Two modifications of the standard method of treatment of ascites in chronic liver disease were investigated in three separate randomised trials involving a total of 201 patients. These modifications were (1) an unrestricted sodium intake and (2) limitation of diuresis to partial removal of ascites, to the point of relief of abdominal tension. Mean serum sodium fell significantly in all patient groups receiving the low sodium diet and did not fall in the groups given an unrestricted diet. Mean serum urea nitrogen rose significantly in the patient groups undergoing complete diuresis and did not change in the groups undergoing partial diuresis. Mean serum uric acid rose only in the groups undergoing complete diuresis. We concluded that the advantages of these two modifications of therapy of ascites were increased dietary palatability and decreased likelihood of hyponatraemia and of rise in serum urea nitrogen and uric acid. Disadvantages included dissatisfaction of patients over incomplete clearing of ascites, occasional difficulty in performing diagnostic studies because of prolonged ascites, and unsuitability of a high sodium intake in patients whose ascites is highly refractory to treatment.

In order to establish whether alcohol in amounts in amounts customarily imbibed during social drinking causes gastro-oesophageal reflux, 12 healthy young individuals, without symptoms of gastro-oesophageal reflux, were studied twice. Each time, distal oesophageal pH was monitored continuously for three hours after a standard meal which included either 180 ml 100 proof vodka or 180 ml water. The order of studies with and without alcohol was random. Peak blood alcohol concentrations ranged between 0.63 and 1.29 g/l. Eleven of the 12 subjects refluxed more after alcohol; and the difference in mean reflux scores for studies with and without alcohol was highly significant. We conclude that relatively modest quanttities of alcohol induce gastro-oesophageal reflux in healthy people.

In a double blind trial, 23 patients with endoscopically confirmed duodenal ulceration received cimetidine (300 mg four times daily in six patients, or 400 mg four times daily in 10 patients) or placebo (seven patients) for six weeks. Before entry into the trial, pentagastrin (6 microgram.kg-1.h-1)--stimulated gastric acid secretion after a single oral dose of 300 or 400 mg cimetidine was lowered by 82.1% and 81.0%, respectively, while no significant inhibition was recorded in the patients receiving placebo (8.8%). The same test repeated after six weeks of continuous treatment showed that the effect of the drug was maintained, the percentage inhibition of acid secretion being of the same order as in the first test.

Twenty-two patients with symptomatic diverticular disease of the colon were randomly allocated to control and high-fibre groups so that the long-term effect (up to 12 months) of bran on serum, faecal and biliary lipids could be studied. Even in cases of high initial values, faecal mass was increased by bran and the change was positively correlated with the change in dietary fibre. Faecal fat and dry weight were also increased. Faecal bile acids were initially slightly raised and were positively correlated with wet weight both off and on bran. The latter significantly decreased the excretion and concentration of bile acids, in particular the high initial values. The change in bile acids was not correlated with the change in dietary fibre or faecal wet weight. Sterol balance values indicated that the bran-induced decrease in faecal bile acids was associated with a lower cholesterol synthesis. Serum cholesterol decreased significantly in two hypercholesterolaemic individuals only. Correlations between different parameters revealed that the higher the initial level or the greater the drop in cholesterol synthesis, the greater the decrease in serum cholesterol. Bran had no effect on the biliary saturation of cholesterol. The percentage of biliary deoxycholate was negatively correlated with faecal mass (less so with faecal bile acid output) both before and during bran and was significantly decreased by bran. The percentage of cholic acid increased correspondingly and that of chenodeoxycholate remained unchanged. Faecal bile acids also indicated that the synthesis of the two primary bile acids was lowered by bran to the same degree.

In a double-blind controlled trial amylopectin sulphate (Depepsen) had no significant advantage over placebo in the symptomatic treatment of duodenal ulcer.

Twenty-two patients with chronic proctitis were treated with metronidazole for 28 days in a double-blind controlled trial, but they did not appear to benefit from the drug.

Seventy-seven patients with gastroduodenal ulcer were treated with two methyl-prostaglandin E2 analogues, m-PGE2, in a double-blind clinical trial. Each of three groups was given 15 S-15 methyl PGE2 methyl ester, 15 R-15 methyl PGE2 methyl ester, and placebo, respectively. Both forms of m-PGE2 analogues appeared to reduce gastric acid secretion, to shorten ulcer healing, and also to produce some side-effects, form 'S' being the more potent. Prompt healing of the ulcer with these agents did not prevent the recurrence of the disease. As the serum gastrin response to a meal after m-PGE2 administration was not reduced, this agent seems directly to affect oxynthic cells.

Loperamide (R 18 553) was compared with placebo in a double-blind crossover study of 21 patients with chronic diarrhoea caused by ileocolic disease or resection. Eighteen patients completed the trial. At a median daily dose of 6 mg the new antidiarrhoeal preparation was found to be superior to placebo in controlling chronic diarrhoea. The frequency and weight of stools significantly decreased, the stools became more solid, and carmine transit time was prolonged during loperamide therapy. Loperamide was consistently preferred to placebo by the patients. Gastrointestinal side-effects were few and comparable during both treatment periods.

A double-blind crossover study using placebo and antibiotics effective against either aerobic or anaerobic organisms has been performed to elucidate the role of intestinal microflora in the pathogenesis of colonic pseudo-obstruction, which is now established as an important complication of jejunoileal bypass. Using strict Virginia Polytechnic Institute (VPI) technique, quantitative bacterial studies of the intestinal flora in the region of bypassed bowel have been correlated with symptoms of abdominal pain and distension. It has been shown that antibiotics effective against obligate anaerobes rapidly relieve the symptoms of pseudo-obstruction and this coincides with the disappearance of these organisms from this region of bowel. Symptoms rapidly recur when anaerobic organisms repopulate the bowel. It is concluded that obligate anaerobes may play a role in the pathogenesis of this complication.

Cimetidine markedly inhibits gastric acid secretion, but from the therapeutic point of view it is important to know whether concurrent treatment with an anticholinergic increases its effect. This possibility has been investigated by measuring the 24 h intragastric acidity and nocturnal output of acid in four duodenal ulcer patients, each receiving on separate occasions cimetidine 1 g/day and placebo, atropine 2-4 mg/day and placebo, cimetidine and atropine, or two placebos. Cimetidine alone decreased mean hourly hydrogen ion activity by 63% of control values, decreased mean hourly hydrogen ion concentration (total acid) by 41%, inhibited nocturnal acid secretion by 83% and resulted in half the nocturnal samples being anacidic. Atropine alone had no effect when compared with control and combined treatment with both drugs was not superior to cimetidine alone. Atropine did not affect the absorption or urinary excretion of cimetidine. Fasting serum gastrin concentrations were not changed by any of the treatments. At the doses studied, the combination of cimetidine with an anticholinergic appears to offer no advantages over treatment with the H2-antagonist alone. Cimetidine is the only potent anti-secretory drug that does not cause acute side-effects and this important advantage would be lost if it were given with a maximal dose of an anticholinergic.

A double-blind controlled trial of oral zinc sulphate as adjuvant treatment in idiopathic ulcerative colitis or proctitis in relapse is reported. Fifty-one patients were treated, and the clinical and sigmoidoscopic improvement in the zinc treated patients was similar to that in patients receiving placebo. No difference was found between plasma zinc levels in a further 46 patients with idiopathic ulcerative colitis or proctitis and those obtained in a group of healthy controls.

In view of promising, but uncontrolled, reports of the use of D-penicillamine in active chronic hepatitis, a randomised, prospective, controlled trial of this drug against prednisone was carried out. Of the 35 patients entered, 18 received D-penicillamine (increasing to 1-2 g daily) and 17 prednisone (15 mg daily). In all patients the disease had already been brought under biochemical control with corticosteroids. During the first year of the trial, the treatment of nine patients in the D-penicillamine group was discontinued (two because of lack of disease control and seven because of side-effects) compared with six patients in the prednisone group (four because of lack of disease control, one because of side-effects, and one because of the development of carcinomatosis. Detailed statistical analysis of the liver function tests in the patients remaining in the trial at the end of the year showed no significant differences. D-penicillamine is associated with a higher frequency of side-effects than is prednisone. However, in some patients it is as satisfactory as prednisone in keeping the disease under control.

During a six year period 43 patients with Crohns disease were included in a double-blind controlled trial of sulphasalazine given for one year as a possible treatment for reducing the relapse rate after resection or in asymptomatic patients with established disease. No trend in favour of sulphasalazine over the control group was observed. The difficulties of such a trial due to the small number of patients entered from nine hospitals, the varied nature of the disease, and the high incidence of complications, such as intraperitoneal abscess formation, are discussed.

To determine the clinical implications of HBSAg in severe chronic active liver disease (CALD), patients with HBSAg positive CALD were compared with those chosen by identical clinical, functional, and morphological criteria in whom this test and anti-HBS were negative. HBSAg positive patients were predominantly males over 40 years of age and more frequently failed to respond to conventional treatment programmes with prednisone. HBSAg negative patients were more often female and younger, had a higher incidence of associated immunopathic disease and immunoserological markers in high titre, and more often responded to treatment with full remission of their disease. HBSAg positive patients failing treatment with conventional doses of prednisone often improved with higher doses, but did not reach full remission of their disease. The benefit-risk ratio of both conventional and high doses of prednisone in HBSAg positive severe CALD needs further clarification.

The efficacy of antifibrinolytic therapy in the management of acute upper gastrointestinal haemorrhage has been investigated in a double-blind clinical trial. Two-hundred patients were studied using tranexamic acid, a potent antifibrinolytic agent. Of these, 103 were in the treatment group and 97 in the control group. Patients were analysed to determine severity of initial blood loss, transfusion requirements, together with the incidence of recurrent bleeding, surgical intervention, and death. Final diagnosis as to the site of bleeding was arrived at using endoscopy, barium studies, and the findings at operation and necropsy. The groups were well matched as regards severity of initial haemorrhage, age, sex, aetiological diagnosis, and precipitating factors. A significant difference was observed in the requirement for surgical intervention to control continuing or recurrent haemorrhage. Twenty-three of 97 in the control group and seven of 103 in the treatment group required surgery. There appeared to be a reduction in the transfusion rate after the first three days of hospitalization in the treatment group. There were no significant differences in mortality or in side-effects between the two groups.

A randomised controlled trial has been performed in 150 patients undergoing biliary operations to determine whether an antibiotic which is excreted almost entirely in bile (rifamide) is to be preferred to one having satisfactory serum levels only (gentamicin). Patients were allocated to one of three groups: 50 received gentamicin, 50 received rifamide, and there were 50 controls who received no antibiotic cover. In the absence of duct obstruction, rifamide achieved extremely high bile levels but low serum concentrations. However, in jaundiced patients, both the bile and the serum concentrations of rifamide were too low to be of therapeutic value. The incidence of postoperative sepsis was not reduced by rifamide compared with controls. In contrast, gentamicin achieved adequate serum concentrations in 88% of patients. Despire poor bile levels, gentamicin was associated with a significant reduction of wound infection from 22% to 6% and septicaemia from 14% to 2% compared with controls. To reduce the septic complications of biliary operations, adequate serum levels of an effective antimicrobial are more important than an antibiotic, which is excreted almost entirely into the bile.

Serum levels of total sulphated and total unsulphated lithocholates were each measured by a specific radioimmunoassay in 66 patients ingesting chenodeoxycholic (chenic) acid for gallstone dissoultion and in 35 gallstone patients ingesting either cholic acid or placebo. No changes occurred in serum lithocholate levels in the control groups. In patients ingesting chenic acid, there was a twofold increase in serum levels of total lithocholate, but the percent sulphation (greater than 75%) remained unchanged during chenotherapy. There was no correlation in the chenic acid treated group between serum lithocholate levels and the proportion of lithocholate in biliary bile acids or changes in serum SGOT. The data suggest that there is effective sulphation of lithocholate in such patients; this may explain the lack of hepatotoxicity observed during ingestion of chenic acid.

The effect of cimetidine, a new histamine H2-receptor antagonist, on gastric acid secretion stimulated by a homogenised meal was studied in six normal volunteers using an in vivo intragastric titration technique. The subjects were studied twice, no more than 48 h apart, receiving either cimetidine 200 mg or placebo in random order. Cimetidine administered either 32 men before (three subjects) or with the meal (three subjects) significantly inhibited gastric acid secretion in all the subjects throughout the period of study; 96 min after food, total acid secretion decreased by 67 and 57% respectively. When the drug was taken with the meal absorption was slower (mean peak blood level 2-34 mumol/l, 80-128 min after dosing) than when administered on an empty stomach (mean peak blood level 5-08 mumol/l, 48-64 min after dosing). Blood cimetidine concentration correlated significantly (P less than 0-01) with percentage inhibition of acid output and the calculated concentration resulting in 50% inhibition of gastric acid secretion (IC50) was 1-6 mumol/l. Secretion of gastrin in response to food was unaffected by cimetidine. The results suggest that 200 mg cimetidine effectively inhibits food-stimulated acid secretion and that the bioavailability of the drug may be affected by the timing of dosage in relation to meals. No unwanted effect were observed.

The effect of H2-receptor blockade on intragastric acidity was studied in nine normal males. The pH of their gastric contents was measured at hourly daytime and two hourly nighttime intervals for 48 hours. The subjects ate identical meals, drank identical volumes of fluid, and smoked the same number of cigarettes during the two study days. Their physical activity was unrestricted in a ward environment. Blood cimetidine and plasma gastrin were measured in serial blood samples. The nine subjects were treated in random sequence with cimetidine 0-8-1-0 g on one day and placebo capsules on the other. The drug was given in four divided doses: four subjects received it before, and five after, the three main meals. All took the fourth dose at bedtime. Replicate studies in an additional subject given placebo on both study days showed good reproducibility (r=0-80, P less than 0-01). Cimetidine therapy decreased intragastric acidity in all nine subjects. The decrease was similar in the two groups taking the drug before or after meals, mean 24 h intragastric hydrogen ion activity being lowered by 70 and 72% respectively. Nocturnal anacidity was recorded in only two of 45 samples. Administration of cimetidine before meals produced earlier and higher drug blood levels than post-prandial medication, but when it was taken after food the blood levels were highest at the time when the buffer capacity of the food was waning. Blood concentrations of cimetidine exceeded the secretory IC50 level for most of the time between doses. The results show that cimetidine 0-8-1-0 g/day in four divided doses produces a striking and consistent decrease of intragastric acidity. Although variation in the timing of the dose in relation to meals did not affect the decrease of acidity, the absorption data suggest that patients should take the drug after meals.