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.

Propranolol, a nonselective beta-adrenergic blocker, has been shown to reduce portal pressure and the risk fo variceal bleeding. The portal pressure-reducing effect of propranolol is mediated by splanchnic arterial constriction, which decreases portal flow. A double-blind randomized control study (crossover on 2 consecutive days) was designed to compare the effects of propranolol vs. placebo on portal flow in cirrhotic patients during fasting and after a standardized meal. Portal flow was measured with an ATL Ultramark 8 echo-Doppler system (Advanced Technological Laboratories, Bothel, WA) in 23 cirrhotic patients. Fasting portal flow and heart rate were obtained at baseline and 2 hours after the administration of propranolol or placebo. A standard test meal was then given, and measurements were repeated 30 minutes later. Thirteen patients (group 1) received placebo on day 1 and propranolol on day 2, whereas 10 patients (group 2) received propranolol on day 1 and placebo on day 2. In group 1 patients, heart rate declined by 20% (P less than 0.0001) and portal flow decreased by 12% (P less than 0.05) after propranolol administration. Similar reductions were found in heart rate (-21%, P less than 0.0001) and portal flow (-17%, P less than 0.001) for group 2 patients. For all 23 patients, 2 hours after propranolol administration, heart rate declined by 21% (P less than 0.0001) and portal blood flow was reduced by 14% (P less than 0.0001). The 10 patients who received propranolol on day 1 (group 2) showed a carryover effect of propranolol on day 2. On day 2, baseline portal flow and heart rate values were significantly lower than baseline values on day 1. This long-lasting effect of a single dose of propranolol may be caused by the longer half-life of propranolol in cirrhotic patients. The postprandial portal blood flow percentage increase after the meal was similar for both placebo and propranolol. Propranolol did not blunt postprandial hyperemia. However, whereas the absolute value of blood flow after the meal increased significantly in comparison with baseline in placebo-treated patients (P less than 0.001), this did not occur with propranolol. Furthermore, in propranolol-treated patients the absolute value of blood flow after the meal was lower than in placebo-treated patients. This may constitute a protective effect of propranolol in portal hypertension.

The aim of the present study was to investigate pain sensations experienced during extracorporeal shock-wave application, comparing an electrohydraulic (MPL 9000; Dornier Medizintechnik, Germering, Germany), an electromagnetic (Lithostar Plus; Siemens, Erlangen, Germany), and a piezoelectric (Piezolith 2300; Wolf, Knittlingen, Germany) shock-wave system. In nine healty volunteers, three therapeutically used intensities were applied in a randomized order with each lithotripter (MPL 9000: 16, 20, and 24 kV; Lithostar Plus: settings 5, 7, and 9; and Piezolith 2300: settings 2, 3, and 4). The subjects received nine series of 20 shock waves amounting to a total of 180 shock waves per session. The treatment was performed under clinical conditions, and no premedication was given. A visual analog scale and the McGill Pain Questionnaire were used for assessment of pain. In addition, somatosensory evoked potentials caused by shock-wave stimulation were recorded. Some of the volunteers were unable to bear the pain caused by the highest shock-wave intensity of the electrohydraulic (n = 3) and the electromagnetic system (n = 4). Estimates using the visual analogue scale showed increased pain sensations with increasing energy settings for each lithotripter. The amplitudes of the somatosensory evoked potentials became larger, and latencies shortened with increasing stimulus intensities (P less than 0.05). Subjective estimates by means of the visual analogue scale (P less than 0.01) as well as the McGill Pain Questionnaire (NS) and the somatosensory evoked potentials (P less than 0.05) showed that stimulation by the piezoelectric lithotripter was less painful than stimulation by the two other generators.

Forty patients with active ulcerative colitis were randomly assigned to receive either 4 g of oral enterically coated 4-aminosalicylic acid (para-aminosalicylic acid) or placebo. The duration of treatment was 12 weeks. Disease activity was assessed by grading clinical symptoms of blood, mucus, urgency, sigmoidoscopic findings, and degree of histological inflammation in rectal biopsy specimens. At 12 weeks, 11 of 20 patients (55%) who received 4-aminosalicylic acid showed improvement in clinical and sigmoidoscopic variables. In contrast, only 1 of 20 patients (5%) who had received placebo showed improvement (P less than 0.005). Eighteen of the 19 patients in the placebo group who showed no improvement were treated subsequently with open-label 4-aminosalicylic acid. Of the 18, 11 showed clinical and sigmoidoscopic improvement. Patients allergic or intolerant to sulfasalazine with extensive disease were more likely to respond to 4-aminosalicylic acid.

The effects of immediate vs. delayed refeeding and the prognostic value of endoscopic findings in patients with major upper gastrointestinal hemorrhage were assessed in a prospective randomized study. Entry criteria were clinical evidence of major hemorrhage and endoscopic evidence of a Mallory-Weiss tear or an ulcer with a clean base, flat spot, or clot. Two hundred fifty-eight patients were randomly assigned to groups receiving a regular diet immediately or nothing by mouth for 36 hours, then clear liquids for 12 hours, and a regular diet thereafter. Outcomes in the immediate and delayed refeeding groups were comparable: rebleeding occurred in 4% vs. 5%; urgent intervention, 2% vs. 2%; and deaths, 1% vs. 1%, respectively. Rebleeding occurred in 2 (2%) of 96 patients with cleanbased ulcers, 5 (8%) of 65 with ulcers with spots, 3 (14%) of 21 with ulcers with clots (P = 0.05, 3 x 2 chi2 test), and 1 (2%) of 66 with Mallory-Weiss tears. It is concluded that the time of refeeding does not influence the hospital course of patients with a low risk of recurrent bleeding. Patients with clean-based ulcers or nonbleeding Mallory-Weiss tears may be refed and discharged home immediately after stabilization.

This prospective study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease. The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support. Patients were randomly assigned a regular diet without or with tube-fed supplementation, delivering 1.5 g/kg protein and 167 kJ/kg daily. Comparisons of encephalopathy, antipyrine clearance, metabolic rate, and biochemical parameters were performed weekly for 4 weeks. Sixteen patients receiving enteral supplementation had antipyrine half-life (50% vs. 3% reduction), serum bilirubin (25% vs. 0% reduction), and median encephalopathy scores that improved more rapidly than those of controls. Initially, 15 controls did not consume adequate calories to meet measured resting energy expenditure. Aggressive nutritional intervention accelerated improvement in alcoholic liver disease. Adverse effects did not offset the demonstrated benefits of a 2-cal/mL, casein-based tube-fed supplement. These findings support the use of standard, casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies.

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of heartburn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. Both omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.6% in the 40-mg omeprazole group, and 37.2% in the placebo group (P less than or equal to 0.05). Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P less than or equal to 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier in the 40-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was well tolerated in this group of patients. No unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-60 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

To assess the effect of cisapride on gastrointestinal motility and gastric emptying in children with chronic intestinal pseudoobstruction, 20 children (mean age, 4.9 years; 14 female and 6 male) who required special means of alimentation or who had severe symptoms confirmed by diary during 2 weeks before the study were studied. A motility catheter with recording sites in the antrum and duodenum was placed on the first day of the study and remained in place until the end of the 5-day study. Cisapride (0.3 mg/kg PO t.i.d.) or placebo was given in double-blind randomized crossover fashion, with a 2-day "washout" interval. Antroduodenal motility was recorded on days 2 and 5. Recording consisted of 4 hours of fasting and 2 hours after a complex liquid meal labeled with 99mTc. Gastric emptying was assessed for 1 hour after the meal. Based on manometry, 16 patients had neuropathic and 4 patients had myopathic disorders. Cisapride had no effect on the discrete, qualitative abnormalities found in individual records. Cisapride increased the postprandial duodenal motility index from 1180 +/- 256 mm Hg/30 min after placebo to 2385 +/- 430 mm Hg/30 min (P less than 0.05) but had no significant effect on the antral motility index. Cisapride did not alter the profound delay in gastric emptying; time to reach 50% of initial activity (T1/2) was 105 +/- 20 vs. 93 +/- 19 minutes and percentage of retention after 60 minutes (R60) 56% +/- 4% vs. 58% +/- 4% in control vs. cisapride, respectively. In summary, in children with chronic intestinal pseudoobstruction, cisapride increased postprandial duodenal motility but did not improve gastric emptying.

The relationship between histological maturity of healed duodenal ulcers and ulcer recurrence after 6 weeks of treatment with colloidal bismuth subcitrate or cimetidine was investigated. There was no significant difference in healing rates between colloidal bismuth subcitrate- and cimetidine-treated patients (85.7% and 71.8%, respectively; P greater than 0.05). Histologically, the regenerating mucosa of healed ulcers was divided into three categories--good, fair, and poor--according to pattern. Sixty percent of healed colloidal bismuth subcitrate-treated and 30.9% of healed cimetidine-treated ulcers had a good pattern; the difference was statistically significant (P = 0.027). The difference in recurrence rates between healed colloidal bismuth subcitrate-treated and healed cimetidine-treated patients was statistically significant at 3 months (3.45% and 20%, respectively; P = 0.044). All recurrent ulcers in both groups had fair or poor patterns of regenerating mucosa. It was concluded that the greater histological maturity of the regenerating mucosa may contribute to the lower recurrence rate in colloidal bismuth subcitrate-treated patients than in cimetidine-treated patients.

Repeated dosing with an H2-receptor antagonist results in a modest decrease in antisecretory potency termed "tolerance." The object of this prospective study was to determine whether tolerance is a progressive phenomenon or whether it levels off during prolonged dosing with a standard maintenance dose of an H2-antagonist. The effect of continuous dosing with ranitidine, 150 mg nightly, was compared with intermittent dosing (27 days of placebo each month) with active ranitidine, 150 mg nightly, only on the night of each experiment. Simultaneous 24-hour intragastric acidity and plasma gastrin concentration were measured monthly for 5 months in 17 healthy subjects (7 continuous and 10 intermittent dosing). In the intermittent-dosing group, the antisecretory response to ranitidine, 150 mg nightly, was preserved throughout the 141-day trial period; the median nocturnal integrated acidity decreased from 557 mmol.h/L (day 0) to 38 mmol.h/L on day 1 of dosing, and it ranged between 32 and 55 (median, 45) mmol.h/L during days 29-141. In the continuous-dosing group, there was a significant return of nocturnal intragastric acidity on days 29 and 85 compared with day 1 of dosing. The median nocturnal integrated acidity decreased in the continuous-dosing group from 554 mmol.h/L (day 0) to 87 mmol.h/L on the first day of dosing, and it ranged between 145 and 287 (median, 170) mmol.h/L during days 29-141. Either intermittent or continuous dosing with ranitidine was associated with an elevation of plasma gastrin concentration, which remained constant throughout the 5-month study. Tolerance does develop in healthy subjects during the first month of dosing with ranitidine, 150 mg nightly, but it is not a progressive phenomenon, and it is probably not of clinical relevance.

This study was performed to investigate the possible influence of repeated omeprazole dosing on the metabolism of caffeine, which has been shown to reflect the activity of one specific enzyme within the hepatic cytochrome P450 family, P450IA2. Ten healthy, nonsmoking young men participated in this placebo-controlled double-blind trial. Each subject was given omeprazole, 20 mg, every morning for 1 week and placebo every morning for 1 week in random order and separated by a 2-3 week washout period. On the sixth and seventh days of each period urine was collected twice daily, and urinary metabolites of caffeine were determined by high-performance liquid chromatography. The urinary metabolite ratio of three paraxanthine 7-demethylation products relative to a paraxanthine-hydroxylation product corresponds to caffeine clearance and, therefore, to P450IA2 activity. This calculated ratio was 4.8 (95% confidence interval, 3.9-5.6) in the placebo and 4.6 (95% confidence interval, 3.6-5.5) in the omeprazole period. These results show that the metabolism of caffeine was unaltered following omeprazole treatment, indicating that omeprazole treatment has no influence on cytochrome P450IA2 activity in the clinical situation.

Controlled trials of sclerotherapy for the prevention of the first variceal hemorrhage in cirrhotics have given conflicting results. In the present study, 106 cirrhotics were randomized to sclerotherapy (55 patients) or control group (51 patients). Admission criteria were no history of previous variceal bleeding and the presence of high-risk varices, i.e., a variceal score less than or equal to 0 according to Beppu et al. Sclerotherapy sessions were performed at time zero, 7 days, 30 days, and then monthly until eradication. Follow-up endoscopies were performed at 6-month intervals thereafter. Control patients underwent repeat endoscopy at 6-month intervals. Bleeding episodes were treated by sclerotherapy in both groups, whenever possible. Mean follow-up was 24 months. Analysis of the results was performed by the intention-to-treat method. Variceal bleeding occurred in 19 sclerotherapy patients (34.5%) and in 17 controls (35.4%, P = NS). Overall mortality was 34.5% in sclerotherapy patients and 50% in controls (P = NS). Seven of the 19 sclerotherapy patients (36.8%) and 11 of the 17 controls (64.7%) who bled died of hemorrhage (P less than 0.05, log-linear model). It is concluded that prophylactic sclerotherapy does not reduce the incidence of first variceal bleeding in cirrhotics. However, there seems to be a trend toward a lower bleeding-related mortality in sclerotherapy patients than in controls.

The role of bacteria in the bioavailability of protein-bound vitamin B12 was examined in eight elderly subjects who had atrophic gastritis and in eight normal controls. On separate days and in random order, vitamin B12 absorption tests were performed using either radiolabeled crystalline or protein-bound vitamin B12. At the same time, bacterial samples were collected from the upper gastrointestinal tract. The tests and gastrointestinal aspirates were performed before and during tetracycline therapy. Crystalline vitamin B12 was absorbed to the same extent in the two study groups. Atrophic gastritis subjects absorbed significantly less protein-bound vitamin B12 than normal controls (mean +/- SEM, 0.7% +/- 0.2% vs. 1.9% +/- 0.5%, respectively). However, protein-bound vitamin B12 absorption in these subjects normalized after antibiotic therapy. These results suggest that the small amounts of vitamin B12 released from the protein binders is readily absorbed (as shown in vitro) and/or metabolized by bacteria.

This study compared the effect of enteral nutrition as the sole therapy of active Crohn's disease with drug treatment. Patients with active Crohn's disease (Crohn's Disease Activity Index greater than 200) were randomized to receive either enteral nutrition with a liquid oligopeptide diet (n = 55) or a combination of 6-methylprednisolone, 48 mg daily, subsequently tapered, and sulfasalazine, 3 g daily (n = 52). The two groups were not different with respect to age, sex, body weight, location of disease, or treatment before the study. The severity of disease was similar at the beginning of the study in both groups [Crohn's Disease Activity Index (mean +/- SEM), 323 +/- 12 vs. 316 +/- 11]. Remission was defined as a decrease of the initial Crohn's Disease Activity Index by 40% or at least 100 points. Twenty-nine patients in the diet group and 41 patients in the drug group reached remission within 6 weeks of therapy (chi 2 test, P less than 0.01). The median elapsed time to remission was 30.7 days in the diet group compared with 8.2 days in the drug group (Mantel Cox, P less than 0.01). To determine whether one of these treatments was more beneficial for a subgroup of patients, the effectiveness of both treatments was analyzed separately in patients with very severe disease (initial Crohn's Disease Activity Index greater than 300) and less severe disease (initial Crohn's Disease Activity Index less than 300), and in patients with different disease location. However, no influence of initial disease activity or disease location on the effect of either treatment could be shown. These data show that enteral nutrition is less effective than a combination of 6-methylprednisolone and sulfasalazine in treating active Crohn's disease.

A 45-minute infusion of an octapeptide of cholecystokinin (Kinevac; Squibb Diagnostics, New Brunswick, NJ) was used to measure the gallbladder ejection fraction during cholescintigraphy in 40 normal volunteers. Cholecystokinin cholescintigraphy was shown to be a reproducible test. The maximum mean gallbladder ejection fraction occurred 15 minutes after cholecystokinin infusion and was 74.5% +/- 1.9% (mean +/- SEM). A gallbladder ejection fraction greater than 40% (mean -3SD) was arbitrarily defined to be normal. The gallbladder ejection fraction test was then used to identify patients with acalculous biliary symptoms who may respond to cholecystectomy. A total of 103 patients was tested; 21 had abnormal gallbladder ejection fractions and were randomized into two groups, cholecystectomy or no operation. These patients were followed up symptomatically at 3-month intervals for 13-54 months (mean, 34 months). Of the 11 patients who underwent cholecystectomy, 10 (91%) lost their symptoms and 1 improved. Of the 10 patients in the group that did not undergo surgery, all continued to be symptomatic, 2 of whom requested cholecystectomy after 13 and 24 months, respectively. Of the 13 gallbladders obtained from surgery, 12 showed evidence of chronic cholecystitis, muscle hypertrophy, and/or narrowed cystic duct. A normal gallbladder ejection fraction was recorded in 82 patients, and further treatment was left to the discretion of their referring clinician. On follow-up, 50 patients were asymptomatic and 10 were symptomatic without specific treatment of the biliary tract; 14 underwent cholecystectomy, 8 of whom were asymptomatic. Pathological abnormalities were recorded in 6 of the removed gallbladders. It is concluded that the gallbladder ejection fraction obtained after a 45-minute infusion of cholecystokinin during cholescintigraphy is a reproducible measure of gallbladder emptying, and that cholecystectomy alleviates the biliary-type pain of patients with a reduced gallbladder ejection fraction.

The antisecretory effects of H2-receptor antagonists are limited by food ingestion. The contributions of the cephalic-vagal and gastrinergic mechanisms to this interaction were examined in two 14-hour randomized, cross-over studies in 24 healthy volunteers. In the first study, either ranitidine or placebo was administered IV by a pH-feedback-controlled infusion pump during fasting, modified sham feeding, or food ingestion. Sham feeding resulted in a well-defined and abrupt interaction with the antisecretory effect of ranitidine (lasting 2-3 hours), after which fasting pH levels were regained. The second study, with the same design, showed that gastrin release occurred during this cephalic-vagal phase but was not attenuated by the additional infusion of the anticholinergic pirenzepine. Following eating, intragastric acidity increased and remained elevated for more than 6 hours. This increase was accompanied by prolonged hypergastrinemia, which was not diminished by pirenzepine. Pirenzepine did, however, enhance the antisecretory effect of ranitidine after both sham feeding and food ingestion. The interaction of food or sham feeding with the antisecretory effect of H2 antagonists is a consistent phenomenon. In both the cephalic-vagal and the gastric phases of secretion, this interaction appears to be partially mediated by a noncholinergic release of gastrin.

In familial adenomatous polyposis, sulindac-induced polyp regression has been reported by several authors. In this study, the goal was to confirm these results by a randomized, placebo-controlled, double-blind crossover study in 10 patients with rectal polyps that had been previously treated by colectomy and ileorectal anastomosis. Patients received sulindac, 300 mg/day, or placebo during two 4-month periods separated by a 1-month wash-out phase. One patient was not compliant and was excluded. With sulindac, the authors observed a complete (6 patients) or almost complete (3 patients) regression of the polyps. With placebo, the authors observed an increase (5 patients), no change (2 patients), and a relative decrease (2 patients) in the number of polyps. The difference between sulindac and placebo was statistically significant (P less than 0.01). In biopsy specimens of polyps and normal rectal mucosa of 6 patients, the authors conducted an immunohistochemical study of the cellular proliferation index using the Ki 67 monoclonal antibody (Ki 67 index), at the beginning and at the end of each treatment period. They were not able to show a sulindac-induced modification of the Ki 67 index. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial adenomatous polyposis.