A randomized, double-blind, controlled trial of insulin and glucagon infusion was conducted in 50 patients with acute alcoholic hepatitis. Twenty-five treatment patients received 24 U regular insulin and 2.4 mg glucagon over 12 h daily for 3 wk. Twenty-five control patients received 200 ml dextrose solution in identical bottles over the same time period. Six control and 2 treatment patients died from liver failure during study, and another treatment patient died from hypoglycemia. In the 34 patients with prothrombin times greater than 3 s prolonged, fewer deaths occurred among the insulin- and glucagon-infused patients (p less than 0.10). Clinical features of liver disease on entry into the study were similar in the two groups, and total serum bilirubin and prothrombin time improved more rapidly in the treatment group (p less than 0.05). Insulin and glucagon infusion is a promising treatment of alcoholic hepatitis and merits further study in the most severely ill patients.

One hundred and forty-one attempts at percutaneous transhepatic variceal obliteration were made in 116 patients with portal hypertension complicated by variceal hemorrhage. Varices were successfully obliterated in 80% of procedures and included 37 patients with continuous, acute variceal hemorrhage. Hemorrhage ceased immediately in these patients. Sixty-five percent of patients rebled a mean of 4.6 mo after successful transhepatic variceal obliteration. A randomized controlled trial against conventional medical therapy (29 treatment, 25 control) failed to show a significant reduction in death rate after transhepatic sclerotherapy, although the onset of further variceal hemorrhage was delayed. Follow-up portography in 50 patients demonstrated new vessel formation in 38 patients and recanalization of previously occluded varices in 5 patients. Complications arose in 29 of 141 procedures. There was one death but all the other complications responded to conservative management. Transhepatic variceal obliteration is an excellent, safe emergency treatment for variceal hemorrhage, especially in patients with decompensated liver disease. A high incidence of rebleeding is a long-term disadvantage and means that transhepatic variceal obliteration should not be used for the prophylaxis of variceal hemorrhage. Successful emergency treatment of variceal hemorrhage should be followed by elective portal decompression in suitable patients.

A controlled trial has been undertaken to evaluate adenine arabinoside in the treatment of hepatitis B surface antigen-positive chronic liver disease. Thirteen patients (7 hepatitis B virus DNA polymerase and hepatitis B e antigen-positive, 6 DNA polymerase negative and hepatitis B e antibody-positive) were treated with adenine arabinoside. Eleven comparable patients served as controls, and follow-up was for 6 mo. In the 7 hepatitis B e antigen-positive patients, adenine arabinoside produced a fall in DNA polymerase activity during treatment. When this effect was sustained, it was followed by a loss of e antigen (3 patients). Hepatitis B surface antigen concentrations and aspartate transaminase levels fell significantly at 6 mo (p less than 0.05) in the treated group compared with controls. In the hepatitis B e antibody-positive patients, adenine arabinoside treatment produced no significant change in hepatitis B surface antigen concentrations or aspartate transaminase levels at 6 mo as compared with controls. Adenine arabinoside would appear to reduce either transiently or permanently, hepatitis B virus replication, and it may therefore be useful in reducing the infectivity of some carriers of this virus. In the dose used, adenine arabinoside was ineffective in clearing hepatitis B surface antigen from the serum and eradicating hepatitis B virus from the liver, but combination with other antiviral or immunostimulant agents may enhance its therapeutic effectiveness.

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.

Oral 16,16-dimethyl prostaglandin E2 is a potent inhibitor of meal-stimulated gastric acid secretion and gastrin release in humans. Experiments were performed in 5 patients with inactive duodenal ulcer to determine the effect of graded doses of intravenous 16,16-dimethyl PGE2 on meal-stimulated gastric acid secretion and gastrin release to demonstrate whether it is necessary for 16-16-dimethyl PGE2 to come into direct luminal contact with the oxyntic and antral gland portions of the stomach to produce its inhibitory effects. All doses of 16,16-dimethyl PGE2, between 0.01 and 0.1 microgram/kg i.v. and between 0.01 and 1.0 microgram/kg orally produced significant postprandial inhibitory effects on both gastric acid secretion and gastrin release as compared with saline control. 0.1 microgram/kg of intravenous of 1 microgram/kg of oral 16,16-dimethyl PGE2 inhibited meal-stimulated acid secretion and gastrin by 80-90%. In 6 unoperated Zollinger-Ellison syndrome patients, 1 microgram/kg of oral 16,16-dimethyl PGE2 significantly inhibited fasting gastric acid hypersecretion by approximately 85% without significantly altering serum gastrin. Each of the oral doses of 16,16-dimethyl PGE2 (0.01-1 microgram/kg) were without untoward effect, as were intravenous doses of 0.01-01 microgram/kg. Maximal inhibition of acid secretion was found with 0.1 microgram/kg 16,16-dimethyl PGE2 i.v. as compared with 1.0 microgram/kg orally. Since 16,16-dimethyl PGE2, whether given orally or intravenously, is a potent inhibitor of both gastric acid secretion and meal-stimulated gastrin release, without apparent untoward side effects, clinical trials with 16,16-dimethyl PGE2 are indicated in patients with acid peptic disease.

The effect of a new calcium antagonist, nifedipine, which has a spasmolytic activity on smooth muscle cells, was studied on the esophageal function of 20 patients with achalasia of mild and moderate degree. The study was carried out by using constantly perfused catheters and recording the pressure variations at the lower esophageal sphincter, before and after sublingual administration of 10-20 mg of nifedipine. The drug significantly decreased the lower esophageal sphincter pressure for more than 1 h. A clinical trial was also carried out by assessing the improvement of symptoms in achalasia patients taking sublingually a dose of 10-20 mg of nifedipine before each meal. After 6-18 mo of nifedipine therapy these patients underwent a placebo treatment, whereas an additional group of 9 achalasia patients was treated first with placebo followed by nifedipine. The nifedipine treatment gave excellent or good results in a large majority of patients of both groups. The moderate results were only 5 and the poor responses only 3. The clinical improvement induced by nifedipine was statistically significant when compared, not only with the pretreatment clinical state, but also with the results of the placebo treatment. No tachyphylaxis and few side effects were seen either during the manometric recordings or the longest periods of therapy. This study suggests that nifedipine may be advantageously used in the medical treatment of achalasia of mild or moderate degree.

The best nonprotein energy source for routine use in patients receiving intravenous nutrition (IVN) for short periods of time is not known. In particular the relative merits of glucose and fat remain controversial. The present study was undertaken to determine if a quantitative difference in the ability to retain nitrogen could be documented between these two energy sources. In a prospective study of two comparable groups of 16 gastroenterologic patients who received IVN for 2 wk the changes in body weight, fat, water, and protein that occurred were measured. The only difference in the IVN between the groups was the nonprotein energy source. Group I received hypertonic glucose alone (49.2 +/- 7.9 kcal/kg day), and group II received an intravenous fat emulsion (60% of the nonprotein energy) in addition to hypertonic glucose (51.5 +/- 5.0 kcal/kg/day). Significant weight gain occurred in both groups (p < 0.001). In group I this was acounted for by gains of water (p < 0.02) and fat (p < 0.01) but not of protein. Patients receiving glucose together with fat (group II) gained protein (p < 0.02), but the gains of fat and water were not significant. Our study shows that protein repletion was achieved with an intravenous fat emulsion over a 2-wk period and the problems of water retention which occurred in the patients fed with glucose alone was not present. The results suggest that the fat in conjunction with glucose may be more effective as an energy source than equicaloric amounts of glucose alone in the type of patients we have studied.

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.

We examined the effect of 150 ml of caffeinated instant coffee at two pHs, 4.5 and 7.0, on lower esophageal sphincter pressure in 20 normal volunteers and 16 patients with reflux esophagitis. When ingested alone coffee at pH 4.5 and 7.0 caused a decrease in basal sphincter pressure in normal volunteers from 19.4 +/- 1.5 to 13.7 +/- 1.0 mmHg (P ¿ 0.01) and from 18.7 +/- 1.5 to 16.0 +/- 0.8 mmHg (P < 0.05) respectively. When coffee at pH 4.5 was drunk with a mixed nutrient test meal, the resting sphincter pressure in normal subjects fell after 30-60 min with the nadir, 11.2 +/- 1.0 mmHg, being recorded at 60 min (P < 0.01). Coffee at pH 7.0 with the test meal resulted in a fall in pressure to 14.3 +/- 1.5 mmHg (P < 0.02) at 60 min. In patients with reflux esophagitis, coffee at pH 4.5 lowered lower esophageal sphincter pressure from 9.1 +/- 1.0 to 5.5 +/- 0.6 mmHg (P < 0.005); coffee at pH 7.0 decreased lower esophageal sphincter pressure from 8.5 +/- 1.1 to 6.9 +/- 0.7 mmHg (P < 0.05). In these patients, mean basal pressure, 9.2 +/- 0.8 mmHg, decreased to 5.2 +/- 0.7 mmHg (P < 0.001) 45 min after drinking coffee at pH 4.5 with the test meal. Coffee at the neutral pH caused a fall in pressure from 8.8 +/- 1.1 to 6.5 +/- 0.7 mmHg at 60 min after the test meal. Thus, coffee at either pH 4.5 or 7.0 caused a decrease in fasting and postcibal lower esophageal sphincter pressure in normal volunteers and patients with reflux esophagitis. The magnitude and the duration of the effect were greater after coffee at the lower pH. These data support the clinical belief that coffee may cause or aggravate heartburn by decreasing lower esophageal sphincter pressure.

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.

The location of food consumption was recorded daily for 3 wk by 130 United States summer students newly arrived in Guadalajara, Jalisco, Mexico, as part of an assessment of bismuth subsalicylate vs. placebo in the irevention of travelers' diarrhea. Eating at locations other than homes and apartments (P < 0.025), and specifically at restaurants, was associated with an increased occurrence of diarrhea. Less eating at restaurants (P < 0.005), street vendors (P < 0.005), and school cafeterias (P < 0.01) was associated with reduced occurrence of travelers' diarrhea, even among persons taking bismuth subsalicylate as a preventive measure.