To determine the relation between the sensation of pain in gastroesophageal reflux and the pH of the refluxate, we studied 25 individuals with symptomatic gastroesophageal reflux and positive Bernstein tests. We quantitatively assessed the sensitivity of the esophageal mucosa to pain associated with the intraesophageal infusion of eight different HCl solutions (pH 1, 1.5, 2, 2.5, 3, 4, 5, and 6). Test solutions were infused at 8 ml/min through an eight-lumen catheter with the orifices placed 5 cm above the lower esophageal sphincter. Each subject received all eight solutions in a double-blind randomized fashion. The time-to-pain onset increased with increasing pH; i.e., there was a highly significant difference between the time-to-pain and pH (p less than 0.001), with the time-to-pain significantly longer with increasing pH (r = 0.77). In addition to more rapid onset of pain, all subjects experienced pain with the pH 1 and 1.5 solutions, 80% had pain with the pH 2.0 solution, and half had pain with solutions of pH 2.5-6. Fifteen of these subjects underwent 24-h pH monitoring and these tests were examined for factors associated with pain. Only 64% of all pain episodes were associated with a pH drop of less than 4; the lowest pH obtained was not different between episodes with and without pain. Reflux episodes resulting in pain were significantly longer than those without pain and were more often associated with a recently preceding painful episode. Overall, none of the data from the 24-h pH monitoring was useful for predicting pain. The acid infusion studies and the 24-h pH data, taken together, suggest episodes of pain sensitize the patient for subsequent pain.

Ninety-seven patients with recent or active variceal bleeding were randomly assigned to oral propranolol, endoscopic sclerotherapy plus oral propranolol, or transhepatic sclerotherapy plus oral propranolol. The effects of treatment on the number of units transfused, rebleeding of any magnitude, major rebleeding, and death were assessed in these patients, 82% of whom were alcoholic and 81% Child's Class C. After a minimum follow-up interval of 2 yr (range, 27-65 mo), major rebleeding rates were 65% for propranolol alone, 45% for endoscopic sclerotherapy plus propranolol, and 60% for transhepatic sclerotherapy plus propranolol. The corresponding death rates were 81% for propranolol alone, 55% for endoscopic sclerotherapy plus propranolol, and 66% for transhepatic sclerotherapy plus propranolol (p = 0.03). Thirty-three patients (34%) never received propranolol; 8 due to medical contraindications and 25 because they died or bled enough to meet the definition of treatment failure within 3 or 4 days of randomizations (no significant differences among treatment groups). Patients assigned to propranolol alone bled sooner, bled more units, and had a higher mortality rate than patients treated by endoscopic sclerotherapy plus propranolol. Patients treated with transhepatic sclerotherapy plus propranolol had intermediate results. Propranolol alone is inadequate treatment for esophageal variceal bleeding in patients with advanced liver disease.

We have investigated the effect of oral cisapride (10 mg t.i.d.) in a double-blind, placebo-controlled trial in 26 patients with upper gut dysmotility: 11 with gastroparesis (8 diabetic, 3 idiopathic) and 15 with chronic idiopathic intestinal pseudoobstruction. Patients were evaluated at entry and at the end of the 6-wk study by upper gastrointestinal manometry, scintigraphic evaluation of gastric emptying of solids and liquids, measurement of body weight, and scoring of the following symptoms: abdominal pain, nausea, vomiting, early satiety, bloating, and distention. Cisapride and placebo groups were strictly comparable for all parameters assessed. Cisapride resulted in a significant increase in the gastric emptying of solids (p less than 0.05) compared with placebo; cisapride also tended to increase the postcibal antral motility and normalize the abnormal manometric features in the patients with intestinal dysmotility, particularly the characteristics of fasting interdigestive motor complexes and the fed motor pattern. Both cisapride and placebo groups showed an improvement in total symptom scores and there was no significant difference in overall symptom response between the two groups. However, the change in abdominal pain was greater with cisapride (p = 0.07). Cisapride facilitates gastric emptying in patients with upper gut dysmotility. The overall symptomatic benefit during a 6-wk trial of cisapride, 10 mg t.i.d., was not greater than that of placebo, and dose-response as well as longer term trials are necessary to determine the clinical efficacy of this medication.

To examine the premise that exercise reduces the gastrointestinal transit time, we evaluated the effect of walking 4.5 km in an hour on mouth-to-cecum transit time. Twenty-three healthy volunteers, 9 men and 14 women, with an age range of 19-28 yr, were studied. After an overnight fast, the subjects ingested 10 g of lactulose in 150 ml of water while breath hydrogen concentrations were analyzed at 15-min intervals. On separate days, in random sequence, subjects either sat in a chair or walked on a treadmill for 60 min. Mean transit time was 55 +/- 8 min when resting and 89 +/- 4 min when exercising (p less than 0.001). In conclusion, light aerobic exercise prolonged the mouth-to-cecum transit time. On the basis of this observation, exercise as a causative factor in runner's diarrhea and its value in the management of chronic constipation may be questioned.

Chronic use of cimetidine and alcohol are commonly associated, but studies on their interactions are the subject of controversy. To investigate this question, a small ethanol dose (0.15 g/kg body wt) was randomly administered on 2 consecutive days either orally or intravenously to 6 normal volunteers, before and after 1 wk of oral administration of 400 mg of cimetidine twice daily. Although cimetidine did not change the areas under the curve of blood ethanol concentrations after intravenous administration, those after oral alcohol intake were twice as large with cimetidine than without. Similar effects were reproduced in rats after intravenous administration of cimetidine (50 mg/kg body wt). In vitro, cimetidine was a noncompetitive inhibitor of gastric alcohol dehydrogenase activity at concentrations as low as 0.01 mM, 100-fold lower than those needed to inhibit the hepatic dehydrogenase. These results indicate that gastric alcohol dehydrogenase activity governs, in part, the systemic bioavailability of ethanol. Consequently, systemic effects of alcohol may be exacerbated in patients receiving cimetidine.

To assess the gastric mucosal protective action of sucralfate against alcohol, a double-blind, controlled, randomized study was carried out in 12 healthy adult men. All subjects received four treatments in a random sequence: sucralfate + ethanol, sucralfate + ethanol placebo, sucralfate placebo + ethanol, and sucralfate placebo + ethanol placebo. Fundal, antral, and duodenal mucosae were submitted to endoscopic examinations, and the antral mucosa underwent histologic examination before and after injury. Biopsy specimens were taken from the antral mucosa to determine by radioimmunoassay its capacity to synthesize prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha. In both the fundus and the antrum, the mean endoscopic injury score after sucralfate plus ethanol administration was significantly lower than that after ethanol alone. All treatments tended to increase prostanoid values but 6-keto prostaglandin F1 alpha increased significantly when sucralfate was given. Sucralfate did not affect serum ethanol levels, nor did ethanol affect prostanoid synthesis. It is concluded that sucralfate provides significant protection to the human gastric mucosa against ethanol injury, and that this may be partly due to increased prostanoid synthesis.

A controlled, randomized trial of a short-term, medium-dose combination therapy of beta- and gamma-interferon was performed in 20 patients with chronic active hepatitis B. According to clinical, biochemical, and histologic findings that were followed up for 16-24 mo, the combined treatment was successful in 5 of 10 patients. Two of the patients eliminated the virus completely, as confirmed by Southern blotting of hepatocellular deoxyribonucleic acid (DNA) against hepatitis B virus DNA. In the other 3 responders hepatitis B surface antigen persisted in the absence of hepatitis B e antigen, replicating hepatitis B virus DNA in the liver and inflammatory disease activity. Two of these responders with persistent hepatitis B surface antigen had hepatitis B virus DNA integrated into the hepatocyte genome and 1 responder had nonreplicating, episomal virus DNA. In the control group of 10 patients one spontaneous remission occurred. Antiviral treatment was significantly (p less than 0.05) more successful within the first 4 yr after infection (5 responders of 6 treated patients) than after longer disease duration (no responder of 4 treated patients). The results of this pilot study suggest that a combination of beta- and gamma-interferon may be an effective therapy for chronic active hepatitis B when started early after infection.

Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid production and may augment mucosal defense. A double-blind trial examined the effect of misoprostol on the endoscopic appearance of gastroduodenum at the end of 1 wk of aspirin ingestion. One hundred thirty healthy subjects were randomized to take either 50, 100, or 200 micrograms of misoprostol, or placebo along with 975 mg of aspirin four times daily. Fewer subjects developed acute endoscopic gastric ulcers in the group taking any dose of misoprostol compared with the placebo group (1% vs. 43%). No subject taking the 100- or 200-micrograms dose of misoprostol developed an acute endoscopic duodenal ulcer compared with 13% of subjects taking placebo (p less than 0.05). Significantly fewer subjects developed gastric erosions and significantly fewer subjects developed duodenal erosions in each of the three groups taking misoprostol compared with the placebo group (p less than 0.01). There were fewer subjects with a gastric erosion (p less than 0.05) and fewer subjects with a duodenal erosion (p less than 0.05) in the group taking the 200-micrograms dose compared with the group taking the 50-micrograms dose of misoprostol. Gastrointestinal symptoms causing a modification in usual activities were infrequent but there was significantly more diarrhea in the 200-micrograms misoprostol group. There was no correlation between endoscopic scores and symptoms in any group. We conclude that misoprostol can protect the normal gastroduodenum from acute ulceration and reduce the chance of erosion after 1 wk of aspirin ingestion.

In a double-blind, randomized, multicenter trial 150 consecutive outpatients with endoscopically verified duodenal ulcer were treated with either a low-dose antacid regimen (1 tablet q.i.d.; acid-neutralizing capacity, 120 mmol/day), or cimetidine (800 mg nocte). After 4 wk of treatment control gastroscopy showed ulcer healing in 54 of 76 patients (71.1%) in the antacid group, as compared with 58 of 74 patients (78.4%) in the cimetidine-treated group. The difference in healing rate of 7.3% (95% confidence interval, -6.5% to +21.1%) was not statistically significant. The symptomatic effect, measured as number of days and nights with ulcer pain, was also quite similar in the two treatment groups. However, the number of days with pain was significantly lower in the first week of treatment in the antacid group (p less than 0.01). Thus, the efficacy of a low-dose antacid tablet regimen approximated that of cimetidine (800 mg nocte) in the treatment of duodenal ulcer patients.

The results of a clinical trial comparing slow-release 5-aminosalicylic acid tablets (Pentasa) and enteric-coated sulfasalazine tablets (Salazopyrin) with regard to the efficacy of maintaining ulcerative colitis patients in remission for 12 mo and with regard to safety of treatment are reported. Seventy-five patients with ulcerative colitis in remission for between 1 mo and 5 yr were included for analysis. Forty-nine men and 26 women, aged between 18 and 79 yr, received either Pentasa t.i.d. (1500 mg) plus Salazopyrin placebo or Salazopyrin t.i.d. (3 g) plus Pentasa placebo daily. Patients were assessed clinically, endoscopically, and histologically before and 3, 6, 9, and 12 mo after the start of treatment. Life-table analysis showed ongoing remission after 6 and 12 mo for Pentasa to be 63% (26 of 41) and 54% (22 of 41) and for Salazopyrin 72% (22 of 31) and 46% (14 of 31). These differences were not statistically significant. Three patients treated with Salazopyrin were withdrawn because of severe erythrodermia, anxiety and backache, and pregnancy, respectively. One patient on Salazopyrin experienced transient rises in serum urea, creatinine, and lactic dehydrogenase and another patient in this group reported slight reversible loss of hair. In the Pentasa group no side effects were recorded. We conclude that Pentasa is a well-tolerated drug, equally effective as Salazopyrin in maintenance of remission of ulcerative colitis.

The purpose of this pilot study was to determine whether daily administration of cyclosporin A to symptomatic patients with primary biliary cirrhosis for 1 yr would lead to a significant and sustained improvement in liver enzyme abnormalities. Twelve adult patients (11 female, 1 male; aged 52.6 +/- 8.9 yr, mean +/- SD) with serologic and histologically defined primary biliary cirrhosis were randomized to receive either oral cyclosporin A or vehicle placebo. Cyclosporin A was administered at sufficient dosages to maintain serum radioimmunoassay trough levels between 100 and 200 ng/ml (starting dosage, 2.5 mg/kg.day). After 1 yr of therapy, significant changes from pretreatment values were seen only in recipients of cyclosporin A. These included a 37% decrease in mean serum alkaline phosphatase and a 43% decrease in gamma-glutamyltransferase (controls +3% and -14%, respectively). Mean serum bilirubin and albumin levels and prothrombin times remained unaltered in the two groups, as did the extent of inflammation and fibrosis and the histologic staging of liver biopsy specimens. Although mean serum creatinine levels increased by 51% in recipients of cyclosporin A (+2% in controls), there were no associated changes in diastolic blood pressure or creatinine clearance values. Other side effects including thrombocytopenia, hirsutism, headaches, tremor, and parasthesiae were common in the treated group but not of sufficient severity to warrant adjustment in the dosage or discontinuation of therapy. The observed changes in hepatic, renal, and hematologic tests tended to return to baseline after discontinuation of therapy. Two patients, both placebo recipients, died of liver failure during the study period. The results of this study indicate that in symptomatic primary biliary cirrhosis, cyclosporin A administration is associated with a significant improvement in cholestatic liver enzyme abnormalities that persists for the duration of therapy. A progressive rise in serum creatinine levels and a high incidence of side effects raise concerns regarding the long-term safety of this agent in primary biliary cirrhosis.

As pectin delays gastric emptying in normal subjects and satiety may be linked to the rate of gastric emptying, we designed this study to evaluate, in a group of obese subjects, the effect of adding pectin to a meal on gastric emptying, sensation of satiety, and postprandial plasma cholecystokinin and pancreatic polypeptide levels. We studied gastric emptying of solids in 9 adult obese subjects on 2 separate days in a randomized fashion. On day 1, 15 g of pectin was added to the meal, and on day 2 15 g of methylcellulose was added and served as control. Satiety was evaluated by an analogue rating scale. Pectin significantly delayed gastric emptying time [t1/2 = 116 +/- 23 min vs. 71 +/- 17 min observed with methylcellulose (p less than 0.001)]. Pectin also significantly increased subjects' sensation of satiety [98 +/- 7 vs. 74 +/- 17 (p less than 0.001)]. Postprandial release of cholecystokinin and pancreatic polypeptide was not modified by pectin. As pectin induces satiety and delays gastric emptying in obese patients, it may be a useful adjuvant in the treatment of disorders of overeating.

Forty-five patients with chronic hepatitis B were entered into a randomized controlled trial of recombinant human alpha-interferon therapy. All patients had hepatitis B surface antigen in serum for at least 1 yr and had stable serum levels of both hepatitis B virus deoxyribonucleic acid and hepatitis B e antigen. During the 4-mo period of therapy, 10 of 31 (32%) treated patients and only 1 of 14 (7%) control patients became negative for serum hepatitis B virus deoxyribonucleic acid and deoxyribonucleic acid polymerase. All 10 patients who became negative for serum hepatitis B virus deoxyribonucleic acid subsequently had a marked improvement in serum aminotransferase activities and lost hepatitis B e antigen from serum, and 9 of them had improvement in liver histology. Comparison of responders to nonresponders indicated that female sex and a high initial level of serum aspartate aminotransferase correlated best with response to interferon therapy. These findings indicate that a 4-mo course of recombinant alpha-interferon can induce a remission in disease in approximately one-third of patients with chronic hepatitis B.

We conducted a double-blind, placebo-controlled, randomized treatment study in Peruvian adults with antral gastritis associated with Campylobacter pylori. Patients received either 400 mg of furazolidone (n = 14), 400 mg of nitrofurantoin (n = 24), or a placebo (n = 31) for 14 days. Endoscopy was carried out at baseline, 1 day after ceasing therapy, and 6 wk after the end of treatment to verify colonization by C. pylori and determine the extent of gastric inflammation. Treatment with nitrofurantoin or furazolidone markedly reduced or, in some cases, cleared C. pylori from the antrum (p less than 0.0005 compared with placebo). Resolution of acute gastric inflammation, as evidenced by decreased polymorphonuclear leukocyte infiltration and regeneration of the mucus layer, paralleled the reduction in bacterial colonization (p less than 0.005 compared with placebo). A high percentage of patients experienced relapse (recolonization by C. pylori and return to pretreatment levels of gastritis) within 6 wk after cessation of treatment. Significant relief of dyspeptic symptoms was not evident during the study.

The indirect, noninvasive technique of breath hydrogen (H2) analysis was evaluated in 45 patients suspected of having bacterial overgrowth of the small intestine. Bacterial overgrowth, defined as a jejunal culture yielding at least 10(5) organisms/ml, was present in 27 patients. After dietary preparation and a 12-h fast, subjects received in random order and on separate days 50 g of glucose or 50 g of rice flour in the form of two pancakes. Normal values were established in 20 healthy controls. Twelve of 27 patients with proven bacterial overgrowth had an elevated (greater than 15 ppm) fasting breath H2 level on at least 1 test day. Fifteen of 18 patients with negative cultures had low fasting breath H2 levels. Based on values in controls, a positive breath test was defined as an increase in breath H2 of greater than or equal to 12 ppm after glucose or greater than or equal to 14 ppm after rice flour. A 2-h glucose breath H2 test had a sensitivity of 93% and a specificity of 78% in the diagnosis of overgrowth. The predictive value of a positive test was 86% and that of a negative test was 88%. The combination of both a high fasting breath H2 level and a diagnostic rise of breath H2 after glucose was present in 41% of patients with overgrowth and in none of the patients without overgrowth. Extending the test to 4 h did not increase sensitivity, but decreased specificity. Rice flour was a less satisfactory substrate in predicting the presence of bacterial overgrowth. In conclusion, a high fasting breath H2 level after dietary preparation suggests bacterial overgrowth but lacks sensitivity. The finding of a rise in breath H2 of at least 12 ppm within 2 h of a 50-g glucose challenge is a simple screen for bacterial overgrowth. The combined criteria of a high fasting breath H2 level and a significant rise after glucose are specific for bacterial overgrowth.

We evaluated the therapeutic efficacy of penicillamine in primary sclerosing cholangitis. In a randomized, prospective, double-blind trial, 39 patients received penicillamine (250 mg t.i.d.) and 31 received a placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, radiologic, and hepatic histologic features. Although a predictable cupruresis and a decrease in levels of hepatic copper were achieved in patients taking penicillamine, there was no beneficial effect on disease progression within 36 mo or on overall survival. Progressive symptoms, deterioration in serial hepatic laboratory values, or histologic progression on sequential liver biopsy specimens were similar in both groups, occurring in greater than 80% of the entire study population. The development of major side effects led to the permanent discontinuation of penicillamine in 21% of the patients taking the drug. We conclude that the use of penicillamine in primary sclerosing cholangitis is not associated with a beneficial effect on disease progression or survival, and has considerable toxicity. The study also suggests that primary sclerosing cholangitis is a progressive disease in many patients.

We have studied the response of erosive or ulcerative esophagitis to treatment with omeprazole and its subsequent relapse on cessation of therapy in 196 patients. In the first phase of the study omeprazole (20 or 40 mg daily) was compared with placebo in 64 patients. After 4 wk there was endoscopic healing in 81% (25 of 31) of omeprazole-treated patients and in only 6% (2 of 32) of placebo-treated patients. Endoscopic healing of esophagitis was accompanied by symptom relief and histologic healing of ulceration. In the second (dose finding) phase a further 132 patients were randomized to omeprazole (20 or 40 mg daily) and endoscopic healing was assessed. In patients with the mildest grade of ulcerative esophagitis (grade 2), healing occurred at 4 wk in 87% receiving 20 mg and in 97% receiving 40 mg. In patients with grade 3 esophagitis, 67% (20 mg) and 88% (40 mg) were healed. Less than half the patients with grade 4 esophagitis (Barrett's ulcers or confluent ulceration) healed with either 20 mg (48%) or 40 mg (44%). Regression analysis in the 164 omeprazole-treated patients showed no evidence that healing was influenced by factors other than severity of esophagitis at entry and omeprazole dose. In phase 3 of the study the rate of endoscopic relapse was determined in 107 endoscopically healed patients after stopping omeprazole. Erosive or ulcerative esophagitis recurred in 88 of 107 (82%) by 6 mo. Neither initial dose, grade of esophagitis, nor smoking was shown to influence relapse rate. Omeprazole is a highly effective treatment for peptic esophagitis. The 40-mg/day dosage produces endoscopic healing slightly more quickly than the 20-mg/day dosage, and the initial endoscopic gradings are of prognostic value. Relapse occurs rapidly when treatment is stopped.

Antral biopsy specimens from 89 consecutive patients with nonulcer dyspepsia and erosive prepyloric changes included in a prospective, randomized, double-blind 4-wk study of the effect of an aluminum-magnesium antacid (120 mmol/day) or pirenzepine (50 mg b.i.d.) vs. placebo were examined histologically. Campylobacter pylori (CP) was found by light microscopy of silver-stained sections in 25 patients (28%). Campylobacter pylori-positive patients were on average older than CP-negative patients (p = 0.02). There was a strong association between CP colonization and acute inflammation (p less than 0.001), both being rare in the absence of chronic inflammation. During treatment with antacids, the density of CP decreased (p less than 0.001) without any improvement of the inflammatory reaction. On the contrary, the number of patients with gastritis tended to increase after antacids as compared with placebo (p less than 0.10). A separate analysis showed no symptomatic effect of the drugs. Thus, neither nonulcer dyspepsia nor erosive prepyloric changes are strongly associated with antral CP colonization or acute inflammation. Aluminum-magnesium antacids may suppress antral CP infection without healing the gastritis or relieving symptoms.

In spite of the widespread use of the Garren-Edwards gastric bubble as an adjuvant device in weight reduction, its efficacy has not been established. Therefore, our purpose was to conduct a randomized, double-blind, crossover study of this device in the management of exogenous obesity. The study group consisted of 23 patients, 21 women and 2 men, ranging in age from 21 to 53 yr. Patients were 25%-111% above their ideal body weight. They were studied for 24 wk, consisting of two separate 12-wk evaluation periods. Patients were randomly assigned either to receive the gastric bubble or to have a sham procedure. After the first 12-wk evaluation period, the gastric bubble and sham were administered in crossover fashion, so that those who had received the gastric bubble initially received the sham later and vice versa. The study coordinator remained blind to the kind of treatment, weighed each patient biweekly, enforced dietary counseling, and provided behavior modification. Those who had passed or were found to have a deflated bubble at the end of the treatment period were excluded from the study. Mean weight reduction in the two evaluation periods did not differ significantly. Patients lost 5.4 +/- 1.7 kg (mean +/- SE) during the gastric bubble period and 5.20 +/- 0.8 kg during the sham period. The order of administration of the gastric bubble and sham did not significantly affect the result. The time-course of mean biweekly values, however, revealed that with the gastric bubble, weight loss was significantly greater only during first (p less than 0.005) and second (p less than 0.025) 2-wk evaluation periods. This difference, however, disappeared after the initial 4 wk of treatment. These observations suggest that although gastric bubble implantation reduced weight significantly more than the sham procedure initially, the mean weight loss during 12 wk of evaluation was not different between the two periods. In our opinion, the gastric bubble is of no value as an adjuvant device in weight reduction.