Whether the adrenergic pathways participate in the control of interdigestive pancreatic function in humans is uncertain. To determine if changes in alpha- or beta-adrenergic tone modulate interdigestive pancreatic enzyme output, 16 healthy subjects were intubated with an orojejunal tube to collect and quantify pancreatic trypsin secretion and record motility. After observation of a complete interdigestive cycle (control period), eight groups of two subjects each received 2-hour intravenous infusions of the alpha- and beta-agonist epinephrine (50 ng.kg-1.min-1), the alpha-antagonist phentolamine (5 mg/2 min followed by 500 micrograms/min), the beta-antagonist propranolol (5 mg/2 min followed by 80 micrograms/min), or saline as control, alone or in combination. Drugs were assigned in a random mode according to a 2(3) factorial design. Analysis of variance showed that epinephrine decreased trypsin output by 43% (P less than 0.05). By contrast, trypsin output was increased fourfold in the presence of phentolamine (P less than 0.01), whereas propranolol had no effect. These data suggest that an inhibitory alpha-adrenergic tone modulates human interdigestive pancreatic enzyme secretion whereas beta inputs are less important.

The effects of 12 weeks of omega-3 fatty acid supplementation on rectal mucosal proliferation were assessed with [3H]thymidine autoradiography in a double-blind, placebo-controlled study of 20 patients with sporadic adenomatous colorectal polyps. In the group of 10 that received fish oil containing eicosapentaenoic acid (4.1 g/day) and docosahexaenoic acid (3.6 g/day), the mean percentage of replicative "S"-phase cells in the upper part of colonic crypts (considered a reliable marker of colon cancer risk) significantly dropped from the baseline level after only 2 weeks of treatment and remained lower throughout the study period; no change in upper-crypt labeling was observed in the 10 placebo patients. Rectal mucosal eicosapentaenoic acid content increased in fish oil patients, whereas arachidonic acid levels decreased. The fish oil-induced kinetic changes represent contraction of the proliferative compartment to the levels of a low-risk population and may be related to omega-3 fatty acid effects on the arachidonic prostaglandin pathway. In this short-term trial, fish oil appeared to exert a rapid effect that may protect high-risk subjects from colon cancer.

This study was undertaken to investigate the role of increased renal thromboxane (TX) A2 production in modulating renal hemodynamics and sodium and water retention in cirrhotic patients with ascites. In a randomized, double-blind, placebo-controlled, crossover trial, 15 nonazotemic cirrhotic patients with ascites and elevated urinary TXB2 excretion received the thromboxane-receptor antagonist ONO-3708 (3 micrograms.kg-1.min-1) in a 4-hour continuous infusion. Administration of ONO-3708 significantly blocked TXA2 receptors; bleeding time showed a twofold increase (432 +/- 65 vs. 131 +/- 17 seconds; P less than 0.005), and platelet aggregation to U-46619 (an agonist of TXA2 receptors) was abolished in all patients studied. The drug induced a significant increase in free water clearance (3.06 +/- 0.70 vs. 1.72 +/- 0.57 mL/min; P less than 0.001) and diuresis (4.74 +/- 0.79 vs. 3.94 +/- 0.66 mL/min; P less than 0.05) compared with placebo, as well as a significant (14%) increase in renal plasma flow. The increases in both free water clearance and diuresis induced by ONO-3708 were directly related to basal urinary TXB2 excretion. These results suggest a role for renal TXA2 as a modulator of water handling in cirrhotic patients with ascites.

A randomized, placebo-controlled multicenter trial was conducted to evaluate the efficacy and safety of a delayed-release formulation of 5-aminosalicylic acid (5-ASA) (Asacol; Giuliani & Bracco, Milan, Italy) for prevention of clinical relapse in 125 patients with inactive Crohn's disease. Patients in remission [Crohn's Disease Activity Index (CDAI) less than 150] between 3 months and 2 years were randomly allocated to receive either 800 mg 5-ASA three times daily (n = 64) or placebo (n = 61) for up to 12 months or until relapse of symptoms. Relapse was defined by a CDAI greater than 150, with a minimum increase of 100 points over the baseline value. The cumulative relapse rates were 12% in the 5-ASA group and 22% in the placebo group at 3 months [95% confidence interval (CI) for the difference, -4 to 24]; 28% and 41%, respectively, at 6 months (95% CI, -4 to 30); and 34% and 55%, respectively, at 12 months (95% CI, 3-39; P = 0.02, log rank test). Significant decrease in the risk of relapse was found in patients with ileitis, in those with previous bowel resection and, in those with prolonged prestudy remission. Eight patients (5 on 5-ASA, 3 on placebo) withdrew from the study because of adverse reactions, but no major clinical or laboratory adverse effect was observed. It is concluded that oral 5-ASA coated with Eudragit S (Rohn Pharma GmbH, Wieterstadt, Germany), 2.4 g daily, is safe and seems superior to placebo in preventing or delaying clinical relapse in Crohn's disease, especially in milder cases and in ileal disease.

The results of three small clinical trials examining the effect of calcium carbonate supplementation on the proliferation cytokinetics of the rectal epithelium in subjects with a current history of sporadic adenoma are reported. In six subjects, a daily administration of 1500 mg of calcium carbonate for 90 days failed to significantly suppress thymidine labeling in normal-appearing mucosa of the rectum. However, a daily dose of 2000 mg of calcium significantly (P = 0.008) altered mucosal proliferation in a second set of six subjects after a 30-day trial. Finally, a placebo-controlled trial of calcium (2000 mg) was conducted in which 20 subjects were randomized to groups receiving a 4-week intervention with calcium (or placebo), followed by the alternative treatment (placebo or calcium). The results of the study show a marked suppression of rectal proliferation during the calcium phase of the study but not during the placebo phase. This study adds to accumulating evidence showing that calcium supplementation regulates the proliferative behavior of colonic epithelium in the individual at high risk for colon cancer. Longer term trials of calcium supplementation will ascertain whether a continuing benefit from increasing dietary calcium translates into inhibition of adenoma recurrence.

Short-chain fatty acid irrigation has been shown to ameliorate inflammation in diversion colitis. In this study the effect of butyrate enemas was tested in 10 patients with distal ulcerative colitis who had been unresponsive to or intolerant of standard therapy for 8 weeks. They were treated for 2 weeks with sodium butyrate (100 mmol/L) and 2 weeks with placebo in random order (single-blind trial). Before and after treatment, clinical symptoms were noted and the degree of inflammation was graded endoscopically and histologically. Rectal proliferation was assessed by autoradiography. After butyrate irrigation, stool frequency (n/day) decreased from 4.7 +/- 0.5 to 2.1 +/- 0.4 (P less than 0.01) and discharge of blood ceased in 9 of 10 patients. The endoscopic score fell from 6.5 +/- 0.4 to 3.8 +/- 0.8 (P less than 0.01). The histological degree of inflammation decreased from 2.4 +/- 0.3 to 1.5 +/- 0.3 (P less than 0.02). Overall crypt proliferation was unchanged, but the upper crypt-labeling index fell from 0.086 +/- 0.019 to 0.032 +/- 0.003 (P less than 0.03). On placebo, all of these parameters were unchanged. These data support the view that butyrate deficiency may play a role in the pathogenesis of distal ulcerative colitis and that butyrate irrigation ameliorates this condition.

In a randomized, controlled trial of recombinant interferon alfa-2b with or without prednisone priming in Chinese adults with chronic hepatitis B virus infection, stratified randomization for pretreatment serum alanine aminotransferase levels was done. Partial or complete antiviral responses were achieved in 17 (21.5%) of 79 treated patients and 3 (8.3%) of 36 controls (P = 0.14). The response to interferon treatment was significantly better in those who had elevated pretreatment transaminase levels and comparable to that reported in white patients [15 (38.5%) of 39 patients compared with 2 (5%) of 40 who had normal pretreatment transaminase levels (P = 0.0005)]. The spontaneous seroconversion rate was also higher among the controls with elevated transaminase levels [3 (18.8%) of 16 compared with 0 of 20 with normal transaminase levels], but this difference was not statistically significant (P = 0.16). Among the interferon-treated patients, prednisone priming appeared to have a marginal benefit over treatment with interferon alone in patients with elevated transaminase levels (43% vs. 33%), but not in those with normal transaminase levels (0% vs. 9.5%). It was confirmed that Chinese patients with normal transaminase levels respond very poorly to interferon alfa therapy. However, the response was significantly better in patients with elevated transaminase levels.

Colonic motor activity and plasma concentrations of cholecystokinin (CCK) both increase after oral intake of a meal. Thus, CCK had been thought to mediate the postprandial increase in colonic motor activity, which is termed gastrocolonic response. The present study used the substance loxiglumide, which acts as a specific antagonist at the CCK-A receptor, to evaluate this hypothesis. In the first set of experiments, eight healthy subjects were studied four times on separate days. A multilumen catheter was endoscopically placed with its tip lying in the descending colon. Motor activity was recorded by a low-compliance perfusion manometry system at six locations 60-45 cm from the anus. Basal activity was recorded for at least 2 hours to achieve steady-state conditions. The order of the following four experiments was randomized: (a) intravenous infusion of the CCK analogue cerulein at increasing doses (7.5, 15, 30, and 60 ng/kg.h, each given for 30 minutes); (b) intravenous cerulein plus 5 mg/kg.h loxiglumide; (c) a 1000-kcal solid/liquid meal consisting of regular German food; and (d) a meal plus 5 mg/kg.h loxiglumide. In the second set of experiments, eight patients with irritable bowel syndrome were studied twice on two separate days, and two experiments were performed n randomized order: (a) a 1000-kcal solid/liquid meal consisting of regular German food; or (b) a meal plus 5 mg/kg.h loxiglumide. The motor index was calculated as the area under contractions by a computerized system. The 1000-kcal meal markedly increased colonic motor activity. This gastrocolonic response was significantly greater in patients with irritable bowel syndrome than in healthy volunteers. Cerulein stimulated motor activity only at pharmacological doses (30-60 ng/kg.h), which resulted in plasma CCK levels markedly exceeding postprandial values. Loxiglumide abolished the effects of cerulein even at pharmacological doses. However, loxiglumide did not inhibit the gastrocolonic response to a regular meal either in healthy volunteers or in patients with irritable bowel syndrome. Loxiglumide also failed to alter the interdigestive colonic motor activity. Therefore, effects mediated by the CCK-A receptor do not play a major physiological role in the regulation of the interdigestive and postprandial motility of the left colon.

The aim of this study was to examine the effects of electrical acustimulation on gastric myoelectric activity and severity of symptoms of motion sickness. In experiment 1, 16 Chinese subjects received electrical acustimulation in one of two sessions. In experiment 2, 45 white and black American subjects were randomly divided into three groups: acustimulation, sham acustimulation, and control. Each subject sat in an optokinetic drum for 15 minutes baseline and 15 minutes of drum rotation. Subjects' electrogastrograms and subjective symptoms of motion sickness were obtained. In experiment 1, the mean symptom score and tachyarrhythmia during acustimulation sessions were significantly lower than during no-acustimulation sessions. In experiment 2, the mean symptom score of the acustimulation group was significantly lower than that of the sham-stimulation group and the control group; tachyarrhythmia in the acustimulation group was significantly less than that of the control group but not the sham-stimulation group. In conclusion, electrical acustimulation reduces the severity of symptoms of motion sickness and appears to decrease gastric tachyarrhythmia.

In patients treated with sclerotherapy, most rebleeding episodes are observed before variceal obliteration. This prospective randomized study aimed to assess if propranolol together with sclerotherapy could reduce the rebleeding rate before variceal obliteration. Seventy-five patients (59 male, 16 female; mean age, 54 +/- 15 years) with cirrhosis (from alcohol abuse in 91%) admitted with upper gastrointestinal bleeding, which was endoscopically proven to originate from ruptured esophageal varices, were included. After initial control of bleeding, the patients were randomized into the following two groups: group 1 treated with sclerotherapy alone (36 patients) and group 2 treated with sclerotherapy plus propranolol (39 patients). They were followed up to variceal obliteration. In group 2, 7 patients rebled as compared with 14 patients treated with sclerotherapy alone (P less than 0.005). When considering only rebleedings from esophageal varices, 4 patients rebled in group 2 vs. 10 in group 1 (P less than 0.10). The total number of rebleeding episodes was lower in group 2 than in group 1 whether considering all causes (8 vs. 17; P less than 0.07) or variceal rebleedings alone (4 vs. 13; P less than 0.01). Mean total blood requirement per patient was lower in group 2 than in group 1 (1.4 +/- 3.4 vs. 2.79 +/- 6.4 units of blood, respectively; P less than 0.01). Mortality was similar in both groups of patients (14% vs. 13% in groups 1 and 2, respectively, NS). It is concluded that patients treated with sclerotherapy should be given propranolol before variceal obliteration.

To determine the physiological role of circulating cholecystokinin (CCK), the effect of the CCK receptor antagonist MK-329 on upper digestive processes was investigated in six normal volunteers after a mixed meal. In a double-blind, two-period, randomized crossover design, the subjects received either 10 mg MK-329 or placebo orally 3 hours 15 minutes before the meal, which contained 51CrCl3 as food marker. A five-lumen tube with the tip in the distal duodenum allowed continuous marker infusion (57Co-B12) and duodenal aspiration as well as recordings of antral and duodenal motility patterns via three pressure sensors. Postprandially, MK-329 caused a significant reduction of 30%-60% (P less than 0.05) in pancreatic trypsin output during the initial three 15-minute periods; thereafter, the output was virtually the same than after placebo. Thus, the integrated enzyme response was only reduced by 15% (NS) during the 3-hour period beginning 15 minutes after the meal. In contrast, gallbladder contraction, determined by total bile acid excretion, was inhibited by 77% (P less than 0.05), indicating a crucial role of CCK in regulating gallbladder motility. Except for the initial 30 minutes postprandially, MK-329 also induced a significant reduction in duodenal pH with mean values ranging from 3.5 +/- 0.2 to 4.1 +/- 0.3 compared with 4.5 +/- 0.3 to 5.0 +/- 0.4 after placebo (P less than 0.05), probably because of lowered secretion of pancreatic bicarbonate. Gastric emptying rate was significantly accelerated by MK-329 during the initial 75 minutes after the meal, but the time for 50% emptying did not differ from placebo [127.5 +/- 7.7 vs. 140.0 +/- 9.0 minutes (NS)]. No changes were observed in the motility pattern of the proximal duodenum after feeding. Whereas MK-329 only caused a slight increase of the basal plasma CCK concentrations, the postprandial levels were markedly enhanced. Peak concentrations were 10.0 +/- 1.3 vs. 4.0 +/- 0.5 pmol/L after placebo (P less than 0.001), and the integrated response exceeded the control value by 175% (P less than 0.01). The results suggest that circulating CCK is not an essential mediator of the postprandial pancreatic enzyme secretion in humans, whereas it plays a critical role in gallbladder emptying.

Cholecystokinin (CCK) has been proposed to serve as a satiety signal in animals and humans. To further explore the role of CCK in humans, the effect on satiety and eating behavior of a specific CCK-receptor antagonist, loxiglumide, that preferentially inhibits peripheral (CCK-A) receptors was investigated. In a randomized, blind, four-period latin square design, 10 subjects received intravenous saline (placebo) or loxiglumide (10 mg/kg per hour) with concomitant intrajejunal perfusions of isotonic saline or fat (containing 50% corn oil and 3% albumin). Food intake and plasma CCK concentrations were assessed, and subjects scored their feelings of hunger and fullness in paired experiments. In placebo-treated subjects, the duration of the meal was shorter during fat perfusion (30 +/- 2 minutes vs. 35 +/- 2 minutes; P less than 0.01; mean +/- SEM). The amount of food intake was reduced (361 +/- 31 g vs. 454 +/- 35 g; P less than 0.05), and fluid ingestion was inhibited (490 +/- 31 mL vs. 625 +/- 38 mL; P less than 0.01). Loxiglumide did not affect any parameter and did not change the pattern of responses. In loxiglumide-treated subjects there was a 4-5-fold elevation in plasma CCK levels. These results confirm that jejunal infusion of lipid reduces the size of the meal and stimulates early satiety. The data imply that these effects are not mediated through peripheral endogenous CCK under these conditions.

A randomized clinical trial was conducted to determine whether colonoscopy is useful in deciding how long to maintain steroid treatment in attacks of Crohn's disease involving the colon. One hundred forty-seven patients with acute attacks of colonic or ileocolonic Crohn's disease were treated by oral prednisolone, 1 mg.kg-1.day-1; 136 achieved clinical remission, but 96 of them still had active endoscopic lesions and were randomized either to immediate start of steroid tapering (group A; n = 46) or to continued prednisolone treatment at the same dosage for 5 more weeks before steroid tapering was begun (group B; n = 50). In the remaining 40 patients (already in endoscopic remission, group C), steroid tapering was begun immediately. After prednisolone discontinuation, patients were followed up for 18 months or until clinical relapse. Prolongation of prednisolone therapy significantly improved the endoscopic scores in group B (30% of endoscopic remission). The frequency of successful steroid weaning was almost identical in groups A and B (82% and 80%, respectively), as was the actuarially calculated relapse clinical rate after steroid withdrawal (P = 0.22). No factor predictive of clinical relapse could be found. The clinical course of patients in group C was similar to that of those in groups A and B. Overall, only 22% of the 147 patients were still in clinical remission and off steroids 18 months after prednisolone discontinuation, outlining the need for maintenance therapy. In conclusion, for patients who have achieved clinical remission, adjustment of steroid treatment duration on the basis of endoscopy results is of no benefit, and the endoscopic aspect has no prognostic value; thus, it appears unnecessary to repeat colonoscopy in such patients before steroid tapering is begun.

Plasma-free choline levels have previously been found below normal in patients receiving long term parenteral nutrition (TPN). In a group of 15 patients receiving home TPN who had low plasma free choline levels (6.3 +/- 0.8 mmol/L), we found 50% had hepatic steatosis. These patients were given oral lecithin or placebo in a double-blind randomized trial for 6 weeks. Lecithin supplementation led to an increase in plasma free choline of 53.4% +/- 15.4% at 2 weeks (P = 0.04), which continued at 6 weeks. The placebo group had no change in plasma-free choline at 2 weeks, but a significant decrease of 25.4% +/- 7.1% (P = 0.01) at 6 weeks. A significant and progressive decrease in hepatic fat was indicated by increased liver-spleen CT Hounsfield units at 2 and 6 weeks (7.5 +/- 1.7 units, P = 0.02; 13.8 +/- 3.5 units, P = 0.03) in the lecithin supplemental group. Nonsignificant changes were seen in the placebo group. It was concluded that hepatic steatosis in many patients receiving long term TPN is caused by plasma-free choline deficiency and may be reversed with lecithin supplementation. Choline is a conditionally essential nutrient in this population.

The present study determined whether the rate of relapse of duodenal ulcer was reduced after ulcer healing with omeprazole compared with ranitidine or placebo. It was made up of a double-blind, randomized, controlled multiple-center trial set within the United States. Patients were candidates if their duodenal or pyloric channel ulcer successfully healed in one of two large multicenter U.S. trials; one compared omeprazole, 20 mg once daily, before breakfast with ranitidine, 150 mg twice daily, and the other compared the same dose of omeprazole with placebo. Two hundred forty (73.8%) of the 325 patients with complete ulcer healing within 4 weeks of starting therapy who were eligible to enter the follow-up study were enrolled. There was no intervention. Endoscopic assessment of ulcer status was performed at 2, 4, and 6 months and whenever patients had symptoms thought to represent return of an ulcer. The lifetable relapse rates for duodenal ulcer according to initial ulcer therapy with omeprazole, ranitidine, or placebo were 76.7% [95% confidence interval (CI), 64%-89.3%], 59.8% (95% CI, 47.8-71.7%), and 50.4% (95% CI, 15.7%-85.2%), respectively. These rates were not statistically significantly different. Seventeen percent of recurrent ulcers occurred at a site different from that of the original ulcer. It is concluded that despite the more rapid rate of duodenal ulcer healing with omeprazole therapy, the rate of ulcer relapse appears similar and independent of whether ulcer healing was accelerated with omeprazole or ranitidine.

Ursodeoxycholic acid (UDCA) dissolves cholesterol gallstones and improves liver function test results in patients with cholestatic liver diseases. Its absorption was studied in patients who had complete extrahepatic biliary obstruction caused by pancreatic carcinoma but no intestinal or liver disease. Six patients received 500 mg chenodeoxycholic acid (CDCA) or 250-2000 mg UDCA in capsules in single oral doses in random order, with an interval of 2 days between the different treatment regimens. In the control period the patients excreted into bile 382.3 +/- 108.0 mumol CDCA (mean +/- SD) and 1866.7 +/- 172.6 mumol cholic acid per 24 hours. After administration of 1273.6 mumol (500 mg) CDCA, biliary excretion of this bile acid increased to 1370.9 +/- 185.7 mumol/24 h, indicating an intestinal absorption rate of 77.6% +/- 9.8%. After oral administration of 636.8 mumol (250 mg), 1273.6 mumol (500 mg), 2547.2 mumol (1000 mg), and 5094.4 mumol (2000 mg) of UDCA, the respective absorption rates were 60.3% +/- 7.4%, 47.7% +/- 9.0%, 30.7% +/- 7.5%, and 20.8% +/- 3.9%, and whereas in the control period no UDCA was detected in the bile, the UDCA percentages measured were 14.6% +/- 8.2%, 19.6% +/- 9.1%, 23.1% +/- 11.3%, and 27.4% +/- 12.1%. The coadministration of CDCA did not enhance the absorption of UDCA. The data indicate that absorption of orally administered CDCA is almost complete, whereas UDCA absorption is incomplete. With increasing doses UDCA absorption decreases. To achieve absorption of adequate amounts of UDCA, high and/or multiple doses are needed.

The distal small intestine is an especially potent site for carbohydrate-triggered intestinal inhibition of gastric emptying of solids. Poorly digestible carbohydrates, such as lentils, may escape proximal absorption, travel over time to reach these inhibitory mechanisms, and slow the gastric emptying of a later meal. A slowing effect on gastric emptying may be associated with a lowering effect on postprandial glucose. The aims of this study were to determine (a) whether lentils (a poorly digestible carbohydrate) vs. bread (an easily digestible carbohydrate) eaten as a premeal (with equal amounts of carbohydrates) slow the gastric emptying of a second solid meal taken 4.0-4.5 hours later and (b) whether a slowing effect on the gastric emptying of the second meal is associated with a lower postprandial glucose response. We found that in 7 dogs and 10 humans, gastric emptying of the second meal was delayed after a lentil premeal compared with a bread premeal. However, there was no difference in the glucose response to the second meal under the two conditions.

Thirteen patients with alcoholic cirrhosis had splanchnic and systemic hemodynamics assessed before and after ingestion of a standard liquid meal of 700 kcal (consisting of isocaloric proteins, lipids, and carbohydrates). Half of the patients (n = 6) were randomized to a treatment group receiving intravenous infusion of propranolol in combination with the meal. No significant effects were observed on systemic hemodynamics after the meal alone. Heart rate (-14%; P less than 0.01) and cardiac index (-24%; P less than 0.01) decreased after meal in combination with propranolol. The mean hepatic venous pressure gradient increased significantly after ingestion of the meal alone with a maximal effect after 30 minutes (+13%; P less than 0.05) and returned to baseline values after 2 hours. Meal in combination with propranolol had no significant effect on the hepatic venous pressure gradient. Hepatic blood flow increased substantially after the meal alone with a maximal effect after 30 minutes (+28%; P less than 0.01), whereas no significant effect was observed after meal in combination with propranolol. Azygos blood flow increased significantly after the meal alone (+36%; P less than 0.05), whereas this effect was abolished in combination with propranolol. In conclusion, ingestion of a peroral mixed meal in cirrhotic patients has, contrary to what is observed in normal controls, no effects on systemic hemodynamics. Substantial changes in splanchnic hemodynamics were observed, and these effects were all abolished when the meal was administered in combination with propranolol.