To determine the influence of inflammation and topical treatment with 5-aminosalicylic acid or prednisolone on arachidonic acid metabolism in vivo, we carried out a double-blind controlled study on the release of prostaglandin E2 and leukotriene B4 to the rectal lumen in 24 consecutive patients with proven distally located ulcerative colitis. Before and at days 15 and 29 a dialysis bag was placed in the emptied rectum for 4 h prior to assessing clinical, endoscopic, and histologic disease activity. A single enema was given daily at bedtime (1 g 5-aminosalicylic acid or 25 mg prednisolone) until complete remission or for a maximum of 4 wk. Clinical and endoscopic remission was obtained in 16 (7 on 5-aminosalicylic acid) and 11 (3 on 5-aminosalicylic acid) patients, respectively. Luminal concentrations of prostaglandin E2 and leukotriene B4 were positively correlated to disease activity and significantly decreased among the prednisolone-treated patients. In both treatment groups a decrease toward normal levels occurred in patients responding to therapy. In retrospect, the pretreatment prostaglandin E2 and leukotriene B4 levels were significantly higher in patients not responding to therapy than in those improving during treatment. In conclusion, luminal prostaglandin E2 and leukotriene B4 levels may prove more useful predictors of the outcome of treatment in relapsing ulcerative colitis than clinical indices of disease activity.

A double-blind, randomized, controlled trial has been undertaken to evaluate treatment of chronic hepatitis type B with levamisole. Ten patients received levamisole (150 mg/day, 3 days/wk) and 10 received placebo until seroconversion to antibody to hepatitis B e antigen eventually occurred, or for a maximum of 18 mo. Final evaluation at 24 mo after starting treatment revealed that 60% of the patients in the levamisole group had become hepatitis B e antigen negative, 90% were hepatitis B virus-deoxyribonucleic acid negative in serum, and 8 of 9 (89%) patients had cleared hepatitis B core antigen from the liver. On the other hand, in the placebo group only 4 of the 10 subjects (40%) were hepatitis B e antigen and hepatitis B virus-deoxyribonucleic acid negative in serum and 3 of 8 (37.5%) of them became hepatitis B core antigen free in the liver. Moreover, in 8 patients of the treated group and in 4 of the control cases aminotransferase activities fell into the normal range. A liver biopsy specimen was obtained after treatment in 17 patients and 7 of 9 levamisole recipients showed marked improvement in hepatic histology, compared with 3 of 8 placebo recipients. These data show that patients treated with long-term levamisole therapy have a tendency toward normalization of aminotransferase activities and suppression of hepatitis B virus replication, suggesting that the drug may be of benefit in chronic hepatitis B e antigen-positive hepatitis.

Nonulcer dyspepsia remains a difficult disorder to treat because it is a heterogeneous syndrome. Once patients with the irritable bowel syndrome, esophagitis, and other organic diseases are excluded, there remain patients with dyspepsia of unknown cause (termed "essential dyspepsia") and patients with dyspepsia plus symptoms of gastroesophageal reflux without esophagitis. The aim of this study was to determine whether cimetidine or pirenzepine is efficacious in relieving the symptoms of these latter subgroups. Sixty-two consecutive patients were studied who had chronic upper abdominal pain or nausea where endoscopy had shown no evidence of peptic ulceration, esophagitis, or malignancy; 47 had essential dyspepsia, and 15 had dyspepsia plus gastroesophageal reflux. They were initially randomized to either cimetidine or placebo, or pirenzepine or placebo. Patients continued each medication for 1 mo, and, after a washout period, crossed over when again symptomatic; 51 patients completed cimetidine and placebo, and 50 completed pirenzepine and placebo. The results showed that cimetidine was superior to placebo in decreasing the number of upper abdominal pain episodes weekly and the severity of pain, but the absolute improvement was small. Pirenzepine was not superior to placebo in decreasing symptoms.

A randomized, double-blind, placebo-controlled trial was conducted to determine the efficacy of a low-dose aluminum-magnesium antacid regimen (Link one tablet q.i.d.) (total neutralizing capacity 120 mmol HCl/day) in combination with a high- or a low-fiber diet in ulcer healing and relief of symptoms in patients with benign gastric ulcer. After 6 wk, the ulcer healed in 28 (67%) of the 42 patients treated with antacids compared with 11 (25%) of the 44 patients treated with placebo (p less than 0.001). Antacids were also significantly more effective than placebo in the relief of symptoms. The dietary treatment did not significantly influence ulcer healing or ulcer symptoms. Constipation was more frequently seen with the low- than with the high-fiber diet (p less than 0.01). No significant side effects from antacids were recorded.

The effects of cisapride on jejunal interdigestive motor activity were studied in 12 healthy men participating in three experiments each. Five minutes after an activity front (phase III) they received, in random double-blind fashion, 10 mg of cisapride, 4 mg of cisapride, or saline placebo by intravenous injection. Motor activity was recorded for 4 h. A pneumohydraulic perfusion system and five catheters with orifices positioned 10-30 cm beyond the ligament of Treitz were used. Cisapride increased phase II-type activity (p less than 0.001) and reduced the number of activity fronts dose-dependently. Compared with phase II after placebo, the activity prevailing after cisapride was characterized by a significantly higher number and amplitude of contractions as well as by a significantly greater area under the pressure curve. Moreover, a significantly higher proportion of contractions was propagated aborally. Self-rated abdominal grumbling increased dose-dependently. Except for mild sedative effects, no side effects occurred. We conclude that cisapride induces a prolonged and highly propagative phase II-like jejunal motor activity in fasting humans.

The effect of cigarette smoking on gastric emptying, gastric secretion, and bile salt reflux was measured in 19 healthy habitual cigarette smokers (greater than or equal to 20 cigarettes per day) and 18 nonsmokers. They were studied both in the fasting state and after being fed a mixed liquid meal. Ten of the smokers were studied twice, when smoking and when not, in randomized order. Smokers had lower basal gastric secretion rates than nonsmokers irrespective of actually smoking or not. In smokers, bile salt reflux and postprandial gastric bile salt concentration were higher than in nonsmokers even when not actually smoking (p less than 0.01). Smoking during the experiment slowed gastric emptying, and increased bile salt reflux rate and gastric bile salt concentration (p less than 0.01). It is concluded that cigarette smoking has both chronic and acute effects on gastric function, and that bile salt reflux may contribute to the increased incidence, and lower healing rate, of gastric ulcers in smokers.

An unselected consecutive series of 826 patients admitted for acute upper gastrointestinal bleeding underwent urgent endoscopy. Peptic ulcers were found in 402 (49%). Of the 329 ulcer craters that could be fully examined, visible vessels were identified in 156 (47%), other stigmata of recent hemorrhage in 66, and no stigmata of recent hemorrhage in 107. One hundred twenty-nine patients with stigmata of recent hemorrhage (93 of whom had visible vessels) randomly allocated to no endoscopic treatment were observed for evidence of further bleeding. Fifty-four of the 93 patients (58%) with visible vessels rebled, compared with 2 of 36 (6%) with other stigmata of recent hemorrhage. No patient without stigmata of recent hemorrhage rebled. Twenty-seven patients in whom a visible vessel in a gastric ulcer was identified at endoscopy underwent urgent partial gastrectomy because of recurrent bleeding. The vessel identified at endoscopy was found in 26 of 27 resection specimens (96%). The arterial vessel wall protruded above the surface of the ulcer crater in 10 specimens, and clot in continuity with a breach in the vessel wall protruded in a further 10 specimens. Postoperative angiography, when technically possible, showed that the breached artery ran across the base of the ulcer in all of these specimens. Pathological changes were common in the bleeding artery and included arteritis in 24 of 29 (83%) eroded arteries found in these specimens, with aneurysmal dilatation in 14 of 27 (52%) bleeding points that could be fully examined. The ulcer had penetrated to serosa in 13 specimens (45%). The bleeding artery had a mean external diameter of 0.7 mm with a range of 0.1-1.8 mm. This study provides new information about the nature of the bleeding vessel in gastric ulcers, and some of this information is relevant in planning studies of endoscopic therapy for bleeding peptic ulcers. It validates the endoscopic identification of a visible vessel, and confirms that such identification has a high predictive value for the development of recurrent hemorrhage.

We performed a double-blind randomized study in 24 healthy volunteers, to evaluate the effects of two doses of lidamidine hydrochloride, loperamide, and placebo on transit of the small intestine and gastric emptying. Transit time of the small intestine was determined by measuring the rise in breath hydrogen excretion after ingestion of lactulose. Although there was a trend for prolonged intestinal transit time in both lidamidine groups, this difference was not significant compared with that in the placebo group. Loperamide significantly slowed transit when compared with placebo or lidamidine (p less than 0.001). Gastric emptying was assessed by using a solid-phase radiolabeled meal. Three parameters of gastric emptying were analyzed: half-emptying time, area under the gastric emptying curve, and beta. Although there was a trend for a longer half-emptying time in the group that received 12 mg of lidamidine, this difference approached, but did not reach, statistical significance (p = 0.06) compared with placebo. The area under the gastric emptying curve, a potentially more sensitive parameter for measuring gastric emptying, was significantly increased in the group receiving 12 and 18 mg of lidamidine (p less than 0.05) compared with the group receiving loperamide or placebo. In summary, lidamidine significantly delayed gastric emptying but had no significant effect on small bowel transit. These data suggest that the antidiarrheal properties of lidamidine are the result of enhanced absorption or inhibition of secretion of fluid and electrolytes.

The effect of ileal infusion of a lipid emulsion, containing 50% corn oil and 3% albumen, on food intake and satiety was measured in paired experiments carried out in 6 healthy volunteers. Subjects ate for shorter periods of time during ileal infusions of fat emulsion compared with control infusions of albumen and saline (25 +/- 1 vs. 32 +/- 3 min, mean +/- SEM) and consumed a smaller amount of food (670 +/- 23 g vs. 884 +/- 89 g) and energy (1016 +/- 79 kcal vs. 1591 +/- 228 kcal). The quantity of liquid drunk and the rates of eating and drinking were not significantly affected by the infusion of fat emulsion. In a further series of experiments carried out in 5 normal volunteers, ileal infusion of corn oil emulsions delayed gastric emptying compared with ileal infusion of albumen and saline (t1/2 = 203 +/- 48 vs. 68 +/- 12 min, p less than 0.02). The possibility that the observed reductions in food intake were related to the effect of absorbed fat was investigated in 6 healthy volunteers during intravenous infusion of either fat emulsion or isosmotic saline. Food intake was not affected by intravenous infusion of lipid. Our results suggest that lipid may interact with ileal receptors to induce early satiety and reduce the amount of food consumed. The earlier inhibition of food intake during lipid infusion is perhaps best explained by early gastric distention caused by delayed gastric emptying, though the data would not exclude the release of an ileal mechanism, which has a direct action on the satiety centers.

The effect of 12.5 mM magnesium chloride on sodium transport in the human ileum in vivo was investigated using segmental perfusion. Choline chloride was used as a control. During perfusion of a balanced electrolyte solution containing isotopes of sodium and chloride, magnesium reduced unidirectional flux of sodium in both directions across the ileum; magnesium had no statistically significant effect on net sodium absorption, on chloride fluxes, or on potential difference. When sodium-free test solutions were infused, magnesium (and calcium) reduced net sodium secretion compared with choline and potassium. These results suggest that magnesium (and calcium) reduce passive sodium movement across ileal mucosa.

A randomized double-blind study was carried out in patients with unresolving antibiotic-associated colitis due to Clostridium difficile, to compare the effect of bacitracin (80,000 U/day) with vancomycin (500 mg/day) on the resolution of symptoms, clearance of organism, and prevention of relapse. Forty-two patients with colitis, 9 of whom had a pseudomembrane, were randomized, 21 patients to each treatment group. The two groups were comparable in age, disease severity, and antibiotic exposure. For a 50% reduction in stool frequency the mean times (+/- SE) were 4.1 +/- 0.4 days for bacitracin and 4.2 +/- 0.4 days for vancomycin. Sixteen patients (76%) had symptom resolution after 7 days of treatment with bacitracin, compared with 18 patients (86%) given vancomycin. Patients who failed to respond were crossed over (blind) to the alternative antibiotic, but tended to be refractory to the alternative medication as well. Vancomycin-treated patients had negative toxin (83% vs. 53%, p = 0.04) and negative stool cultures (81% vs. 52%, p = 0.02) more frequently than did those patients given bacitracin. Similar numbers of patients in each group had symptomatic relapse during 1 mo of follow-up, but most of them relapsed yet again after blinded crossover therapy. Although bacitracin was significantly less effective than vancomycin in clearing C. difficile from the stools, both were of similar value in the control of symptoms in a group of patients with predominantly nonpseudomembranous colitis. In view of its low cost, bacitracin is a reasonable first-line alternative to vancomycin in the treatment of antibiotic-associated colitis.

Intractable epigastric pain associated with nausea and bilious vomiting often follows gastric surgery and has been attributed to reflux of bile and the irritating effects of endogenous bile acids on the gastric remnant. To test the effect of changing bile acid composition of the refluxed material on the symptoms and gastric mucosal histology, 12 patients with symptomatic alkaline reflux gastritis were treated for 1 mo with placebo and for 1 mo with ursodeoxycholic acid, 1000 mg/day. Before treatment, all patients were symptomatic and manifested epigastric pain, nausea, and bilious vomiting. The gastric mucosa was erythematous, friable, and bile stained, and the histology revealed chronic inflammation. No significant change in symptoms was noted during administration of placebo. In contrast, ursodeoxycholic acid treatment resulted in a profound decrease in the intensity and frequency of pain and almost abolished nausea and vomiting. During bile acid therapy the proportion of ursodeoxycholic acid in gastric bile rose to 50% of total bile acids, whereas cholic and deoxycholic acids decreased and chenodeoxycholic acid remained unchanged. The macroscopic and microscopic appearance of the gastric mucosa, however, did not change after 1 mo of ursodeoxycholic acid treatment. These results suggest that increasing the proportion of ursodeoxycholic acid in refluxed gastric bile reduces the pain and frequency of symptoms associated with bile reflux.

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

A randomized, controlled trial was conducted to investigate the ability of indomethacin and chloroquine to reduce intestinal secretion in 29 adult patients with severe cholera. All patients received intravenous infusion to restore fluid balance, but no antibiotics were given. Patients treated with oral indomethacin (total 200 mg) and chloroquine (total 1.5 g) did not have significantly different stool output than untreated controls during the five 8-h posttreatment periods (40 h).

The gastric emptying of six infant feedings (20 kcal/oz; whey to casein ratio, 60:40) with varying fat and carbohydrate composition was studied. Feedings contained either predominantly long-chain triglycerides (94%) or predominantly medium-chain triglycerides (94%) as the fat and lactose, glucose, or glucose polymers (Polycose) as the carbohydrate. Eleven premature infants were fed 22 ml/kg body wt of all six feedings over a 3-4-day period, and the volume of gastric contents was measured every 20 min using polyethylene glycol 4000 as the marker. Analysis of variance demonstrated that the use of medium-chain triglycerides resulted in faster gastric emptying than long-chain triglycerides (p less than 0.001). Analysis of variance and Tukey's test showed that use of glucose polymers instead of glucose resulted in less volume of gastric contents at 40 min (p less than 0.05). Use of glucose polymers instead of lactose resulted in less volume of gastric contents at 60 and 80 min (p less than 0.05). Gastric emptying can be altered by changes in nutrient composition. The difference between medium-chain and long-chain triglycerides was more pronounced than the differences between the carbohydrates studied. Feedings with medium-chain triglycerides may be more suitable than long-chain triglycerides in patients with delayed gastric emptying.

To examine the effect of proximal small intestinal stimulants of gastric acid secretion in cirrhotic patients with portacaval shunt, unshunted cirrhotics, and normal subjects, a mixture of L-amino acids was administered intraduodenally, into the proximal jejunum, or intravenously to 8 cirrhotic patients with portacaval shunt and to 8 unshunted subjects (4 cirrhotic and 4 healthy volunteers). In addition, the effect of intrajejunally administered hyperosmolar mannitol (850 mosmol/kg) and intrajejunal balloon distention (40 mmHg) was determined. In the shunted and unshunted groups gastric acid secretion significantly increased equally in response to intravenous and intraduodenal amino acid infusion, whereas amino acids administered intrajejunally did not significantly alter acid secretion. Perfusion of the jejunum with hyperosmolar mannitol resulted in significant stimulation of acid secretion in the shunted subjects, whereas in the unshunted subjects it caused significant inhibition. In addition, jejunal balloon distention significantly stimulated secretion in the shunted subjects, but not in the unshunted group. Serum gastrin did not change significantly during any of the experiments and plasma amino acids were not different after jejunal compared with duodenal perfusion. These studies indicate the following: Enteral and parenteral amino acids increase gastric acid secretion similarly in subjects with and without portacaval shunt. The intestinal phase of gastric acid secretion is initiated by intraduodenal, but not intrajejunal, amino acids. As plasma amino acid concentrations were similar regardless of the route used, this suggests that the intestinal phase of acid secretion cannot be fully explained by the postabsorptive stimulation by amino acids. Intrajejunal distention with a balloon or infusion of hyperosmolar mannitol into the proximal jejunum stimulates acid secretion only in subjects with portacaval shunt.

We examined motility of the ileocecal region, pressures at the ileocecal sphincter, and ileal flow after therapeutic doses of morphine and atropine. Using a factorial design in two cells of 8 (2(3] subjects, drugs were given during fasting and postcibally. Morphine (100 micrograms/kg body wt as a bolus intravenously) and atropine (7 micrograms/kg body wt as a bolus) stimulated migrating bursts of phasic activity (similar to phase III of the migrating motor complex). Morphine initially stimulated ileal flow, but atropine could not be shown to have this effect. Atropine reduced markedly the occurrence of sporadic pressure waves in the ileum, but morphine did not. Whereas atropine delayed mouth-to-ileum transit of polyethylene glycol, given in a mixed meal, morphine did not. Naloxone, in the dosage used (40 micrograms/kg body wt as a bolus, followed by 10 micrograms/kg body wt X h) had no independent effects on motility or flow, but did blunt the stimulatory effects of morphine and atropine on migrating motor complexes. We could not demonstrate an effect of any drug on the transit of lactulose from terminal ileum to cecum. Neither morphine nor atropine had impressive effects on tone at the ileocecal sphincter. These observations, while not specifying the mechanisms for constipation after opiates or anticholinergics, highlight the complexities of small bowel transit in humans and point out that the antidiarrheal effects of drugs are probably multifactorial.

Previous studies suggest that antacids are more effective than intravenous cimetidine in maintaining the gastric pH above 4.0 in acutely ill patients. We hypothesized that this was because blood levels of cimetidine are not sustained at therapeutic levels with the bolus doses. The purpose of this study was to compare gastric pH and serum cimetidine levels when cimetidine was administered as bolus versus infusion. We studied 23 acutely ill patients who received intravenous cimetidine given as boluses and primed infusions. The gastric pH could be maintained above 4.0 with infusions of up to 50 mg/h (1200 mg/day) in 20 patients, compared with only 5 patients with bolus administrations of up to 300 mg every 6 h (1200 mg/day). The differences in ability to maintain the gastric pH above 4.0 were entirely due to the reduced ability of bolus infusion to maintain an adequate serum level. Neither technique could maintain the pH above 4.0 in 3 patients, all of whom had received cimetidine recently. A gastric pH greater than 4.0 correlated directly with a therapeutic serum cimetidine level. We conclude that infusions of cimetidine are better able to sustain therapeutic blood levels and, therefore, are superior to bolus cimetidine in maintaining gastric pH above 4.0. Some patients, however, may not respond to cimetidine even if therapeutic levels are achieved and may require supplemental antacids.