Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones.

In a double blind study, 24 hour intragastric acidity and 24 hour plasma gastrin concentrations were measured simultaneously in seven duodenal ulcer subjects on the fifth day of receiving either sufotidine 600 mg bd or placebo. Compared with placebo, during treatment with sufotidine 600 mg bd the median integrated 24 hour intragastric acidity was decreased by 95% (range 74% to 99%) from 1000 to 51 mmol/h/l, whilst the median integrated 24 hour plasma gastrin concentration increased from 416 to 927 pmol/h/l.

Forty six consecutive patients admitted for the relief of malignant dysphagia were prospectively randomised to receive laser therapy only or initial laser therapy followed by endoscopic intubation. Twenty patients were treated in each group with six exclusions. The patients' swallowing ability was assessed before and during the remainder of their life on a 0-4 scale with 0 being normal swallowing and 4 total dysphagia. The patient's quality of life was measured at the same times, using a physician's assessment (QL index) and the patient's own assessment using a linear analogue self assessment (LASA). There was a significant correlation between all the QL index and the LASA scores collected (n = 126; rs = 0.594, p less than 0.001). The mean monthly dysphagia grade correlated with the QL index (rs = 0.433, p less than 0.001) and the LASA (rs = 0.272, p less than 0.002). There was no significant difference in the dysphagia grade before or after treatment in either group. Dysphagia fluctuated more in those treated with the laser only, however, than in those with a tube inserted. There was also no significant difference in the quality of life measured between the two groups of patients. The complication rate (laser only 10%, laser/intubation 40%, p less than 0.05) was significantly higher in intubated patients. The recurrent dysphagia rate (laser only 25%, laser/intubation 45%, NS) was higher in patients treated with intubation, but they required fewer endoscopic procedures. Overall both procedures were effective in relieving dysphagia and in maintaining quality of life. There was no procedure related mortality in either group.

This study tests the hypothesis that reactivation of a latent herpes simplex virus infection may be a cause of recurrent duodenal ulceration. Patients with recently healed duodenal ulcer were entered into a double blind, randomised study of maintenance treatment with the antiviral drug acyclovir (400 mg bid) versus placebo, to determine if suppression of herpes virus infection would influence the natural history of the ulcer disease. One hundred and fifteen patients entered the trial and 76 patients completed it according to the protocol. Endoscopy was performed when ulcer symptoms recurred and at the end of the 25 week trial period. In the acyclovir group the cumulated relapse rate was 63% compared with 56% in the placebo group (NS). This result suggests that reactivation of herpes simplex virus is not a cause of recurrent duodenal ulcer.

Two separate studies of 24 hour intragastric acidity were carried out in normal volunteers and duodenal ulcer patients to define the interaction of food and the antisecretory effects of H2-receptor blockers. Both investigations were double blind randomised comparisons using ranitidine 300 mg with either different meal times or ad libitum snacks after an evening meal. Meals taken after drug administration nearly abolished measurable antisectory effects. Median 24 hour pH was 1.3 on placebo, 2.6 when ranitidine was administered after the evening meal and 1.9 when administered before the evening meal. Snacks taken after evening dosing with ranitidine also significantly decreased pharmacodynamic efficacy. During placebo, median night-time pH was 1.3 without snacks and 1.4 with snacks. pH rose to 5.9 during ranitidine treatment when snacks were forbidden but was only 3.1 when snacks were allowed. These findings could be of therapeutic importance and should rationalise dietary advise to patients receiving H2 blockers. The timing of drug administration can be adjusted according to individual life styles.

The effect of cisapride, a new gastrointestinal prokinetic drug, on oesophageal motility and acid reflux was studied in 14 children with gastro-oesophageal reflux disease, receiving either placebo or cisapride 0.15 mg/kg intravenously. Cisapride significantly (p less than 0.01) increased the lower oesophageal sphincter pressure (+124%), the amplitude (+84%) and duration (+24%) of oesophageal peristaltic waves, whereas the placebo treatment did not produce any changes. Subsequently, all 14 children underwent 24 hour oesophageal pH-monitoring before and after four weeks of treatment with oral cisapride 0.2 mg/kg tid given in addition to postural therapy and thickened feedings. The 24 hour intraoesophageal pH recordings and symptomatic scores were compared with those of 10 control patients treated only by postural therapy and thickened feedings. When compared with baseline pH data, cisapride significantly reduced the oesophageal acid exposure time, the mean duration of each reflux episode, the duration of the longest reflux episode and the number of long lasting reflux episodes; the number of reflux episodes was not influenced. The effect of cisapride was marked and consistent during fasting and sleep periods. Oesophageal acid exposure was reduced more significantly in patients given cisapride (-61%) than in controls (-24%; p less than 0.001). Symptom improvement was greater after four weeks of cisapride treatment (score reduction: 61%) than after postural and dietary therapy alone (score reduction: 42%; p less than 0.01). No adverse effects occurred. These findings suggest that cisapride is a valuable drug in the management of gastro-oesophageal reflux disease in children.

This presentation describes interim findings in a series of 319 patients referred from 41 hospitals on the basis of histopathological findings of 'early gastric cancer', 'dysplasia', or 'worrying mucosal appearances'. Data were recorded using a predefined proforma, and histopathological material circulated amongst a 'panel' of three further pathologists. After this process, 132 patients were classified as having early gastric cancer and 63 as dysplasia. There was good agreement between pathologists as to whether the cases had cancer or dysplasia - but 39 cases said by referring pathologists to have early gastric cancer were classified by the panel as having more extensive disease. Most early gastric cancer cases were diagnosed only after histopathological examination. Cancer or 'possible cancer' was only mentioned after 36% of the radiological investigations and 40.5% of the endoscopies. Computer aided analysis of the patients' symptoms placed 91.3% of the early gastric cancer cases into a 'high risk' group - but was unable to distinguish between early gastric cancer and dysplasia. The five year survival rate of the cases agreed to be early gastric cancer by the panel was well over 90%, but the four year survival rate of cases registered as 'early gastric cancer' but said by the panel to have more advanced disease was under 75%. These findings may account for some of the differences between series, and emphasise the need for precise, widely agreed criteria for the diagnosis of early gastric cancer and gastric dysplasia.

The efficacy of ranitidine (150 mg nocte), and sucralfate (1 g tds) as maintenance therapy to prevent gastric ulcer relapse was evaluated in a 12 month trial in 363 patients. The relapse rates were 8.8% at three months, 14.7% at six months, 18.1% at nine months, and 21.0% at 12 months for the ranitidine group and 14.7%, 21.3%, 29.9%, and 30.2% respectively for the sucralfate group. At nine and 12 months the cumulative relapse rates for the ranitidine group were significantly lower than those for the sucralfate group (p less than 0.05). In both groups ulcers recurred mainly from red scars observed at the endoscopic scarring stage. This indicated the necessity of drug treatment up to the white scar stage. The results suggest that ranitidine is effective in preventing gastric ulcer relapse.

Biopsies of 17 peptic ulcer patients, randomly treated by partial gastrectomy with either Billroth-II (n = 9) or Roux-en-Y (n = 8) anastomosis were studied before and six months after surgery to determine the role of bile reflux in the early postoperative histological alterations of the gastric mucosa. After BII-gastrectomy bile acid reflux (median 16.1 mumol/h) was significantly higher (p less than 0.0001) than after RY-gastrectomy (0.1 mumol/h). Campylobacter pylori was present in the preoperative biopsies of all 17 patients. After RY-gastrectomy biopsies of all eight patients were positive for Campylobacter pylori, but was detected in only five of the nine patients with BII-gastrectomy. Preoperative scores of gastritis grading were similar in both groups and no significant differences were found postoperatively. Gastritis scores of the anastomotic mucosa in patients with BII-gastrectomy were significantly higher (p less than 0.02) than in the RY-gastrectomy group. Moreover, the reflux gastritis score in the four BII-gastrectomy patients cleared from Campylobacter pylori was significantly higher (p less than 0.02) than in the postgastrectomy patients harbouring Campylobacter pylori. The results suggest that reflux gastritis and Campylobacter pylori related gastritis are distinct microscopic entities and that bile reflux may play a role in the eradication of Campylobacter pylori after gastrectomy.

A series of three experiments were performed on healthy adult volunteers to investigate the possible role played by beta-adrenoreceptor mediated pathways in the disturbance of human upper intestinal motor function by hand immersion in cold water. In the first experiment, (an extended pilot study on one individual), orocaecal transit of a standard meal was measured on 36 occasions with and without cold water stimulation and with and without a series of alpha and beta blocking drugs. Cold water stimulation consistently delayed transit in this individual, an effect which was attenuated by prior beta-blockade. In a double blind trial of the effect of beta-blocker atenolol v placebo on transit in nine individuals, a consistent reduction in the cold water induced transit delay was observed (p less than 0.01) independent of any direct effect of beta-blockade. In the third experiment seven individuals underwent repeated studies of antroduodenal pressure activity comparing the effects of cold and warm water stimulation with and without beta blockade to determine whether the observed transit effect could be related to an action on gastrointestinal motility. Cold water stimulation reduced antroduodenal motility, but no consistent effects of previous beta blockade were noted. These studies indicate the presence of a beta-adrenoreceptor mediated pathway in the cold water induced delay of orocaecal transit but not in the inhibition of gastroduodenal motility. Further studies are indicated to determine the site and mode of action of this transit effect more precisely.

The effect of olsalazine, an analogue of sulphasalazine, consisting of two molecules 5-aminosalicylic acid linked by an azobond has been investigated for the treatment of ulcerative colitis. In a randomised double blind trial we compared 2 g olsalazine with placebo for four weeks. Of the 105 patients, with mild to moderate ulcerative colitis, entered in the trial 52 received olsalazine, and 53 placebo. Treatment had to be terminated prematurely because of untoward effects of olsalazine (mainly diarrhoea) in three patients and treatment failure--that is, increased rectal bleeding in four patients (olsalazine group: one placebo group: three). After four weeks' treatment, a statistically significant improvement in the endoscopic findings in rectum and a positive trend in the reduction of rectal mucus and blood discharge was observed in the patients treated with olsalazine. No statistically significant difference was found for other factors, including stool frequency, consistency, urge to defecate, abdominal pain, and biopsy findings. A comparison between these clinical and endoscopic parameters at study entry and those at study completion (within drug evaluation) showed significant improvement in six of 10 parameters during treatment with olsalazine and in two of 10 during placebo treatment. This difference suggests the significant effect of olsalazine. We conclude that 2 g olsalazine was tolerated as well as placebo, apart from causing diarrhoea in some patients and was slightly superior to placebo during four weeks' treatment of mild to moderate ulcerative colitis. A study with 3 or 4 g olsalazine per day may show a more definite effect.

In a randomised, double blind, parallel group study in patients with symptomatic gastric ulcer (94% greater than or equal to 5 mm diameter), 102 received omeprazole 20 mg om and 87 cimetidine 400 mg bd. After four weeks 73% and 58% (p less than 0.05) respectively had healed (eight weeks: 84% and 75%, ns). After four weeks, a greater proportion (81%) of omeprazole treated patients was symptom free than of those receiving cimetidine (60%; p less than 0.01). Over the first two weeks, patients receiving omeprazole had less day pain, less night pain and took fewer antacids than those receiving cimetidine (all p less than 0.05). The difference between omeprazole and cimetidine was not appreciably affected by age, smoking, size of the ulcer and trial centre. Tolerability was similar in the two treatment groups. In the treatment of symptomatic gastric ulcer, omeprazole relieves the symptoms more quickly than cimetidine and heals a greater proportion of ulcers within four weeks.

Fifty consecutive patients with non-ulcer dyspepsia and a Campylobacter associated gastritis (CAG) were randomly assigned to treatment with colloidal bismuth subcitrate (CBS) 240 mg twice daily or placebo, according to a double blind study design. After the blind treatment an 'open' treatment with CBS was started in both groups. Twenty six patients treated with CBS showed a significant reduction in colonisation with Campylobacter pylori and a significant improvement in the Whitehead gastritis score. No significant changes were recorded in twenty four patients treated with placebo. After an additional course of CBS no further improvement in gastritis score was noted but there was a further reduction in Campylobacter colonisation. CBS did not greatly alter subjective complaints. Subjective complaints were improved in both treatment groups except for nausea and meteorism that improved more in the CBS treated patients. This finding again questions the clinical significance of gastritis and also casts doubt on the clinical relevance of therapeutical measures aimed at eradication of C pylori.

We studied the effect of cisapride on oesophageal motor function and postprandial gastro-oesophageal reflux in a randomised, double blind, placebo controlled crossover study. In 16 patients with symptomatic gastro-oesophageal reflux, cisapride 10 mg orally and placebo were studied on separate days according to identical protocols. Cisapride and placebo were given 30 minutes before a standard meal. Each study day was preceded by corresponding three day oral loading of cisapride (10 mg tds) or placebo. Lower oesophageal sphincter pressure, oesophageal body motility and oesophageal pH were monitored for 30 minutes before and three hours after the meal. Plasma cisapride concentrations were measured before and after dosing on both study days. With cisapride treatment, the plasma cisapride levels ranged from 48.1 (5.0) to 75.9 (6.9) ng/ml. Plasma levels were undetectable during placebo treatment. Cisapride enhanced acid clearance but had no significant effect on the duration of acid exposure, the rate of reflux episodes, the pattern of lower oesophageal sphincter pressure associated with the reflux episodes, basal lower oesophageal sphincter pressure or oesophageal peristalsis. These findings do not suggest a major role for cisapride, at the dosage tested, for the control of troublesome postprandial gastro-oesophageal reflux.

The purpose of the present study was to compare omeprazole 20 mg once daily and ranitidine 150 mg twice daily in healing duodenal ulcers unhealed by previous treatment with cimetidine greater than or equal to 0.8 g or ranitidine greater than or equal to 0.3 g daily for at least six weeks. In a double blind multicentre trial, 151 patients were randomly assigned to either omeprazole or ranitidine. Clinical assessments and endoscopies were carried out at two and four weeks. Patients characteristics were similar in both groups. Statistical analysis (chi 2 test) did not show any significant difference in healing rate (p greater than 0.20) irrespective of the method of calculation. On an 'intent-to-treat' analysis (n = 151), healing was: omeprazole 46.6%, ranitidine 43.3% at day 15 and omeprazole 70.7%, ranitidine 68.4% at day 29; and among the patients who completed treatment, healing was: omeprazole 48.3%, ranitidine 46.3% at day 15 (n = 125; 95% confidence interval of the difference--17 to 21) and omeprazole 79.6%, ranitidine 75.4% at day 29 (n = 115; 95% confidence interval of the difference--13 to 21). After a further four weeks treatment with omeprazole, healing occurred in 16/20 (80%) who still had active disease at day 29. Patients on omeprazole and on ranitidine experienced similar decrease in day time and night time epigastric pain and in heartburn. Multivariate analysis (logistic regression) did not indicate any influence on age, sex, smoking and alcohol habits, previous drug administered, duodenitis and duodenal erosions on the healing rate. In this model, healing rate was not significantly influenced by previous treatment duration (p = 0.09 at day 15 and p greater than 0.2 at day 29) but was significantly influenced by ulcer size (p = 0.04 at day 15 and p = 0.02 at day 29). Forty one patients complained of adverse events: 19 on omeprazole (four trial withdrawals), 22 on ranitidine (three trial withdrawals).

The effects of meal volume and luminal digestion of carbohydrates on the release of pancreatic polypeptide (HPP) were investigated in eight healthy subjects and in six patients who had non-insulin dependent diabetes mellitus. On one occasion each subject ingested a placebo with 200 ml water and a starch (50 g) pudding meal (400 ml) 30 minutes later. On another occasion an amylase inhibitor that retards intraluminal starch digestion was given with the water and starch. In normal subjects, water caused a moderate rise in HPP plasma levels (16.9 (10.9) pg/ml; p less than 0.02) and ingestion of starch increased HPP in a double peaked pattern. The mean increments of the peaks were 45.0 (15.2) pg/ml (p less than 0.02) and 41.1 (17.3) pg/ml (p less than 0.05), respectively. In the diabetic subjects, the HPP concentrations did not increase in response to water. After ingestion of starch the diabetics had two peaks of HPP that were similar in magnitude, but the early postprandial peak was delayed significantly compared to normal subjects (37.5 (5.1) min v 23.4 (3.9) min; p less than 0.05). The amylase inhibitor (5 or 10 g) reduced the early postprandial HPP peak by 79% (p less than 0.05) in normal subjects and 4 g of the inhibitor reduced the early HPP peak by 58% (p less than 0.05) in the diabetics. In both groups ingestion of the amylase inhibitor abolished the late HPP peak (p less than 0.05). In conclusion, carbohydrate induced HPP release is dependent on undisturbed intraluminal starch digestion.

This study examines whether eating food at different times has differential effects on intragastric pH. Experiments were done in 23 healthy volunteers (12 men). Intragastric acidity was monitored by ambulatory 22 hour pH-metry. Composition of meals was standardised: breakfast and lunch at 7 am and 12 noon respectively, and dinner at 6 or 9 pm, in random order. The time of going to bed and getting up was also standardised. With early dinner nocturnal pH was higher, than with late dinner (pH median: 1.67 and 1.39, p less than 0.001). During the remaining time periods, pH values were similar. Thus early dinner may be helpful in conditions where low intragastric acidity is desirable.

The mechanism by which intragastric balloons induce weight loss is not known, although they may act simply by reducing the amount of food needed to induce satiety. The knowledge that a balloon is present may influence the patients' eating patterns and reduce caloric intake and weight. In order to test whether the balloon or the secondary psychological effect caused weight loss, a double blind balloon versus sham procedure was devised with both groups receiving identical outpatient dietary advice (800 kcal/day). Twenty four obese women with body mass index greater than 30 kg/m2 from an obesity clinic were studied. Twelve had the balloon and 12 the sham procedure. The balloon was removed after three months and the patients were followed for a further three months. There was significantly greater weight loss in the balloon group, mean weight loss (SD) of 7.33 (6.12) kg compared with the sham group, mean weight loss (SD) of 3.33 (3.9) kg (p less than 0.05). Weight loss was not maintained in all patients after balloon removal. Side effects were more common in the balloon group (abdominal pain, nausea, and vomiting) but resolved by the second week. We conclude that the intragastric balloon is a safe and effective method of inducing weight loss in well motivated obese patients.

In a randomised controlled trial recombinant interferon alpha 2A (Roferon-A, rIFN alfa A) given at a dosage of 10 million units (MU)/m2 thrice weekly for six months was significantly better (p less than 0.02) than no treatment in producing a sustained loss of hepatitis Be antigen (HBeAg) in hepatitis B virus (HBV) chronic carriers. Although lower doses (5 MU/m2 and 2.5 MU/m2) also produced some responses, the seroconversion rate was not significantly greater than that observed in the control group. Sixteen of the 45 patients receiving interferon were human immunodeficiency virus (HIV) antibody positive: none of these responded. Forty one per cent of the anti-HIV negative patients receiving interferon (12/29, p less than 0.005) lost HBeAg and 17% (5/29) lost hepatitis B surface antigen (HBsAg). The response rate among these anti-HIV negative patients receiving at least three months therapy was 46% and 19% respectively. Low pretreatment HBV-DNA and absence of anti-HIV were the only significant independent variables predicting response to therapy (p less than 0.03 and p less than 0.05 respectively). In six patients, neutralising antibodies to alpha interferon were detected during therapy, the majority being non-responders.