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.

Histomorphometric, electron microscopic, and cell kinetic studies of gastric mucosa were performed in 12 healthy men treated with 100 micrograms of 15(R)-15-methyl prostaglandin E2 (PGE2) orally q.i.d. for 2 mo followed by 2 mo of placebo. Results were compared with 13 control subjects receiving placebo for 4 mo. After PGE2 administration, total antral mucosal thickness and antral and corpus foveolar thicknesses increased 36%, 44%, and 51%, respectively, over baseline values. The total number and height of the foveolar cells also increased. These morphologic changes reversed completely within 2 mo of stopping PGE2 therapy. After PGE2 administration, no evidence of mucosal inflammation or atypia was observed, nor was there any evidence of ultrastructural changes in the overall appearance of the parietal and gastrin cells. The increased thickness of the gastric mucosa could not be explained by alteration of the proliferative activity, as the labeling index and localization of the proliferative compartment remained unchanged after PGE2 therapy. Presumably PGE2 retards senescence and exfoliation of epithelial cells, which explains the foveolar expansion in the presence of unaltered proliferation.

Synthesis of prostaglandin E2 and 6-keto prostaglandin F1 alpha by cultured antral and fundic gastric mucosa obtained from 86 patients with active duodenal ulcer who were not receiving medication was 50% lower (p less than 0.01) than their respective synthesis by cultured gastric mucosa in normal subjects. Antral and fundic prostanoid synthesis in patients receiving chronic therapy with nonsteroidal antiinflammatory drugs was almost completely inhibited. The decreased synthesis of antral and fundic prostaglandin E2 and 6-keto prostaglandin F1 alpha in duodenal ulcer patients was not affected following ulcer healing achieved after 4 wk of therapy with placebo, arbacet, misoprostol, sucralfate, and pirenzepine. In contrast, following 4 wk of therapy with ranitidine, both antral and fundic prostaglandin E2 synthesis were significantly increased when compared with their respective synthesis before therapy. These results confirm that gastric prostanoid synthesis is decreased in patients with active duodenal ulcer and in subjects treated with nonsteroidal antiinflammatory drugs, suggesting that decreased endogenous prostanoid synthesis may contribute to the pathogenesis of mucosal damage. The induction of endogenous prostanoids by ranitidine may contribute to its therapeutic effect.

One hundred sixty patients intolerant of or allergic to sulfasalazine (Salazopyrin, Azulfidine) participated in an open tolerance study of azodisal sodium (Dipentum). More than 4 of every 5 patients tolerated azodisal sodium well, but 12.5% of patients stopped medication because of diarrhea. Even after 7 patients who had also experienced diarrhea when taking sulfasalazine were excluded, there still remained a group of patients (9.8%) who had to discontinue azodisal sodium because of diarrhea. Apart from this, only minor side effects occurred. No serious drug-related changes were seen in hematologic or biochemical parameters. Male fertility appeared to be unaffected. One hundred two patients, who were in clinical and sigmoidoscopic remission, took part in a double-blind, placebo-controlled maintenance trial. Of these, 23.1% of the patients treated with azodisal sodium and 44.9% of the patients treated with placebo had a clinical and sigmoidoscopic relapse during a 6-mo trial period (p = 0.02). Azodisal sodium appears to be an effective agent for the maintenance treatment of ulcerative colitis.

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.

Primary sclerosing cholangitis is a chronic cholestatic liver disease that is commonly associated with chronic ulcerative colitis. We observed the development of varices in the abdominal wall surrounding the ileostomy stoma of patients with primary sclerosing cholangitis who underwent proctocolectomy and ileostomy for chronic ulcerative colitis. In 10 of 19 patients, the development of peristomal varices was documented 12-133 mo after operation. Risk factors for the development of peristomal varices included splenomegaly, esophageal varices, advanced histologic stage at liver biopsy, low serum albumin, thrombocytopenia, and an increased prothrombin time. Recurrent bleeding from peristomal varices was a major problem; 7 of 10 patients required repeated blood transfusions. The only therapy of long-term benefit was surgical decompression of the portal venous system in 1 patient and liver transplantation in a second patient. In contrast, there was no perirectal bleeding in 4 patients with primary sclerosing cholangitis who underwent proctocolectomy with an ileoanal anastomosis.

Effects of opiates on intestinal motor activity and transport of water and electrolytes have been studied separately in previous investigations. The aim of these experiments was to evaluate simultaneously the effects of a synthetic opiate, loperamide, on motor activity and transport in the human intestine. Jejunal, ileal, and colonic perfusions were performed in 9 healthy volunteers. After application of loperamide (12 mg), cyclically recurring migrating motor complexes in the small intestine occurred at a significantly higher frequency than after application of placebo. This was primarily due to a decrease in the duration of irregular motor activity (phase II). Loperamide increased the transit time in the jejunum but not in the ileum or in the colon. Transport rates of water and electrolytes and transmural electrical potential differences were not significantly affected by the drug. These results suggest that opiates exert their constipating effect by inhibiting phase II-related irregular motor activity.

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.

Gastric test meals of Polycose, with volumes of 300, 400, and 600 ml and energy densities of 0.5, 0.7, 1.0, 1.3, 1.5, and 2.0 kcal/ml, were given to 21 men and recovered after 30, 60, or 120 min. Polycose, a polymer of glucose, was chosen as a soluble homolog of food. The results of 1134 Polycose meals were analyzed in terms of the rates of energy delivery to the duodenum. The rates of emptying in the initial 30 min were significantly greater than in either the 30-60- or 60-120-min periods. Increases in either energy density or meal volume increased the rate of energy delivery in all time periods (p less than 0.001). The steady rate of energy delivery, which was evident after the initial 30 min, was correlated with increases in the initial meal volume and energy density, such that doubling the volume of meals from 300 to 600 ml increased the rate of emptying by a mean of 0.72 kcal/min, whereas doubling the energy density of the meals from 0.7 to 1.3 kcal/ml raised the rate of emptying by 0.62 kcal/min, with an overall mean rate of caloric emptying of 2.5 kcal/min. Thus, increases in either the initial volumes or the energy densities of the test meals significantly increased the rate of acceptance of energy by the duodenum.

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.

Clonidine, an alpha 2-adrenergic agonist, has been reported to stimulate the rate of electrolyte absorption in vitro, to alter intestinal motility in vivo, and to have antidiarrheal effects in animals. Experiments were performed in 8 healthy volunteers in order to evaluate the antidiarrheal effect of clonidine in humans. When diarrhea was induced by intragastric infusion of 2700 ml of balanced electrolyte solution over 90 min, oral administration of 0.3 mg of clonidine reduced the volume of rectal effluent by 48% (from 1233 +/- 62 to 640 +/- 77 ml, p less than 0.001), a clear-cut antidiarrheal effect. Clonidine increased total gut volume significantly (from 987 +/- 91 to 1830 +/- 142 ml, p less than 0.001), suggesting that clonidine exerted its antidiarrheal effect by altering gut motility, i.e., increasing the capacity of the gut and slowing the transit of fluid through the intestine. In other experiments, the net absorption rate of the whole gut during steady state total gut perfusion was measured. The rate of absorption of fluid was transiently stimulated by clonidine by 15% (from 696 +/- 77 to 799 +/- 55 ml/h, p less than 0.02), indicating an additional effect on mucosal cell function. These studies indicate that in this experimental diarrhea model, clonidine has antidiarrheal properties that are due largely to effects on motility of the gut but that clonidine also modestly stimulates the net rate of absorption by intestinal mucosa.

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.

In 1971 interest in the role of prostaglandins in the gastrointestinal tract was stimulated by the publication of two hypotheses--that aspirin damaged the gastric mucosa by inhibiting prostaglandin synthesis (1) and that cholera toxin caused diarrhea by stimulating it (2). Subsequent research into the gastrointestinal actions of prostaglandins has been considerable and now impinges on clinical practice. This paper reviews the involvement of prostaglandins and related compounds in mucosal protection, in ulcer healing, in diarrhea, and in gastrointestinal inflammation, with particular reference to the growing body of human data.

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.