The effects of different types of adrenoreceptor blocking agents on portal venous pressure were studied in patients with cirrhosis and portal hypertension. Oral atenolol (selective beta 1 blocker), propranolol (non-selective beta 1 and beta 2 blocker), and prazosin (alpha blocker) were compared in three groups of eight patients. Haemodynamic measurements were made before and after two or three and eight weeks of therapy. The dose of beta blockers was sufficient to reduce the exercise heart rate by more than 25%. Propranolol and prazosin produced a sustained reduction in the mean portohepatic venous pressure gradient of the order of 25% and 18% respectively. The cardiac index was significantly reduced by propranolol but not altered by prazosin. Atenolol produced an early reduction in portohepatic venous pressure which, although not sustained, showed a good correlation with reduction in cardiac index. No such relationship was found with propranolol. All three drugs were well tolerated by these patients with advanced cirrhosis. Therefore propranolol and prazosin have proved to be effective agents for the reduction of portal venous pressure.

Forty patients with duodenal ulcer were randomly allocated to treatment with either tripotassium dicitrato bismuthate tablets or cimetidine for six weeks. Endoscopically confirmed healing of the ulcer occurred in 80% treated with tripotassium dicitrato bismuthate tablets and in 85% treated with cimetidine. Symptomatic improvement was also similar in the two groups. Treatment with cimetidine was associated with an increase in pH of gastric aspirate during treatment and increased numbers of bacteria were isolated from the gastric aspirate during treatment, while the pH and bacterial flora of gastric aspirate did not change during tripotassium dicitrato bismuthate treatment. Serum and urinary bismuth levels rose during treatment with tripotassium dicitrato bismuthate and urinary excretion remained raised two weeks after cessation of treatment. Tripotassium dicitrato bismuthate tablets appear to be as effective as cimetidine in the treatment of duodenal ulcer without the potentially undesirable effects of a reduction in gastric acid secretion.

Symptom scores, stool data, and the transit of a standard, solid meal were measured in 25 patients with irritable bowel syndrome during baseline conditions and after four weeks treatment with placebo and domperidone in the form of a double-blind cross-over trial. All patients had previously undergone a comprehensive series of diagnostic investigations and had failed to respond to dietary supplementation with coarse wheat bran (10-30 g daily). Compared with placebo treatment, domperidone had no significant effect on gastric emptying, small bowel or whole gut transit times, stool weight, frequency, or consistency. Most symptoms improved significantly with both placebo and domperidone treatments, compared with the baseline period, but there was no significant difference between placebo and domperidone for any of the symptoms. Abdominal distension, however, was reported on more days per week during domperidone treatment (p = 0.02). The findings in this study do not support the use of domperidone in the management of irritable bowel syndrome.

Forty patients with bleeding oesophageal varices were studied during treatment by endoscopic sclerotherapy to discover what factors determine successful outcome. Large varices required more injections than small varices for obliteration, and rebleeding during treatment occurred only in patients with large varices. Radiological studies with sclerosant contrast mixture showed that in two groups of varices of comparable size, intravenous sclerosant was significantly more effective, leading to thrombosis in 8/10 as opposed to only 3/10 after paravasal injection (p less than 0.05). Intravenous contrast was rapidly cleared upwards, whereas paravasal contrast formed a rounded opacity alongside the vein that persisted for approximately 90 minutes, responsible for the complications of oesophageal ulceration and stenosis.

The efficacy of ranitidine was evaluated using a two-staged trial in patients with endoscopically moderate or severe reflux oesophagitis. The results of a six week double blind placebo controlled trial (stage I) in 36 patients shows that ranitidine (150 mg bd) is superior to placebo in the acute treatment with significant symptomatic improvement concerning heartburn and regurgitation, and in healing or improvement of endoscopic lesions. Prolonged treatment with ranitidine for another six weeks (stage II) proved to be effective in more resistant cases. No clinical side effects or significant biochemical changes were noted during this trial.

Twenty four hour intragastric acidity and nocturnal acid output have been measured over five separate 24 hour periods in each of 12 patients with duodenal ulcer receiving either placebo, cimetidine 400 mg bd, cimetidine 300 mg nocte, ranitidine 150 mg bd, or ranitidine 300 mg nocte. In these doses ranitidine was significantly more effective at decreasing intragastric acidity and nocturnal acid output than cimetidine. There was no significant difference between twice daily ranitidine and night time ranitidine or between twice daily cimetidine and night time cimetidine in the reduction of intragastric acidity. Nocturnal acid output was controlled significantly better with ranitidine at night, twice daily dosage of ranitidine, and cimetidine at night, than by the twice daily dosage of cimetidine. It is suggested that a single nocturnal dose of cimetidine or ranitidine should be evaluated in a clinical trial.

One hundred and forty six gastric ulcer patients were given open treatment using 1 g cimetidine daily to heal their ulcers. Of 130 who completed the acute treatment period of eight weeks, 112 (86%) had healed ulcers. Of these 112 patients with healed ulcers, 108 entered a one year double blind study to compare the effect of cimetidine maintenance therapy (400 mg at night) with placebo. Of the 84 patients available for assessment at the end of one year, 86% in the cimetidine treated group were in remission compared with 45% in the placebo treated group (chi 2 = 15.03; p less than 0.001). There were similar losses from non-compliance and drop out in both groups. The incidence of untoward effects and significant drug related laboratory abnormalities was low. The results indicate that cimetidine heals nearly 90% of acute gastric ulcers within eight weeks and that subsequent low dose maintenance treatment at night offers a considerable benefit over placebo therapy.

In a double-blind study we have compared the effect of 50 mg acarbose, 100 mg acarbose, 4.2 g pectin, a combination of 50 mg acarbose with 4.2 g pectin, and placebo on plasma glucose, plasma insulin, breath hydrogen and hypoglycaemic symptoms after a normal carbohydrate rich meal in nine patients with previous gastric surgery. Fifty milligrams acarbose, 100 mg acarbose and the combination of 50 mg acarbose with 4.2 g pectin significantly inhibited the postprandial peak glucose concentration (p less than 0.01). The lowest plasma glucose concentration, observed 60-150 minutes after ingestion of the meal, was significantly increased by the addition of 50 mg acarbose (p less than 0.01) and the combination of acarbose with pectin (p less than 0.05). The combination of acarbose with pectin was the only treatment that significantly inhibited the plasma insulin peak (p less than 0.05). Eight of nine patients had symptoms of hypoglycaemia on placebo, two on 50 mg acarbose (p less than 0.05), two on 100 mg acarbose (p less than 0.05), five on pectin (ns), and two on the combination of acarbose and pectin (p less than 0.05). All treatments with acarbose induced significant increases in breath hydrogen excretion (p less than 0.05).

Twenty-eight patients with radiolucent biliary duct stones without cholangitis and jaundice were randomly allocated into two treatment groups receiving ursodeoxycholic acid 12 mg/kg (group A) or placebo (group B) in three daily doses for 24 months. In group A stones disappeared completely in seven patients and partially in one; placebo administration had no effect on stone size and three patients of group B (only one of group A) went to surgery for complications. Ursodeoxycholic acid treatment did not adversely affect liver function tests, and alkaline phosphatase decreased. Abdominal and biliary colics also became less frequent in the first six months of therapy in group A, but not in the placebo group. The bile was supersaturated with cholesterol in both groups, but decreased significantly only in patients receiving ursodeoxycholic acid even though the lithogenic index remained high. Cholesterol saturation of bile does not seem to be the only factor determining the dissolution of biliary duct stones which sometimes contain cholesterol as the main component.

Prophylactic maintenance therapy for one year using ranitidine 150 mg at night or a placebo was assessed in 68 patients whose gastric or duodenal ulcers had previously healed after therapy with ranitidine 150 mg twice daily or placebo. Gastroscopy was carried out on symptomatic relapse and at the end of the year. Of the duodenal ulcer group, seven out of 20 relapsed on ranitidine compared with 15 out of 17 on placebo (p less than 0.001). Of the gastric ulcer group one of 15 patients relapsed on ranitidine compared with 11 of 16 patients on placebo (p less than 0.005). There were no adverse effects from ranitidine during the trial period. Ranitidine in low dose maintenance therapy is therefore reasonably effective in the prevention of relapse of duodenal ulcers and appears to be particularly effective in preventing relapse of gastric ulcers at least for one year. As gastric ulcers occur more frequently in the older patients in whom there are often medical contraindications to surgery, maintenance treatment may be appropriate for many such patients.

To study the effects of stressful stimulus (cold pain) upon postprandial gastric, duodenal, and pancreatic function, nine healthy adult volunteers were intubated and then given two identical liquid meals, (199 cal (789 KJ) 240 ml), each being ingested during a period of irregular fasting gastroduodenal motility. Ten minutes after each meal the subjects received, in randomised order, either a test or control stimulus. The test stimulus consisted of repeated one minute immersions of a hand into ice water, with 15 seconds recovery between immersions, for a total of 20 minutes, while for the control, water at 37 degrees C was used. Serial samples of gastric and duodenal contents allowed estimation of changes in gastric emptying and acid secretion, together with pancreatic trypsin output, by a double marker perfusion technique. Measurements of blood pressure, pulse, and finger temperature acted as extra-intestinal indices of autonomic response to the stimuli. Cold pain significantly delayed gastric emptying and produced a biphasic alteration in both gastric secretion and pancreatic trypsin output, with an initial reduction during the response to the stress followed by an increase during the post-stress period. Our findings show that the normal postprandial function of the upper gut can be measurably disturbed by a stressful stimulus. The coincidence of these disturbances with other extra-intestinal autonomic changes suggests that they are a further manifestation of the somatic response to a stress.

The prevalence of cholesterol gall stones in young women has increased since the introduction of oral contraceptives. The synthetic female sex hormones used in these preparations, increase the degree of cholesterol saturation in bile. To determine whether oestrogens, progestagens, or both, are responsible for the change in biliary cholesterol saturation index, a prospective randomised, controlled study was performed. A significant increase in the cholesterol saturation index of bile was observed when either 30 micrograms ethinyloestradiol plus 150 micrograms norgestrel (p = 0.01) or 50 micrograms ethinyloestradiol plus 250 micrograms norgestrel (p less than 0.01) were ingested daily for two months. No change in the cholesterol saturation index was observed when 30 micrograms ethinyloestradiol alone, or 30 micrograms ethinyloestradiol plus 2.5 mg norethisterone were used. The mechanism for the increase in cholesterol saturation index did not appear to involve bile acid metabolism. These results indicate that the progestagen, norgestrel, and not as previously thought the oestrogen, ethinyloestradiol, is responsible for the increase in cholesterol saturation of bile which accompanies the use of oral contraceptives.

The effect of bombesin, a possible neurotransmitter of gastrin release, upon gastrin and gastric acid secretion was investigated in 25 patients with duodenal ulcer and in 16 normal subjects. In patients with duodenal ulcer bombesin (10 ng/kg/min) produced an increase in plasma gastrin output (median 22.4 (range 7.5-75.8) pmol/l/min) similar to that obtained in normal subjects (median 24.4 (range 5.8-56.5) pmol/l/min), whereas gastrin stimulated by a meal was significantly higher in the group of patients with duodenal ulcer (median 20.7 (range 9.2-42.9) vs 16.2 (range 3.4-22.2) p<0.05). Peak acid output induced by bombesin was significantly higher in patients with duodenal ulcer than in normal subjects (median 24.4 (range 9.0-63.8) vs 14.0 (range 3.0-24.8) mmol/h, p<0.05) despite identical gastrin outputs. The ratio (%) obtained by dividing the acid secretory response to bombesin by the response to pentagastrin, however, was similar in both normal subjects and patients with duodenal ulcer (median 55 (range 20-116) vs 58 (range 31-95) respectively). The difference between the gastrin response to food and bombesin could be explained by the fact that bombesin releases gastrin directly, whereas a protein meal involves several mechanisms (neural, peptidergic, paracrine, endocrine), either stimulatory or inhibitory. The above results indicate that a higher concentration in antral and/or duodenal gastrin is unlikely to be present in patients with duodenal ulcer. An increased parietal cell mass could explain the higher gastric acid response after bombesin infusion in our group of patients with duodenal ulcer.

Changes in serum immunoreactive prolyl hydroxylase protein (IRPH), galactosylhydroxylysyl glucosyltransferase activity (GGT) and the aminoterminal propeptide of type III procollagen [Pro(III)-N-P] were studied in 21 patients with primary biliary cirrhosis during a follow-up period of up to three years. The patients received either D-penicillamine (600 mg/day), medroxyprogesterone acetate (5 mg/day), or a placebo, or no treatment after the D-penicillamine or medroxyprogesterone medication, each period lasting from nine to 15 months. The individual serum IRPH, GGT, and Pro(III)-N-P concentrations exceeded the upper normal limit in most patients. No significant changes were found in any of these three serum markers during any of the five different periods, nor was there any evidence for a decrease in the raised prolyl 4-hydroxylase activity in the hepatic biopsy specimens in response to any of the treatments. Galactosylhydroxylysyl glucosyltransferase activity decreased significantly in these specimens during medroxyprogesterone therapy, but the interpretation of this, the only positive change, remains unclear. The data suggest that D-penicillamine or medroxyprogesterone therapy may have no favourable effect on the increased hepatic collagen formation involved in primary biliary cirrhosis.

In a prospective controlled clinical trial, 70 patients with normal gastrointestinal function were randomised to receive either an elemental diet based on Vivonex HN or an isonitrogenous isocalorie polymeric diet based on Clinifeed 400, administered by continuous 24 hour nasogastric infusion. The two groups of patients were well matched for age, sex, diagnosis, prior starvation, duration of feeding, initial nutritional status, and metabolic status. Nitrogen losses were significantly less on the polymeric feed, despite similar intakes. Serum transferrin rose significantly (1.85 +/- 0.2 to 2.30 +/- 0.2 g/l, p less than 0.05) only in the Clinifeed group, but nutritional parameters were otherwise maintained in both groups. The incidence of diarrhoea (Vivonex, 23.5%; Clinifeed, 30.6%) was not significantly different and was attributable to antibiotics in most cases. Hypokalaemia, which occurred in nearly half the patients, was equally distributed in the two groups, but hypophosphataemia occurred more often in the Vivonex group (p less than 0.05). Liver enzyme disturbances were similar in both groups. The present findings, therefore, provide no evidence that chemically defined 'elemental' diets containing free amino acids as their nitrogen source are in any way superior to polymeric diets containing whole protein and fat when administered to patients with normal gastrointestinal function.

Eight stable cirrhotic patients with mild or subclinical portal-systemic encephalopathy (PSE) were studied after shunt surgery when they were off all antiencephalopathic therapy. Equal amounts of mixed proteins were alternated with animal or vegetable protein in a crossover protocol under metabolic conditions for five consecutive, one week periods. The different dietary periods were not associated with either a change in the neurological impairment score or the Trailmaking Tests, which showed a learning effect. The peak frequencies of the computer analysed EEG (CAEEG) were lower during the animal (6.58 +/- 0.42 Hz) than the vegetable (7.10 +/- 0.44 Hz) diet (p 0.01). Neither arterial ammonia levels nor plasma amino acid ratios changed with the diets, whereas urinary 3-methyl-histidine excretion increased during the animal diet. During the vegetable diet the apparent nitrogen balance tended to be more positive than during either the mixed or animal diets associated with decrease in the urinary nitrogen excretion. The peak frequency of the CAEEG is the most sensitive test to monitor methods of treatment in portal-systemic encephalopathy. A vegetable protein diet, rather than overall protein restriction, should be considered in the management of this disorder, particularly when the nutritional state is poor.

It has been suggested that consumption of refined carbohydrate foods (notably sugar and white flour) increases bile cholesterol saturation and hence the risk of cholesterol gall stone formation. To test this hypothesis, 13 subjects with probable cholesterol gall stones ate refined and unrefined carbohydrate diets, each for six weeks in random order. On the refined carbohydrate diet, subjects ate more refined sugar (mean = SEM: 106 +/- 7 vs 6 +/- 1 g/day, p less than 0.001), less dietary fibre (13 +/- 1 vs 27 +/- 3 g/day, p less than 0.001), and had a higher energy intake (9.17 +/- 0.66 vs 7.16 +/- 0.64 MJ/day, p less than 0.001). After each diet, the lipid composition of duodenal bile and bile acid kinetics was determined. The cholesterol saturation index of bile was higher on the refined carbohydrate diet in all but one subject, with a mean value of 1.50 +/- 0.10 compared with 1.20 +/- 0.12 on the unrefined diet (p less than 0.005). On the refined carbohydrate diet, bile contained relatively less cholic acid and slightly more deoxycholic acid. There were, however, no significant differences in total or individual bile acid pool sizes. There were also no differences in the rates of primary bile acid synthesis or fractional turnover on the two diets. Consumption of carbohydrate in refined form increases bile cholesterol saturation. The risk of gall stones might be reduced by avoidance of refined carbohydrate foods.

A randomised double-blind trial of thioctic acid (alpha-lipoic acid), 300 mg/day versus placebo was carried out in 40 patients with pre-cirrhotic alcohol-related liver disease over a six month period. Twenty patients received the active drug and 20 placebo. Twenty-two of the 40 patients (55%) abstained from alcohol and showed significant improvements (p less than 0.01) in mean values for serum aspartate transaminase, serum glutamyl transpeptidase, and mean corpuscular volume. Seventeen of the 22 (77%) showed overall histological improvement on liver biopsy. The remaining 18 patients (45%) continued to drink but significantly reduced their mean daily alcohol intake (p less than 0.001). No significant changes occurred in their laboratory indices, but five of the 18 (28%) showed overall histological improvement. Changes occurred irrespective of treatment with thioctic acid, which suggested that, over six months, this drug did not influence the course of alcohol-related liver disease.

The therapeutic efficacy of orally administered branched-chain amino acids in patients with liver cirrhosis and chronic encephalopathy was examined in a double blind, randomised crossover study. Seven patients with manifest hepatic cirrhosis and encephalopathy of six months' duration or longer ingested 30 g branched-chain amino acids or placebo during two 14-day periods. Psychometric tests and electroencephalograms were used to evaluate cerebral function. Neither clinical observations nor psychometric testing or electroencephalogram indicated a significant difference in the patients' response to branched-chain amino acids as compared with placebo. In four patients given branched-chain amino acids for longer periods (five to 22 weeks), psychometric tests also remained unchanged. The plasma concentrations of these acids after oral intake increased significantly, demonstrating adequate absorption. Basal plasma amino acid concentrations were unchanged, however, after branched-chain amino acid therapy. No side-effects were seen, which indicates that these amino acids are well tolerated as an extra protein supply in patients with chronic hepatic encephalopathy. As compared with placebo, however, no effect of branched-chain amino acids on the encephalopathy could be detected.