Labyrinthine stimulation and cold pain inhibit feeding antral pressure activity, delay gastric emptying, and increase blood concentrations of beta-endorphin and norepinephrine. Further, labyrinthine stimulation induces, in approximately one-third of healthy individuals, a migrating burst of motor activity in the proximal intestine that interrupts the normal fed pattern. Our hypothesis was that endogenous opiates and catecholamines act as mediators of such disruptive effects of centrally acting stressful stimuli on gut motility. Thus, we studied feeding gastrointestinal pressure activity in healthy volunteers who were exposed to labyrinthine stimulation or cold pressure test, or both (both stimuli being either in their active or in their control forms), while receiving an intravenous infusion of either placebo (saline), or an opioid blocker (naloxone), or a combination of alpha- and beta-adrenergic blockers (phentolamine and propranolol), or all the drugs together. Neither opioid nor adrenergic blockers affected motility during control stimulations. Active stressful stimuli (labyrinthine stimulation, cold pain, or both) significantly inhibited antral feeding activity (p less than 0.05), but these effects were prevented by concomitant infusion of naloxone (p less than 0.05). Adrenergic blockade also prevented the antral motor inhibition caused by stress (p less than 0.05), but it was more effective for cold pain than for labyrinthine stimulation, and, when performed concomitantly with opiate blockade, the preventive effects disappeared. Furthermore, during adrenergic blockade labyrinthine stimulation invariably induced the appearance of a migrating duodenal burst of motor activity. Neither opioid nor adrenergic blockers modified the stress-induced rise of plasma beta-endorphin and norepinephrine. Our results suggest that opioids and catecholamines are involved in the mediation of the disruptive effects induced by centrally acting stressful stimuli on postprandial motor activity in the proximal human gut.

An efficacy trial of hepatitis B immune globulin in the prevention of perinatal transmission of hepatitis B virus infection was conducted in Los Angeles. Ten infants born to hepatitis B surface antigen (HBsAg)-and hepatitis B e antigen (HBeAg)-positive carrier mothers as well as 4 infants born to mothers with acute hepatitis B in the third trimester of pregnancy received hepatitis B immune globulin without randomization. Twenty infants born to HBsAg- and antibody to hepatitis B e antigen (anti-HBe)-positive carrier mothers were randomized to receive hepatitis B immune globulin or a placebo. All infants were followed for up to 18 mo. Four infants (2 born to HBeAg carrier mothers, 1 to an anti-HBe carrier, and 1 to a mother with acute hepatitis) became HBsAg-positive carriers, whereas another infant, whose mother was an HBeAg carrier, developed a transient anicteric hepatitis B infection. All infants who became infected did so after 9 mo of age as hepatitis B immune globulin protection waned. In infants born to HBsAg-positive carrier mothers, active immunoprophylaxis with the hepatitis B vaccine must be used in conjunction with hepatitis B immune globulin.

Measurements of biliary lipid secretion rates were performed in 10 patients with radiolucent gallstones before and after 4 wk of administration of chenodeoxycholic acid and ursodeoxycholic acid (1 g/day) in a randomized crossover study. The results of both bile acid feeding periods were similar in many respects: expansion of the bile acid pool, increase in bile acid and phospholipid secretion, reduction in cholesterol output, and decrease in percent saturation of hepatic bile, which was more pronounced with ursodeoxycholic than chenodeoxycholic acid therapy. Despite these similarities, the mechanisms by which these two litholytic bile acids induced these changes were quite different. Ursodeoxycholic acid, in contrast to chenodeoxycholic acid, only partially suppresses bile acid synthesis. During chenodeoxycholic acid feeding, the ratio of phospholipids to bile acids increased from 0.264 to 0.307 (p less than 0.05), indicating an increased coupling of phospholipids by chenodeoxycholic acid, whereas ursodeoxycholic acid did not alter this ratio. The molar ratio of cholesterol to bile acid during the chenodeoxycholic- and ursodeoxycholic-acid periods decreased significantly from 0.073 to 0.058 and 0.041, respectively. However, this ratio during the ursodeoxycholic-acid period was unchanged when the amount of ursodeoxycholic acid was subtracted from total bile acid (0.069), indicating that UDCA has little, if any, effect on the mobilization of hepatic cholesterol into bile.

We studied 20 critically ill patients receiving ventilatory support to determine both their metabolic requirements and the effect of providing energy substrate regimens containing different lipid to glucose calorie ratios on whole-body protein economy. The measurements used included indirect calorimetry, substrate hormone profile, and whole body protein turnover by [14C]leucine. Measurements were done while patients were receiving all their nonprotein calories as dextrose ( D100 ) and were compared with results obtained when they received all their nonprotein calories as a combination of dextrose and lipid in a calorie ratio either of 3:1 ( D75 ) or 1:3 ( D25 ). To maintain euglycemia, exogenous insulin was infused by attending physicians not cognizant of the total parenteral nutrition regimen used. Energy expenditure before receiving total parenteral nutrition was only 4.6% above basal, and did not rise significantly during any of the regimens. The insulin infusion rate, plasma insulin, CO2 production, and serum lactate were significantly higher with D100 than with D25 , but not with D75 . Correspondingly, plasma free fatty acids were significantly lower with D100 when compared with D25 but not with D75 . Despite this, there were no significant differences in whole-body protein synthesis, breakdown, or net synthesis (synthesis - breakdown) and, in general, the patients in all groups were close to zero protein balance. These data suggest that critically ill patients are not severely hypermetabolic, and that they can maintain protein balance with a modest excess of calories while using a wide range of fuel mixtures.

Aspirin and ethanol damage the gastric mucosa in humans, whereas acetaminophen does not. Acetaminophen increases prostacyclin activity in animals and thus may increase endogenous prostaglandin synthesis. The effect of acetaminophen was examined in five healthy subjects after intragastric aspirin or ethanol. Hydrogen and sodium ion fluxes were measured in the pylorus-occluded stomach that prevents duodenogastric reflux and gastric fluid losses. Studies were in random order and on 8 separate days. Potential difference was measured throughout and mucosal erosions were endoscopically quantitated (endoscopist masked, no premedication). The isoosmolar test solution (200 ml, 100 mM HC1, 54 mM mannitol, [14C]polyethylene glycol) was instilled into the stomach and removed 15 min later for four 15-min periods. Either aspirin (1300 mg) or ethanol (20% vol/vol) was added to the test solution only during the second 15 min. Acetaminophen (2600 mg) was given orally 1 h before aspirin or ethanol administration. To determine if the effect of acetaminophen was related to prostaglandin synthesis, prostaglandin production was inhibited with indomethacin (50 mg orally 12 h and 1 h before acetaminophen). Aspirin and ethanol alone each produced significant changes in net hydrogen and sodium fluxes, potential difference, and endoscopic changes. Acetaminophen significantly inhibited hydrogen ion flux, change in potential difference, and endoscopic damage; however, it did not totally abolish these changes. The protective effect of acetaminophen was abolished by pretreatment with indomethacin, suggesting that the effect of acetaminophen is likely to be prostaglandin-mediated. Indomethacin alone was without effect. These results demonstrate that oral acetaminophen protects the human gastric mucosa against the damaging effects of aspirin and ethanol.

The deleterious effects of aspirin on gastric mucosa have been well documented in experimental and clinical studies. Prostaglandins offer a potential method by which this injury may be prevented. In these studies, we developed a single-dose endoscopic assay system of aspirin-induced gastric mucosal injury in normal volunteers. With this system, 27 of 30 volunteers (90%) demonstrated severe mucosal injury after ingestion of aspirin. Subsequently, we evaluated whether pretreatment with 15-R-15 methyl prostaglandin E2 prevented severe injury after ingestion of aspirin. Following an initial dose-response study, a double-blind crossover trial was performed using pretreatment with placebo or with 10-micrograms doses of 15-R-15 methyl prostaglandin E2 for 24 h before treatment with aspirin. The results of this trial indicate that prostaglandin pretreatment significantly prevented the occurrence of endoscopically visible severe gastric mucosal injury after single-dose aspirin administration.

A multicenter double-blind study of the effectiveness of sulfasalazine and 6-methylprednisolone, alone and in combination, was conducted on 452 patients with Crohn's disease. One hundred sixty patients were previously untreated; 292 patients were previously treated. The Crohn's disease activity index (CDAI) was used to determine whether a patient had active (CDAI greater than or equal to 150, n = 215) or quiescent disease (CDAI less than 150, n = 237). Treatment of active disease consisted of high-dose 6-methylprednisolone, 6-methylprednisolone combined with 3 g of sulfasalazine, 3 g of sulfasalazine alone, or placebo, and lasted 6 wk. Patients in remission received maintenance doses of one of these drug regimens for periods of up to 2 yr. One hundred ninety-two patients completed the 2-yr study period. Results were evaluated using life-table analysis and outcome ranking. These methods showed 6-methylprednisolone to be the most effective drug in overall comparison of all patients (p less than 0.001); in previously treated patients (p less than 0.001); and in subgroups: active disease (p less than 0.001), only small bowel disease (p less than 0.05), and both small bowel and colon disease (p less than 0.05). Combination of 6-methylprednisolone and sulfasalazine was the most effective regimen in previously untreated patients (p less than 0.05) and when disease was localized in the colon (p less than 0.001). Sulfasalazine alone was least effective in overall comparison of all patients (p less than 0.05) and in all strata. Drug treatment was of no significant benefit to patients with quiescent disease. Continuous administration of low doses of 6-methylprednisolone, or the combination regimen, was beneficial in patients who responded initially to treatment of active disease. The addition of sulfasalazine, however, offered no advantage.

We studied the effects of the calcium-channel blocker nifedipine on esophageal smooth muscle function in 10 normal volunteers. Lower esophageal sphincter pressure and relaxation and esophageal contraction amplitude, peristalsis, velocity, and duration after wet swallows were determined before and for 120 min after the sublingual/buccal administration of placebo and of nifedipine in doses of 10, 20, 30, and 40 mg. Blood samples for measurement of plasma nifedipine concentration were obtained at baseline and every 30 min during this 120-min period. Nifedipine led to decreases in sphincter pressure of 13.3%, 29.9%, 34.3%, and 35.1% as the dose was increased from 10 mg to 40 mg. These changes were significantly (p less than 0.05) different from baseline and placebo for the 20-, 30-, and 40-mg doses and were more sustained with the higher doses, lasting as long as 90 min. Contraction amplitude fell 5.3%, 5.9%, 13.5%, and 19.6% at the corresponding doses. These changes were significantly (p less than 0.05) different from baseline and placebo only for the 30- and 40-mg doses, with the effect lasting up to 60 min. Peak plasma nifedipine concentration ranged from 28.7 +/- 3.7 ng/ml (mean +/- SEM) after 10 mg to 138.7 +/- 43.7 ng/ml after 40 mg of the drug, and occurred at either the 30- or 60-min measurement. The mean percent of decrease in sphincter pressure and contraction amplitude in the esophageal body correlated (p less than 0.001) with plasma nifedipine levels. There were no changes in sphincter relaxation or in peristalsis, velocity, or duration of contraction with any dose of nifedipine. It is concluded that (a) nifedipine significantly decreases lower esophageal sphincter pressure and contraction amplitude in the body of the esophagus, (b) the effect on sphincter pressure requires a lower dose of nifedipine and is more marked than that on contraction amplitude, and (c) the effects on both sphincter pressure and contraction amplitude correlate with plasma nifedipine levels. Calcium-channel blockers such as nifedipine may have a role in the treatment of motility disorders of the lower esophageal sphincter or esophageal body, and further controlled clinical studies are indicated.

Systemic and splanchnic hemodynamics, renal blood flow, and renal function were studied in 13 patients with cirrhosis both before and 1 h after oral administration of 40 mg of propranolol (acute administration) and 1 mo after continuous administration of this substance at doses reducing the heart rate by 25% (chronic administration). Cardiac output and the gradient between wedged and free hepatic venous pressures significantly decreased after acute and chronic administration of propranolol; mean arterial pressure did not change significantly and systemic vascular resistance significantly increased. Renal blood flow and renal vascular resistance did not change significantly after acute administration of propranolol and renal function did not change significantly after acute or chronic administration of propranolol. We conclude that propranolol does not alter renal function in patients with cirrhosis who are in good physical condition.

Twenty patients with chronic type B hepatitis were entered into a randomized, controlled study of adenine arabinoside monophosphate. Before entry, all patients were documented to have stable levels of hepatitis B surface antigen, hepatitis B e antigen, serum hepatitis B virus deoxyribonucleic acid, and deoxyribonucleic acid polymerase activity. Ten patients received adenine arabinoside monophosphate and 10 received no treatment. The two groups were well matched with respect to age, sex, known duration of hepatitis B surface antigen, presence of symptoms, serum aminotransferase levels, and hepatic histopathology. During the 4 wk of therapy, serum levels of hepatitis B virus fell dramatically. However, serum hepatitis B virus-deoxynbonucleic acid or deoxyribonucleic acid polymerase activity, or both, remained detectable, and levels of hepatitis B virus invariably rose once therapy was stopped. From 2 to 9 mo after therapy, 4 of the 10 treated patients became hepatitis B e antigen or hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase negative, or both, and the results of routine serum biochemical tests improved. However, 2 of these 4 patients later relapsed. In the control group, 2 patients became seronegative for hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase and manifested improvement in serum biochemical results by 18-24 mo after randomization. Thus, long-term improvements in clinical and serologic features of disease occurred in 20% of both treated and control patients. Side effects of adenine arabinoside monophosphate therapy were common, and 3 patients developed a severe and prolonged neuropathic pain syndrome. These results suggest that a 4-wk course of adenine arabinoside monophosphate therapy does not induce an increased rate of long-term remissions in chronic type B hepatitis.

In a placebo-controlled, double-blind, crossover, and randomized trial, the effect of 30, 60, and 90 mg of oral omeprazole on peptone-stimulated gastric acid secretion and synchronously measured gastrin release was studied in 8 healthy subjects. Peptone-stimulated acid output was reduced dose-dependently by 42%, 80%, and 92%, respectively. In spite of a short mean plasma half-life of 52 min, the inhibitory effect lasted for greater than 4.5 h and was significantly correlated to the area under the plasma concentration time curve for omeprazole. Mean basal serum gastrin and gastrin profiles increased insignificantly without alteration of integrated gastrin output and did not show any correlation either to the omeprazole area under the plasma concentration time curve or to the inhibition of peptone-stimulated acid secretion. Side effects, significant alterations of laboratory screen, or alterations of serum concentrations of thyroid hormones were not detected. In conclusion, omeprazole is a potent and, under the conditions tested, well-tolerated inhibitor of meal-stimulated gastric acid secretion in humans.

Eighteen patients with active Crohn's disease entered an open trial with 5-aminosalicylic acid in a slow-release preparation. All had lesions of the small bowel. Ten of them also had Crohn's disease of the colon. 5-Aminosalicylic acid, 500 mg three times daily, was administered for 6 wk. Even with meticulous monitoring, no side effects of any kind were observed, particularly no cases of renal affection, which could have been expected from animal studies. The clinical course was estimated as improved in 13 patients (72%), unchanged in 2 patients (11%), and aggravated in 3 patients (17%); 2 of these 3 were withdrawn from the study and switched to alternative treatment. The Crohn's disease activity index decreased from a median of 226 points to 99 points. On the basis of these results, large-scale controlled therapeutic trails seem warranted in order to establish clinical evidence for the benefit of peroral treatment with 5-aminosalicylic acid in patients with Crohn's disease.

In a double-blind controlled study of ursodeoxycholic acid (400 and 800 mg/day) and chenodeoxycholic acid (375 and 750 mg/day), in comparison with placebo, ursodeoxycholic acid was significantly more effective than chenodeoxycholic acid in dissolving gallstones after 12 mo of treatment. Although there continued to be better dissolution during ursodeoxycholic acid treatment (dissolution complete in 30% and partial in another 30% of the patients) than during chenodeoxycholic acid treatment (dissolution complete in 7% and partial in 40%) at 24 mo, this difference between the treatment groups was no longer statistically significant. The incidence of floating stones was significantly higher in the patients who dissolved their stones than in those who did not (p less than 0.001). The three failures of dissolution of floating stones during bile acid treatment were associated with chenodeoxycholic acid therapy--two of them with the 750-mg and the third with the 375-mg doses. Gallstone dissolution with ursodeoxycholic acid occurred in spite of a rise in biliary cholesterol saturation, which was consistent with a nonmicellar mechanism of cholelitholysis. Furthermore, more than threefold serum elevations of L-alanine aminotransferase were observed only during chenodeoxycholic acid therapy. They occurred in 2 patients treated with 375 and 750 mg/day, respectively. The enzyme levels normalized after discontinuation of chenodeoxycholic acid and have remained normal for 13 and 8 mo, respectively, after the institution of treatment with 800 mg/day of ursodeoxycholic acid. There was no correlation between the liver tests and biliary levels of lithocholic acid. Of all the symptoms studied, only constipation showed changes that approached statistical significance (p = 0.0681). There was a significant improvement of constipation in the combined chenodeoxycholic acid groups when they were compared with the combined ursodeoxycholic acid groups. The total bile acid pool expanded significantly in both the chenodeoxycholic acid and in the 800-mg ursodeoxycholic acid treatment groups. The marked increases of biliary ursodeoxycholic acid and chenodeoxycholic acid, respectively, indicated compliance with the treatment in all but 1 bile acid-treated patient. Neither serum triglycerides nor serum cholesterol showed significant changes in any of the treatment groups. The study shows that ursodeoxycholic acid dissolves gallstones faster and with fewer side effects than chenodeoxycholic acid. The results of the study are also consistent with the view that ursodeoxycholic acid is cholelitholytic at a lower dose than is chenodeoxycholic acid.

Enterotoxigenic Escherichia coli cause most traveler's diarrhea in Third World countries. We tested bismuth subsalicylate as prophylactic therapy and as treatment for enterotoxigenic E. coli-induced diarrhea. Thirty-two healthy hospitalized volunteers were challenged orally with enterotoxigenic E. coli, strain H10407 (serotype 078:K80:H11). Administration of 600-mg doses of bismuth subsalicylate or placebo was begun 8 h before bacterial challenge. Doses were taken at 8 h and 2 h before, and at 2 h and 4 h after, the E. coli challenge and were continued four times a day for 3 additional days. The maximum prophylactic bismuth subsalicylate dose was 9.6 g. Those experiencing diarrhea were rerandomized to receive bismuth subsalicylate or placebo, given as 300 mg every 30 min for a total of 2.4 g of bismuth subsalicylate, in eight doses. Diarrhea occurred in 9 of the 16 (56%) subjects receiving placebo and in 2 of the 15 (13%) subjects receiving bismuth subsalicylate, p less than 0.03. This study confirms the effectiveness of bismuth subsalicylate in preventing traveler's (enterotoxigenic E. coli) diarrhea, and shows that bismuth subsalicylate in other than liquid form is effective. Enterotoxigenic E. coli were recovered less frequently from those receiving bismuth subsalicylate than from those receiving placebo, suggesting that bismuth subsalicylate prevents diarrhea by reducing the number or multiplication of enterotoxigenic E. coli. In vitro studies revealed that bismuth subsalicylate and its components each were bactericidal at concentrations possibly attained during the clinical trial.

This study was designed to compare the rates of duodenal ulcer healing and recurrence after treatment with cimetidine or antacid. Patients with endoscopically documented duodenal ulcer received cimetidine, 1200 mg daily, or Mylanta II, 7 oz daily, in a randomized, double-blind trial. For the 69 patients in each group who completed the healing phase of the trial, endoscopic ulcer healing was almost identical. At 2, 4, and 6 wk, the cumulative percent healed on antacid was 33%, 64%, and 80%, and on cimetidine it was 25%, 62%, and 86%. The 114 patients with healed ulcer were observed on no therapy and underwent additional endoscopy to detect recurrences when symptomatic or at 3, 6, and 12 mo. There was no difference in the frequency of recurrences between treatments. At 3 and 6 mo, the cumulative percentages of patients with recurrence were 29% and 56% after antacid therapy and 36% and 55% after cimetidine therapy. Some patient variables were associated with delayed ulcer healing or ulcer recurrence. These included sex, pain frequency, smoking, disease duration, and acid secretion.

There are conflicting reports on the influence of cigarette smoking on healing in patients with duodenal ulcer; some studies show an adverse effect on healing rate and others no effect. This study reports the influence of smoking on short-term healing and relapse rate in 135 patients with duodenal ulcer who were treated with cimetidine (90), ranitidine (25), and oxmetidine (20), all powerful H2-receptor antagonists. Ulcer healing and relapse were documented endoscopically and all studies were performed in a double-blind manner. In the short term, 95% of nonsmokers healed compared with 63% smokers (p less than 0.01) and there was a positive correlation between failure to heal and number of cigarettes smoked. During a 12-mo follow-up examination after healing and on no treatment, 53% of nonsmokers and 84% of smokers relapsed (p less than 0.01). These results show that smoking adversely affects healing of duodenal ulcer with H2-receptor antagonists and that continued smoking leads to a higher relapse rate.

We have investigated the fasting and postprandial patterns of gastrointestinal pressure activity in a group of patients with extensive (greater than 100 cm) resections of the distal small bowel. Each short bowel patient was studied on 2 consecutive days with random single blind administration of either loperamide (6 mg at 5 h and at 30 min before the meal) or placebo, and 20 healthy controls were studied on single days (13 basal fasting, 7 placebo). During fasting, the duration of the interdigestive motor complex was significantly shorter in patients with short bowel syndrome (71.1 +/- 15.6 min vs. 109 +/- 7.8 min for controls, p less than 0.03); hence, the frequency of complexes was increased. The duration of phase 2 was strikingly shorter in patients (18.7 +/- 7.0 min vs. 52.9 +/- 8.5 min for controls, p less than 0.03). Gastric emptying and postprandial motor activity were identical in patients and controls. During fasting, loperamide prolonged phase 3 (7.6 +/- 2.2 min vs. 4.3 +/- 1.1 min for placebo, p less than 0.03). Postprandially, loperamide shortened the time from meal ingestion to the first phase 3 by 50% (p less than 0.003), and increased motility index and frequency of contraction in the gut (p less than 0.01). Thus, gut motor activity in the short bowel syndrome is characterized by more frequent interdigestive motor complexes, marked reduction in phase 2 activity, and a normal feeding pattern. Loperamide therapy increases feeding activity while at the same time shortening its duration.