Ninety-seven patients with recent or active variceal bleeding were randomly assigned to oral propranolol, endoscopic sclerotherapy plus oral propranolol, or transhepatic sclerotherapy plus oral propranolol. The effects of treatment on the number of units transfused, rebleeding of any magnitude, major rebleeding, and death were assessed in these patients, 82% of whom were alcoholic and 81% Child's Class C. After a minimum follow-up interval of 2 yr (range, 27-65 mo), major rebleeding rates were 65% for propranolol alone, 45% for endoscopic sclerotherapy plus propranolol, and 60% for transhepatic sclerotherapy plus propranolol. The corresponding death rates were 81% for propranolol alone, 55% for endoscopic sclerotherapy plus propranolol, and 66% for transhepatic sclerotherapy plus propranolol (p = 0.03). Thirty-three patients (34%) never received propranolol; 8 due to medical contraindications and 25 because they died or bled enough to meet the definition of treatment failure within 3 or 4 days of randomizations (no significant differences among treatment groups). Patients assigned to propranolol alone bled sooner, bled more units, and had a higher mortality rate than patients treated by endoscopic sclerotherapy plus propranolol. Patients treated with transhepatic sclerotherapy plus propranolol had intermediate results. Propranolol alone is inadequate treatment for esophageal variceal bleeding in patients with advanced liver disease.

We have developed a measure of subjective health status (quality of life) for patients with inflammatory bowel disease (IBD). Ninety-seven patients with IBD described problems they had experienced as a result of the disease; the 32 most frequent and important items were included in the Inflammatory Bowel Disease Questionnaire (IBDQ). Sixty-one IBD patients were evaluated twice. One month separated the evaluations, at which disease activity indices, the IBDQ, and a number of other questionnaires were administered. Reproducibility studies in 19 stable patients showed improvement in scores, but also a small within-person standard deviation. Responsiveness studies revealed large changes in scores in patients who had improved or deteriorated and suggested that the IBDQ was more responsive than a general health status measure. Responsiveness appeared greater in patients with ulcerative colitis than in those with Crohn's disease. Predicted and observed correlations between changes in IBDQ score and changes in other measures were similar. We conclude that although further testing is required, particularly in examining the relation between changes in the IBDQ and changes in the activity of Crohn's disease, the IBDQ shows promise as a measure of health status for clinical trials in IBD.

In this study, the pharmacokinetics, efficacy, and tolerability of 25 and 100 micrograms of octreotide given t.i.d. for 7 days subcutaneously were investigated in 12 healthy male subjects. Serum concentrations of the drug were well reproducible within 1 wk. Octreotide significantly raised 24-h median intragastric pH on day 1, but no longer on day 6. Peptone-stimulated gastric acid and volume secretion were markedly less suppressed by octreotide on day 7 compared with day 2. Peptone-stimulated gastrin release was abolished on days 2 and 7, as was peptone-stimulated insulin release. Blood glucose was altered in a biphasic pattern on days 2 and 7. All effects of octreotide were without clear-cut dose-response relationship. A mean half-life of 115 min was calculated. Dose-unrelated side effects (e.g., abdominal cramps, diarrhea, and fatty stools) were registered. In conclusion, octreotide is a powerful inhibitor of gastric acid and volume secretion during acute treatment. Its loss of efficacy during a 1-wk administration may be due to the adaptation of somatostatin receptors and hormonal counterregulation.

We have investigated the effect of oral cisapride (10 mg t.i.d.) in a double-blind, placebo-controlled trial in 26 patients with upper gut dysmotility: 11 with gastroparesis (8 diabetic, 3 idiopathic) and 15 with chronic idiopathic intestinal pseudoobstruction. Patients were evaluated at entry and at the end of the 6-wk study by upper gastrointestinal manometry, scintigraphic evaluation of gastric emptying of solids and liquids, measurement of body weight, and scoring of the following symptoms: abdominal pain, nausea, vomiting, early satiety, bloating, and distention. Cisapride and placebo groups were strictly comparable for all parameters assessed. Cisapride resulted in a significant increase in the gastric emptying of solids (p less than 0.05) compared with placebo; cisapride also tended to increase the postcibal antral motility and normalize the abnormal manometric features in the patients with intestinal dysmotility, particularly the characteristics of fasting interdigestive motor complexes and the fed motor pattern. Both cisapride and placebo groups showed an improvement in total symptom scores and there was no significant difference in overall symptom response between the two groups. However, the change in abdominal pain was greater with cisapride (p = 0.07). Cisapride facilitates gastric emptying in patients with upper gut dysmotility. The overall symptomatic benefit during a 6-wk trial of cisapride, 10 mg t.i.d., was not greater than that of placebo, and dose-response as well as longer term trials are necessary to determine the clinical efficacy of this medication.

To examine the premise that exercise reduces the gastrointestinal transit time, we evaluated the effect of walking 4.5 km in an hour on mouth-to-cecum transit time. Twenty-three healthy volunteers, 9 men and 14 women, with an age range of 19-28 yr, were studied. After an overnight fast, the subjects ingested 10 g of lactulose in 150 ml of water while breath hydrogen concentrations were analyzed at 15-min intervals. On separate days, in random sequence, subjects either sat in a chair or walked on a treadmill for 60 min. Mean transit time was 55 +/- 8 min when resting and 89 +/- 4 min when exercising (p less than 0.001). In conclusion, light aerobic exercise prolonged the mouth-to-cecum transit time. On the basis of this observation, exercise as a causative factor in runner's diarrhea and its value in the management of chronic constipation may be questioned.

Chronic use of cimetidine and alcohol are commonly associated, but studies on their interactions are the subject of controversy. To investigate this question, a small ethanol dose (0.15 g/kg body wt) was randomly administered on 2 consecutive days either orally or intravenously to 6 normal volunteers, before and after 1 wk of oral administration of 400 mg of cimetidine twice daily. Although cimetidine did not change the areas under the curve of blood ethanol concentrations after intravenous administration, those after oral alcohol intake were twice as large with cimetidine than without. Similar effects were reproduced in rats after intravenous administration of cimetidine (50 mg/kg body wt). In vitro, cimetidine was a noncompetitive inhibitor of gastric alcohol dehydrogenase activity at concentrations as low as 0.01 mM, 100-fold lower than those needed to inhibit the hepatic dehydrogenase. These results indicate that gastric alcohol dehydrogenase activity governs, in part, the systemic bioavailability of ethanol. Consequently, systemic effects of alcohol may be exacerbated in patients receiving cimetidine.

To assess the gastric mucosal protective action of sucralfate against alcohol, a double-blind, controlled, randomized study was carried out in 12 healthy adult men. All subjects received four treatments in a random sequence: sucralfate + ethanol, sucralfate + ethanol placebo, sucralfate placebo + ethanol, and sucralfate placebo + ethanol placebo. Fundal, antral, and duodenal mucosae were submitted to endoscopic examinations, and the antral mucosa underwent histologic examination before and after injury. Biopsy specimens were taken from the antral mucosa to determine by radioimmunoassay its capacity to synthesize prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha. In both the fundus and the antrum, the mean endoscopic injury score after sucralfate plus ethanol administration was significantly lower than that after ethanol alone. All treatments tended to increase prostanoid values but 6-keto prostaglandin F1 alpha increased significantly when sucralfate was given. Sucralfate did not affect serum ethanol levels, nor did ethanol affect prostanoid synthesis. It is concluded that sucralfate provides significant protection to the human gastric mucosa against ethanol injury, and that this may be partly due to increased prostanoid synthesis.

Endoscopic distinction between ulcers and erosions is difficult. Consequently, existing literature, which must be taken at face value, may be misleading. Nevertheless, from published studies most gastric and duodenal ulcers associated with nonsteroidal antiinflammatory drugs appear to heal on antacids or H2-antagonists. Sucralfate appears useful for duodenal but not gastric ulcers. Continuing nonsteroidal antiinflammatory drugs does not prevent or delay healing of duodenal or small gastric ulcers; their effects on large gastric ulcers remain uncertain. Thus far, only full doses of H2-antagonists, or their combinations with antacids, have been shown to heal ulcers and prevent recurrences. Ulcer recurrences and complications have occurred in small numbers of patients on maintenance doses of H2-antagonists. Available antiulcer drugs (antacids, H2-antagonists, sucralfate) reduce severe acute injury when taken before or with nonsteroidal antiinflammatory drugs. They also reduce ulcerlike symptoms due to nonsteroidal antiinflammatory drugs. Inexplicably, chronic prophylaxis with H2-antagonists for 4 wk or more appears ineffective in preventing gastric ulcers, although duodenal injury is reduced. As the efficacy of available prophylactic therapy (H2-antagonists, sucralfate, and antacids) has not been established, routine use in all cases seems unjustified at present.

A controlled, randomized trial of a short-term, medium-dose combination therapy of beta- and gamma-interferon was performed in 20 patients with chronic active hepatitis B. According to clinical, biochemical, and histologic findings that were followed up for 16-24 mo, the combined treatment was successful in 5 of 10 patients. Two of the patients eliminated the virus completely, as confirmed by Southern blotting of hepatocellular deoxyribonucleic acid (DNA) against hepatitis B virus DNA. In the other 3 responders hepatitis B surface antigen persisted in the absence of hepatitis B e antigen, replicating hepatitis B virus DNA in the liver and inflammatory disease activity. Two of these responders with persistent hepatitis B surface antigen had hepatitis B virus DNA integrated into the hepatocyte genome and 1 responder had nonreplicating, episomal virus DNA. In the control group of 10 patients one spontaneous remission occurred. Antiviral treatment was significantly (p less than 0.05) more successful within the first 4 yr after infection (5 responders of 6 treated patients) than after longer disease duration (no responder of 4 treated patients). The results of this pilot study suggest that a combination of beta- and gamma-interferon may be an effective therapy for chronic active hepatitis B when started early after infection.

Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid production and may augment mucosal defense. A double-blind trial examined the effect of misoprostol on the endoscopic appearance of gastroduodenum at the end of 1 wk of aspirin ingestion. One hundred thirty healthy subjects were randomized to take either 50, 100, or 200 micrograms of misoprostol, or placebo along with 975 mg of aspirin four times daily. Fewer subjects developed acute endoscopic gastric ulcers in the group taking any dose of misoprostol compared with the placebo group (1% vs. 43%). No subject taking the 100- or 200-micrograms dose of misoprostol developed an acute endoscopic duodenal ulcer compared with 13% of subjects taking placebo (p less than 0.05). Significantly fewer subjects developed gastric erosions and significantly fewer subjects developed duodenal erosions in each of the three groups taking misoprostol compared with the placebo group (p less than 0.01). There were fewer subjects with a gastric erosion (p less than 0.05) and fewer subjects with a duodenal erosion (p less than 0.05) in the group taking the 200-micrograms dose compared with the group taking the 50-micrograms dose of misoprostol. Gastrointestinal symptoms causing a modification in usual activities were infrequent but there was significantly more diarrhea in the 200-micrograms misoprostol group. There was no correlation between endoscopic scores and symptoms in any group. We conclude that misoprostol can protect the normal gastroduodenum from acute ulceration and reduce the chance of erosion after 1 wk of aspirin ingestion.

Chenodeoxycholic acid (CDC) and ursodeoxycholic acid (UDC) have distinct physicochemical and metabolic properties which, being complementary, should favor more rapid removal of cholesterol from gallstones when both bile acids are administered together. To see if the combination is more effective and well tolerated, we have compared 5 mg/kg of CDC plus 5 mg/kg of UDC with a 10-mg/kg dose of UDC alone in 120 patients with radiolucent, sonographically confirmed gallstones and characteristics favoring complete dissolution. Ursodeoxycholic acid was chosen as the reference because it dissolves stones faster and is better tolerated than CDC. To minimize the influence of stone size, the major determinant of dissolution, patients were divided, on admission, into two groups according to the maximum stone diameter: 50 had stones less than or equal to 5 mm, 70 had stones greater than 5 mm but less than 15 mm. The effects of treatment on stone dissolution evaluated by cholecystography and ultrasonography at 6, 12, and 24 mo, were analyzed by the actuarial life-table method. In the group with smaller stones, significantly more patients had obtained complete dissolution after treatment with the combination (52%) than after treatment with UDC alone (24%) at 6 mo. After longer periods, results were still better with the combination, although the differences from UDC alone became smaller. In the patients with larger stones, rates of complete and partial dissolutions were higher after treatment with the combination (51% vs. 24% with UDC) at 6 mo and again the differences had become smaller after longer treatment. Although not statistically significant, stone calcification occurred more often with UDC (7 cases) than with the combination (1 case). We conclude that CDC plus UDC is preferable to UDC alone because it dissolves stones more quickly, with a lower incidence of stone calcification, and may result in reduced cost of treatment.

A prospective uncontrolled multicenter trial was performed on 113 patients with bile duct stones in whom routine endoscopic approaches for removal of the calculi had failed. These represented 8.3% of the patients referred to the participating centers for endoscopic extraction of the stones. Extracorporeal shock-wave lithotripsy using the Dornier kidney lithotripter achieved stone disintegration in 103 patients (91%). Complete stone clearance from the bile ducts was obtained in 97 patients (86%) after a median of 4 days following extracorporeal shock-wave lithotripsy. Adverse effects, mostly mild, occurred in 36% of the patients. A 30-day mortality rate of 0.9% (in-hospital mortality rate = 1.8%) of this high-risk group with a mean age of 72 yr and a cholangitis rate of 26% compared favorably with the data given for open surgery. We therefore consider extracorporeal shock-wave lithotripsy a useful method for the treatment of bile duct stones not amenable to routine endoscopic measures.

The prevalence and course of sexual dysfunction was evaluated in 221 alcoholic cirrhotic men participating in a double-blind, placebo-controlled study on the effect of oral testosterone treatment on liver disease. At entry, 67% (95% confidence limits, 61%-74%) complained of sexual dysfunction. Sexual dysfunction was significantly (p less than 0.05) associated with lower serum concentrations of testosterone, non-protein-bound testosterone, and non-sex hormone-binding globulin-bound testosterone. The significant associations between sexual dysfunction and non-protein-bound and non-sex hormone-binding globulin-bound testosterone concentrations disappeared, however, when age, ethanol consumption, and severity of liver disease were included as covariates in the analysis. During follow-up (median 30 mo, range 1-48 mo) sexual dysfunction improved significantly (p less than 0.05) at 6, 12, and 24 mo. Furthermore, the reported libido and erectile and ejaculatory function improved significantly at the end of the follow-up period (p less than 0.01). However, the testosterone-treated patients did not differ significantly from the placebo-treated patients regarding any of the changes in sexual function. In conclusion, oral testosterone treatment does not significantly influence the type or course of sexual dysfunction in alcoholic cirrhotic men. However, sexual function improved after reduction of ethanol consumption in these patients.

To study the impact of starch on colonic function and metabolism, 12 healthy volunteers consumed a controlled diet rich in starch for two 4-wk periods. In one of the study periods they received the glucosidase inhibitor acarbose (BAY g 5421) and placebo in the other. Stool wet weight increased by 68%, stool dry weight by 57%, fecal water content by 73%, and the mean transit time by 30% on acarbose. Breath hydrogen was significantly higher on acarbose, indicating stimulated carbohydrate fermentation in the colon. Fecal bacterial mass (+78%), total stool nitrogen (+53%), bacterial nitrogen (+200%), and stool fat (+56%) were higher in the acarbose than in the control period. The stimulation of fermentation in the human large intestine may be important in colonic and possibly other diseases.

In a double-blind, randomized, multicenter trial 150 consecutive outpatients with endoscopically verified duodenal ulcer were treated with either a low-dose antacid regimen (1 tablet q.i.d.; acid-neutralizing capacity, 120 mmol/day), or cimetidine (800 mg nocte). After 4 wk of treatment control gastroscopy showed ulcer healing in 54 of 76 patients (71.1%) in the antacid group, as compared with 58 of 74 patients (78.4%) in the cimetidine-treated group. The difference in healing rate of 7.3% (95% confidence interval, -6.5% to +21.1%) was not statistically significant. The symptomatic effect, measured as number of days and nights with ulcer pain, was also quite similar in the two treatment groups. However, the number of days with pain was significantly lower in the first week of treatment in the antacid group (p less than 0.01). Thus, the efficacy of a low-dose antacid tablet regimen approximated that of cimetidine (800 mg nocte) in the treatment of duodenal ulcer patients.

The results of a clinical trial comparing slow-release 5-aminosalicylic acid tablets (Pentasa) and enteric-coated sulfasalazine tablets (Salazopyrin) with regard to the efficacy of maintaining ulcerative colitis patients in remission for 12 mo and with regard to safety of treatment are reported. Seventy-five patients with ulcerative colitis in remission for between 1 mo and 5 yr were included for analysis. Forty-nine men and 26 women, aged between 18 and 79 yr, received either Pentasa t.i.d. (1500 mg) plus Salazopyrin placebo or Salazopyrin t.i.d. (3 g) plus Pentasa placebo daily. Patients were assessed clinically, endoscopically, and histologically before and 3, 6, 9, and 12 mo after the start of treatment. Life-table analysis showed ongoing remission after 6 and 12 mo for Pentasa to be 63% (26 of 41) and 54% (22 of 41) and for Salazopyrin 72% (22 of 31) and 46% (14 of 31). These differences were not statistically significant. Three patients treated with Salazopyrin were withdrawn because of severe erythrodermia, anxiety and backache, and pregnancy, respectively. One patient on Salazopyrin experienced transient rises in serum urea, creatinine, and lactic dehydrogenase and another patient in this group reported slight reversible loss of hair. In the Pentasa group no side effects were recorded. We conclude that Pentasa is a well-tolerated drug, equally effective as Salazopyrin in maintenance of remission of ulcerative colitis.

The purpose of this pilot study was to determine whether daily administration of cyclosporin A to symptomatic patients with primary biliary cirrhosis for 1 yr would lead to a significant and sustained improvement in liver enzyme abnormalities. Twelve adult patients (11 female, 1 male; aged 52.6 +/- 8.9 yr, mean +/- SD) with serologic and histologically defined primary biliary cirrhosis were randomized to receive either oral cyclosporin A or vehicle placebo. Cyclosporin A was administered at sufficient dosages to maintain serum radioimmunoassay trough levels between 100 and 200 ng/ml (starting dosage, 2.5 mg/kg.day). After 1 yr of therapy, significant changes from pretreatment values were seen only in recipients of cyclosporin A. These included a 37% decrease in mean serum alkaline phosphatase and a 43% decrease in gamma-glutamyltransferase (controls +3% and -14%, respectively). Mean serum bilirubin and albumin levels and prothrombin times remained unaltered in the two groups, as did the extent of inflammation and fibrosis and the histologic staging of liver biopsy specimens. Although mean serum creatinine levels increased by 51% in recipients of cyclosporin A (+2% in controls), there were no associated changes in diastolic blood pressure or creatinine clearance values. Other side effects including thrombocytopenia, hirsutism, headaches, tremor, and parasthesiae were common in the treated group but not of sufficient severity to warrant adjustment in the dosage or discontinuation of therapy. The observed changes in hepatic, renal, and hematologic tests tended to return to baseline after discontinuation of therapy. Two patients, both placebo recipients, died of liver failure during the study period. The results of this study indicate that in symptomatic primary biliary cirrhosis, cyclosporin A administration is associated with a significant improvement in cholestatic liver enzyme abnormalities that persists for the duration of therapy. A progressive rise in serum creatinine levels and a high incidence of side effects raise concerns regarding the long-term safety of this agent in primary biliary cirrhosis.