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.

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.

Nifedipine, a calcium channel blocker, inhibits lower esophageal sphincter pressure but has only minimal effect on esophageal contractions. We investigated the effects of nifedipine on esophageal contractions in 5 healthy volunteers and 10 patients with the nutcracker esophagus. Nifedipine (10, 20, 30 mg) or placebo was ingested as capsules in a double-blind design on 4 separate days. In volunteers, mean distal amplitude decreased 16.6%, 38.4%, and 49.0% as the nifedipine dose was increased. These changes were significantly (p less than 0.05) different from the placebo response and were sustained with higher doses. Patients with the nutcracker esophagus had a similar response, decreasing mean distal amplitude significantly (p less than 0.05) by 16.3%, 36.2%, and 54.2%. In both groups, nifedipine also had a significant (p less than 0.05) dose-dependent depressant effect on distal duration, although to a lesser degree than on amplitude. The percent decrease in distal amplitude showed good correlation (p less than 0.01) with plasma nifedipine concentrations at 60 min. These studies suggest nifedipine may be useful in the treatment of motility disorders of the esophageal body.

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.

This study was designed to compare the effects of enprostil, a synthetic dehydro-prostaglandin E2, on 24-h intragastric pH and serum gastrin profile in patients with duodenal ulcer disease. The dosing regimen included 3 enprostil groups: 35 microgram h.s. (at bedtime), 70 micrograms h.s., and 35 micrograms b.i.d., compared with cimetidine 600 mg b.i.d., and with placebo. Ten patients with inactive duodenal ulcer disease were randomly assigned to all five treatment regimens for 1 wk each according to a Latin Square design. There was a 1-wk washout period between each treatment. Intragastric pH and serum gastrin measurements were carried out on the last day of each treatment week. In placebo-treated patients, intragastric pH rose after each meal and fluctuated between 1.5 and 3.5. Enprostil 35 micrograms b.i.d. and cimetidine elevated pH after breakfast and during the night (p less than 0.05). The single nighttime dose of enprostil had a marked effect on pH only when given in the dose of 70 micrograms and this effect lasted over 13.5 h. The pH values during the night were similar in the groups treated with enprostil 35 micrograms b.i.d. and 70 micrograms h.s. During the daytime, the readings at or above pH 4 were placebo, 5%; cimetidine, 21%; enprostil 35 micrograms b.i.d., 34%. During the nighttime, the readings greater than or equal to 4 were placebo, 12%; cimetidine, 29%; enprostil 35 micrograms b.i.d., 39%; 35 micrograms h.s., 19%, and 70 micrograms h.s., 38%. The postprandial rise in serum gastrin was greatly enhanced by cimetidine, but the change after breakfast was dramatically blunted by enprostil 35 micrograms b.i.d. Gastrin concentration was increased with cimetidine during the night but there was no difference in gastrin concentration overnight between all regimens of enprostil and placebo. This study suggests that (a) enprostil 35 micrograms b.i.d. is as effective as cimetidine 600 mg b.i.d. in suppressing postprandial and nocturnal intragastric acidity; (b) enprostil 35 micrograms b.i.d. and 70 micrograms at night are similarly potent in suppressing nocturnal acidity; and (c) in addition to its cytoprotective effect, enprostil has potent antisecretory and antigastrin properties.