, oxidase positive, catalasepositive, and urease positive spiral rods werepresent. The degree of colonisation with H pyloriwas estimated by examination of sections andsmears stained with Giemsa and was gradedsemiquantitatively as follows: 0=no organism;1= occasional; 2= moderate; 3= large numbers.H pylon status was regarded as positive if culturewas positive or if the urease test and Giemsa stainwere positive.The term 'clearance' was used ifH pylon status

was negative immediately after stopping treat-ment. 'Eradication' was used if H pylon wasabsent four weeks after the end of treatment.

HISTOPATHOLOGYFor histological examinations, formalin fixedbiopsy samples were embedded in paraffin andsections (4 ,tm) were stained with haematoxylinand eosin and Giemsa. Each biopsy specimenwas assessed for the presence, type, density andlocalisation of the inflammatory infiltrate. Thedegree of activity of gastritis was graded (0-3) byestimating the density of polymorphonuclearleukocyte infiltrates as described previously.6

TABLE I Patient characteristics and treatment schedules

BSS Ranitidine BSS (3x600 mg) plus(3 x 600 mg) (300 mg) ranitidine (300 mg)

Patients (n) 19 20 20Sex (male) 15 13 16Median age (yrs) 46 47 43Duration of ulcer history (median (yrs)) 97 8Smokers (n) 14 13 11Pain free (n) 4 6 6H pylori positive (n) 19 20 20Pretreatment (6 wks):

Cimetidine 800 mg/day (n) 14 12 16Ranitidine 300 mg/day (n) 5 8 4

BBS=bismuth subsalicylate.

TABLE II Ulcer healing rates and Helicobacter pylori status afterfour and eight weeks'treatment

Ulcer healed H pylori negative

Treatment 4 Weeks 8 Weeks 4 Weeks 8 Weeks

BSS 14/19 (74%* 18/19 (95%)* 11/19 (58%) 4/19 (21%)Ranitidine 8/20 (40%) 13/20 (65%) 0/20 (0%) 0/20 (0%)BSS+ranitidine 16/20 (80%)* 19/20 (95%)* 11/20 (55%) 4/20 (20%)

*p<0.05; BSS v ranitidine and BSS plus ranitidine v ranitidine. BSS=bismuth subsalicylate.

STATISTICSStatistical analysis was carried out by the X2 testfor the evaluation of the healing rates and by thematched pairs Wilcoxon signed rank test foranalysis ofH pylon and gastritis scores. Differ-ences with p values less than 0 05 were con-sidered significant.

ResultsFour of the 63 patients who entered the trial werelost during follow up (bismuth subsalicylate, n=2, ranitidine, n= 1, bismuth subsalicylate plusranitidine, n= 1). Fifty nine patients completedthe study and their characteristics are shown inTable I. There were no major differencesbetween the three treatment groups. Medianage, sex ratio, mean duration of ulcer history,smoking habits, and previous H2 blockertherapy were comparable (Table I). All patientswere H pylon positive. No relevant side effectswere observed in any treatment group.

Figure 1 summarises the outcome of thepatients under the different regimens. After fourweeks, ulcer healing had occurred in 74% (14/19)of patients receiving bismuth subsalicylate, in40% (8/20) of those receiving ranitidine, and in80% (16/20) of those treated with a combinationof both regimens (Table II). In patients withincomplete ulcer healing the same therapeuticregimen was continued for another four weeks.After eight weeks' treatment the cumulativehealing percentages were 95% on bismuth sub-salicylate, 65% on ranitidine, and 95% on bis-muth subsalicylate plus ranitidine. The healingrate on bismuth subsalicylate alone or in combi-nation with ranitidine was significantly highercompared with that on ranitidine, both at fourand at eight weeks (p<005). There was, how-ever, no significant difference between bismuthsubsalicylate as a single agent and in combinationwith ranitidine. After eight weeks there was noulcer relapse in patients whose ulcers had healedduring a four week course of bismuth subsali-cylate while two ulcers relapsed in the ranitidinegroup.

After four weeks H pylori was cleared in 58%of patients receiving bismuth subsalicylate andin 55% of those treated with bismuth subsalicy-late plus ranitidine, while none of the patients inthe ranitidine group wasH pylon negative (TableII). At eight weeks only a small group of patientswas still negative forHpylon (bismuth subsalicy-late 21%, bismuth subsalicylate plus ranitidine20%).The degree of mucosal infestation with

H pylorn was similar in all treatment groups attrial entry (Fig 2). At four weeks a noticeablereduction in H pylon scores was observed ingroups treated with bismuth subsalicylate, eitheralone or in combination with ranitidine. At eightweeks the density of colonisation with H pyloriincreased again in the bismuth groups becausetreatment had been stopped in the majority ofpatients whose ulcers had healed after fourweeks. In a subgroup of patients who receivedbismuth subsalicylate for eight weeks H pyloriscores resembled those at four weeks (data notshown). Ranitidine monotherapy had no signifi-cant effect onH pylori scores at any time.

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Bismuth subsalicylate in the treatment ofH2 blocker resistant duodenal ulcers: role ofHelicobacter pylori

Figure 1: Healing ofH2blocker resistant duodenalulcers with bismuthsubsalicylate, ranitidine, orboth, atfour and at eightweeks. *Two relapsed ateight weeks.

Bismuthsubsalicylate

Ranitidine

Bismuthsubsalicylate+

ranitidine

0

14 Healed

19

8 Healed *

2012 _

20

4

16 Healed

4 >~~~~~~~~~~~~~~18

Time (weeks)

4 Healed

1 Not healed7 Healed

5 Not healed

3 Healed

1 Not healed

12

In the biopsy specimens of the antrum takenbefore entry active chronic gastritis was found toa similar extent in all study groups (Fig 3).Gastritis scores fell after four weeks of bismuthsubsalicylate and were still somewhat lower ateight weeks in these patients when comparedwith basal values. In parallel to the H pylonscores, ranitidine monotherapy failed to improvegastric inflammation at any time.

Table III shows ulcer healing in relation toclearance of H pylon in patients treated withbismuth subsalicylate alone or in combinationwith ranitidine. Ulcer healing was higher afterclearing of H pylon in comparison with thepermanently infected patients, but this differ-ence did not reach statistical significance (healingrate 86% v 65%; odds ratio 3 15; NS). Some 65%(11/17) of ulcers healed during a four weekcourse of bismuth (alone or combined withranitidine) despite persistence of H pylon ingastric mucosa, even though there had been a

reduction in the overall bacterial load.In order to study the efficacy of bismuth

subsalicylate in eradicating H pylori, patientswere reinvestigated four weeks after stoppingbismuth treatment. Thirty patients received bis-muth subsalicylate for four weeks, and of thesethree were still H pylon negative four weeks aftercompleting treatment, resulting in an eradica-tion rate of 10%. Nine patients were treated withbismuth subsalicylate for eight weeks, only one

patient (11%) eradicated H pylon in this sub-group.At trial entry epigastric pain was recorded in

14/19, 16/20, and 14/20 respectively in treatmentgroups (i), (ii), and (iii). Most patients becameasymptomatic after two weeks and there was no

difference in the proportion of patients withresidual symptoms in the three treatmentgroups.

DiscussionThere is no general aggreement on the definitionof H2 blocker resistant duodenal ulcers.2 Sincemost ulcers heal after six weeks' treatment with

3-

2-

Figure 2: Mean (SD) ofHpylori colonisation in antralbiopsy specimens underdifferent therapies beforetreatment and atfour andeight weeks. A significantdecrease in H pyloricolonisation in comparisonwith the preentry level isindicated by an asterisk.

O:- 1.,o..... Before entry 8 Weeks

I[_Bismuth subsalicylate L Ranitidine - Bismuthsubsalicylate + ranitidine

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4 Weeks..--

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3-

2-

1-

Figure 3: Mean (SD) scoresofgastritis in antral biopsyspecimens under differenttherapies before treatmentand atfour and eight weeks.A significant decrease in thegastritis score in comparisonwith the pre-entry level isindicated by an asterisk.

0- _.

fore entry

.*1<S;;; *i I;.

I-.i4 Weeks

I8 Weeks

| e Bismuthsubsalicyate [ Ranitidine Bismuth.subsalicylate + ranitidine

a standard dose of an H2 blocker, this timecriterion was chosen in the present study for thedefinition of a resistant ulcer.7 In our series afurther four week course of treatment withranitidine 300 mg was able to heal 40% of theresistant duodenal ulcers, and 65% were healedafter eight weeks. Therefore, only a small groupof patients is truly resistant to H2 blockers, whilemost represent slow ulcer healing.Our controlled trial shows that bismuth sub-

salicylate is superior to standard dose ranitidinein the treatment of resistant ulcers. Both at fourand at eight weeks, the healing rate was signifi-cantly higher with bismuth subsalicylate thanwith ranitidine treatment. The combination ofbismuth subsalicylate and ranitidine resulted inhealing rates similar to those with bismuthsubsalicylate alone.While the efficacy of colloidal bismuth sub-

citrate in the treatment of duodenal ulcers is wellestablished,8`10 only two reports have addressedthe role of bismuth in the treatment of refractoryduodenal ulcers.45 Lam et al have shown thattripotassium dicitratobismuthate (120 mg fourtimes daily) heals cimetidine resistant ulcerssignificantly better than high dose cimetidine(1-6 g/day) (healing rates 85% v 40%). Similarresults have been obtained by Bianchi Porro et al,who reported significantly higher healing rateson tripotassium dicitratobismuthate (120 mgfour times daily) than on cimetidine (1 -2 g and 2g). Our study shows for the first time thatbismuth subsalicylate is effective in the treat-ment of resistant duodenal ulcers. The healingrates on bismuth subsalicylate in our study are

TABLE III Ulcer healing in relation to clearance ofH pyloriin patients treated with bismuth subsalicylate alone or incombination with ranitidine

Ulcer healed Ulcer not healedat 4 weeks at 4 weeks Total

H pylonr-ve 19 3 22Hpylor +ve 11 6 17Total 30 9 39

comparable with those achieved with tripo-tassium dicitratobismuthate in the trials of Lamet al and Bianchi Porro et al. Thus, the efficacy ofbismuth salts in ulcer healing seems to be relatedsolely to the bismuth component while the anionmay be of minor importance.Bismuth salts are site protective agents which

have various cytoprotective properties."'`Additionally, they have recently been shown toexert bactericidal effects on H pylori.' , Thepresent study is the first which attempts toelucidate the role of H pylori in the healing ofresistant duodenal ulcers. None of the patientstreated with ranitidine cleared H pylon, nor didthey show a decrease in the degree of bacterialinfestation. Some 65% (11/17) of the duodenalulcers healed with bismuth subsalicylate despitepersistance ofH pylori, although at a decreasednumber. Thus, bacterial elimination is not aprerequisite for healing of resistant duodenalulcers.

After four weeks' treatment with bismuth,however, 86% (19/22) of ulcers had healed if thebacterium was cleared, whereas only 65% (11/17)had healed ifH pylori persisted. This differencedid not reach statistical significance due to thesmall number of patients but the finding maylend support to the hypothesis that bacterialclearance promotes ulcer healing. Recently,Marshall et al showed that duodenal ulcer heal-ing is significantly higher in patients in whomH pylori has been eliminated than in those withpersistent bacterial infection. 16 In our study,14% (3/22) of duodenal ulcers did not healdespite of clearance ofH pylon, suggesting thatclearance ofH pylori does not necessarily resultin ulcer healing. It could be, however, thatbacterial eradication is a stronger promoter ofulcer healing than temporary clearance ofH pylori.Bismuth treatment reduced the density of

bacterial colonisation of the gastric mucosa, butthere was only a transient clearance ofH pylon.Stopping treatment was frequently associatedwith a recurrence of the organism in the gastric

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Bismuth subsalicylate in the treatment ofH2 blocker resistant duodenal ulcers: role ofHelicobacter pylori 183

mucosa showing that eradication ofH pylon is arare event during bismuth treatment. In agree-ment with previous studies,'7" 1 we found a closerelation between the grade of chronic gastritisand the degree of infestation of gastric mucosawith H pylon. A reduction in the H pylon scorewas associated with an improvement in gastricinflammation. Therefore, the difference in ulcerhealing rates in patients treated with bismuth vthose treated with ranitidine may be partly aresult of an improvement of histology.The role of H pylon in acute ulcer healing

seems to be of less importance than its role in therecurrence of duodenal ulcers. A growing bodyof evidence has accumulated indicating thateradication of H pylori is associated with asignificant reduction in ulcer relapses and mayeven cure duodenal ulcer disease. 5 16 19The causes of H2 blocker ineffectiveness in

acute ulcer healing have not been fully clarified.Inadequate acid suppression has been frequentlyobserved in H2 antagonist non-responders.2"23 Inaddition, almost all H2 blocker resistant duo-denal ulcers can be healed by the potent protonpump inhibitor omeprazole.2425 Therefore,inadequate control of acid secretion by H2 block-ers seems to be the most important factor intreatment failures.

In conclusion, our study shows that bismuthsubsalicylate is effective in the treatment of H2blocker resistant duodenal ulcers. In addition,bismuth subsalicylate is superior to a prolongedadministration of standard dose H2 antagonists.The beneficial effects of bismuth subsalicylate inthe treatment of resistant ulcers may result fromsuppression of H pylon and the associatedimprovement of gastritis in addition to its wellknown cytoprotective properties

Part of this work was presented at the 92nd Meeting of theAmerican Gastroenterological Association in New Orleans, onMay 20, 1991, and was published in abstract form: Gastro-enterology 1991; 100: A180.

1 Wormsley KG. Duodenal ulcers which do not heal rapidly.BMJ 1984; 289: 1095.

2 Domschke W, Lam SK, Pounder RE, Andersen D. H2-blocker-resistant duodenal ulceration. GastroenterolInternational 1989; 2: 85-91.

3 Gledhill T, Buck M, Hunt RH. The effect of no treatment,cimetidine 1 g/d, cimetidine 2 g/d and cimetidine combinedwith atropine on nocturnal gastric secretion in cimetidinenon-responders. Gut 1984; 25: 1211-6.

4 Lam SK, Lee NW, Koo J, Hui WM, Fok KH, Ng M.Randomised crossover trial of tripotassium dicitratobismuthate versus high dose cimetidine for duodenal ulcersresistant to standard dose cimetidine. Gut 1984; 25: 703-6.

5 Bianchi Porro G, Parente F, Lazzaroni M. Tripotassiumdicitrato bismuthate (TDB) versus two different dosages ofcimetidine in the treatment of resistant duodenal ulcers. Gut1987; 28: 907-11.

6 Wagner S, Freise J, Bar W, Fritsch S, Schmidt FW.Epidemiologie und Therapie der Campylobacter-pylori-Infektion. Dtsch Med Wochenschr 1989; 114: 407-13.

7 Delchier JC, Isal JP, Eriksson S, Soule JC. Double blindmulticentre comparison of omeprazole 20 mg once dailyversus ranitidine 150 mg twice daily in the treatment ofcimetidine or ranitidine resistant duodenal ulcers. Gut 1989;30: 1173-8.

8 Lee FI, SamloffIM, Hardman M. Comparison of tripotassiumdicitratobismuthate tablets with ranitidine in healing andrelapse of duodenal ulcers. Lancet 1985; i: 1299-302.

9 Hamilton I, O'Connor HJ, Wood NC, Bradbury I, AxonATR. Healing and recurrence of duodenal ulcer aftertreatment with tripotassium dicitrato bismuthate (TDB)tablets or cimetidine. Gut 1986; 27: 106-10.

10 Tytgat GNJ. Colloidal bismuth subcitrate in peptic ulcer - Areview. Digestion 1987; 37 (suppl 2): 31-41.

11 Konturek SJ, Radecki T, Piastucki I, Drozdowics D.Advances in the understanding of the mechanism of cytopro-tective action by colloidal bismuth subcitrate. Scand JGastroenterol 1986; 21 (suppl 122): 6-10.

12 Wagstaff AJ, Benfield P, Monk JP. Colloidal bismuth sub-citrate. A review of its pharmacodynamic and pharmaco-kinetic properties, and its therapeutic use in peptic ulcerdiseases. Drug 1988; 36: 132-57.

13 Hall DWR. Review of the modes of action of colloidal bismuthsubcitrate. Scandj Gastroenterol 1989; 24 (suppl 157): 3-6.

14 Ericsson CD, Tannenbaum C, Charles TT. Antisecretory andantiinflammatory properties of bismuth subsalicylate. RevInfect Dis 1990; 12 (suppl 1): S11-5.

15 Coghlan JG, Humphries H, Dooley C, Keane C, Gilligan D,McKenna D, et al. Campylobacter pylon' and recurrence ofduodenal ulcers - a 12-month follow-up study. Lancet 1987;ii: 1109-11.

16 Marshall BJ, Goodwin CS, Warren JR, Murray R, BlincowED, Blackbourn SJ, et al. Prospective double-blind trial ofduodenal ulcer relapse after eradication of Campylobacterpylori. Lancet 1988; ii: 1437-42.

17 Rauws EAJ, Langenberg W, Houthoff H, Zanen HC, TytgatGNJ. Campylobacter pyloridis-associated chronic activeantral gastritis. Gastroenterology 1988; 94: 33-40.

18 Stolte M, Eidt S, Ritter M, Bethke B. Campylobacterpylori undgastritis - association oder induktion. Pathologe 1989; 10:21-6.

19 Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associatedwith eradication of Helicobacter pylori. Lancet 1990; i:1233-5.

20 Savarino V, Mela GS, Scalabrini P, Celle G. H2-receptorantagonist non-responders. Lancet 1987; ii: 1281.

21 Wagner S, Freise J, Schmidt FW. H2-receptor antagonistnon-responders. Lancet 1988; i: 128.

22 Johnston DA, Wormsley KG. The effects of fasting on 24-hgastric secretion of patients with duodenal ulcers resistant toranitidine. AlimentPharmacol Therap 1989; 3: 471-9.

23 Collen MJ, Stanczak VJ, Ciarleglio CA. Refractory duodenalulcers (nonhealing duodenal ulcers with standard doses ofantisecretory medication). Dig Dis Sci 1989; 34: 233-7.

24 Tytgat GNJ, Lamers CBHW, Hameetman W, Jansen JMBJ,Wilson JA. Omeprazole in peptic ulcers resistant to hista-mine H2-receptor antagonists. Aliment Pharnacol Therap1987; 1: 31-8.

25 Brunner G, Creutzfeldt W, Harke U, Lamberts R. Therapywith omeprazole in patients with peptic ulcerations resistantto extended high-dose ranitidine treatment. Digestion 1988;39: 80-90.

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