During a 7-yr period (1967-1974), 89 patients with alcoholic liver disease and at least one severe upper gastrointestinal hemorrhage thought to be from esophageal varices entered a randomized, controlled trial of medical therapy vs. end-to-side portacaval shunt. Follow-up continued to September, 1979, so that all surviving patients had at least 5 yr observation after randomization. Among 45 patients randomized to surgical therapy, 4 did not receive portacaval shunt, for various reasons. Among shunted patients there were 11 episodes of upper gastrointestinal bleeding, none fatal and none thought to be from esophageal varices. Thirty-seven percent of eligible patients have had moderate or severe hepatic encephalopathy ascribed to the shunt. Of 44 patients randomized to medical therapy, 7 eventually received portacaval shunt after multiple bleeding episodes. Since randomization there have been 190 episodes of bleeding requiring 589 transfusions and resulting in 23 deaths from bleeding or hepatic failure precipitated by bleeding. THere are 12 survivors in the surgically treated group and 8 in the group treated medically. Life-table analysis shows a small increase in survival in the surgically treated group throughout the study, which is not statistically significant. From our data, we could not identify risk factors that would improve the selection of patients for medical or surgical therapy.

A prospective and randomized study was performed comparing pneumatic forceful dilatation and surgical esophagomyotomy as primary treatment of patients with achalasia of the esophagus. Eighteen dilated and 20 operated patients were studied before and after treatment with 1 patient lost. Clinical, radiologic, and manometric evaluations were performed before and after treatment and acid reflux test in the late follow-up period. Immediately after treatment, a significant improvement was seen clinically, by radiologic studies and after manometric evaluation. In the late follow-up period, operated patients showed a permanent improvement in all of them, but dilated patients remained a symptomatic in about 50% of the cases. The rest had to be redilated or reoperated on due to a failure of primary dilatation leading to final good or excellent results in 60% and failure in 40% of patients. Acid reflux test showed a positive test in 31% of the operated patients and in 7% of the dilated patients. This controlled study suggests that surgical treatment of achalasia, used as primary treatment, is accompanied by significantly better long-term results compared with pneumatic dilatation according to the technique utilized by us.

The effect of natural motilin on the rate of gastric emptying of 200 ml 25% glucose was studied in seven subjects using a 99mtechnetium tin colloid marker. On the control day the subjects received intravenous saline while on the test day they received a motilin infusion of 0.2 pmol/kg/min. Infusions were blind and given in random order. Thirty minutes after glucose ingestion, 25.5 +/- 2% of the isotope had emptied during motilin infusion, compared with 11.0 +/- 1.5% with saline (p < 0.005). Plasma motilin concentrations rose from a basal value of 23 +/- 5 pM to 57 +/- 9 pM during the motilin infusion. The faster emptying rates after motilin were reflected in a faster rise of plasma glucose and insulin. The rate of emptying of 99mtechnetium-labeled double cream (200 ml, 24 g fat) was measured in 5 subjects. The rate of gastric emptying of the cream was unaffected by exogenous motilin. Gel chromatographic analysis of basal plasmas revealed two immunoreactive motilin peaks. After ingestion of cream during motilin infusion, there was an increase of the second peak but a reduction of the first peak whereas both peaks rose on the control day. Thus low-dose exogenous motilin stimulates the gastric emptying of glucose but not of fat.

A prospective, double-blinded, randomized trial of corticosteroid therapy in patients with severe acute viral hepatitis has been conducted. At the same time, we have examined the prognostic significance of the presence of bridging necrosis in liver biopsies obtained from such patients as well as the predictive value of certain serologic markers. Forty-two of the 77 patients admitted to the trial were shown to have bridging necrosis on their initial biopsies. Two patients progressed to death with massive hepatic necrosis, while 5 patients developed chronic liver disease. A complicated course could not be predicted by the initial biopsy findings nor by any of the serologic markers assessed. We could not identify any clinical or epidemiologic features with prognostic impact. No advantage was demonstrated to be associated with the use of corticosteroids early in the course of severe viral hepatitis.

The effects of tiotidine, a new histamine H2-receptor antagonist, and cimetidine on food-stimulated gastric acid secretion were evaluated in duodenal ulcer patients. Homogenized steak meals were infused immediately after, 1 h after, 5 h after, and 10 h after an oral dose of medication, and food-stimulated acid secretion was measured by in vivo intragastric titration. Tiotidine and cimetidine had a similar onset of action; however, tiotidine was more potent and had a longer duration of effect. Increased potency was demonstrated by the fact that from 1 to 2 h after medication 150 mg tiotidine inhibited acid secretion to approximately the same extent as did 300 mg cimetidine, and by the fact that for a given percent inhibition of acid secretion, plasma tiotidine concentration was eight to nine times lower than plasma cimetidine concentration. Longer duration of effect was demonstrated by the fact that from 5 to 7 h after medication, acid secretion was inhibited by 80% and 97% with 150 and 300 mg tiotidine, respectively, whereas 300 mg cimetidine inhibited acid secretion by only 22%. Also, 10-12 h after medication, 150 and 300 mg tiotidine inhibited acid secretion by 22% and 53%, respectively, while 300 mg cimetidine had no inhibitory effect. The long duration of effect was due in part to increased potency and in part to a plateau in plasma concentration of tiotidine, which was maintained from 2 to 6 h after medication. Neither tiotidine nor cimetidine had a significant effect on food-stimulated gastrin release or gastric emptying of a nonabsorbable marker.

Despite numerous observations indicating the deleterious effect of refluxed intestinal contents upon the stomach, the mechanism of injury and symptoms in the reflux gastritis syndrome is unclear. Much speculation has centered around the role of bile acids in the production of symptoms and histologic damage. Accordingly, the aims of our study were (a) to determine whether administration of autologous intestinal contents into the stomach can produce the symptoms of the reflux gastritis syndrome, (b) to measure and conpare the concentrations of bile acids in upper intestinal contents of postsurgical patients with and without the syndrome, and (c) to determine whether artificial bile acid solutions can reproduce the symptoms reported by the patients. Eleven patients with reflux gastritis syndrome and 10 asymptomatic postgastric surgery patients were evaluated. Autologous intestinal contents obtained after cholecystokinin injection and normal saline were infused in a random, double-blind fashion into the stomach of the patients. Determinations for total and individual bile acids, as well as the bile acid conjugated/unconjugated and glycine/taurine ratios were made on aliquots of upper intestinal contents of symptomatic and asymptomatic patients. Finally, saline and two artificial bile acid solutions with bile acid compositions similar to those of upper intestinal contents from symptomatic and asymptomatic patients were infused in random, double-blind fashion into the stomach of 8 patients from each group. Positive symptom responses to autologous intestinal contents were found in 10 of 11 symptomatic patients and only 2 of 10 asymptomatic patients (P < 0.01), both of whom showed positive responses to both autologous intestinal contents and saline. No symptomatic patients had a positive response to saline. Symptomatic patients had bile acid concentrations significantly greater (P < 0.001) than asymptomatic patients. A positive response to artificial bile acid solution infusion was found in only 1 symptomatic patient. It is concluded that (a) symptoms of the reflux gastritis syndrome are reproduced by gastric infusion of upper intestinal contents and (b) bile acids alone are not responsible for the production of symptoms.

As no adequate comparison of these widely used drugs has been made, we have performed a double-blind cross-over trial in 30 individuals with chronic diarrhea. Each underwent three randomized treatment periods of 4 wk duration. Patients were instructed to increase the daily dose gradually until control was achieved or side effects became intolerable. Stool frequency, consistency, urgency, and incontinence were then compared when a stable dose was reached. Though 2.3 capsules (4.6 mg) of loperamide, 2.3 capsules (103.5 mg) of codeine and 2.5 capsulses (12.5 mg) of diphenoxylate all reduced stool frequency to the same extent, diphenoxylate was significantly less effective in producing a solid stool. Before treatment 95% of patients experienced urgency, sometimes associated with fecal incontinence, often as their major diability. Loperamide and codeine were more effective in relieving this than was diphenoxylate. Side effects, particularly central nervous effects, were greatest with diphenoxylate and least with loperamide. Approximately equal numbers discontinued each preparation; poor control and central-nervous-system side effects were the usual reasons for stopping diphenoxylate and codeine, and abdominal pain and constipation for stopping loperamide. We conclude that both loperamide and codeine phosphate are superior to diphenoxylate in the symptomatic treatment of chronic diarrhea.

Thirty-six patients (27 with ulcerative colitis and 9 with Crohn's disease) completed a prospective controlled therapeutic trial of intravenous hyperalimentation (IVH) and total bowel rest in acute colitis. All patients received prednisone 40 mg/day which was reduced every 3 days or more depending on the response to treatment. The trial was completed either when the prednisone was reduced to 10 mg/day or when the patient came to colectomy. In the control group (5 males, 12 females; mean age 44.7 yr), 6 came to surgery and 11 responded medically in a mean time of 23.7 days. In the IVH group (8 males, 11 females; mean age 37.4 yr) 9 came to surgery and 10 responded medically in a mean time of 21.2 days. The results of this trial show that IVH with total bowel rest has no primary therapeutic effect in acute colitis.

Intraduodenal fat is a potent inhibitor of all forms of gastric acid secretion in humans. Studies were performed in random order on 3 separate days in 5 normal subjects to determine if intravenous fat (Intralipid) altered gastric acid secretion stimulated by intravenous amino acids in humans. Mean (+/- SE) gastric acid output during a 4-hr intravenous amino acid infusion (21 g L-amino acids; Freamine II) plus glucose (50 g. to maintain isocaloric and isoosmolar solutions) was 43.2 +/- 3.2 meq/4 hr. Intraduodenal fat fusion (20 g of Intralipid) significantly (P < 0.02) suppressed amino acid-stimulated acid output. Interestingly, intravenous fat (20 g of Intralipid) also significantly (P < 0.02) inhibited acid secretion (14.8 +/- 6.3 meq/4 hr); similar to the effect observed with intraduodenal fat (12.7 +/- 4.9 meq/4 hr). Serum levels of CCK, gastrin, and GIP were measured at 30-min intervals throughout each study. Cholecystokinin and GIP increased significantly from basal during intraduodenal fat infusion. There were no other changes in serum CCK, gastrin, or GIP during any of the other tests. It is concluded that in normal subjects intravenous fat is a potent inhibitor of intraveous amino acid-stimulated gastric acid secretion, similar in effect to intraduodenal fat. The inhibitory effect of intravenous fat on amino acid-stimulated gastric acid secretion is probably not mediated by release of either CCK of GIP. Circulating fat may play a role in the control of some forms of gastric acid secretion.

It has been suggested that hepatic encephalopathy could be due to the accumulation of false neurotransmitters and that the administration of a neurotransmitter precursor such as L-dopa would be beneficial to cirrhotic patients with hepatic encephalopathy. A prospective randomized controlled study was carried out to determine whether L-dopa has any effect on the course of cirrhotic hepatic encephalopathy. L-Dopa, L-Dopa and dopa-decarboxylase inhibitor, or placebo was given orally for 7 days to 75 cirrhotic patients with hepatic encephalopathy. The effect was assessed by clinical parameters as well as serial electroencephalograms. There was no statistically significant difference with respect to clinical improvement or deterioration in patients treated with either L-dopa or L-dopa and dopa-decarboxylase inhibitor or placebo. It is concluded that L-dopa is ineffective in the treatment of cirrhotic hepatic encephalopathy. Inefficacy was not due to late onset of treatment, to poor intestinal absorption of L-dopa, to destruction of L-dopa in the blood, or to impaired passage of L-dopa into the cerebrospinal fluid.

The therapeutic efficacy of bismuth subsalicylate was examined in a randomized double-blind fashion in 59 volunteers who were inoculated with Norwalk agent. Sixty-eight percent of the volunteers demonstrated seroconversion; 57% became ill. The severity and duration of the illness in 32 volunteers in the treatment and placebo groups were compared. Significant reduction in the severity and duration of abdominal cramps (P less than 0.01) and in the median duration of GI symptoms (P less than 0.05) was noted in the treatment group. There was no difference in the number, weight, or water content of stools, or in the rate of viral excretion between the two groups. The median duration of illness was 20 hr in the treatment group and 27 hr in the placebo group (0.1 greater than P greater than 0.05).

Steatorrhea persists in most cystic fibrosis patients with exocrine pancreatic insufficiency despite enzyme replacement, perhaps because gastric acid inactivates oral enzymes. Bile acid malabsorption may parallel steatorrhea. We studied the effect of adding cimetidine (300 mg a.c.) to pancreatic enzyme therapy in 8 patients with cystic fibrosis and steatorrhea. Fecal bile acid, weight and fat, and postprandial serum bile acids were measured with and without cimetidine. D-Xylose absorption was normal in all patients. On constant diets, 72-hr stools were collected during enzyme therapy and during a 5-day course of enzymes plus cimetidine. Addition of cimetidine to enzyme decreased fecal weight (257 +/- 32.6 to 198.6 +/- 32.5 g/day), increased the percent of dietary fat absorbed (75.0 +/- 4.9 to 80.1 +/- 4.1%, P less than 0.05), but had no effect on fecal bile acids (4.7 +/- 0.9 to 4.2 +/- 1.0 mmol/m2/day). Compared with no therapy, enzymes increased postprandial serum bile acid at 60 min (9.56 +/- 1.0 to 14.0 +/- 1.3 muM/liter, P less than 0.05) and at 120 min (9.4 +/- 1.2 to 12.4 +/- 1.6 muM/liter, P less than 0.02). The addition of cimetidine to enzymes abolished this postpranidial bile acid rise. In conclusion, addition of cimetidine to oral pancreatic enzyme therapy decreases stool weight and fat but perhaps not stool bile acids in cystic fibrosis. However, correction of fat absorption is incomplete. Enzyme therapy increases postprandial serum bile acids, and this increase is abolished with oral cimetidine. In view of the incomplete correction of steatorrhea and the alterations in serum bile acids induced by cimetidine, further research with this new medication is needed before it can be recommended for routine clinical use in patients with cystic fibrosis.

The effects of azathioprine on the course of primary biliary cirrhosis were studied prospectively in a multinational, double-blind randomized clinical trial involving 236 patients, of which 124 received azathioprine and 112 placebo. No significant effects were seen on survival, clinical course, hepatic histologic features, hepatic tests, or immunologic abnormalities after a median follow-up period of 18 mo, but most of the trends observed were in favor of azathioprine. The results obtained so far indicate that the effect of azathioprine as a single treatment is limited and probably of little clinical importance, but more years of follow-up will be needed to provide a definite conclusion.

Six patients with cirrhosis and severe chronic hepatic encephalopathy were treated with bromocriptine. All showed significant overall improvement clinically and in 3, the electroencephalogram became normal. The cerebral blood flow increased significantly from 32.7 +/- 2.4 (mean +/- 1 SE) to 40.5 +/- 1.5 ml/100 g brain/min (P less than 0.05). Similarly, there were significant improvements in the cerebral oxygen consumption from 2.2 +/- 0.4 to 3.3 +/- 0.4 ml/100 g brain/min (P less than 0.02) and in cerebral glucose consumption from 2.1 +/- 0.6 to 6.6 +/- 1.6 mg/100 g brain/min (P less than 0.02). Cross-over to placebo produced overall deterioration, more marked in the patients who had received the active drug for the shorter time period. No serious side effects were seen; the drug was well tolerated in doses of up to 15 mg daily and is a useful treatment for chronic hepatic encephalopathy when the response to conventional therapy has been poor.

Nonsteroidal antiinflammatory drugs (NSAID) induce the formation of bleeding gastric and intestinal ulcers in experimental animals. The damage can be prevented by prior local administration of prostaglandins, indicating that prostaglandins have protective properties on the gastrointestinal mucosa. The protective effect was studied in humans by measuring the fecal blood loss during indomethacin treatment of 18 patients with rheumatic diseases with and without concomitant oral supplementation with 1 mg prostaglandin E2 three times daily. The study had a randomized double-blind crossover design using 51Cr-labeled erythrocytes as marker of gastrointestinal bleeding. Indomethacin increased the daily fecal blood loss from 1.0 +/- 0.3 to 2.8 +/- 0.6 ml (P less than 0.005). When oral PGE2 was taken concomitantly, the blood loss was reduced to 1.1 +/- 0.2 ml daily (P less than 0.01), i.e., to the control level. Side effects of prostaglandin E2 were negligible, and the beneficial effect of indomethacin on joint status and symptoms was not interfered with. No changes were recorded in repeated blood tests except for a slightly reduced hemoglobin and a small but statistically significant reduction of serum-calcium during indomethacin treatment, an effect hitherto not described in normocalcemic human subjects. A protective effect on the gastrointestinal mucosa by oral prostaglandin E2 has by the present study been demonstrated also in humans. The protection is unrelated to the gastric acid secretion, which is not inhibited by oral prostaglandin E2. The finding may have clinical application, as gastrointestinal side effects and bleeding are common reasons for discontinuation of NSAID in patients with rheumatic diseases.

Fifteen patients with chronic diarrhea and fecal incontinence were admitted to a clinical research center and treated for 3 days with either placebo or diphenoxylate with atropine (Lomotil). The patients were then crossed over to the alternate medication. Lomotil had no effect on rectal or anal sphincter pressure or on continence for saline that had been infused into the rectum. However, Lomotil therapy reduced average stool frequency (from 4.9 to 2.6 times/day) and average stool weight (from 460 to 256 g/day). These results suggest that temporary or intermittent therapy with Lomotil and related drugs might benefit patients with chronic diarrhea and fecal incontinence. They should do this by virtue of a reduction in stool frequency and stool volume, without a deleterious effect on the defense mechanisms against incontinence.

The cholelitholytic action of ursodeoxycholic acid (UDCA) was investigated by a double-blind clinical trial. The trial started with 151 subjects all confirmed by radiographic examination as having radiolucent gallstones in a functioning gallbladder. The subjects were divided into three groups receiving 600 mg/day of UDCA, 150 mg/day of UDCA, and placebo (lactose) per day, respectively. Seventy-nine cases were classed as dropouts or were excluded due to incomplete follow-up or inadequate patient selection, and the data on the remaining 72 cases were analyzed. After 6--12 mo of treatment, dissolution of decrease in size or number of stones occurred in 10 of the 29 cases in the 600 mg/day group (34.5%), 4 of 23 cases in the 150 mg/day group (17.4%), and 1 of 20 cases in the control group (5.0%). For those cases with noncalcified, less than 15 mm in diameter, and floating stones, efficacy increased to 83.3% in the 600 mg/day group. Lithogenic index of bile defined by Thomas and Hofmann became unsaturated after treatment in the 600 mg/day group. Neither diarrhea nor hepatic toxicity was noted. The results indicate that UDCA is a safe and effective litholytic agent.