Oral isosorbide-5-mononitrate (Is-5-Mn) was given in doses of 10 and 40 mg acutely and chronically (twice daily for four weeks), allowing a nitrate free interval to 25 patients with cirrhosis. Both 10 mg and 40 mg Is-5-Mn reduced the hepatic venous pressure gradient acutely and chronically, without evidence of tolerance. This was achieved by a reduction in the wedged hepatic venous pressure. The effect on mean azygos blood flow was variable with no significant mean change seen acutely or after chronic use with either dose. The variability was dependent not on the dose used but on the initial azygos flow; the flow in patients with initially low values increased and those with high azygos flows decreased after nitrate challenge. The development of the porto-collateral flow seems an important parameter in predicting haemodynamic response to Is-5-Mn.

This study reports an open randomised controlled trial of cyclical antibiotics and ursodeoxycholic acid in prevention of plastic biliary stent occlusion. Seventy patients with malignant distal bile duct obstruction were randomised to either active treatment with cyclical antibiotics (ampicillin, metronidazole, ciprofloxacin) and ursodeoxycholic acid or no treatment after successful stent insertion. The two groups were well matched. The follow up was complete with stent occlusion or death being the end points. There was no difference in the incidence of stent occlusion between the two groups and the overall survival was similar. In conclusion, this study did not show any benefit of treatment with antibiotics and ursodeoxycholic acid in prolonging stent patency or improving survival.

The digestibility of ispaghula, a mucilage from Plantago ovata composed mainly of arabinoxylans, and its faecal bulking effect were studied in seven healthy volunteers who ingested a low fibre controlled diet plus either placebo or 18 g/day of ispaghula for two 15 day periods. Whole gut transit time and gas excretion in breath and flatus were not different during the periods of ispaghula and placebo ingestion. Faecal wet and dry weights rose significantly, however, during ispaghula ingestion. Faecal short chain fatty acid concentrations and the molar proportions of propionic and acetic acids also increased. Most of the ispaghula had reached the caecum four hours after ingestion in an intact highly polymerised form. During ispaghula ingestion, the increase in the faecal output of neutral sugars was accounted for by the faecal excretion of arabinose and xylose in an intact highly polymerised form; the apparent digestibilities of these sugars were 24 (11) and 53% (6) respectively (mean (SEM)). In conclusion, ispaghula is more resistant to fermentation than previously reported in humans, and its bulking effect largely results from intact material.

The effect of zinc supplementation on intestinal permeability changes and protein loss was studied in 32 children aged between 1 and 12 years during bouts of acute shigellosis and after recovery. An intestinal permeability test and then a 48 hour balance study were performed on all patients. They were then blindly assigned to receive vitamin B syrup either with or without zinc acetate (15 mg/kg per day) for a month. All patients received a five day course of nalidixic acid. The balance study was repeated during convalescence and follow up, but a permeability test was done only at follow up after one month. Intestinal permeability, expressed as a urinary lactulose:mannitol excretion ratio, improved significantly (p = 0.001) along with a significant increase (p = 0.005) in mannitol excretion in the zinc supplemented children, suggesting a resolution of small bowel mucosal damage. The latter was associated with a higher coefficient of nitrogen absorption (p = 0.03), suggesting a possible role of zinc in the treatment of shigellosis. Enteric protein loss, as assessed by faecal alpha 1 antitrypsin clearance, was not influenced by zinc supplementation.

The indications for percutaneous endoscopic gastrostomy (PEG) and patient outcome, were examined prospectively in the setting of a general hospital. In the course of 26 months, 76 patients underwent PEG (median age 62 years (range 18-99)) and were followed up for 6887 patient days. The median (range) duration of PEG feeding was 93 (3-785) days. The procedure was carried out for neurological indications in 76% of cases (stroke 51%) and 53% of patients were severely malnourished (body mass index < 17 kg/m2) at the time of referral. In 12 (16%) patients swallowing recovered and the PEG was removed after a median (range) of 55 days (20-150). Three (4%) deaths were related to PEG (one oesophageal perforation, one haemorrhage, and one aspiration pneumonia). One patient developed peritonism and ileus, which resolved with conservative treatment. Minor complications included local sepsis 3%, tube blockage 12%, and tube connector leak 5%. During seven days of observation, demands on nursing time for routine care of the PEG were the same as for nasogastric tube feeding, median (range) 21 (4-42) v 16 (4-40) min/day respectively, but in about half the latter cases the tube had to be replaced at least once. Over 15 months, 29 patients were randomised to receive a 1.9 mm inner, 2.9 mm (9F) outer diameter Fresenius and 27 a 3.0 mm inner, 4.0 mm (12F) outer diameter Bower polyurethane tube and were followed for 2920 and 2388 patient days respectively. There was no difference in the insertion time (median (range) 20 (10-45) v 24 (10-45) min respectively) or number of patients with complications (three v eight patients NS), although there were more minor mechanical problems (three v 12, p < 0.01) with the 12F tube. The internal anchoring device of the 12F tube allowed its non-endoscopic removal, a method applicable too 16% of cases. No tubes were removed because of blockage.

Drug induced oesophageal injury is an important and preventable cause of iatrogenic injury. In most cases the injury is considered to be due to mucosal contact from formulations lodged in the oesophagus. A scintigraphic study was performed comparing the oesophageal transit of enteric coated tablets with similar sized and shaped gelatin capsules, using a population of elderly healthy volunteers similar in age (50-79 years) to the population most likely to be receiving regular treatment. Twenty three volunteers injected the radiolabelled tablet or capsule with 50 ml of water while sitting on two separate occasions according to a randomisation schedule. Oesophageal transit was assessed by gamma scintigraphy. Gastric residence was also assessed in 11 of 23 subjects. While the tablet was readily cleared from the oesophagus, mean transit time 4.3 seconds (range 1.0-14.0), the capsule often showed a comparatively prolonged holdup, mean transit time 20.9 seconds (range 1.5-174.5). Ten of 11 tablets emptied from the stomach intact, while all 11 capsules broke up in the stomach. Gelatin capsules showed a clear tendency to remain within the oesophagus of healthy elderly volunteers, while similar sized enteric coated tablets did not. These studies show the importance of assessing oesophageal transit when designing the formulation of drugs with a potential for oesophageal injury.

Forceful dilatation under endoscopic control is a well established treatment of achalasia; several different types of dilators can be used. This study prospectively compared the clinical and manometric efficacy of a single dilatation using two different dilators. Forty one patients were randomly assigned to forceful dilatation under endoscopic control with either a pneumatic dilator (n = 17) or a metallic dilator (n = 24). Thereafter, the patients received periodic clinical and manometric evaluation for one year (before and one, six, and 12 months after dilatation). One month after dilatation all but one of the subjects in each group had experienced good to excellent results and their clinical improvement persisted for the one year follow up. Two patients (one in each group) were perforated during the procedure and required surgical treatment. Recovery was uneventful in both cases. Resting lower oesophageal sphincter pressure (mean (SEM)) significantly and similarly decreased after both methods of dilatation (pneumatic dilator: before dilatation 37 (3) mm Hg, one year after dilatation 18 (3) mm Hg; metallic dilator: before dilatation 34 (2) mm Hg, one year after dilatation 17 (3) mm Hg; p < 0.05 for both). It is concluded that in the treatment of achalasia a single dilatation under endoscopic control with either pneumatic or metallic dilator yield comparable clinical and manometric results and similar complication rates. The use of one or other dilator should depend more on the preference and experience of the endoscopist than on the type of device.

beta Adrenoceptor blockade is known to accelerate transit through the small intestine without changing either the number or pattern of intestinal contractions. This study therefore tested the hypothesis that an increase in intraluminal aboral propulsive force may contribute to this transit acceleration. Twenty paired studies were performed, in 10 healthy volunteers, after oral administration of either 100 mg atenolol (a selective beta 1 antagonist) or matched dummy tablets according to a double blind, randomised protocol. The frequency of occurrence of, and the propulsive force exerted by, traction events related to intestinal contractions were measured, using a combined traction force detector and manometry assembly. After atenolol, a consistent increase in the force generated per traction event was noted, both for propagating contractions mean (SEM) (12.0 (1.8) g v control 5.9 (0.07) g; p < 0.05) and for stationary (11.6 (1.4) g v control 7.0 (0.7) g; p < 0.05). In contrast no change in the number of traction events was noted (control v atenolol = 1.6 (0.3) v 1.64 (0.4) per min for propagating and 0.7 (0.1) v 0.85 (0.16) per min for stationary contraction; p > 0.05). beta Adrenoceptor blockade thus increases the propulsive force generated by intestinal contractions, possibly by removing a sympathetic neural inhibition of intestinal tone.

The relative cost effectiveness of adjuvant urso and chenodeoxycholic acid treatment in extracorporeal shockwave lithotripsy (ESWL) has been assessed as part of a pragmatic randomised controlled trial of ESWL as a treatment of gall bladder stones. Of the first patients with gall stone volume < 4 cm3 randomised to ESWL in the main trial, 24 were randomised to have ESWL alone and 26 to have adjuvant bile acid treatment, one of whom died before the end of the 12 month follow up period. At 12 months after treatment, differences in gall stone clearance between ESWL alone (3/24 (13%) clear, 5 (21%) referred for surgery) and ESWL and bile acids (6/25 (24%) clear, 2 (8%) referred for surgery) were not significant (p = 0.36, log rank test). Patients in both groups had substantial and significant health gains (according to biliary pain frequency and severity, Nottingham Health Profile scores, visual analogue scale symptom scores, and complications) but there were no significant differences between the groups. Improvements in both groups usually occurred within a few weeks of treatment and were unrelated to gall stone clearance. Costs were greater in the bile salt group (95% confidence intervals for estimated cost difference: 90 pounds to 630 pounds). If the purpose of treatment is symptom relief rather than gall stone clearance then adjuvant bile salt treatment seems to be unnecessary.

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.

4-Aminosalicylic acid (4-ASA) has been suggested as an effective treatment for both active and quiescent ulcerative colitis. 5-Aminosalicylic acid (5-ASA) is well accepted for the maintenance treatment of inactive ulcerative colitis. Moreover, recent studies suggest that 5-ASA may also be effective in maintaining remission in Crohn's colitis. As treatment with 4-ASA may result in less side effects, the efficacy of a one year's maintenance treatment with oral 4-ASA (1.5 g/d, slow release tablets, n = 19) and oral 5-ASA (1.5 g/d, slow release tablets, n = 21) was compared in a double blind, randomised trial in patients with quiescent Crohn's ileocolitis. Patients with ileocolonic or colonic involvement were enrolled if in stable remission for more than two months but less than one year. Baseline demography and clinical severity were similar in both groups. Total colonoscopy and ileoscopy were performed at enrollment and at the end of the study. After one year seven of 19 patients receiving 4-ASA (36%) and 8 of 21 receiving 5-ASA (38%) had developed a clinical relapse, as defined by a rise in the Crohn's disease activity index (CDAI) of more than 100 points to values higher than 150. The relapse rates between the 4-ASA and the 5-ASA groups were not statistically different although no comparison with the spontaneous relapse rate in a placebo group could be made. Clinical relapse was accompanied by a statistically significant rise in serum concentrations of soluble interleukin 2 receptor and by an increased percentage of activated peripheral blood T cells. There were no statistical differences between the 4-ASA and the 5-ASA groups regarding the height of rise in CDAI or of soluble interleukin 2 receptor concentrations during relapse, thus showing a similar severity relapsed disease activity. In conclusion, 4-ASA maybe as effective as 5-ASA in the maintenance treatment of quiescent Crohn's disease and there were no differences in the severity of relapse between both treatment groups.

In a prospective randomised study, the effect of acupuncture on sham feeding stimulated gastric acid secretion was investigated. In eight healthy volunteers (five men, three women, mean (SEM) age 26.3 (4.7) years) various methods of acupuncture were performed. Apart from the sham procedure, the acupuncture was performed at the classic acupuncture points. Electroacupuncture reduced gastric acid secretion expressed as median (range) significantly during the first 30 minute period to 1.6 (0-5.2) mmol compared with 3.8 (2.3-14.5) mmol (p < 0.05) during control period (sham feeding without acupuncture). Inhibition of gastric acid secretion by electroacupuncture was also significant during the second 30 minute period (0.2 (0-5.6) v 3.6 (0.3-9.1) mmol; p < 0.05) and for peak acid output (0.8 (0.2-5.1) v 7.6 (3.4-12.1) mmol; p < 0.05). Transcutaneous electrical nerve stimulation also resulted in significant reduction of gastric acid secretion during the first 30 minute period (1.0 (0-3.6) mmol v 3.8 (2.3-14.5) mmol; p < 0.05), and peak acid output (3.6 (1.2-12.0) v 7.6 (3.4-12.1) mmol; p < 0.05). The classic needle acupuncture, laser acupuncture, and sham acupuncture had no significant effect on gastric acid secretion. This study shows firstly that in healthy volunteers, only the versions of acupuncture using more pronounced stimulation (electroacupuncture, transcutaneous electrical nerve stimulation), but not those with only mild stimulation of the nerves (classic needle acupuncture, laser acupuncture), and secondly only acupuncture performed at defined points lead to significant reduction in gastric acid secretion.

This study compared healing rates, relief of symptoms, frequency of adverse events, and proportion of patients in remission after one year follow up in 104 patients with active prepyloric ulcer during treatment with 40 mg omeprazole once daily or 2 g sucralfate twice daily, using a randomised double blind controlled trial. Healing rates after two, four, and six weeks were (omeprazole/sucralfate) 49%/23%; 83%/59%; 90%/70% respectively. After two weeks, omeprazole was more efficient than sucralfate in relief of daytime and nocturnal epigastric pain, nausea, and heartburn. The proportion of patients in remission after one year follow up was significantly higher in the omeprazole group (p < 0.01). Of the healed patients ulcers recurred in 36% in the omeprazole group and in 46% in the sucralfate group. It is concluded that the ulcer healing rate was higher and symptom relief was more pronounced in the omeprazole group compared with the sucralfate group, and that more patients were still in remission after a one year follow up period.

Elemental diets are considered an effective primary treatment for active Crohn's disease. This study examined the hypothesis that improvement occurs because of the presence of amino acids or the low fat content, or both. A randomised, controlled trial was undertaken in 40 patients with active Crohn's disease to evaluate clinical and nutritional outcomes after an amino acid based diet containing 3% fat was given by a feeding tube compared with a peptide based diet containing 33% fat. After three weeks' treatment, clinical remission occurred in 84% of patients who were given the amino acid diet and 75% of patients who received the peptide diet (p = 0.38). Plasma linoleic acid concentration was reduced after the amino acid but not the peptide diet. An increase in total body nitrogen was associated with the magnitude of nutritional depletion before treatment and at six months' follow up, only patients who showed gains in total body nitrogen after enteral nutrition had a sustained clinical remission. This study shows that peptide based high fat diets are as effective as amino acid low fat diets for achieving clinical remission in active Crohn's disease. Improved total body protein stores but not essential fatty acid depletion may be an important indicator of a sustained remission.

Short term sclerotherapy (by injection(s) around the bleeding point) is used for immediate control of massive haemorrhage from oesophagogastric varices. The usefulness of longterm sclerotherapy once short term sclerotherapy has been successfully carried out was assessed. Two treatment groups were studied: 50 patients were treated by 'combined' (short term followed by longterm) sclerotherapy; 56 patients were treated by short term sclerotherapy only. Patients included in the second group were treated by short term sclerotherapy only if a variceal rebleeding was present. The overall cumulative proportion of patients rebleeding was not significantly different in either group. Combined sclerotherapy patients, however, experienced less episodes of variceal haemorrhage and the source of haemorrhage was different (p < 0.002). Combined sclerotherapy was more efficient in preventing bleeding from oesophageal bleeding points but not those arising from a junctional source (p < 0.05). A greater incidence of oesophageal rebleeding was found in those patients whose first source of bleeding was oesophageal (p < 0.05). No significant difference was detected in survival expectancy between either group. In conclusion, after short term sclerotherapy is carried out successfully, those patients with bleeding from variceal bleeding points located on oesophageal mucosa should benefit most from a longterm sclerotherapy programme.

The effects of the 5-hydroxytryptamine (5-HT3) receptor antagonist, ICS 205-930 (tropisetron), on basal and 5-HT induced jejunal secretion of water and electrolytes were examined using a double blind, randomised crossover design. In seven healthy volunteers steady state perfusions of the proximal jejunum were performed twice with the Loc-I-Gut tube after 5+5 mg ICS 205-930 or placebo capsules were given. After equilibration for 60 minutes and completion of a 120 minute basal period 5-HT (10 micrograms/kg x min intravenously) was infused for 120 minutes. Net water absorption (mean (SEM)) in the basal period was 0.55 (0.84) ml/cm x h and 0.74 (0.72) ml/cm x h after placebo and ICS 205-930, respectively (p > 0.05). Infusion of 5-HT caused significant net secretion of water after placebo (2.05 (0.58) ml/cm x h; p < 0.02) as well as ICS 205-930 (2.60 (0.89) ml/cm x h; p < 0.05). As ICS 205-930 excerted no effects on either basal or 5-HT induced water and electrolyte transport in the intact human jejunum the compound is probably not efficacious as an anti-secretory drug in patients with 5-HT induced diarrhoea.

Epidermal growth factor (EGF), present in saliva and gastric juice, is a potent mitogen and an important element of mucosal defence. Changes in salivary and gastric juice epidermal growth factor in response to non-steroidal anti-inflammatory drug (NSAIDs) ingestion were measured to assess the role of EGF in gastric mucosal adaptation to NSAIDs. Patients with arthritis underwent endoscopy with collection of saliva and gastric juice for EGF measurement, before and two weeks after continuous NSAID ingestion. During this period patients also received either the prostaglandin analogue misoprostol or placebo in addition to their NSAID. In the misoprostol group (n = 5) there was no observed mucosal damage and no change in either salivary or gastric juice EGF. In the placebo group (n = 10) three patients developed erosions. Salivary EGF did not change (mean (SEM) 3.02 (0.54) ng/ml v 2.80 (0.41) ng/ml) but gastric juice EGF increased from 0.42 (0.12) ng/ml to 0.69 (0.14) ng/ml (p < 0.05). This increased EGF could contribute to the increased cellular proliferation observed during NSAID ingestion and may represent an important mechanism underlying gastric mucosal adaptation.

One hundred and seven consecutive patients presenting with significant peptic ulcer haemorrhage were randomised to endoscopic injection with 3-10 ml of 1:100,000 adrenaline (55 patients, group 1) or to a combination of adrenaline and 5% ethanolamine (52 patients, group 2). All had major stigmata of haemorrhage and endoscopic injection was undertaken by a single endoscopist. The groups were well matched with regard to risk factors. Rebleeding occurred in eight of the group 1 patients and seven in the group 2 patients; surgical operation rates, median blood transfusion requirements, and hospital stay were similar in both groups. The efficacy of either form of injection was similar whether patients presented with active bleeding or a non-bleeding visible vessel. No complications occurred. In patients presenting with significant peptic ulcer bleeding, the addition of a sclerosant confers no advantage over injection with adrenaline alone.

The aim of this study was to compare recurrence rates of reflux oesophagitis (after endoscopic healing with omeprazole) over a 12 month period of randomised, double blind, maintenance treatment with either daily omeprazole (20 mg every morning; n = 53), weekend omeprazole (20 mg on three consecutive days a week, n = 55) or daily ranitidine (150 mg twice daily, n = 51). Patients were assessed for relapse by endoscopy (with gastric biopsy) at six and 12 months, or in the event of symptomatic recurrence, and serum gastrin was monitored. At 12 months, the estimated proportions of patients in remission (actuarial life table method) were 89% when receiving daily omeprazole compared with 32% when receiving weekend omeprazole (difference 57%, p < 0.001, 95% confidence intervals: 42% to 71%) and 25% when receiving daily ranitidine (difference 64%, p < 0.001, 95% confidence intervals: 50% to 78%). Median gastrin concentrations increased slightly during the healing phase, but remained within the normal range and did not change during maintenance treatment. No significant pathological findings were noted, and no adverse events were attributable to the study treatments. In conclusion, for patients who respond favourably to acute treatment with omeprazole 20 mg every morning, the drug is a safe and highly effective maintenance treatment for preventing relapse of reflux oesophagitis and its associated symptoms over 12 months. By contrast, weekend omeprazole and daily ranitidine were ineffective.

This study examined the hypothesis that 5HT3 mechanisms mediate the postprandial gastrocolonic response in humans. Fasting and postprandial colonic tone and motility were studied in 12 healthy volunteers and the effects of a selective 5HT3 antagonist, ondansetron assessed in a double blind, randomised, placebo controlled fashion. A manometry barostat assembly was positioned in the transverse or descending colon to quantitate contractile activity fasting, after drug infusion and postprandially after a 1000 kcal meal. Fasting colonic tone and motility indices were similar in the placebo and ondansetron groups; ondansetron did not affect fasting motility. The placebo group showed a significant reduction in barostat balloon volume (signifying increased tone) from 232 ml (median, interquartile range (IQR) 179-261) during fasting to 181 ml (median, IQR 128-208) (postprandially) (p = 0.02). In contrast, the ondansetron group did not have a tonic colonic response (median 248 ml (IQR 199-300) fasting to median, 226 ml (IQR 185-290) postprandially) after the meal. Phasic volume events measured by the barostat increased postprandially in both groups. Postprandial motor activity measured by manometry increased significantly in the placebo group, but not in the ondansetron group. In conclusion, a 5HT3 mechanism participates in the physiological contractile responses in the human transverse and descending colon after ingestion of a high energy meal.