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.

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).

The present study was undertaken to determine whether or not spironolactone could induce drug-metabolizing enzymes in patients with ascites due to alcoholic cirrhosis of the liver. The disposition of antipyrine was therefore studied in 15 patients with cirrhosis before and after 13 days of spironolactone treatment (200 mg/day) and in 15 comparable patients not treated by spironolactone. In spironolactone-treated patients, a 40% increase in elimination rate constant of antipyrine (P less than 0.01) was due both to a decrease in apparent volume of distribution by 11% (P less than 0.01) and to a 20% rise in metabolic clearance rate (P less than 0.01). In control patients treated with furosemide or by paracentesis no significant change in metabolic clearance rate of antipyrine was found. As with spironolactone, furosemide decreased the apparent volume of distribution (9%, P less than 0.05) in proportion to the loss in body weight. Since spironolactone treatment was not associated with improvement in the fractional clearance of bromosulfophthalein, nor in serum albumin, prothrombin time, and factor V, the data are compatible with the idea that even in cirrhosis the hepatic drug-oxidizing enzymes were induced by spironolactone. Thus, the consequences of enzyme induction should be considered when spironolactone is associated with other drugs for the treatment of cirrhotic patients.

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.