Since its approval by the Food and Drug Administration in September 1985, the Garren-Edwards gastric bubble has been extensively used as an adjunct to diet and behavioral modification in the treatment of exogenous obesity. In an attempt to evaluate the efficacy of the Garren-Edwards gastric bubble, a double-blind crossover study was undertaken. Ninety patients were randomized into three groups: bubble-sham, sham-bubble, and bubble-bubble in two successive 12-wk periods. Sixty-one patients completed the entire 24-wk study. All groups participated in ongoing diet and behavioral modification therapy in a free-standing obesity program, the members of which were blinded to randomization arms. All patient groups lost weight during this study. The mean cumulative weight loss in pounds at 12 wk was as follows: bubble-sham = 19, sham-bubble = 12, and bubble-bubble = 8; and at 24 wk: bubble-sham = 23, sham-bubble = 16, and bubble-bubble = 18. The mean cumulative change in body mass index (kg/m2) at 12 wk was as follows: bubble-sham = -3.1, sham-bubble = -2.3, and bubble-bubble = -2.9; and at 24 wk: bubble-sham = -3.1, sham-bubble = -3.0, and bubble-bubble = -3.3. Although weight loss occurred more consistently in patients with a Garren-Edwards gastric bubble, there were no significant differences between any of the three groups at 12 or 24 wk with respect to weight loss or change in body mass index. The major part of the weight loss noted during this study occurred during the first 12-wk period, irrespective of therapy (bubble or sham). Side effects observed during this study included gastric erosions (26%), gastric ulcers (14%), small bowel obstruction (2%), Mallory-Weiss tears (11%), and esophageal laceration (1%). We conclude that, in this study, the use of a Garren-Edwards gastric bubble did not result in significantly more weight loss than diet and behavioral modification alone in the management of exogenous obesity, and it may result in significant morbidity.

A total of 1192 consecutive patients with diffuse liver disease were randomized to have percutaneous liver biopsy specimens taken with the Menghini or the Tru-Cut needle, to compare tissue yield, safety, and accuracy of the two needles for diagnosing cirrhosis. The sites of puncture were determined by prebiopsy ultrasound scans. Adequate samples were obtained from 94% with the Tru-Cut needle and from 79.2% with the Menghini needle (p less than 0.001). Accuracy in diagnosing cirrhosis was 89.5% for the Tru-Cut needle and 65.5% for the Menghini needle (p less than 0.05). Complication rates were very low and similar for both needles. Under these conditions, the Tru-Cut needle is superior to the Menghini needle for diagnosing cirrhosis.

Ninety normal volunteers were entered into a double-blind, placebo-controlled study to compare the efficacy of misoprostol (200 micrograms q.i.d.) vs. cimetidine (300 mg q.i.d.) in protecting the gastric and duodenal mucosa from tolmetin-induced (400 mg q.i.d.) injury. After 6 days of treatment, the degree of mucosal injury between treatments was compared by endoscopy, using a predetermined rating scale of 0 (normal mucosa) to 4+ (greater than 25 hemorrhages or erosions or an invasive ulcer). Utilizing a score of less than or equal to 2+ (2-10 hemorrhages or erosions) as a therapeutic success, the overall success rates were 8/30 (26.7%) for placebo, 19/30 (63.3%) for cimetidine, and 27/29 (93.1%) for misoprostol (p less than 0.001). Pairwise comparisons were also significant: misoprostol vs. placebo (p less than 0.001), misoprostol vs. cimetidine (p = 0.006), and cimetidine vs. placebo (p = 0.004). A separate analysis of the gastric scores alone revealed success rates identical to those in the overall evaluation; however, success rates in the duodenum for both misoprostol (29/29) and cimetidine (29/30) were extremely high and did not differ. It is concluded that misoprostol is highly effective and significantly better than cimetidine in protecting the gastric mucosa from tolmetin-induced injury; however, both agents were highly protective in the duodenum.

We have conducted a double-blind controlled trial of colchicine in patients with primary biliary cirrhosis. Fifty-seven patients with biopsy-proven primary biliary cirrhosis were randomized to receive either 0.6 mg of colchicine twice daily or an identically appearing placebo. Patients underwent clinical and laboratory evaluation every 3 mo and liver biopsy annually. Differences in mean alkaline phosphatase and alanine aminotransferase values between the colchicine and placebo recipients were statistically significant at 4 yr. Differences in mean bilirubin and immunoglobulin M values, although lower in the colchicine group, did not reach statistical significance. In colchicine-treated patients, mean alkaline phosphatase values fell significantly compared with controls, from 281 to 112 IU/L (p less than 0.01). Similarly, mean alanine aminotransferase values fell significantly compared with controls, from 129 to 86 IU/L (p less than 0.05). Bilirubin values remained stable in drug-treated patients, even in those patients with initially elevated bilirubin values, whereas they nearly doubled in subjects receiving placebo. Although biochemical parameters of disease activity improved or stabilized in colchicine-treated subjects, no difference in histologic progression was detected between the two treatment groups. We conclude that colchicine is of clinical benefit to patients with primary biliary cirrhosis as judged by improvement in alkaline phosphatase and alanine aminotransferase activities as well as a tendency for stabilization of bilirubin values.

It has recently been shown that repeated large-volume paracentesis associated with intravenous albumin infusion is a rapid, effective, and safe therapy of ascites in cirrhosis. To investigate whether intravenous albumin infusion is necessary in the treatment of cirrhotics with large-volume paracentesis, 105 patients with tense ascites were randomly allocated into two groups. Fifty-two patients (group 1) were treated with paracentesis (4-6 L/day until disappearance of ascites) plus intravenous albumin infusion (40 g after each tap), and 53 (group 2) with paracentesis without albumin infusion. After disappearance of ascites, patients were discharged from the hospital with diuretics. Patients developing tense ascites during follow-up were treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 50 patients from group 1 and in 48 from group 2, with the duration of the hospital stay being approximately 11 days in both groups. Paracentesis plus intravenous albumin did not induce significant changes in standard renal function tests, plasma renin activity, and plasma aldosterone. In contrast, paracentesis without albumin was associated with a significant increase in blood urea nitrogen, a marked elevation in plasma renin activity and plasma aldosterone concentration, and a significant reduction in serum sodium concentration. One patient from group 1 and 11 from group 2 developed renal impairment or severe hyponatremia after treatment, or both (chi 2 = 9.19; p less than 0.01). The development of these complications could not be predicted by clinical and laboratory data before treatment. Although the probability of survival after entry into the study was similar in patients from both groups, a multivariate analysis identified the development of hyponatremia or renal impairment, or both, following the first paracentesis treatment and the occurrence of other complications during the first hospitalization (encephalopathy, gastrointestinal bleeding, and severe infection) as being the only independent predictors of mortality. These results indicate that intravenous albumin infusion is important in avoiding renal and electrolyte complications and activation of endogenous vasoactive systems in cirrhotics with ascites who are treated with repeated large-volume paracentesis. The development of such complications may impair survival in these patients.

To assess the safety and efficacy of delayed-release mesalazine (5-aminosalicylic acid) as maintenance treatment for patients with ulcerative colitis, 100 patients with quiescent colitis were randomly grouped to receive either delayed-release mesalazine or an equivalent dose of enteric-coated sulfasalazine in a 48-wk trial. Groups were comparable for age, sex, and duration and extent of disease. Relapse rates at 48 wk were as follows: sulfasalazine 38.6% (95% confidence limits, 24%-54%) and mesalazine 37.5% (95% confidence limits, 24%-53%), chi 2 = 0.01, p greater than 0.90. Mean time to relapse, cumulative relapse rate, and relapse severity were similar in the two groups. Headaches and upper gastrointestinal symptoms--common at trial entry--improved to a greater extent in patients receiving mesalazine. Delayed-release mesalazine is an effective treatment for maintaining ulcerative colitis remission and is associated with fewer side effects than equivalent doses of enteric-coated sulfasalazine.

In this study we investigated the site and nature of the signal responsible for the generation of the gastrocolonic response at the rectosigmoid region. Sixteen healthy subjects participated in this study. Motor activities were recorded with pressure transducers placed in the rectosigmoid colon. Balloon distention of the stomach with 100, 200, or 300 ml of water caused a volume-dependent increase in rectosigmoid motility that was abolished by atropine. To investigate the intestinal phase of the gastrocolonic response, we infused into the duodenum isocaloric (178 kcal) solutions of normal saline, lipid, glucose, or essential amino acids at 1.5 ml/min for 30 min in random order on separate days. Only lipid infusion caused an increase in rectosigmoid pressure and this was accompanied by an elevation of plasma cholecystokinin from 1.2 +/- 0.1 to 4.3 +/- 1.0 fmol/ml. The increase in motility associated with lipid infusion was antagonized (58% +/- 7%) by atropine. To further investigate the possible role of cholecystokinin as a mediator of the gastrocolonic response, we infused cholecystokinin-octapeptide intravenously at doses of 5, 10, and 20 ng/kg.h. A significant increase in rectosigmoid motility was observed only at 20 ng/kg.h and this was accompanied by an increase in plasma cholecystokinin levels to 12 +/- 2 fmol/ml, a value threefold greater than that produced by lipid infusion. These studies demonstrate that gastric distention and intestinal lipid are potent stimuli for the generation of the gastrocolonic response involving the rectosigmoid region. The gastric phase can be generated by mechanoreceptors utilizing the cholinergic pathways, whereas the intestinal phase is nutrient-specific, partially atropine-sensitive, and independent of cholecystokinin.

We conducted a double-blind, randomized, parallel group study in 169 patients with acute duodenal ulcers to compare omeprazole, 20 mg daily, with cimetidine, 600 mg twice daily. After 2 wk, 58% of the omeprazole-treated patients and 46% of the cimetidine-treated patients were completely healed (p = 0.056). After 4 and 6 wk 84% and 88% healed with omeprazole, and 80% and 89% healed with cimetidine (p = NS). After 2 wk, pain was completely gone in 62% of the omeprazole-treated patients versus 46% of the cimetidine-treated patients (p = 0.04). Clinical or laboratory adverse events were reported in 6 (7%) of the omeprazole-treated patients and 11 (13%) of the cimetidine-treated patients (p = NS). An adverse event caused withdrawal of 1 patient on omeprazole (anxiety and depression) and 2 patients on cimetidine (diarrhea and fall in hemoglobin). We conclude that omeprazole (20 mg daily) resulted in a trend toward more rapid ulcer healing compared with a relatively high dose of cimetidine (600 mg b.i.d.), and was preferred by patients for relief of ulcer pain.

One hundred thirty-seven patients with fulminant hepatic failure were entered into two controlled trials of charcoal hemoperfusion carried out concurrently. In trial A, 75 patients with grade 3 encephalopathy were randomized to receive 5 or 10 h of hemoperfusion daily. Overall survival rates for the two groups were similar (51.3% vs. 50.0%) as was the frequency of major complications including cerebral edema and renal failure. In trial B, in which 62 patients with established grade 4 encephalopathy on admission were randomized to a no-perfusion group or to have 10 h of hemoperfusion daily, overall survival rates for the two groups were again similar (39.3% and 34.5%, respectively). There was in both trials a significant relationship between survival and etiology quite independent of the use or duration of hemoperfusion. Thus, percentage survival for the acetaminophen-overdose cases was 52.9%, for hepatitis A 66.7%, for hepatitis B 38.9%, for presumed non-A, non-B hepatitis 20%, and for halothane or drug reaction 12.5%. Within the etiologic subgroups survival was also influenced by the three major complications that developed, being inversely related to their frequency and combination, except in the non-A, non-B hepatitis and halothane or drug reaction subgroups, which had a high mortality throughout. In the latter cases particularly, orthotopic liver transplantation merits early consideration and in the group with better "intrinsic" survival (acetaminophen, hepatitis A and B) intensive management of complications (rather than charcoal hemoperfusion) would appear to be of major importance.

The efficacy of 5-aminosalicylic acid enemas in maintaining remission in left-sided ulcerative colitis was studied. Twenty-five patients in remission for at least 2 mo were randomized to receive either 1-g 5-aminosalicylic acid or placebo enemas daily and were followed up for 1 yr. Eleven of 13 patients randomized to placebo relapsed after a mean of 16 wk. Nine of 12 patients randomized to 5-aminosalicylic acid remained in remission for 1 yr, 2 others in remission withdrew by request, and 1 relapsed at 10 wk. The difference between relapse rate on 1-g 5-aminosalicylic acid versus placebo was significant (p less than 0.005). Seven patients entered the blinded trial a second time. Three of 4 patients randomized to 5-aminosalicylic acid remained in remission and 1 relapsed. Three randomized to placebo relapsed at a mean of 14 wk. One-gram 5-aminosalicylic acid enemas are safe and effective in maintaining remission in patients with left-sided ulcerative colitis.

The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.

A randomized controlled trial of hepatic arterial embolization was conducted in 63 consecutive patients who had unresectable but still embolizable hepatocellular carcinoma. Patients were randomized into three groups. Patients in group 1 received multiple hepatic arterial embolizations; patients in group 2 were given hepatic arterial embolization once, followed by monthly chemotherapy with high doses of 5-fluorouracil; and patients in group 3 received only monthly chemotherapy with high doses of 5-fluorouracil. Complete response was achieved in only 1 patient who received multiple hepatic arterial embolizations. Partial responses were observed in 13 patients (61.9%) in group 1, 10 patients (47.6%) in group 2, and 2 patients (9.5%) in group 3. The survival rates of patients in group 1 at the end of the ninth, 12th, 15th, 18th, and 21st months were 53.2%, 42.2%, 42.2%, 42.2%, and 42.2%, respectively, which were not significantly different from those of patients in group 2 but were better than the survival rates of patients in group 3. The results suggest that hepatic arterial embolization is an effective palliative treatment that prolongs survival of patients with unresectable hepatocellular carcinoma.

Hepatic and systemic hemodynamics were measured in 19 cirrhotic patients with variceal bleeding enrolled in a controlled trial of propranolol for the prevention of rebleeding. The patients were studied on three separate occasions. The first study was performed before randomization within 24 h of the bleeding episode, once hemodynamic stabilization had been achieved. The second study was performed after 10 days of treatment, and the third after 6 mo without rebleeding. Propranolol dosage was titrated according to blood levels. Wedged and free hepatic venous pressures and the hepatic venous pressure gradient were recorded. Hepatic blood flow and cardiac output were also measured. Before treatment, the groups of patients treated with propranolol (n = 11) or placebo (n = 8) were comparable according to clinical, biochemical, and hemodynamic parameters. After 10 days, hepatic venous pressure gradient decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group). Cardiac output fell only in the propranolol group (-40%). Hepatic blood flow remained unchanged in either group. After 6 mo, hepatic venous pressure gradient remained lower than the values from the first (within 24 h of bleeding) study in both the propranolol group (n = 5) and the placebo group (n = 6). Our results suggest that portal pressure increases shortly after hemorrhage with a return to baseline values 10 days later, and that propranolol does not further magnify these changes. Spontaneous changes in hepatic hemodynamics after variceal hemorrhage must be taken into account when evaluating the effect of pharmacologic agents on portal pressure.

The results of a prospective randomized controlled trial of elective endoscopic intravariceal sclerotherapy carried out over a 36-mo period in comparison with elective percutaneous transhepatic obliteration of varices (PTO) are presented. Sixty-six patients with nonalcoholic cirrhosis were randomized after they had stabilized, usually between 7 and 14 days after variceal bleeding had stopped following medical treatment (balloon tamponade and vasopressin infusion). Thirty-three patients were assigned to the sclerotherapy group and the other 33 patients were assigned to the PTO group. The mean follow-up period was similar in both groups. There was no significant difference in demographic, clinical, and laboratory data between the two groups. Six patients (18%) in the sclerotherapy group and 21 (64%) in the PTO group had at least one episode of gastrointestinal bleeding during the follow-up period (p less than 0.005). Three patients in the sclerotherapy group and 1 patient in the PTO group bled from lesions other than varices; therefore the incidence of variceal bleeding was 9% in the former and 61% in the latter (p less than 0.005). The cumulative variceal bleeding rate was significantly lower in the sclerotherapy group than the PTO group (p less than 0.05). Five patients in the sclerotherapy group died during the follow-up period but none died of recurrent variceal bleeding. Nineteen patients in the PTO group died and 10 of them died of bleeding from varices. The cumulative survival rate was significantly better in the sclerotherapy group (p less than 0.05). These results indicate that elective endoscopic intravariceal sclerotherapy is superior to elective PTO in the prevention of recurrent variceal hemorrhage and mortality in nonalcoholic cirrhosis.

Sixty-six outpatients with active ulcerative colitis who were intolerant of sulfasalazine were treated in a double-blind randomized trial. They received placebo or olsalazine sodium in daily doses of 0.75, 1.5, or 3 g. Overall, 35% of patients receiving olsalazine improved clinically, compared to 16% of patients receiving placebo. When the colitis activity at study entry was compared with that observed at the completion of the study period, statistically significant or nearly significant improvement was demonstrated within the combined olsalazine group (p = 0.01) and within patient groups receiving olsalazine at daily doses of 1.5 g (p = 0.04) and 3 g (p = 0.055). A dose-response relationship was suggested because 16%, 29%, 27%, and 50% of patients improved in the placebo and 0.75-, 1.5-, and 3-g olsalazine groups, respectively, (p = 0.04). A similar pattern of improvement was seen when sigmoidoscopic criteria were used, although a dose-response relationship was not demonstrated. There were no differences between the treatment and placebo groups for any of the adverse effects or laboratory variables reported at baseline or during the trial period. Four patients were withdrawn because of adverse reactions: 2 developed a skin rash while receiving olsalazine and 2 had diarrhea, one while on olsalazine and the other while on placebo. The data suggest that olsalazine is effective for the treatment of ulcerative colitis and is well tolerated among patients intolerant to sulfasalazine.

In a prospective controlled study, 68 patients undergoing maintenance sclerotherapy were randomized to have intravariceal sclerotherapy based on either manometric assessment (n = 35) or visual assessment (controls, n = 33) of varix patency. For manometric assessment, a perfused variceal needle punctured each variceal column and, if low pressures fluctuating with respiration were obtained, the varix was injected. Control patients had patent varices injected based on visual assessment alone. During a mean follow-up of 13 mo (range 4-16 mo), 1 manometrically assessed patient bled once (0.002 bleeds/patient month) and 7 visually assessed patients bled 14 times from varices (0.03 bleeds/patient-month) (p less than 0.05). Two and nine episodes of ulceration occurred in manometric and visually assessed patients, respectively, (p less than 0.05). Varices were obliterated (i.e., disappeared) in 11 patients undergoing manometric assessment and in 2 patients undergoing visual assessment (p less than 0.01). Comparing results of visual and manometric assessment within "manometric" patients showed a consistent 25% error rate in diagnosing patency or thrombosis by visual assessment. Manometric assessment of varices during maintenance sclerotherapy reduces rebleeding and ulceration to very low levels.