In a double blind endoscopically controlled study, 100 patients with gastric ulcers were treated with either ranitidine or ranitidine plus Caved-S. On single therapy, 58% of ulcers were healed at four weeks, 92% at eight weeks and 96% at 12 weeks. Combination therapy did not alter the healing rate, nor improve on the control of dyspeptic symptoms. No difference in healing rate was found between good and poor drug compliance patients. This suggests that ranitidine may be equally effective at lower dosages. Thirty seven patients had developed their ulcer while taking non-steroidal anti-inflammatory drugs. These patients were mainly elderly women who had a higher risk of bleeding (p = 0.006) from a large ulcer (p = 0.009).

The endoscopic healing rates and factors related to healing of two cimetidine regimens designed to reduce respectively postprandial and nocturnal acid secretions were studied in a randomised trial of cimetidine 200 mg tds with meals, vs 600 mg at bedtime, vs 200 mg tds with meals plus 400 mg at bedtime in 246 patients with duodenal ulcer. The respective healing rates were 62.3%, 63.1%, 77.5% at four weeks and 86.6%, 83.3%, 91.2% at eight weeks. The healing rates at four weeks of both meal time and bedtime regimens were inferior (p less than 0.05) to that of the standard regimen. Analysis of 45 prospectively obtained factors showed that (i) habitual cigarette smoking adversely affected healing with the meal time regimen but not with the others, indicating that its adverse effect disappeared once nocturnal acid secretion was reduced, (ii) habitual use of analgesics impaired and their abstinence favoured healing by both meal time and bedtime regimens but these effects were lost with the standard regimen, suggesting that if analgesics cannot be withdrawn during ulcer treatment, a reduction of both meal time and night time acid secretions should be ensured, (iii) responders with the meal time and bedtime regimens had respectively significantly higher postprandial serum gastrin and higher basal acid output than the corresponding non-responders suggesting that these responders had different pathophysiology, and (iv) high maximal acid output and large ulcers healed less well by any regimen.

In a randomised clinical trial, patients with moderately active Crohn's disease received either prednisolone 0.5 mg/kg/day plus a normal diet, or an elemental diet plus oral framycetin, colistin and nystatin. Patients were assessed using the Crohn's disease activity index (CDAI), ESR, and faecal granulocyte excretion quantified by 111In-autologous leucocytes. Five patients were intolerant of the elemental diet plus antibiotics and were withdrawn from the trial within 72 hours. Sixteen patients completed 10 days treatment on each regime. Fifteen of 16 patients on elemental diet plus antibiotics and all 16 patients on prednisolone improved with marked, but statistically indistinguishable falls in CDAI, ESR, and faecal granulocyte excretion between the two groups. Thus a regime decreasing the intraluminal concentration of bacteria and complex food molecules, was associated with rapid improvement in activity of Crohn's disease. This suggests that these intraluminal factors play a role in maintaining inflammation and that their removal or alteration offers an approach to management.

A six month, double blind, controlled study was performed in 107 asymptomatic duodenal ulcer patients who, after short term cimetidine treatment, showed complete or incomplete endoscopic healing. Patients were stratified according to the type of healing and randomly allocated to cimetidine (200 mg at lunch, 400 mg at bedtime) or placebo. Endoscopic examinations were carried out after six months or when symptoms recurred. Eighty seven patients completed the maintenance trial. Of the 56 patients admitted to the study with complete healing, 30 were placed on cimetidine and 26 on placebo. Of the 31 patients admitted with incomplete healing, 15 were placed on cimetidine, and 16 on placebo. Results showed that, regardless of maintenance treatment, patients with incompletely healed ulcers had a higher ulcer crater recurrence rate, than patients with complete healing (71% vs 34%; p less than 0.005). A significantly higher ulcer crater recurrence was observed in incompletely healed ulcer patients, even when cimetidine or placebo treatment groups were considered separately. Irrespective of the type of healing, ulcer crater recurrence was more frequent in placebo treated patients than in those treated with cimetidine (67% vs 29%; p less than 0.001). We conclude that, in order to prevent a high ulcer recurrence rate, maintenance treatment should start only after the assessment of a complete endoscopic healing of duodenal ulcers.

Seventy patients with non-stenosing Crohn's disease were randomly assigned to follow a low residue diet or a normal Italian diet for a mean of 29 months. The two groups were comparable at the onset in various measures of disease severity and diet. Patients complied well with the diet prescriptions, the low residue group eating a mean of 8.1 portions a week of fibre containing foods and the liberalized group a mean of 26.6 portions (p less than 0.005). There was no difference in outcome between the two groups, including symptoms, need for hospitalisation, need for surgery, new complications, nutritional status, or postoperative recurrence. Eighty six per cent of patients eating ad libitum and 65% of patients who avoided roughage eliminated one or more permitted foods because of subjective intolerance. Lifting of dietary restrictions, which results in a more appetizing and nutritious diet, does not cause symptomatic deterioration or precipitate intestinal obstruction in Crohn's disease.

Twenty four hour intragastric acidity was measured in five duodenal ulcer patients studied at least three times. The effects of different dosage regimens of intravenous omeprazole was compared with placebo. Mean intragastric acidity from 1000 to 0800 was 34.3 +/- 4.3 mmol/l on placebo. After omeprazole 80 mg at 0900 and 40 mg at 1700 mean acidity was 2.1 +/- 0.9 mmol/l and after omeprazole 80 mg at 0900 and 80 mg at 1700 it was 0.7 +/- 0.2 mmol/l. pH remained above 4.0 for about 80% of recordings with these regimens and for only 5% with placebo. Three of the five patients also received omeprazole 80 mg at 0900, 40 mg at 1700 and 40 mg at 0100 when pH remained above 4.0 for 90% of recordings with 99% inhibition of acidity. Omeprazole rapidly raised intragastric pH in all patients and maintained a gastric pH of greater than 4.0 for most of the time. Large doses of IV omeprazole were required compared with studies using the oral compound.

Forty patients with biopsy proven chronic active hepatitis were studied, 22 received (+)-cyanidanol-3 in a dose of 3 g daily and 18 placebo. Side effects related to cyanidanol were fever (four patients), haemolysis (one patient) and urticaria (one patient). All side effects subsided on discontinuation of the medication. Cyanidanol had an effect no better than placebo on symptoms, laboratory tests, and histological findings on liver biopsy.

In pancreatic steatorrhoea, both pH-dependent bile acid precipitation and enzyme inactivation may limit the efficacy of pancreatic enzyme supplements and both may be preventable by addition of cimetidine. To separate these effects we compared postprandial jejunal aspirate from eight adults with steatorrhoea due to cystic fibrosis on three randomised treatment regimens (pancreatin, cimetidine, and both together). We also compared the results with those of previous studies of patients on no treatment, and of healthy subjects. On pancreatin 60% of the test meal entered the jejunum at pH less than 5 compared with 17% in health. Lipase concentration and lipolysis increased over the values on no treatment (14.2 vs 4.4 U/l, p less than 0.01; 16% vs 11%, p less than 0.02) but bile acid precipitation was not reduced (38% vs 27%, NS), and aqueous-phase lipid concentration decreased (6.7 vs 8.6 mM/l, p less than 0.05). On cimetidine, bile acid precipitation fell (19% vs 38%, p less than 0.05); although lipase concentration and lipolysis were lower than on pancreatin (4.8 U/l vs 14.2 U/l, p less than 0.01; 9% vs 16%, p less than 0.01) lipid solubilisation increased (8.8 vs 6.7 mM/l, p less than 0.05). On the combination, there was a marked improvement (p less than 0.02) in lipid solubilisation (18.3 mM/l), reflecting the improvement both in lipase (38.4 U/l) and lipolysis (24%), and in bile acid precipitation (5.6%). We conclude that the efficacy of pancreatin is limited by pH-dependent bile acid precipitation in addition to enzyme inactivation. The action of cimetidine in improving the efficacy of pancreatin depends on prevention of both these effects.

A randomised controlled trial was conducted in 29 HBV carriers who had been HBs and HBe antigen positive for more than six months. Fifteen patients were treated with ARA-AMP 10 mg/kg/day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days. The 14 controls received no treatment. Serum HBV-DNA polymerase, and HBV-DNA decreased in all patients during therapy. Six treated patients lost serum HBV-DNA polymerase, HBV-DNA and HBeAg, HBsAg concentrations decreased, and five developed anti-HBe. One of these six patients lost HBsAg and developed anti-HBs. No such changes were observed in the control group over a similar 18 month period of observation. A four week course of ARA-AMP inhibits HBV replication and in a significant minority of patients this is long lasting and is associated with a reduced level of inflammatory activity in the liver.

Oral metoprolol, in a dose sufficient to reduce resting pulse rate by 25%, was compared with repeated injection sclerotherapy for the long term management of variceal bleeding. The prospective, randomised study was undertaken in 32 patients with biopsy proven cirrhosis and variceal bleeding who were Grade A or B on a modified Child's classification. In the 15 patients receiving metoprolol, portal pressure showed a mean fall of 3.7 mmHg (17.3 +/- 1.2 to 13.6 +/- 1.2 mmHg, p less than 0.01) after four weeks of continuous therapy, as compared with pretreatment levels. Nine of the 15 patients taking metoprolol had further bleeding (total of 21 episodes) compared with six of 17 in the sclerotherapy group (nine episodes). The risk of bleeding per patient/month of follow up was three times higher in the metoprolol group compared with those treated by sclerotherapy (0.14 and 0.04 respectively, p less than 0.025). Rebleeding in the metoprolol group occurred in six of the patients who had a fall in portal pressure of 10% or more.

Cisapride is a newly developed substance that stimulates gastrointestinal motility, possibly enhancing acetylcholine release in the gut wall. The aim of our study was to investigate the effect of cisapride on oesophageal motor function in man. In a blind fashion and in random order six healthy volunteers received cisapride (0.5 mg/h intravenously, preceded by a three day oral loading at 10 mg tid) and matching placebo. Oesophageal contractions and lower oesophageal sphincter pressure were constantly recorded during a complete cycle of the interdigestive migrating motor complex and during two and half hours after a mixed test meal. Cisapride did not disturb the interdigestive migrating motor complex. In the fasting state the lower oesophageal sphincter pressure showed considerable interdigestive migrating motor complex phase-related variations, whereas amplitude and duration of the oesophageal contractions did not. In the dosis used cisapride was found to increase lower oesophageal sphincter pressure in the interdigestive and in the late postprandial state, but to have no effect in the early postprandial period. Amplitude and duration of oesophageal contractions were not affected by cisapride.

In order to evaluate the effect of somatostatin in the treatment of massive upper gastrointestinal bleeding a randomised double blind trial of 95 patients has been undertaken during a 28 months period. Patients with oesophageal varices have been excluded as well as patients with diabetes. All patients were endoscoped within eight hours of admission to the hospital, whereupon the source of bleeding and types of stigmata were assessed. Forty six patients, chosen at random, were given a 72 hour infusion of somatostatin, while the remaining 49 patients received infusion of placebo. The two groups were well matched for sex, age, and source of bleeding. On the day after admission, an additional endoscopy was performed at which eight patients in the somatostatin group and 16 in the placebo group were found to have a persistent bleeding. A total of five patients in the somatostatin group and 14 in the placebo group underwent surgery (Fisher's exact test, 2-tail, p = 0.04). Rebleeding occurred in six patients in the somatostatin group, of whom five experienced rebleeding after completion of the somatostatin treatment. In the placebo group, rebleeding occurred in five patients, of whom four rebled on the day after admission. The need for blood transfusions and the mortality rate did not differ significantly between the two groups. No toxic side effects were found as a result of the infusion of somatostatin. In this study, somatostatin reduced the number of patients needing surgery with massive upper gastrointestinal bleeding.

One hundred and eighty nine patients with primary biliary cirrhosis were entered into a double blind, placebo controlled randomised trial starting in January 1978 to assess the therapeutic value of d-penicillamine 1200 mg daily. Eighteen of the 98 patients receiving d-penicillamine and 22 of the 91 placebo treated patients died during the study. Thirty six per cent of those on d-penicillamine and 8% of those on placebo were withdrawn from the study. No difference in overall survival was noted between the two groups of patients whether the results were analysed for the entire period of observation or only during the period in which the patients were receiving therapy. The mortality rate of those receiving d-penicillamine in histological stage I to II, however, was one third of that of the placebo group although this difference did not reach statistical significance. Using the occurrence rate ratio as the statistical method of analysis, no effect of d-penicillamine was noted on any clinical, biochemical or histological features examined, except the serum alanine aminotransferase activity which was greater in those on active treatment. In this trial we have been unable to establish any therapeutic benefit from the drug.

Antacids are widely used in the management of duodenal ulcer but the optimum dose of antacid required for ulcer healing has not been determined. We therefore studied 107 patients with endoscopically diagnosed duodenal ulcer who were allotted at random to one of the following treatment groups; placebo (group P) and antacid (groups A, B and C). A liquid antacid (Aludrox MH, Wyeth) with neutralising capacity of 2.3 mmol HCl/ml was administered in graded doses of 7.5 ml (Group A), 15 ml (Group B), and 30 ml (Group C), one hour and three hours after each meal, six times a day for four weeks. Patients in group P received 15 ml liquid placebo in a similar fashion. Complete symptomatic relief was obtained in 33% of patients in the placebo group, 54% in antacid group A, 89% in group B, and 92% in group C. Endoscopic assessment at the end of four weeks of treatment gave an ulcer healing rate of 29% in the placebo group, 46% in group A (103.5 mmol antacid/day), 85% in group B (207 mmol/day), and 88% in group C (414 mmol/day). There was no significant difference in the healing rates and pain relief between placebo and antacid group A, while both groups B and C had significantly higher ulcer healing rates and pain relief compared with placebo (p less than 0.001) and antacid group A (p less than 0.01). Drug related unwanted effects were recorded only in group C - 28% of patients suffered from diarrhoea. It is concluded that the optimum antacid requirements for the treatment of duodenal ulcer is 90 ml (acid neutralising capacity, 207 mmol HCl) per day.

The Celestin and Eder-Puestow methods of dilating benign oesophageal strictures have been compared prospectively in a randomised trial. One hundred and thirty three dilatations were performed on 72 patients. There was no significant difference between the two techniques with regard to the long term relief of symptoms. Celestin dilatation was quicker, less likely to cause pharyngeal trauma, and less damaging to guide wires. It could not be used, however, in those patients in whom only a short length of guide wire could be passed through the stricture.

Forty patients with endoscopically proven persistent duodenal ulcer who had been treated for six weeks with cimetidine (1 g/day) were randomly allocated to receive a further six weeks' treatment with cimetidine (1 g/day) or ranitidine (300 mg/day). Ulcers healed in 12 of 19 patients given cimetidine (63%) and in 13 of 21 given ranitidine (62%); two patients on cimetidine and two on ranitidine dropped out. In the unhealed ulcer group the ulcer size was reduced in most patients. There was no change in basal acid output, peak acid output, plasma gastrin and pepsinogen I levels after either treatment. Clinical data, gastric function tests, and endoscopic features did not predict ulcer healing. Both treatments were effective in the relief of pain: 72% of patients with unhealed ulcers were asymptomatic at the end of the trial.

The effects of pentagastrin and the putative gastrin antagonist proglumide on interdigestive motility of the upper small bowel were studied in a randomised double blind study in 10 healthy human volunteers. Intraluminal pressures were recorded manometrically in the duodenum and jejunum for five hours. Sixty minutes after starting a pentagastrin infusion (0.15 micrograms/kg/h) either placebo or proglumide was infused intravenously. Pentagastrin converted the normal interdigestive motility to irregular motor activity, while proglumide restored the periodic fasted pattern. We conclude that gastrin is a likely candidate involved in the conversion of the fasted to the fed motility pattern in the human upper gut.

The effectiveness of two commonly available liquid diets was assessed in 40 severely malnourished black African patients. All patients were shown to have normal xylose absorption. The diets were given according to the manufacturer's recommendations. One diet was lactose containing (LC diet) (150 g/d) and high protein (112 g/d), the other normal protein and lactose free (LF diet) (protein 67 g/d), total energy content being similar. Patients were randomly divided into two equal groups and allocated (blind) to one of the diets. Tolerance and nitrogen balance were assessed over two three day periods on half and then full strength formulations. Severe intolerant symptoms were observed in 50% of patients on half strength and 94% of patients on full strength lactose containing diet with evidence of malabsorption of fluid, nitrogen, and fat. Despite high stool nitrogen losses (3.75 +/- 1.04 g/d), however, positive nitrogen balance was achieved in most patients receiving the full strength LC formulation. On the other hand, the full strength LF diet was generally well tolerated and was associated with significantly lower faecal losses and positive nitrogen balance. The results indicate that high density lactose containing liquid formulae are poorly tolerated by severely malnourished black African patients, while lactose free formulae containing approximately 10 g nitrogen/d are well tolerated and result in positive nitrogen balance.

In a single blind multicentre study, the efficacy and safety of ranitidine was compared with cimetidine in patients with gastric ulcer confirmed by endoscopy. Patients were randomly allocated to receive either 150 mg ranitidine twice daily, or 200 mg cimetidine three times a day and 400 mg at night for four weeks; patients with unhealed ulcers continued the same treatment for a further two weeks. Out of 260 patients, 197 were analysed. Of the ranitidine treated patients, 66% were healed after four weeks and 78% after six weeks and of the cimetidine treated patients 62% were healed after four weeks and 87% after six weeks. These differences are not significant. These results confirmed that ranitidine is as effective as cimetidine in the acute treatment of gastric ulcer.

A multiple linear regression analysis was carried out on 75 inpatients with gastric ulcer. In order to elucidate the effects of various factors - endoscopic and roentgenological findings, age, sex, medical history, and drugs such as antacids, anticholinergics or both - on the healing rate, these factors were compared between those with ulcer which healed within eight weeks after treatment and those which did not. In patients over 50 years of age, alcohol consumption of over 60 g per day until admission, duration of present ulcer pain for over three months, single ulcer, ulcer located in the lesser curvature and uneven elevation around the ulcer, there was significant delaying effect on ulcer healing. Drug ingestion, sex, smoking habits until admission, size, depth, and shape of ulcer, coexisting gastritis, and past and family history of ulcer disease had no significant effect on healing after eight weeks. The patients with less than two unfavourable factors (n = 46) had the best healing rate (100%) compared with those with three (n = 20) or four or more (n = 9) unfavourable factors. The healing rate of the latter two groups was 60% and 22%, respectively (p less than 0.001). A prognostic score based on these six factors represents the severity of gastric ulcer disease with regard to the healing rate in patients prescribed antacids, and/or anticholinergic drugs.