Sixty-seven patients with rheumatic disease, treated with non-steroidal anti-inflammatory drugs (NSAIDs), entered a controlled trial with a diagnosis of duodenal (n = 51), gastric (n = 14), or gastric and duodenal (n = 2) ulcers. The main objectives of the study were a comparison of ranitidine and sucralfate in ulcer treatment, and to observe the influence of continued NSAID administration during peptic ulcer therapy. Ulcers healed within nine weeks in 52 patients. The mean healing time was similar in 27 patients given ranitidine 150 mg bd (4.9 weeks) and 25 patients given sucralfate 1 g qid (4.6 weeks). In patients with unhealed ulcers after nine weeks of treatment, healing was obtained in seven after further therapy for 3-9 weeks. Of the 30 patients who continued NSAIDs during treatment with either ranitidine or sucralfate, 23 ulcers healed (mean healing time: 5.0 weeks). Of 32 patients in whom NSAIDs were stopped, ulcer healing was documented in 29 (mean healing time: 4.6 weeks). The difference in healing rates was not statistically significant (p greater than 0.10). The outcome of ulcer treatment did not differ in patients with rheumatoid arthritis and patients suffering from osteoarthritis. During a 12 month follow up 14 symptomatic ulcer recurrences were recorded.

Twenty eight patients with classical irritable bowel syndrome completed a double blind placebo controlled crossover trial in which they added to their normal diet a daily supplement of either 12 bran biscuits (1 = 1.3 g fibre) or 12 placebo biscuits (1 = 0.23 g fibre). Each biscuit was given for three months in random order with crossover to the alternative biscuit at three months. After the initial three months therapy, there was a significant symptomatic improvement compared with pretreatment in both the bran treated (p less than 0.01) and placebo treated groups (p less than 0.01), but there was no significant difference in symptom scores between these two groups. There was no further improvement in either group after the second three months treatment with the alternative therapy. When crossover data for all 28 subjects were combined, symptoms scores after three months bran therapy and after three months placebo therapy did not differ significantly. Twenty four patients completed three day stool collections in both treatment periods. When the symptomatic response to bran among 15 subjects in whom stool weights rose on bran was compared with that among nine subjects whose stool weights were static or fell on the bran, it was shown that symptomatic improvement was independent of an increase in stool weight. These data suggest that in irritable bowel syndrome, especially that associated with abdominal pain, the beneficial effects of bran are due to a placebo response which is independent of an increase in stool weight.

To determine the optimum dose of ispaghula husk in patients with irritable bowel syndrome (IBS) and to assess the correlation, if any between the relief in patients' symptoms and the whole gut transit time, and the increase in stool weight, a two part study was carried out. In part 1, 14 male patients were given ispaghula husk in increasing doses of 10 g, 20 g, and 30 g a day for a duration of 17 days each (14 days of study period + three days of stool collection). Ten patients completed the trial. The symptom score improved significantly with all the three doses of ispaghula. Both 20 g and 30 g doses of ispaghula were superior to the 10 g dose but there was no significant difference between the 20 g and 30 g doses. There was a significant (p less than 0.001) increase in the daily stool weight with 10 g dose of fibre with further significant increases with the 20 g and 30 g doses. A positive correlation was seen between the improvement in the symptom score and the increase in stool weight with the 10 g dose of ispaghula but not with the 20 g and 30 g doses. Whole gut transit time remained fairly constant throughout the study period and there was no relationship with either the dose of ispaghula, the alteration in stool weight, or the improvement in the patients symptoms. Ten patients completed part 2 of the study in which ispaghula husk was given in the same dose (10 g, 20 g, and 30 g) but in a random order and with a "washout" period of one week between individual doses. Again all the three doses of ispaghula produced a significant improvement in the symptoms; 20 g and 30 g doses were equally effective and both were significantly superior to the 10 g dose. Assessed individually, all the three symptoms improved significantly; improvement in constipation and pain abdomen was more pronounced than diarrhoea. It is concluded that the optimum dose of ispaghula husk in irritable bowel syndrome is 20 g per day. There is some correlation between the increase in stool weight and the improvement in symptom score but the whole gut transit time remains unchanged despite alterations in stool weight and patients' symptoms.

A double blind multicentre study comparing sodium cromoglycate (600 mg/100 ml) by enema with prednisolone (20 mg/100 ml) by enema is reported. The study was conducted over a nine week period in the treatment of 70 patients with ulcerative colitis. Analysis of symptoms showed significant decreases in scores for patients in both groups, both at four and eight weeks; the only difference between the two groups was a significantly greater improvement in the reduction of rectal bleeding after four weeks in the prednisolone group. On sigmoidoscopy, both treatment groups showed a highly significant improvement after four and eight weeks with no significant differences being seen between the groups. Histology of the rectal biopsies showed a significant improvement in the inflammation of the mucosa for both treatment groups after four and eight weeks with no differences being observed between the groups. There were no significant changes in eosinophils from baseline and no difference between the groups at four and eight weeks.

Refeeding starved rats with a fibre free 'elemental' diet increased crypt cell production rate (CCPR) in the proximal small intestine but not in the distal regions of the gut. Little effect on CCPR was seen when inert bulk (kaolin) was added to the 'elemental' diet. Addition of a poorly fermentable dietary 'fibre' (purified wood cellulose) had little effect on intestinal epithelial cell proliferation except in the distal colon where it significantly increased CCPR. A more readily fermentable 'fibre' (purified wheat bran) caused a large proliferative response in the proximal, mid and distal colon and in the distal small intestine. A gel forming 'fibre' also stimulated proliferation in the distal colon. There was no significant correlation between CCPR and plasma gastrin concentrations, but plasma enteroglucagon concentrations were significantly correlated with CCPR in almost all the sites studied. Plasma PYY concentrations also showed some correlation with CCPR, especially in the colon. Thus, whilst inert bulk cannot stimulate colonic epithelial cell proliferation, fermentable 'fibre' is capable of stimulating proliferation in the colon, and especially in the distal colon: it can also stimulate proliferation in the distal small intestine and it is likely that plasma enteroglucagon may have a role to play in this process.

The effect of combined treatment with sulpiride plus cimetidine was compared against that of cimetidine alone on the healing of duodenal ulcer and on the subsequent relapse rate. In a double blind study, 35 patients with duodenal ulcer diagnosed by endoscopy were randomly assigned to receive cimetidine 800 mg daily and 38 patients to receive cimetidine 800 mg plus sulpiride 200 mg daily. Sixty patients whose ulcers were healed at three months continued to be observed after stopping treatment and underwent endoscopy to detect recurrences when symptomatic or at three and at six months if asymptomatic. Recurrence was observed in 18 (72%) of 25 patients whose ulcers had healed on cimetidine alone, but in only 11 (38%) of 29 patients whose ulcers healed on cimetidine plus sulpiride.

Transdermal scopolamine is an antimuscarinic preparation approved for use in the United States for prevention of motion sickness. A recent study using this drug (0.5 mg/patch) suggested that enough scopolamine was absorbed through the skin to reduce basal gastric acid secretion in patients with duodenal ulcer. We have compared the effect of transdermal scopolamine and oral cimetidine (400 mg twice daily) in seven men with chronic duodenal ulcer, both alone and in combination, on acid secretion throughout an entire 24 hour period in a placebo-controlled, randomised, double blinded cross over study. The effect of these drugs on basal, interprandial, and nocturnal gastric juice volume and hydrogen ion concentration also was measured. Transdermal scopolamine had no significant effect on mean 24 hour acid secretion (placebo, 409.4 mmol/day; scopolamine, 364.0 mmol/day) nor did it have a significant effect on gastric juice volume or hydrogen ion concentration. The combination of transdermal scopolamine plus cimetidine was not more effective than cimetidine alone in reducing total 24 hour acid secretion (mean, 231.8 versus 235.3 mmol/day) nor in reducing gastric juice volume or hydrogen ion concentration.

Two groups A and B each comprising 12 healthy young male subjects were used in a double blind, placebo controlled trial to assess the effects of 1.0 g sucralfate qid on prostaglandin (PG) generation and mucosal integrity in the intact and aspirin-treated stomach. Mucosal formation and luminal release of PGE2, 6-keto-PGE1 alpha and thromboxane B2, gastric microbleeding and DNA loss (integrity indicators) and basal and pentagastrin induced acid secretion were measured after placebo and sucralfate treatment in subjects without (group A) and with administration of 2.5 g aspirin (group B). Sucralfate significantly reduced spontaneous gastric microbleeding and DNA loss in group A and prevented blood loss but not DNA loss caused by aspirin in group B. The protective effects of sucralfate on spontaneous gastric microbleeding were accompanied by increased mucosal biosynthesis and luminal release of PGE2 and 6-keto-PGF1 alpha with a reduction in release of thromboxane B2. In aspirin treated subjects both mucosal generation and luminal release of prostaglandins and thromboxane B2 were greatly suppressed although sucralfate treatment did not influence these prostaglandins in spite of the reduction in mucosal damage. It is concluded that sucralfate has a potent protective action on spontaneous and aspirin treated gastric microbleeding in man and that this protection may be partly because of the increased mucosal biosynthesis of prostaglandins.

Thirty seven patients with established cirrhosis of the liver were subjected to measurement of body protein metabolism using L-(1-14C) labelled leucine as a tracer. The effects of disease severity and those of solutions containing 0%, 16%, 35%, 53%, and 100% branched chain amino acids were evaluated. Significant increases in protein synthesis were noted with solutions containing 35%, 53%, and 100% branched chain amino acids, but in patients receiving 100% branched chain amino acids without additional essential amino acid supplement the increase in synthesis was matched by a significant increase in protein breakdown. Protein balance was thus improved only in patients receiving 35% and 53% branched chain amino acids. It was concluded that the high increase in protein breakdown in patients receiving 100% branched chain amino acids was undesirable, and such a solution should not be recommended for clinical use.

The efficacy of branched chain amino acids in two consecutive clinical studies in patients with severe hepatic encephalopathy was tested. In the preliminary uncontrolled study 19 patients with grade 3-4 hepatic encephalopathy were given an intravenous solution containing leucine 11 g/l, isoleucine 9 g/l, and valine 8.4 g/l in 20% dextrose. A complete recovery of mental state was obtained in all patients in a mean time of 20.5 hours. In a subsequent controlled study 40 patients with grade 3-4 hepatic encephalopathy were randomly assigned to receive intravenous branched chain amino acid in 20% dextrose (group A) or oral lactulose (group B). Twelve patients (70.6%) in group A and eight (47%) in group B regained consciousness in a mean time of 27.6 and 31.5 hours, respectively. The difference in the recovery rate between the two groups, although evident, was not significant. Intravenous branched chain amino acids are thus at least as effective as lactulose in reversing hepatic coma. These data argue strongly in favour of a therapeutic effect of branched chain amino acids in the treatment of hepatic encephalopathy in patients with chronic liver failure.

Forty patients who were managed conservatively after haemorrhage from an endoscopically verified duodenal ulcer were randomised at discharge from hospital to enter a blind study of ranitidine therapy (150 mg bd) versus a placebo tablet. The patients were re-endoscoped after four weeks, ulcer status defined and the trial code broken revealing that five of 20 placebo patients had healed their duodenal ulcer compared with 16 of 20 ranitidine patients (p = 0.001). Lifestyle parameters of both groups improved during the study period but no directly related benefit in duodenal ulcer healing could be shown. We conclude that effective anti-ulcer therapy, such as ranitidine, is required to heal a duodenal ulcer which presents with haemorrhage.

Although malnutrition is associated with poor clinical outcome, it cannot be inferred that better nutrition will improve clinical outcome. Efficacy of a proposed regimen is best established by prospective, randomised, controlled trials. Cost effectiveness is only an issue if efficacy exists. Patients with long term temporary, or permanent, inadequate bowel syndrome are candidates for parenteral nutrition. Most of the prospective, randomised, controlled trials testing the value of nutritional support in other diseases, however, have failed to show that this treatment has a beneficial clinical effect. Areas where these trials have shown a possible clinical benefit include the perioperative care of patients with upper gastrointestinal cancer, elemental diet treatment of Crohn's disease, and branched chain amino acid infusions in hepatic encephalopathy. Even in these instances, it is not clear that such treatment will prove to be cost effective (compared with other currently available treatments).

Azodisal sodium is a highly effective means of oral delivery of 5-amino-salicylic acid to the colonic mucosa. Administration of this drug to patients intolerant of sulphasalazine, however, occasionally results in liquid stools. In preliminary experiments, which comprised 10 healthy volunteers treated with colectomy for ulcerative colitis, ileostomy fluid output increased (p less than 0.001) during oral intake of azodisal sodium (1 g/day). In a double blind, placebo controlled crossover study, comprising eight similar volunteers, ileostomy fluid output increased (p less than 0.05) in a dose related manner during intake of azodisal sodium (1 g/day vs 2 g/day) compared with placebo or sulphasalazine (2 g/day). Concentrations of prostaglandin (PG)F2 alpha in free ileal water determined by equilibrium in vivo dialysis of ileostomy contents decreased (p less than 0.05) during intake of azodisal sodium (2 g/day), whereas concentrations of PGE2 and the output of PGE2, PGF2 alpha, and 'PGE2 + PGF2 alpha' remained unchanged. Thus increased formation of PGs is apparently not the cause of increased ileostomy fluid output associated with azodisalicylate intake.

The effects of cimetidine on the healing and recurrence of duodenal ulcers and gastric ulcers were compared. The extent of the acid secreting areas was examined by the endoscopic Congo red methylene blue test. Using the extent of acid secreting areas gastric ulcers were classified into ulcers with and without extensive acid secreting areas. Duodenal ulcers were all associated with extensive acid secreting areas. The gastric acid outputs in the basal state and after maximal stimulation with gastrin were highest in duodenal ulcers, and lowest in gastric ulcers without extensive acid secreting areas. Cimetidine treatment significantly promoted the healing of duodenal ulcers and gastric ulcers with extensive acid secreting areas when compared with placebo, but not of the gastric ulcers without extensive acid secreting areas. Cimetidine also significantly diminished the recurrence of duodenal ulcers, but not gastric ulcers with and without extensive acid secreting areas. These findings indicate that in Japan cimetidine promotes the healing of duodenal and gastric ulcers associated with high gastric acid production and prevents recurrence of duodenal ulcers, but has little or no influence on the healing and recurrence of gastric ulcers associated with low acid secretion.

Gastrointestinal motor function in patients with primary anorexia nervosa has rarely been investigated. We studied oesophageal motor activity in 30 consecutive patients meeting standard diagnostic criteria for primary anorexia nervosa (Feighner et al; DSM III). Seven were found to suffer from achalasia instead of primary anorexia nervosa, one from diffuse oesophageal spasm and one from severe gastro-oesophageal reflux and upper oesophageal sphincter hypertonicity, while partly non-propulsive and repetitive high amplitude, long duration contractions prevailed in the lower oesophagus of another six. In four patients with oesophageal dysmotility not responding to therapy and in 12 of 15 patients with normal oesophageal manometry, gastric emptying of a semisolid meal was studied. Emptying was normal in only three but markedly delayed in 13 cases (half emptying times 97-330 min, median: 147 min, as compared with 21-119 min, median: 47 min, in 24 healthy controls). In eight patients, the effects of domperidone 10 mg iv and placebo were compared under random double blind conditions. Half emptying times were shortened significantly (p less than 0.01) by domperidone.

A prospective double blind controlled trial was undertaken to examine the role of metronidazole as an adjunct to corticosteroids in the management of severe ulcerative colitis. Thirty nine patients with severe ulcerative colitis were randomised on admission to hospital to receive either intravenous metronidazole 500 mg eight hourly (19 patients) or an identical intravenous placebo (20 patients). The two groups were similar with respect to age, sex, and the extent of colitis. In addition all patients received a standard intravenous regimen consisting of methyl prednisolone 16 mg six hourly and parenteral nutrition together with a twice daily hydrocortisone 100 mg enema. Treatment was continued for five days when the patients were formally assessed. Fourteen of 19 patients (74%) receiving metronidazole and 14/20 (70%) receiving placebo were substantially improved, or in remission at the end of five days. Five patients treated with metronidazole and six with placebo had no improvement and all proceeded to urgent colectomy with no operative mortality. There were three late deaths, one in the metronidazole and two in the placebo group. These results do not support the routine use of intravenous metronidazole in the treatment of severe ulcerative colitis.

A randomised double blind clinical trial was undertaken in the UK and Ireland to compare ranitidine 300 mg given as a single bed time tablet with ranitidine 150 mg twice daily in the acute treatment of duodenal ulcers. Of the 594 patients with endoscopically diagnosed duodenal ulcer entered into the trial, 424 patients had complete endoscopic findings on which healing rates at four weeks were determined. By this time 156 of 201 (78%) patients healed with ranitidine 300 mg nocte compared with 186 of 223 (83%) receiving ranitidine 150 mg twice daily (p = 0.28). After eight weeks of treatment 97% of the patients in each group were healed. The healing rates for smokers and non-smokers did not differ significantly at either four or eight weeks. Each regimen was equally effective in reducing day and night-time pain. Adverse events were reported in 23 patients overall; 12 were withdrawn from the trial. Minor abnormalities in liver function tests were noted in three patients. The trial confirmed that a single dose of ranitidine 300 mg given at night is a safe, effective alternative treatment to ranitidine 150 mg bd for the acute treatment of duodenal ulcer.

Although early studies attributed an important role to acid in the pathogenesis of duodenal ulcer pain, recent reports are conflicting. The aim of the present study is to determine whether direct acidification of the duodenal ulcer crater in symptomatic patients reproduces ucler pain. Patients with endoscopically diagnosed duodenal ulcers were studied. No premedication or sedation was given. A washing tube was passed via the endoscope and 0.1 N hydrochloric acid as well as normal saline were sequentially administered on to the ulcer crater, the sequence of infusion being randomised and double blind. Forty patients were studied. Sixteen developed typical ulcer pain during acid infusion compared with four with saline (p less than 0.005). Ten patients who developed pain on acid were rechallenged with acid after their pains disappeared. Typical pain recurred in all. Twenty patients without duodenal ulcer did not develop pain when 200 ml of 0.1 N hydrochloric acid was infused into the duodenum. Acid therefore appears to have a definite role in the pathogenesis of duodenal ulcer pain although other factors may also be important.

Endotoxins in plasma were monitored during treatment in 18 patients hospitalised for acute exacerbation of Crohn's disease: systemic endotoxaemia was found on admission in all but one. The patients were randomly divided into two groups: one receiving treatment with total parenteral nutrition and steroids. To decrease the absorbable endotoxin pool, the other group was additionally treated with whole gut irrigation and 5-aminosalicylic acid was added to the lavage fluid. In most of these patients endotoxaemia cleared after intestinal lavage and they needed shorter hospitalisation. Earlier improvement was also indicated by a faster decrease of the Crohn's disease activity index and vanHees index. In the group receiving conservative treatment alone, endotoxaemia was controlled within three weeks. We conclude that endotoxaemia occurs in most patients suffering from active Crohn's disease. Control of endotoxaemia after intestinal lavage suggests that systemic endotoxaemia is caused by absorption of endotoxins from the gut. Earlier improvement after whole gut irrigation indicates its beneficial effect in active Crohn's disease.