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Objective: Observations showing that bile acid malabsorption is frequent in irritable bowel syndrome (IBS) suggest that alterations in bile acid-induced secretion and absorption could contribute to IBS-associated diarrhoea. The secretory response to bile acids, fluid transport and bile absorption was examined in intestinal tissues from a Trichinella spiralis mouse model of postinfectious gut dysfunction in vitro. Changes in the protein expression of apical sodium-dependent bile acid transporter (ASBT) were also measured., Design: T. spiralis-infected mice were killed at 18 and 25 days postinfection. Jejunal, ileal, proximal and distal colon segments were exposed to taurodeoxycholic acid (TDCA) or cholic acid. Short circuit current (SCC) increases were determined. Tritiated taurocholic acid (3H-TCA) absorption was determined in everted jejunal and ileal sacs. ASBT protein expression was determined by Western blot analysis and immunohistochemistry., Results: Basal SCC increased in ileum and distal colon at 18 and 25 days postinfection, respectively. Ileal SCC responses to TDCA and cholic acid were enhanced at 18 days postinfection. Distal colon SCC response to TDCA was raised at 18 days postinfection but was significantly reduced by 25 days. Ileal 3H-TCA uptake was significantly reduced at 18 and 25 days postinfection. Surprisingly, increased ASBT expression was observed in infected animals., Conclusions: In a T. spiralis model of postinfectious gut dysfunction, decreased bile absorption and enhanced secretion in response to bile acids was observed. Decreased absorption was not, however, caused by decreased ASBT as increased expression was observed. If similar events occur postinfection, the combined effects of these disturbances may contribute to some symptoms observed in postinfectious IBS patients.

Background and Aims: One of the key components of inflammation is changes in vascular structure and function. This suggests that the microcirculation may be a key target of Helicobacter pylori released factors. It has previously been shown in vivo that pooled H pylori extracts from duodenal ulcer/gastritis patients induce platelet aggregation but no leucocyte activation within rat gastric mucosal microcirculation (GMMC). However, infection with strains associated with ulcer disease as compared with gastritis may exert greater effects on the microcirculation. This study used fluorescent in vivo microscopy to determine the acute effects of extracts of genotypically different H pylori strains on the GMMC., Methods: Three H pylori extracts, with different cagA and VacA toxigenic status, were individually administered to the gastric mucosa of anaesthetised Wistar rats. The mucosal surface was visualised via an incision made in the exteriorised stomach. Fluoroscein isothiocyanate conjugated to bovine serum albumin (FITC-BSA) or acridine orange was used to quantify macromolecular leak (MML) and leucocyte/platelet activity respectively for 120 minutes. Changes in capillary and post-capillary venule (PCV) diameters were also monitored., Results: The cagA(+) VacA toxigenic strain 60190 induced significant and sustained MML by five minutes (p<0.01). Transient and less leakage was observed with its isogenic VacA(-) mutant and other non-toxigenic strains regardless of cagA status. Significant increases in leucocyte adhesion (p<0.05), platelet aggregation (p<0.05), and PCV vasoconstriction (p<0.05) were only observed with the cag A(+) and toxigenic strain., Conclusion: Extracts of H pylori are capable of inducing marked disturbances within the rat GMMC. These disturbances seem to be dependent on the production of an active vacuolating cytotoxin. Varying effects on the GMMC may explain the clinically diverse outcomes associated with genotypically different strains.

Aims: To investigate the efficacy of daily maintenance treatment with omeprazole 10 mg in reducing the relapse rate of healed erosive oesophagitis., Methods: Three hundred patients with erosive oesophagitis (grade 2 or greater) received omeprazole 20 mg daily for 12 weeks, followed by 40 mg daily for a further 12 weeks if required. After healing, patients were randomised to double blind treatment with omeprazole 10 mg daily or placebo for up to 18 months. On relapse the treatment cycle was repeated., Results: The cumulative healing rate at 12 weeks in the initial healing period was 95%, and 96% and 98% on rehealing courses after relapse in the first and second maintenance periods respectively. After 12 weeks of treatment, 98% of patients were free from heartburn and 97% were free of all reflux related symptoms. Relapse in the subgroup of patients who relapsed in both maintenance periods was infrequent on omeprazole 20 mg daily: only 9% at two years. Gastrin concentrations rose above normal in one third of patients. One patient had linear hyperplasia of endocrine cells and another had micronodular hyperplasia. There were no side effects definitely attributable to omeprazole., Conclusion: Maintenance treatment with omeprazole 10 mg daily keeps about 60% of patients with erosive oesophagitis in prolonged remission. Patients relapsing once are likely to do so again; they can subsequently be treated effectively with omeprazole 20 mg daily.

Background: Eradication of Helicobacter pylori cures and prevents the relapse of duodenal ulceration and also results in histological resolution of chronic active gastritis., Aim: To compare four treatment regimens lasting seven days of a proton pump inhibitor and two antibiotics in the eradication of H pylori., Patients: Men or women with H pylori positive duodenal ulceration or gastritis, or both., Methods: A single blind, prospectively randomised, parallel group, comparative, multicentre study. After a positive CLO test, patients underwent histology, H pylori culture, and a 13C urea breath test to confirm H pylori status. Treatment with one of four regimens: LAC, LAM, LCM, or OAM, where L is 30 mg of lansoprazole twice daily, A is 1 g of amoxycillin twice daily, M is 400 mg of metronidazole twice daily, C is 250 mg of clarithromycin twice daily, and O is 20 mg of omeprazole twice daily, was assigned randomly. A follow up breath test was done at least 28 days after completing treatment., Results: H pylori eradication (intention to treat) was 104/121 (86.0%) with LAC, 87/131 (66.4%) with LAM, 103/118 (87.3%) with LCM, and 94/126 (74.6%) with OAM. There was a significant difference (p < 0.001) in the proportion of patients in whom eradication was successful between LAC and LCM when compared with LAM, but no significant difference (p = 0.15) between LAM and OAM. Metronidazole resistance before treatment was identified as a significant prognostic factor with regard to eradication of H pylori. The regimens which contained metronidazole were significantly less effective than those without metronidazole in the presence of pretreatment resistant H pylori. There was no difference among the treatment groups with regard to the incidence and severity of adverse events reported., Conclusions: All four treatment regimens were safe and effective in eradicating H pylori in the patient population studied. LAC was the most efficacious treatment in patients with pretreatment metronidazole resistant H pylori, and was significantly better than LAM and OAM in this group of patients.

Background: The exact mechanisms by which Helicobacter pylori infection results in gastric mucosal injury are unclear., Aims: To assess in vivo whether H pylori extracts could initiate an inflammatory response in the rat gastric mucosal microcirculation., Methods: Extracts of H pylori, Escherichia coli, or distilled water were administered topically to the gastric mucosa of anaesthetised animals. Fluorescence in vivo microscopy assessed macromolecular leakage of labelled albumin from mucosal vessels, leucocyte adherence/rolling, and platelet activity for 90 minutes., Results: H pylori induced increases (p < 0.001) in adherent platelet thrombi and circulating platelet emboli after five and 15 minutes respectively. Adherent platelet thrombi (mean of four per field of view) remained significantly increased throughout the experiment, but circulating emboli (maximum of five at 30 minutes) decreased with time. Leucocyte adherence did not occur although early transient rolling was observed. An 11% increase (p < 0.02) in albumin leakage occurred after five minutes only. The induction of platelet aggregation was only observed following H pylori administration., Conclusion: This in vivo study demonstrated the ability of H pylori extracts to promote platelet aggregation within gastric mucosal microvessels. Recruitment of leucocytes was not observed. The results suggest that the early events associated with H pylori infection are platelet aggregation with perhaps subsequent leucocyte recruitment by activated platelets.

Background: Peripheral kappa receptor agonists may provide a new therapeutic approach for the treatment of functional dyspepsia., Aims: To evaluate, in a large multicentre trial, the use of the kappa receptor agonist fedotozine to improve symptoms associated with functional dyspepsia., Methods: Two or more of the following persistent symptoms were required for inclusion: epigastric pain, early satiety, epigastric fullness or distension, nausea, vomiting, and a feeling of slow digestion. On completing a two week placebo washout, 271 patients were randomised into two groups to receive 30 mg fedotozine three times daily or placebo for six weeks under double blind conditions., Results: The improvement in the overall intensity of dyspeptic symptoms (main efficacy criterion) was significantly more pronounced in the fedotozine group (p = 0.002) compared with placebo, as was epigastric pain (p = 0.004) and nausea (p = 0.01); the improvement in postprandial fullness was nearly significant (p = 0.052). Inability to finish a meal and slow digestion were unaffected. The patient global score, the average of the five individual symptoms, was notably ameliorated with fedotozine (p = 0.021). The safety of fedotozine was excellent., Conclusions: Fedotozine at 30 mg three times daily is safe and more effective than placebo for the relief of key symptoms associated with functional dyspepsia.

Background/aims: To investigate the effect of the new Helicobacter pylori eradication regimen, ranitidine bismuth citrate (RBC) and clarithromycin (CLAR) dual therapy, on duodenal ulcer healing and absence of ulcer recurrence during 24 weeks follow up (overall success)., Methods: Two hundred and thirty two H pylori positive patients with active duodenal ulcer received four weeks treatment with RBC 400 mg twice daily alone (RBC400) (n = 82), or RBC 400 or 800 mg twice daily co-prescribed with clarithromycin 250 mg four times daily for 14 days, followed by 14 days of RBC 400 mg twice daily alone (RBC400+CLAR and RBC 800+CLAR, respectively, n = 75 for each)., Results: The co-prescription regimens gave high H pylori eradication rates determined using two tests (CLOtest and 13C-urea breath test) for the presence of the organism. These rates were 92% and 81% for RBC400+CLAR (n = 62) and RBC800+CLAR (n = 63) respectively, compared with 2% for RBC400 (n = 66) (p < 0.001). With respect to overall success as estimated by life table analysis, RBC400+CLAR (89%) and RBC800+CLAR (87%) were significantly more effective than RBC400 alone (51%) (p < 0.001). All regimens were safe and well tolerated. Trough plasma bismuth concentrations at week 4 were low (treatment medians less than 6.6 ng bismuth/ml)., Conclusions: Ranitidine bismuth citrate is a well tolerated and efficacious ulcer healing drug which, when co-prescribed with clarithromycin, affords effective H pylori eradication therapy and prevents ulcer relapse in most patients with duodenal ulcer.

Background/aims: The focal nature of gastric ulcers raises the possibility of underlying regional disturbances in gastric mucosal microcirculation. This study employed fluorescent in vivo microscopy with the aim of directly investigating the response of several areas of the gastric mucosa to 60% ethanol., Methods: Changes in macromolecular leakage of fluorescein labelled albumin, vessel diameter, and acridine red labelled leucocyte adhesion and rolling were assessed over a period of two hours. A total of 0.5 ml 60% ethanol was topically applied for five minutes to the exteriorised gastric mucosa of anaesthetised rats. RATS: Three distinct patterns of response were found. Areas of lesion formation were small and occurred within five minutes. These areas showed persistent blood flow stasis throughout the course of the experiment, increased leakage (p < 0.02), and no leucocyte adhesion. Peripheral to the lesion, sustained leakage (p < 0.02) was found with adherence of leucocytes (p < 0.01) after lesion formation. Sites more remote to any lesion showed transient leakage and significant numbers of 'rolling' leucocytes (p < 0.01) were observed again after the lesion had formed., Conclusions: Despite widespread exposure of the entire gastric mucosa to 60% ethanol the resultant mucosal injury was limited. Widespread vascular damage was found reflected by macromolecular leakage, the pattern of which showed regional variation.

Prostaglandins are widely used in the prevention and healing of non-steroidal anti-inflammatory drug (NSAID) induced gastric and duodenal ulcers, but their longterm effect on the human gastric mucosa is unknown. This study assessed the effect of coadministration of prostaglandins with NSAIDs on the histology of the gastroduodenal mucosa. Histological appearances (using the Sydney system) of gastric biopsy specimens from 180 patients receiving longterm NSAID treatment of whom 90 had been receiving misoprostol (400-800 micrograms/day) for one to two years were studied. Both groups of patients were comparable with regard to clinical and demographic details. There was no significant difference (p > 0.1) in the prevalence of chronic gastritis (total, corpus or antrum only) between patients receiving (36 of 90 (40%)) or not receiving misoprostol (35 of 90 (39%)). Chronic gastritis was equally associated with the presence of Helicobacter pylori, 86% and 73% (p > 0.1), respectively, in the two groups. Significantly fewer patients receiving misoprostol had reactive gastritis than those receiving only NSAIDs (8 (9%) versus 27 (30%), p < 0.01). Reactive gastritis was not associated with H pylori. Thirty nine (43%) of the misoprostol treated patients had normal histology compared with 16 (18%) receiving only NSAIDs (p < 0.01). These results show two different patterns of gastric damage in patients receiving NSAIDs, namely chronic and reactive gastritis. Misoprostol treatment was associated with a significantly reduced prevalence of reactive gastritis and it is suggested that this, along with its antisecretory action, may explain the reduced prevalence of gastroduodenal lesions when coadministered with NSAIDs.

The gastroduodenal mucosa has a rich blood supply. An active fibrinolytic system is presumably required to maintain vascular patency, and impairment may result in reduced blood flow, focal tissue necrosis, and peptic ulcerogenesis. Tissue type and urokinase type plasminogen activator activity (expressed as mIU/mg protein) and plasminogen activator inhibitor type-1 antigen were assayed in homogenates of gastric and duodenal biopsy specimens taken from patients with: normal endoscopy (controls) (n = 14); active duodenal ulcer (n = 21); healed duodenal ulcer (n = 12); and active benign gastric ulcer (n = 15). In controls mean duodenal tissue type plasminogen activator activity was 4110 and urokinase type plasminogen activator activity 150; gastric tissue type plasminogen activator was 2760 and urokinase type plasminogen activator 170; plasminogen activator inhibitor type-1 was generally undetectable. At the edge of active duodenal ulcers tissue type plasminogen activator was considerably reduced, 2220 (p < 0.001) whereas urokinase type plasminogen activator was raised, 290 (p < 0.01). At the edge of active benign gastric ulcers tissue type plasminogen activator was substantially reduced, 1160 (p < 0.001) but urokinase type plasminogen activator was unchanged. At the scar of healed duodenal ulcers tissue type plasminogen activator was slightly reduced, 3290, but urokinase type plasminogen activator was increased, 308 (p < 0.05). H2 receptor antagonist treatment had little effect on tissue type or urokinase type plasminogen activator activity. Plasminogen activator inhibitor type-1 was increased at the edge of active ulcers (p < 0.05) especially when tissue type plasminogen activity was low (r = -0.61, p < 0.05). These findings are consistent with the hypothesis that impaired fibrinolytic activity may be implicated in peptic ulcerogenesis.

The purpose of this study was to compare duodenal ulcer healing, symptom relief, and safety of lansoprazole (a new proton pump inhibitor) given at doses of 30 mg and 60 mg, in the morning with ranitidine 300 mg at bedtime. Two hundred and eighty nine patients were enrolled over a 20 month period in a double blind randomised parallel group comparative study set in outpatient endoscopy units of six United Kingdom medical centres. Patients were randomised to receive lansoprazole 30 mg in the morning (n = 95), 60 mg in the morning (n = 96), or ranitidine 300 mg at bedtime (n = 98) for four weeks. Efficacy was assessed by gastroscopy at study entry and after two and four weeks of treatment. Symptom relief was monitored by patient diaries and physician review at two and four weeks. Both doses of lansoprazole resulted in significantly greater ulcer healing than ranitidine after two and four weeks. Respective healing rates on lansoprazole 30 mg, 60 mg, and ranitidine 300 mg were 78%, 80%, and 60% after two weeks and 93%, 97%, and 81% after four weeks. Patients on lansoprazole 30 mg (p = 0.002) and lansoprazole 60 mg (p = 0.026) also recorded greater relief of night time pain in the diary cards during the first seven days of treatment than those on ranitidine. Patients on lansoprazole 60 mg reported significantly better pain relief at their two week visit compared with those receiving ranitidine (p = 0.007). There were no differences between treatment groups in the occurrence or pattern of adverse drug reactions during the trial. It is concluded that for patients with duodenal ulcer, lansoprazole 30 mg or 60 mg is associated with faster ulcer healing and better symptom relief than ranitidine 300 mg at bedtime. There were no significant differences between lansoprazole 30 mg and 60 mg. These data indicate that lansoprazole should be used at a once daily dose of 30 mg for the treatment of duodenal ulcer.

We tested the hypothesis that the gastric H+/K+ adenosine triphosphatase inhibitor, omeprazole, because of its different mode of action and pronounced inhibitory effect on gastric acid secretion, may be more effective in peptic ulcer that is refractory to histamine H2 receptor antagonist treatment than continuing the same therapy. Altogether 107 patients (duodenal ulcer, n = 88; prepyloric ulcer, n = 14; gastric ulcer, n = 3; mixed sites, n = 2) with refractory peptic ulcer - that is ulcer unhealed after at least two months' treatment with cimetidine 0.8 g or 1 g daily or with ranitidine 0.3 g daily - were randomly allocated to receive either omeprazole 40 mg daily (n = 54) or to continue treatment with the same H2 receptor antagonist and at the same dose (n = 53) for up to eight weeks. The patients in the two treatment groups were well matched demographically. Healing by 'intent to treat' analysis was as follows: at four weeks, omeprazole 46 of 54 (85%), H2 receptor antagonist 18 of 53 (34%) (p less than 0.0001); and at eight weeks, 52 of 54 (96%) and 30 of 53 (57%) respectively (p less than 0.0001). One patient was lost to follow up but of the 22 patients whose ulcers were shown to be unhealed at endoscopy after receiving continued H2 receptor antagonist treatment, 21 healed in four to eight weeks when changed to omeprazole. Daytime epigastric pain cleared at four weeks in 43 of 47 (91%) patients on omeprazole and in 32 of 46 (70%) on H2 receptor antagonists (p=0.01) and relief of all dyspeptic symptoms occurred in 39 of 47 (83%) and 23 of 45 (51%) (p=0.0009) patients respectively. Adverse events occurred in 11 of 54 (20%) patients on omeprazole and in 12 of 35 (34%) on cimetidine but in none on ranitidine. The events were mild and none required treatment withdrawal. The commonest event in patients on omeprazole was loose stools or diarrhoea (n=5). Omeprazole was significantly better than continued H2 receptor antagonist treatment for the short term management of refractory peptic ulcer as judged by healing rate and pain relief, and it was safe.

Forty five patients with refractory oesophagitis, defined as persisting erosive changes or ulceration despite a minimum of three months' treatment with cimetidine 3.2 g daily or ranitidine 0.9 g daily, were treated in an open trial with omeprazole 40 mg daily for up to eight weeks. Endoscopically defined healing was observed in 73% of patients after four weeks' treatment and in 91% after eight weeks' treatment. Symptoms were completely relieved in 60% of patients, improved in 34%, unchanged in 4%, and worsened in 2%. After healing patients returned to maintenance treatment with cimetidine 1.6-3.2 g daily, depending on the severity of their illness before treatment with omeprazole. By six months and 12 months only 55% and 33% of patients respectively were still in remission. This study suggests that when erosive oesophagitis is refractory to treatment with high dose cimetidine or ranitidine, treatment with omeprazole 40 mg daily for up to eight weeks is effective in inducing healing and relieving symptoms.

The effectiveness of antacid maintenance therapy in preventing duodenal ulcer (DU) relapse was investigated. Two hundred and fifty one asymptomatic patients with healed DU were stratified into smokers and non-smokers and randomised to receive for one year either placebo, or Maalox TC three tablets (81 mmol) at bedtime (hs), or Maalox TC three tablets in the morning plus three tablets at bedtime (bd) (162 mmol), or cimetidine 400 mg at bedtime. A double dummy technique was used to render the study double blind. In 176 patients evaluable for efficacy, the cumulative relapse at one year was: placebo 57%; Maalox TC hs 39%; Maalox TC bd 23%; cimetidine 25%. Maalox TC bd and cimetidine were equally effective and superior to placebo (p less than 0.01) and bedtime Maalox TC (p less than 0.04). The benefit of treatment was significant for the overall sample and for the subgroup of smokers. The results for the non-smokers also supported efficacy for these two treatments but, perhaps because of small sample sizes, these comparisons were not significant. All 251 patients were assessed for safety. Approximately half the patients in each treatment group had adverse events, leading to withdrawal in three, seven, 12, and four patients on placebo, Maalox hs, Maalox bd, and cimetidine respectively. Diarrhoea occurred in 12 patients in Maalox TC bd and eight in each other group. Serum magnesium concentrations were unchanged; aluminium concentrations were higher than baseline at six and 12 months in both antacid groups and at 12 months in the cimetidine group but the differences were not significant. Maalox TC three tablets bd are as effective as cimetidine 400 mg at bedtime in reducing DU relapse and both are superior to placebo.

A refractory duodenal ulcer was arbitrarily defined as one that had failed to heal completely after treatment with cimetidine 1 g daily for three months. Of 66 patients with refractory duodenal ulcer, healing eventually occurred in 37 patients, after treatment for an average of 7.4 months. But 28 patients did not heal despite treatment for an average of 9.4 months; and one patient defaulted. In 41 patients the daily dose of cimetidine was increased to 2 g: the ulcers in 31 patients healed. In eight patients the daily dose was increased to 3 g and healing occurred in four patients. Eighteen patients required admission on 22 occasions because of severe symptoms despite treatment. Nine patients underwent surgery but in five the results were poor. Differences in clinical and endoscopic features between refractory and non-refractory ulcer patients were small. Acid and pepsin secretion were similar and gastrin concentrations normal. Blood levels of the drug and suppression of acid secretion were both satisfactory. Identification of refractory ulcer patients at the start of treatment was therefore not possible. Refractoriness could occur at any time during the course of the disease, previous treatment with cimetidine often having resulted in rapid healing, but subsequent relapses were also usually refractory. The cause of refractoriness remains unknown and the rather poor results of surgery in this series suggests that optimal management of these patients remains to be determined. Refractoriness probably indicates a changed natural history of the disease and in some patients a more poor prognosis.

We tested the hypothesis that the production of prostaglandin E2 (PGE2) is impaired in duodenal ulcer disease and affected by treatment and healing. This was investigated by a study of maximal PGE2 synthesis rates in duodenal and antral mucosal biopsies obtained at endoscopy. The patients were divided into three groups. Group (a): endoscopically normal controls (n = 56); group (b): treatment controls (non-DU disease: gastric ulcer or oesophagitis treated by histamine H2 receptor antagonists) (n = 41); and group (c): patients with DU disease (n = 183) further subdivided into group (c1) active ulcer not on treatment (n = 47), (c2) treated active ulcer (n = 35), (c3) healed ulcer on treatment (n = 86), and (c4) healed ulcer not on treatment (n = 15). Group (a) synthesised (mean (SD] 106.6 (39.0) pg PGE2/mg wt of tissue from the duodenal bulb and 129.9 (56.9) from the second part of the duodenum. No difference was found between group (a) and (b) at either site. Group (c1) ulcer rim made 49.8 (22.7) and at all stages ulcer rim and scar made less than the control duodenal bulb (p less than 0.02). Uninvolved duodenal bulb form groups (c1) (63.4 (31.0], (c2) (83.6 (38.5], and (c3) (81.5 (31.1], however, also made significantly less than controls (p less than 0.02) and a similar though non-significant trend was seen in group (c4). Biopsies from the second part of the duodenum did not synthesise significantly less than the control group but a similar trend was noticed at each stage of ulcer treatment. Biopsies of control antrum synthesised 124.5 (32.2) but only 93.7 (44.2) in group (cl) (p < 0.005). All stages of duodenal ulcer healing were associated with a decreased capacity to synthesise the major prostaglandin PGE2 at the ulcer site and the uninvolved duodenal bulb and, in acute untreated duodenal ulcer, the uninvolved antrum. This decreased capacity may be the consequence of the disease process itself and not secondary to the treatment, indicating a basic pathophysiological abnormality which may explain the characteristic tendency of the disease to relapse.

Ninety-six patients with gastric ulcer were randomly allocated to treatment either with deglycyrrhizinised liquorice or placebo. After four weeks no differences were found between the treatment groups in the proportions with complete healing, whether assessed by gastroscopy or radiology, or in the percentage reduction in ulcer area, or in clinical improvement.

Patients suffering from chronic duodenal ulceration were allocated at random to treatment with either cimetidine (400 mg twice daily) or matching placebo for six months. Before entry to the trial all patients were shown to have healed ulcers on endoscopy. Most of the patients had participated in a one-month trial of cimetidine during which their ulcers healed. The trial showed that four of 29 patients relapsed on maintenance treatment with cimetidine, which therefore did not confer complete immunity from relapse. However, cimetidine treatment was very much better than placebo treatment, on which 18 of 31 patients relapsed. Of the 22 patients who relapsed clinically, 20 were submitted to endoscopy and 19 of these were shown to have ulcerated again. Endoscopy at the end of the trial showed that ulcers had also redeveloped in five of 28 asymptomatic patients. Length of previous dyspeptic history had no bearing on the results of the trial but there was evidence that relapse on placebo was less likely if the ulcer had originally healed on a high dose of cimetidine. Clinical relapse was associated with worsening duodenitis. Symptoms, clinical observation, and laboratory tests showed no important abnormalities in the patients.

The purpose of this study was to determine if pirenzepine and cimetidine given together was superior to cimetidine alone in inducing healing of refractory duodenal ulcers which remained unhealed after treatment with cimetidine or ranitidine for at least eight weeks. One hundred and thirty one patients from six centres were randomised to receive either cimetidine (C) 800 mg daily or cimetidine 800 mg plus pirenzepine (C + P) 100 mg daily under double blind conditions for six weeks. The healing rate was similar in both groups, irrespective of the method of calculation. On an intent-to-treat analysis, healing was: C 66%, C + P 57%, and amongst the patients who completed treatment, healing was 70% in both groups. Patients on C and on C + P experienced a similar decrease in daytime and in night time pain. Side effects of treatment, notably dry mouth and blurred vision, were reported more often by patients on combination therapy. Combined treatment with cimetidine plus pirenzepine in patients with refractory duodenal ulcer is unlikely to be beneficial.