This study was designed to compare the effects of enprostil, a synthetic dehydro-prostaglandin E2, on 24-h intragastric pH and serum gastrin profile in patients with duodenal ulcer disease. The dosing regimen included 3 enprostil groups: 35 microgram h.s. (at bedtime), 70 micrograms h.s., and 35 micrograms b.i.d., compared with cimetidine 600 mg b.i.d., and with placebo. Ten patients with inactive duodenal ulcer disease were randomly assigned to all five treatment regimens for 1 wk each according to a Latin Square design. There was a 1-wk washout period between each treatment. Intragastric pH and serum gastrin measurements were carried out on the last day of each treatment week. In placebo-treated patients, intragastric pH rose after each meal and fluctuated between 1.5 and 3.5. Enprostil 35 micrograms b.i.d. and cimetidine elevated pH after breakfast and during the night (p less than 0.05). The single nighttime dose of enprostil had a marked effect on pH only when given in the dose of 70 micrograms and this effect lasted over 13.5 h. The pH values during the night were similar in the groups treated with enprostil 35 micrograms b.i.d. and 70 micrograms h.s. During the daytime, the readings at or above pH 4 were placebo, 5%; cimetidine, 21%; enprostil 35 micrograms b.i.d., 34%. During the nighttime, the readings greater than or equal to 4 were placebo, 12%; cimetidine, 29%; enprostil 35 micrograms b.i.d., 39%; 35 micrograms h.s., 19%, and 70 micrograms h.s., 38%. The postprandial rise in serum gastrin was greatly enhanced by cimetidine, but the change after breakfast was dramatically blunted by enprostil 35 micrograms b.i.d. Gastrin concentration was increased with cimetidine during the night but there was no difference in gastrin concentration overnight between all regimens of enprostil and placebo. This study suggests that (a) enprostil 35 micrograms b.i.d. is as effective as cimetidine 600 mg b.i.d. in suppressing postprandial and nocturnal intragastric acidity; (b) enprostil 35 micrograms b.i.d. and 70 micrograms at night are similarly potent in suppressing nocturnal acidity; and (c) in addition to its cytoprotective effect, enprostil has potent antisecretory and antigastrin properties.

A randomized placebo-controlled double-blind trial was carried out in 24 patients with biliary colic pain in order to evaluate the analgesic effect of caerulein (CRL). Caerulein (1 ng/kg . min infused intravenously over 15 min) showed an analgesic effect that was significantly higher than placebo (p less than 0.001). The analgesic action of CRL was not inhibited by naloxone (0.4 mg intravenously, administered two times). Further, the effect of i.v. CRL or saline on artificially induced biliary tree hypertension was studied in 7 patients with a T-tube common bile duct drainage. During saline intravenous administration, increasing biliary tree pressure resulted in pain in 5 patients, with the threshold for pain being 40 cmH2O. During CRL intravenous infusion, significantly higher perfusion pressures were required to achieve a given common bile duct pressure and the pressure threshold for pain was not reached. Consequently, pain was prevented in all patients. These data suggest that CRL relieves biliary colic pain by reducing biliary tract pressure.

Dioctyl sodium sulfosuccinate (DSS) is an anionic detergent that is used widely as a laxative and promoted as a stool softener. Although many anecdotal reports attest to the laxative and stool softening efficacy of DSS, no controlled trials have been performed to document the effect of DSS on small or large bowel function in humans. We have compared, therefore, the effects of 100 mg of DSS three times daily (the maximum recommended dose) with placebo in a randomized, single blind, crossover study in two groups of subjects. First, 6 healthy ileostomates were studied while they ate a constant diet for 8 days. Dioctyl sodium sulfosuccinate administered for 4 days did not increase the daily ileal output of carbohydrate, total fatty acids, bile acids, nitrogen, or water. Cholesterol excretion was decreased while taking DSS (p less than 0.05). Second, 6 healthy volunteers were studied while eating a constant diet of 20 g of fiber plus 30 radiopaque markers daily so that mean daily transit time could be measured. After equilibration, a 7-day collection of stool was weighed and lyophylized to measure fecal water. Dioctyl sodium sulfosuccinate had no effect on stool weight, stool frequency, stool water, or mean transit time. We conclude that 300 mg/day of DSS does not increase ileal or colonic output of solids or water in healthy human subjects.

The efficacy of adenine arabinoside (Ara-A) alone or in combination with prednisolone utilizing its withdrawal effect was studied in 43 patients with deoxyribonucleic acid polymerase- and hepatitis B e antigen-positive chronic hepatitis. Ten patients were treated with 10 mg/kg body wt of Ara-A alone for 4-8 wk. In 9 cases, prednisolone (40 mg/day) was given at a constant dosage for 4 wk before Ara-A treatment. Fourteen patients received oral prednisolone alone for 4 wk, and 10 patients served as untreated controls. Six of 9 patients (67%) undergoing the combination therapy became seronegative for hepatitis B e antigen, whereas only 4 of 24 patients (17%) treated either with Ara-A alone or prednisolone alone lost the antigen. Two of the 10 untreated patients became seronegative for hepatitis B e antigen during the same follow-up period of 9 mo. This prospective controlled study suggests that the combination of immunomodulation by steroid withdrawal and subsequent Ara-A is more effective in the treatment of patients with chronic liver disease and active hepatitis B virus replication than treatment with Ara-A alone.

To determine whether intravenous nutritional repletion can influence oxidative drug metabolizing capacity, antipyrine metabolism was studied in 6 malnourished patients on the second day of a 2-day baseline period and on the last day of two sequential, 8-day intravenous nutritional repletion periods. During the baseline period they received 5% dextrose, 440 kcal per day, intravenously. During the repletion periods they received 20 mg of nitrogen per kilocalorie of baseline resting energy expenditure and, in random order, dextrose to provide a total caloric intake of either 0.95 or 1.75 times baseline resting energy expenditure. There were no statistically significant differences between the high- and low-dextrose repletion regimens in their effects on antipyrine metabolism. Seven days of nutritional repletion resulted in a 42% decrease in mean half-life (range 12%-52%) and an 87% increase in mean metabolic clearance rate (range 29%-155%) for antipyrine. An additional 8 days of nutritional repletion resulted in no further change in these pharmacokinetic parameters.

In animal and human studies, the gastric emptying of large (greater than 1 mm) indigestible solids is due to the activity of the interdigestive migrating myoelectric complex. The gastric residence time (GRT) of an orally administered, nondigestible, pH-sensitive, radiotelemetric device (Heidelberg capsule) was evaluated in three studies in healthy volunteers. In 6 subjects, the GRT of the Heidelberg capsule was compared with the half-emptying time (t1/2) of diethylenetriaminepentaacetic acid labeled with technetium 99m after a 4-ml/kg liquid fatty meal. The mean (+/-SD) GRT (4.3 +/- 1.4 h) was significantly (p less than 0.001) longer than the mean t1/2 (1.1 +/- 0.3 h); the GRT was prolonged compared with the t1/2 in each subject. In a randomized, crossover trial in 10 subjects, frequent feeding caused a dramatic prolongation in mean GRT of the capsule compared with the fasting state (greater than 14.5 vs. 0.5 h, p less than 0.005). In another crossover study in 6 subjects, the GRT of the capsule was evaluated after an overnight fast, a standard breakfast including solid food, and a liquid meal (i.e., 200 ml of diluted light cream). The mean GRT was 2.6 +/- 0.9 h after the liquid meal vs. 1.2 +/- 0.8 h after fasting (p less than 0.025). The mean GRT after the breakfast was 4.8 +/- 1.5 h, which was significantly greater than that after fasting (p less than 0.001) and after the liquid meal (p less than 0.01). These data suggest that the GRT of the Heidelberg capsule is a marker of the interdigestive migrating myoelectric complex in humans, the interdigestive migrating myoelectric complex can be markedly delayed by frequent feedings with solids, and the interdigestive migrating myoelectric complex is delayed by both liquid and solid meals.

The effect of misoprostol and cimetidine on gastric cell turnover was studied. Endoscopic biopsy specimens of fundic and antral mucosa were obtained from duodenal ulcer patients before and after 4 wk of therapy with cimetidine 1.2 g/day or misoprostol 800 micrograms/day. Biopsy specimens were incubated with [3H]thymidine. Glandular column length and number of labeled cells were determined after autoradiography. There was no significant difference in column length of antral or fundic glands before or after therapy with cimetidine and misoprostol. The number of antral and fundic labeled cells was significantly decreased after misoprostol treatment (3.6 +/- 0.3 and 4.6 +/- 0.4, mean +/- SE), as opposed to their respective number before therapy (6.9 +/- 0.5 and 8.3 +/- 0.8) (p less than 0.01). On the other hand, after treatment with cimetidine, the number of antral and fundic labeled cells was significantly higher (11.8 +/- 0.9 and 7.5 +/- 1.0, respectively) as compared with their number before therapy (5.7 +/- 0.5 and 5.6 +/- 0.6, respectively). The decreased gastric cell turnover induced by misoprostol indicates that the trophic effect of prostanoids on gastric mucosa is not due to an increase in cellular kinetics. The increased gastric cell turnover induced by cimetidine may contribute to its therapeutic effect in peptic ulcer disease.

The objective of this study was to improve recording techniques for the recognition of gastric electrical dysrhythmias, and to explore the potential of pharmacologic agents to "evoke" gastric dysrhythmias. Eighteen healthy volunteers participated in 22 individual recordings, divided into two separate studies--a dose-response study and a randomized, double-blind study. The internal or mucosal electrogastrogram was recorded with a novel approach, using magnetic force to maintain internal electrodes in apposition with the gastric wall, whereas the external or cutaneous electrogastrogram, manometric activity, and respiration were measured by conventional methods. Analysis of simultaneous internal and external electrogastrographic signals, including both dysrhythmia and dysrhythmia-free intervals, revealed a good correspondence between the internal and external signals. In the dose-response study, 5 of the 6 volunteers intravenously infused with glucagon, in doses ranging from 3 to 22 micrograms/kg, developed gastric electrical dysrhythmias. In the randomized, double-blind study, 4 of 5 volunteers intravenously infused with glucagon (7 micrograms/kg) developed gastric dysrhythmias that were recognized by our improved techniques. Dysrhythmias, defined by visual analysis, consisted either of "tachygastria" (greater than or equal to 6 cycles/min for greater than or equal to 1 min) or "bradygastria" (greater than or equal to 1 cycle/min for greater than or equal to 1 min) and were evident on both internal and external electrogastrograms. Dysrhythmias were usually associated with absence of antral phasic pressure activity and frequently with nausea.

The effect of the presence of food in the intestinal lumen on fluid transport by an intestinal loop isolated from nutrients is debatable and seems to be species dependent. The aim of the present study was to investigate this effect in humans. Fluid and ion transport by a 30-cm-long jejunal loop was measured by the perfusion of a plasmalike electrolyte solution below an occlusive balloon inflated at the angle of Treitz. At the same time, the duodenum was infused at the papilla by saline (control period) or one of the following solutions (test period): protein hydrolysate, starch hydrolysate, lipids, or mixed nutrients. The four solutions (pH 7; 300 mosmol/L; 540 kcal/L) were infused in 6 normal subjects in a randomized order. In 6 further subjects, two other loads of intraduodenal lipids (120 and 1080 kcal/L) were tested according to a similar protocol. Blood samples were taken serially for radioimmunoassays of gastrin, secretin, cholecystokinin, pancreatic polypeptide, gastric inhibitory polypeptide, vasoactive intestinal polypeptide, motilin, and somatostatin. Intraduodenal mixed nutrients, proteins, and lipids significantly reduced water and ion jejunal net absorption or induced a net secretion (without dose-effect relationship for lipids) and stimulated plasma cholecystokinin, pancreatic polypeptide, and gastric inhibitory polypeptide. Intraduodenal lipids also stimulated circulating levels of gastrin and vasoactive intestinal polypeptide. Intraduodenal sugars did not change jejunal fluid and ion transport and significantly increased plasma gastric inhibitory polypeptide. Covariance analysis showed transjejunal fluid movements to be linked with plasma levels of cholecystokinin. We conclude that an intraduodenal mixed meal exerts a secretory effect on a jejunal loop isolated from the nutrients and that this effect is due to the lipid and protein content of the meal; our data are compatible with a mediation of this phenomenon by cholecystokinin.

Branched chain amino acids have been recommended for the treatment of portosystemic encephalopathy based on the false neurotransmitter hypothesis. This hypothesis implies that by correction of the deranged amino acid pattern in the blood of cirrhotics, false neurotransmission and then portosystemic encephalopathy is improved. We conducted a double-blind crossover placebo-controlled trial in 22 inpatients with liver cirrhosis and obtained evidence of latent (subclinical) portosystemic encephalopathy using an extensive psychometric test program. Patients received a defined diet of 35 cal/kg X day containing 1 g of protein. In addition, branched chain amino acids or casein in a dosage of 0.25 g/kg X day was administered in a crossover fashion, each for 1 wk. Semiquantitative nitrogen balance increased during both treatments, with a tendency of a larger increase during branched chain amino acid treatment. At the same time ammonia concentration tended to decrease during branched chain amino acid treatment. Taking into account the crossover design, significant improvements attributable to branched chain amino acid treatment could be demonstrated in psychomotor functions (line tracing, tapping, steadiness, auditory reaction time), attention (digit table), and practical intelligence (digit symbol, number connection test).

A controlled crossover study was performed in 8 diabetic patients with chronic portal-systemic encephalopathy. After a basal period the patients were treated during periods A and B. During period A, a meat protein diet (0.8 g/kg body wt, approximately 1800 kcal/day) was consumed and neomycin plus laxatives were given. During period B patients received vegetable protein (0.8 g/kg body wt, 1800 kcal/day). This diet was supplemented with psyllium fiber to reach 35 g of fiber per day. Four patients were randomly assigned to receive the treatments in the order A-B and the other 4 patients in the order B-A. At the end of the first experimental period, fasting glucose levels were 204 +/- 86 mg% in the meat protein diet group and 127 +/- 8 mg% in the vegetable protein diet group (p less than 0.014). The patients were receiving 2.5 +/- 0.2 g/day and 2.1 +/- 0.5 g/day of tolbutamide at the end of the meat protein diet and vegetable protein diet, respectively. In all cases, fasting glucose levels decreased at the end of the vegetable diet period regardless of the previous treatment. An improvement of greater than or equal to 25 mg% of fasting glucose levels was observed in 7 of the 8 patients after the vegetable protein diet and in no case after the meat protein diet (p less than 0.0078). The parameters of encephalopathy were comparable at the end of both the meat protein diet and the vegetable protein diet. A significant increase in the number of bowel movements was noticed after the vegetable diet plus fiber (p less than 0.01). We propose the use of vegetable diet plus fiber to facilitate the treatment of patients with both diabetes and hepatic encephalopathy.

A double-blind comparison of metoclopramide versus placebo was performed on 8 cirrhotic patients with nausea (8 cases) and heartburn (3 of the 8 cases) plus mild portal-systemic encephalopathy. As metoclopramide is a dopamine antagonist and dopamine-inadequate neurotransmission has been implicated in the pathogenesis of hepatic coma, this study was also designed to evaluate the effects of metoclopramide on mental state. The study included basal, placebo, metoclopramide, and final periods; each period lasted for 2 wk. Throughout the study patients received 3 g/day of neomycin and an 1800-cal diet containing 40 g/day of mixed protein. During the placebo and metoclopramide phases patients received either two 10-mg metoclopramide capsules t.i.d. or identical placebo capsules. During the study, biweekly liver function tests and portal-systemic encephalopathy parameters were evaluated. A self-evaluation for the presence of nausea and heartburn was also obtained. To monitor the dopamine-blockade effect of metoclopramide, serum prolactin levels were measured. Metoclopramide significantly suppressed the subjective signs of nausea (7 of 8 cases) and heartburn (all cases). Serum prolactin levels were 22 +/- 21 ng/ml, 30 +/- 31 ng/ml, 110 +/- 57 ng/ml (p less than 0.01), and 18.6 +/- 2 ng/ml during basal, placebo, metoclopramide, and final periods, respectively. In spite of these signs of dopamine blockade, no deterioration in mental state, asterixis, electroencephalograms, blood ammonia levels, or psychometric testings were observed. In addition, no extrapyramidal signs were noticeable during any period of the study. One patient presented transient somnolence at the end of the metoclopramide period. We conclude that dopamine blockade is not associated with the appearance of portal-systemic encephalopathy. Metoclopramide is a safe and effective treatment for nausea and heartburn in patients with advanced liver disease.

Thirty-eight patients with chronic active hepatitis type B received antiviral therapy. In one trial, 22 patients were randomized to either no treatment or treatment with a 28-day cycle of adenine arabinoside 5' monophosphate (ARA-AMP); in a second trial, 13 patients were randomized to no treatment or treatment with two 28-day cycles of ARA-AMP separated by a 4-wk rest interval; during a third trial, 11 individuals were treated with 8 wk of prednisone therapy followed by 28 days of ARA-AMP therapy. The response rate (73%) to the regimen with prednisone was significantly greater than that achieved in the first or second trial (0% and 15%, respectively). The data indicate that the combination of short-term prednisone and ARA-AMP therapy may offer more promise for successful treatment of chronic active hepatitis type B than does ARA-AMP alone. Synergism may possibly occur by the combined effects of immune rebound provided by corticosteroid withdrawal and the inhibition of viral proliferation by ARA-AMP.

We prospectively studied the changes of colonic mucosa in patients receiving two different preparations for colonoscopic examination. Eighteen consecutive patients undergoing colonoscopy for polyps or mass lesions, properly age- and sex-matched, were randomized to receive Golytely lavage (3-4 L) or a standard preparation (48-h clear liquid diet, 240 ml of magnesium citrate and "X-Prep" senna derivative). Patients with diarrhea or inflammatory bowel disease, or both, were excluded. Biopsy specimens were obtained from normal-appearing mucosa of the right and left side of the colon (none in the distal 10 cm of rectum). Blind review of coded slides was performed with 0-3 scoring for artifact, edema and hemorrhage of the lamina propria, surface epithelial and goblet cells, crypts, and cells in the lamina propria including eosinophils and polymorphonuclear leukocytes. Statistically significant differences were found for preservation of surface epithelial and goblet cells and less edema in favor of patients receiving Golytely. We conclude that the standard form of colon preparation flattens the surface epithelial cells and depletes the goblet cells as well as causes an increase in lamina propria edema, whereas colon lavage preserves normal mucosal histology.

Vitamin A therapy has been claimed in isolated reports to be of benefit to patients with Crohn's disease. To investigate this further, 86 patients were entered into a long-term double-blind study of vitamin A, 50,000 U twice daily, as compared with placebo. After a mean of 14.1 mo of treatment there was no significant difference between the groups as measured by a variety of activity indices (including the National Cooperative Crohn's Disease Activity Index), the number of acute attacks, and the surgical rate. No toxic effects of vitamin A were observed during the study. In this study vitamin A has not been shown to be of benefit to patients with Crohn's disease who are in remission.

Bicozamycin was compared with a placebo in a prospective, randomized, double-blind study of the prevention of acute diarrhea among 30 American travelers newly arrived in Guadalajara, Mexico. None of the 11 subjects given bicozamycin orally for 3 wk at a dosage of 500 mg four times a day developed diarrhea as compared with an incidence of 53% diarrhea (10 of 19 subjects) in the placebo group (p = 0.003). Bicozamycin was well tolerated. Studies of changes in predominant aerobic fecal flora among the 11 subjects treated with bicozamycin showed the appearance of only one highly resistant Citrobacter freundii at the end of 1 wk of therapy and only a total of six resistant isolates at the end of 3 wk. All resistant isolates failed to transfer this resistance to a recipient Escherichia coli. Bicozamycin seems to be well suited and safe as a prophylactic agent against traveler's diarrhea.

The impact of endoscope diameter and the presence of systemic sedation on the cardiopulmonary risk of esophagogastroduodenoscopy was investigated. One hundred and forty-six patients undergoing elective esophagogastroduodenoscopy were randomly assigned to one of three groups which differed in either endoscope diameter or use of sedation: group 1 (8.5-mm endoscope with no sedation), group 2 (8.5-mm endoscope with diazepam), and group 3 (11.5-mm endoscope with diazepam). Esophagogastroduodenoscopy was tolerated best by group 2, and this group had the fewest electrocardiographic changes observed on a Holter recording during esophagogastroduodenoscopy. The incidence of electrocardiographic changes during esophagogastroduodenoscopy correlated with patient tolerance (p less than 0.001) and the use of the smaller endoscope (p less than 0.05). The most common arrhythmia was sinus tachycardia (49 patients), but more serious electrocardiographic changes were observed in 21 patients. Serious arrhythmias were more common in patients with a prior history of cardiovascular disease compared with patients with no such history (30% vs. 6%, p less than 0.001). Arterial oxygen desaturation (measured by ear oximetry) during intubation and esophagogastroduodenoscopy was usually modest (2%-5%). However, 16 patients receiving diazepam experienced high levels of desaturation exceeding 7%; this small group of patients also experienced more electrocardiographic changes than other patients. The use of diazepam sedation and an 8.5-mm endoscope may offer the safest and most comfortable combination for most patients undergoing esophagogastroduodenoscopy. Diazepam sedation, however, may represent a potential danger to a small number of patients with marginal baseline arterial saturation.

We electively compared the distal splenorenal ("selective") shunt with the end-to-side portacaval shunt in 80 prospectively randomized patients with variceal bleeding. Selective shunts required more operative time (3.9 vs. 2.8 h) and blood replacement (4.6 vs. 2.5 U) and postoperative mortality was slightly higher (5 of 38 selective vs. 0 of 40 portacaval). Postoperative complication rates were similar. After 65-mo mean follow-up, both shunts have protected well against late gastrointestinal bleeding (5 selective, 4 portacaval episodes). However, after selective shunts, spontaneous encephalopathy occurred less often (23% vs. 40% of patients), was severe in fewer patients (12% vs. 33%), and precipitated fewer hospital admissions (6 admissions in 4 selective patients vs. 26 admissions in 13 portacaval patients). Furthermore, selective shunt patients remained longer without functional disability (83% vs. 70% of postoperative patient months). Long-term survival was not significantly different in the two groups (5-yr survival: selective 51%, portacaval 56%).

Although penicillamine is used in the treatment of primary biliary cirrhosis, its mechanism of action in this disease is unknown. As an immunologic action had been attributed to the drug, we investigated whether penicillamine might alter serum immunoglobulin levels or immune complex-reactive material in patients with primary biliary cirrhosis. Immunoglobulin levels and immune complex reactivity were measured and clinical tests were performed in 53 consecutive patients entering a double-blind randomized trial of 750 mg vs. 250 mg of penicillamine. Measurement of immune complex reactivity was determined by laser nephelometry, 125I-C1q binding, and Raji cell assays. Immune complex reactivity was detected by at least one assay in 75% of patients tested before treatment. Sixty-two percent were positive in the C1q assay, 28% in the Raji cell assay, and 39% by nephelometry. After therapy with either dose, we found no change in immune complex-reactive material by any assay. Concentrations of immunoglobulins G and M fell (p less than 0.05) after 12 mo of therapy. Concentrations of immunoglobulin A decreased (p less than 0.05) only in the high-dose group. Correlation was not consistent between results of immune complex assays and clinical liver tests. Although immunoglobulin levels fell during penicillamine therapy, no decrease in immune complex-reactive material was detected. The effect of penicillamine in primary biliary cirrhosis is not mediated through alteration of immune complex-reactive material.

The purpose of this study was to investigate the effects of cimetidine and ranitidine on human lower esophageal sphincter pressure (LESP) and plasma levels of gastrin in all phases of the interdigestive motor complex and after a test meal. In a random, double-blind manner, placebo, cimetidine (1.0 mg/kg X h), and ranitidine (0.16 mg/kg X h) were administered by intravenous infusion to nine healthy volunteers. By using a sleeve catheter assembly, LESP was constantly monitored, as were esophageal, fundic, antral, and duodenal pressures. Considerable minute-to-minute and interdigestive motor phase-related LESP variations were observed. Cimetidine and ranitidine decreased the interdigestive LESP, but did not abolish the gradual increase in LESP from phase I to phase III. During the first 2 h after the meal, cimetidine and ranitidine had no significant effect on LESP. Plasma gastrin levels were increased by cimetidine and ranitidine, both in the interdigestive and in the postprandial state. The results indicate that the effect of H2-blockers on LESP is not gastrin-mediated. The results further indicate that, in studies on the effects of drugs on LESP, prolonged recording of LESP in all motor states is a prerequisite.