The effect of oxmetidine 800 mg/day, a new histamine H2-receptor antagonist, on duodenal ulcer healing was compared with cimetidine 1000 mg/day in a two-centre double-blind trial. Ninety-nine patients completed the study. After four weeks, ulcers were healed in 74% of the cimetidine-treated patients and in 78% of the oxmetidine-treated patients (p greater than 0.05). Healing rates after eight weeks increased to 90% in the cimetidine group and to 94% in the oxmetidine group. Healing rates after four weeks were, however, different in the two centres (p less than 0.01): in centre 1 88% of the cimetidine-treated, but 63% of the oxmetidine-treated patients healed, in centre 2 rates were 60% (cimetidine) and 92% (oxmetidine). Analysis of patient data revealed that in the two centres treatment success was inversely correlated (p less than 0.01) with the percentage of smokers in each treatment group. Smoking significantly influences duodenal ulcer healing with histamine H2-receptor antagonists.

Aspirin causes gastroduodenal erosions and/or ulcers in man when taken for prolonged periods. The effects of shorter periods of aspirin, Bufferin, or paracetamol (acetaminophen) intake as used for self-medication are unknown. In a four way, crossover, blinded endoscopic study, we compared the effects of aspirin, Bufferin, paracetamol, and placebo, two tablets four times a day for 24 hours, on the gastroduodenal mucosa of 10 normal volunteers. Both regular aspirin and bufferin produced multiple gastric (p less than 0.005) and duodenal erosions (p less than 0.05, compared with baseline and placebo studies). Paracetamol did not cause significant gastric or duodenal mucosal damage. Two subjects developed duodenal ulcer-like lesions in the course of the study. We conclude that the use of unbuffered aspirin and Bufferin, but not paracetamol, in recommended doses for one day causes significant gastroduodenal mucosal damage.

Changes in markers of hepatitis B viral replication and standard liver function tests were studied in 30 patients with HBsAg positive chronic liver disease starting or stopping prednisolone/azathioprine therapy, and compared with those occurring in 15 patients who did not receive therapy. On stopping prednisolone/azathioprine, 10 out of 11 HBeAg positive patients and one out of three patients negative for HBeAg and anti-HBe, lost HBV-DNA polymerase activity (p less than 0.01), five lost HBeAg, three developed anti-HBe and HBsAg concentration decreased (p less than 0.01). Only one out of seven untreated HBeAg positive patients lost HBeAg and there were no significant changes in DNA polymerase activity. In the anti-HBe positive patients, 14 starting therapy and eight untreated, there were no significant changes in the markers of viral replication - although two patients developed DNA polymerase activity on high maintenance doses of prednisolone - but a significant decrease (p less than 0.05) in aspartate transaminase in the treated group. It is concluded that the cessation of prednisolone/azathioprine therapy in HBeAg positive patients will result in a reduction in viral replication. In anti-HBe positive patients such therapy may be beneficial.

Fifty patients with endoscopically proven gastric ulcers completed a one month double-blind randomised trial of tripotassium dicitrato bismuthate (TBD) (DeNol) compared with an identical placebo. Ulcer healing occurred in 18 (72%) of the 25 patients given TDB and in nine (36%) of the patients given placebo. The TDB group experienced significantly less pain than the placebo group. During a follow-up of 29 patients with healed ulcers for up to 44 months, relapse occurred in 13 (45%). It was highest in the first three months (27%) and had risen to 41% at two years.

A controlled trial of 44 patients was undertaken to evaluate the use of dexamethasone (32 mg stat, 8 mg qds) in preventing, and intravenous mannitol (1 g/kg) in reversing the cerebral oedema of fulminant hepatic failure. Diagnosis of cerebral oedema was based on intracranial pressure recordings or the presence of defined clinical signs. Cerebral oedema developed in 34 patients with similar frequency in those treated with and without dexamethasone (16 of 21 and 18 of 23 respectively). In those 34 patients episodes of cerebral oedema resolved significantly more frequently in the 17 patients who received mannitol than in the 17 patients who did not (44 of 53 and 16 of 17 respectively, p less than 0.001). Dexamethasone did not affect survival but among patients who developed cerebral oedema those who received mannitol had a significantly better survival than those who did not receive it (47.1% and 5.9% respectively, p 0.008, Fisher's one-tail test).

One hundred patients with benign gastric ulceration were treated in a single-blind, endoscopically controlled trial to assess the relative efficacy of cimetidine (1 g daily) and Caved-S (six tablets daily). Ulcer healing was assessed after six weeks' treatment, and, if incomplete, after a further six weeks. There was no significant difference between the two drug regimens (approximately 63% at six weeks and 91% at 12 weeks). If an ulcer remains unhealed after 10 weeks' treatment the patient should undergo surgery. There was no difference in the relief of day pain between the two drug regimens but cimetidine was more effective over the first two weeks of treatment relieving night pain, than was Caved-S (p less than 0 . 02). After ulcer healing, drug dosage was reduced (cimetidine to 400 mg at night and Caved-S to two tablets twice daily). So far, 56 patients, 28 in each group, have completed the first year's maintenance treatment, and there have been four ulcer recurrences in each group (14%).

During a double-blind randomised clinical trial of cimetidine and ranitidine in the management of duodenal ulcer, the response of patients' peripheral blood lymphocytes to optimal mitogenic stimulation in vitro has been measured. Treatment with cimetidine, but not ranitidine, was associated with a significant increase in the proportion of peripheral blood lymphocytes responding to this optimal mitogenic stimulation. We conclude that these effects of cimetidine may not be mediated at classical histamine H2-receptors.

The aim of this study was to determine whether bedtime administration and a low cholesterol diet reduce the minimum effective dose of chenodeoxycholic (chenic) acid, defined as the dose giving a mean cholesterol saturation index of 0.8. Dose response studies were carried out in 10 patients with radiolucent gallstones in a functioning gallbladder during three different treatment regimens. On each regimen, all patients received three different doses of chenodeoxycholic acid in random order for one month each. Bedtime chenic acid plus a low cholesterol diet gave the greatest reduction in saturation index. A significant dose/response relationship was found on each regimen. On the conventional regimen of mealtime chenic acid, the minimum effective dose was 14 mg/kg/day; on bedtime chenic acid it was 12.4 mg/kg/day; and on bedtime chenic acid plus low cholesterol diet it was further reduced to 8.4 mg/kg/day (p less than 0.01). There was a dose-related increase in bowel frequency, which was absent at 10.6 mg/kg/day and below. We conclude that administration of chenic acid at bedtime with a low cholesterol diet enables the minimum effective dose for gallstone dissolution to be approximately halved, thus preventing diarrhoea and reducing the cost of treatment.

Eighteen patients with diffuse varioliform gastritis were enrolled in a double-blind, placebo-controlled trial of sodium cromoglycate, 200 mg a day, and sodium cromoglycate, 400 mg a day, for 28 days. An additional six patients were treated with cimetidine 1 g daily for 28 days. The improvement in terms of patient's subjective assessment, endoscopic assessment, and immunohistochemical measurements of IgE cells in the mucosa was significantly greater in patients given sodium cromoglycate than that in those given cimetidine or placebo. The results provide evidence that type 1 hypersensitivity plays some part in the pathogenesis of varioliform gastritis. It is, therefore, important to differentiate this condition from other types of gastritis, as treatment with sodium cromoglycate appears to be affective.

Sixty patients, whose duodenal ulcers had healed endoscopically after six weeks of treatment with cimetidine 1 g/day in divided doses, were treated with maintenance cimetidine 800 mg at bedtime for six months. Eighteen relapsed endoscopically (30%). Of the 42 still in remission, 36 then completed a six month double-blind comparison of bedtime cimetidine 400 mg and placebo. Twelve of the 19 (63%) cimetidine-treated patients and 10 of 17 (59%) placebo-treated patients relapsed within six weeks (NS). This high relapse rate on cimetidine contrasts with our earlier trial, in which the six week relapse rate was only two out of 21 (10%) on bedtime cimetidine 800 mg and 16 out of 24 (66%) on placebo (P less than 0.0005). Apart from the difference in the dose of cimetidine, both our trials used the same experimental protocol during the double-blind part of the trial. In the earlier trial, however, there was no period of pretreatment with maintenance cimetidine as in the present trial. The pattern of placebo relapse was similar in both trials. We conclude that bedtime cimetidine maintenance treatment does not alter the long-term natural history of duodenal ulcer once it has been withdrawn; and that either tolerance to cimetidine develops during long-term maintenance treatment, or that bedtime cimetidine maintenance treatment in the conventional dose of 400 mg is not as effective as 800 mg in prevention of endoscopic relapse, although it does reduce symptoms.

The efficacy of methylprednisolone (1 g daily or three days), which is effective in reversing transplant rejection, was assessed in a randomised controlled trial of 55 patients with severe acute alcoholic hepatitis, 34 of whom had encephalopathy. The clinical progress, frequency of bleeding and sepsis, and cause of death were similar in the treatment (27 patients) and control groups (28 patients). There was no significant difference in mortality rate between the two groups: 57% of the control group and 63% of the treatment group died during the study. Patients' survival depended on the presence of absence of the following features: encephalopathy, serum bilirubin concentration more than 340 micromol/l, serum creatinine concentration more than 250 micromol/l, and histological evidence of cirrhosis as well as severe acute alcoholic hepatitis.

Neomycin, an antibiotic which is primarily active against the aerobic gut flora and hence reduces the endogenous production of ammonia, is a well-recognised form of treatment for acute or acute on chronic hepatic encephalopathy. This study suggests that metronidazole may be a useful alternative or even adjunctive treatment for such patients. Theoretical and practical justifications for the use of this drug are presented. The results of a week's prescription of each drug have been assessed by changes in clinical and biochemical criteria, including electroencephalograms and arterial ammonia sample. In the treatment of a series of 11 mildly or moderately, and seven severely affected, patients with histologically confirmed cirrhosis, metronidazole is shown to be as effective as neomycin.

Thirty-two patients with duodenal ulceration took trimipramine 50 mg or placebo. Fifteen patients on each treatment completed the study. Endoscopy at four weeks showed ulcer healing in seven (46%) patients on trimipramine, compared with only two (15%) on placebo (P less than 0.05). However, by eight weeks there were eight (53%) patients in both groups with healed ulcers. There were no significant differences between the two groups in ulcer symptoms. Drowsiness was reported by eight patients on trimipramine compared with only one on placebo. Trimipramine 50 mg appears to increase the rate of ulcer healing in the short term. Side-effects at the dose used may limit its long-term usefulness.

In a double-blind, placebo controlled and randomised secretory study the effectiveness of pirenzepine, ranitidine, and their combination was compared intraindividually in eight healthy subjects receiving intravenous bolus injections. Pirenzepine (0.15 mg/kg) plus ranitidine (0.6 mg/kg) suppressed peptone-stimulated gastric acid secretion from 69 +/- 11 to 2 +/- 0.4 mmol H+/3 h; the mean percentage inhibition was 97%. Postprandial gastrin was unaffected. There were only minor side-effects in a few experiments (reduction of salivation, brief blurring of vision), but no prolactin stimulation after ranitidine or ranitidine plus pirenzepine. The combined application of ranitidine and pirenzepine inhibited meal-stimulated acid secretion more effectively and produced fewer side-effects than the combination of cimetidine plus pirenzepine studied previously.

The response of active Crohn's disease to sulphasalazine (4-6 g per day) has been studied in a placebo-controlled trial. The study was carried out at two hospitals. From August 1977 to August 1979 all patients with established Crohn's disease were examined for their eligibility for the trial. A nine-item index of inflammatory activity was used as the primary measure of response. The variables in this index were serum albumin, ESR, body weight released to height, abdominal mass, temperature, stool consistency, bowel resection, and extraintestinal symptoms related to Crohn's disease. A favourable response to therapy was defined as a decrease of the activity index with 25% or more at the end of the trial period, compared with the initial value. Twenty-six patients (13 in each treatment group) have been followed up for six months. The response of active Crohn's disease to sulphasalazine was significantly better than to placebo.

In order to determine some of the factors involved in the response of duodenal ulcers to placebo treatment, the following factors were studied prospectively during a double-blind, placebo-controlled trial: demographic data; duration of illness and effect of treatment; expectation of success or failure of the new drug; presence of psychiatric problems; and suggestibility. Healing (measured by endoscopy) occurred in 37 patients, 17 of whom were receiving placebo; relief of symptoms occurred in 35 patients, 16 of whom were receiving placebo. There was no significant difference between drug and placebo. Healing was significantly associated with relief of symptoms but with no other variable. Relief of symptoms was more common in male patients and in those from higher social classes, as well as in patients who expected a complete cure and those without evidence of psychiatric problems. the natural history of the disease may be different in these patients. Unexpectedly, suggestibility was not associated with healing or relief of symptoms in the patients receiving placebo.

One hundred and three outpatients with endoscopically diagnosed duodenal ulcer were randomly allocated to treatment with either cimetidine 200 mg tds and 400 mg nocte, or ranitidine 150 mg bd for four weeks. The endoscopists were not aware of the treatment and took no part in the clinical management. On completion of treatment ulcers had healed in 43 of 51 (84%) patients given cimetidine and in 40 of 52 (77%) patients given ranitidine. There were no serious unwanted effects in either treatment group. The results show no significant difference between healing rates after four weeks of standard cimetidine therapy or ranitidine 150 mg bd.

Emergency endoscopy on 332 patients with acute upper gastrointestinal bleeding showed that 178 had peptic ulcers; 28 of these were actively bleeding (spurting) and 108 showed stigmata of recent haemorrhage (vessels or spots in the ulcer base) suggesting a risk of rebleeding. These 136 patients were randomly allocated to Argon laser photocoagulation or to no additional therapy (controls) at the time of initial endoscopy. All patients received conventional management, and the controlling clinicians did not know whether or not the laser had been used in any individual patients. The laser system proved both simple and safe in use. Initial haemostasis was achieved by the laser in 10 of 15 'spurting vessels', but four of 13 'control' spurting vessels also stopped bleeding spontaneously. Overall, there were no statistically significant differences between the laser treated and control groups in terms of rebleeding, the need for surgical intervention, or death. These results require amplification in larger trials, and comparison with other studies using different protocols and other haemostatic methods.

A controlled clinical study on disodium cromoglycate (DSCG) at a dose of 800 mg per day versus placebo was carried out in 141 patients with ulcerative colitis and 25 patients with Crohn's disease. Those of the ulcerative colitis patients who had been on sulphasalazine treatment continued that treatment during the trial (101 patients). Forty patients were intolerant of sulphasalazine. No patient received steroids during the last month before the study. Patients with Crohn's disease had their possible sulphasalazine treatment stopped before the trial. No beneficial effect of DSCG as compared with placebo was found, as the DSCG and the placebo group showed the same number of relapses in patients with a clinically inactive ulcerative colitis at the start of the trial and the same number of patients improving, deteriorating, and maintaining steady state in patients with clinically active ulcerative colitis at the start of the trial. There was no difference between relapse rate in DSCG and placebo groups in patients with Crohn's disease. No correlation between the eosinophil count in rectal mucosa and the outcome of the attack of ulcerative colitis could be demonstrated.

Twenty-four hour intragastric acidity and nocturnal acid secretion were measured in 10 males with duodenal ulcer in four separate 24 hour studies, during which the subjects ate normal meals, had unrestricted physical activity, and consumed their customary quantities of tobacco. The medication consisted of either placebo, cimetidine 200 mg tds and 400 mg at night, or ranitidine 150 mg bd, or 200 mg bd. Ranitidine 150 mg bd decreased mean 24 hour hydrogen ion activity from 41.8 mmol/l to 13.1 mmol/l (-69%, P less than 0.001) and nocturnal acid output from 6.1 mmol/h to 0.6 mmol/h (-90%, P less than 0.01). This degree of inhibition was significantly greater than that due to cimetidine (P less than 0.001 for 24 hours acidity, less than 0.05 for night time acid output). Plasma concentrations of ranitidine were greater than the IC50 for more than eight hours after the 150 mg dose. Ranitidine 200 mg conferred no additional advantage. Ranitidine 150 mg bd should be tested in therapeutic trials.