Large doses of recombinant leukocyte A interferon were administered to 20 patients with deoxyribonucleic acid polymerase- and hepatitis B e antigen-positive chronic hepatitis B to study the maximum tolerated dose, its pharmacokinetics, and its antiviral activity. The first group of 5 patients received a constant dose of 36 X 10(6) U/day for 28 consecutive days. When it was well tolerated, the second, third, and fourth groups (5 patients each) received 50, 72, and 100 X 10(6) U/day, respectively. All 20 patients completed the 28-day treatment. Hourly and daily profile of serum interferon level showed a dose-dependent effect with an increasing dosage, and cumulative effects during the treatment. The mean peak serum interferon concentration ranged from 93 U/ml on day 1 in the first group to 1271 U/ml on day 28 in the fourth group. Inhibition of serum deoxyribonucleic acid polymerase activity and hepatitis B virus-deoxyribonucleic acid during the treatment was compared between the groups with low doses (36 and 50 X 10(6) U) and high doses (72 and 100 X 10(6) U). Low doses of interferon suppressed deoxyribonucleic acid polymerase activity to the same extent as did the high doses. Prednisolone withdrawal was combined with interferon in 5 patients. Three patients treated with such combination became seronegative for hepatitis B e antigen during the treatment, whereas all 15 with interferon alone remained seropositive. These results suggest that a maximum antiviral effect of recombinant leukocyte A interferon is below the maximum tolerated doses.

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.

Prostaglandins protect against aspirin-induced damage to the gastrointestinal tract. This study tested the ability of enprostil, a synthetic analog of prostaglandin E2, given concurrently to prevent gastroduodenal injury. Twenty-four healthy subjects were randomly assigned to one of three groups. All received aspirin 650 mg q.i.d. for 5 days. One group received placebo and the other groups were given either 7 or 70 micrograms of enprostil b.i.d. for 5 days. Upper endoscopy was performed at entry and 2 h after the final dose of aspirin. Enprostil 70 micrograms b.i.d. afforded significant protection of both the antral and duodenal mucosa. The 7-micrograms dose protected only the antral mucosa. Side effects were not observed with the lower dose of enprostil. Serum salicylate levels did not differ significantly between the groups.

Pharmacodynamic and pharmacokinetic studies of omeprazole, a new gastric antisecretory agent, were undertaken in 8 healthy subjects. The drug was administered orally as an encapsulated enteric-coated granulate (40 mg daily at 9 am or 9 pm for 5 days), and its effect on the integrated 24-h gastric pH was determined, together with its apparent bioavailability. The pretreatment 24-h median pH was 1.9 (interquartile range 1.4-2.9). After 5 days of treatment, the median pH had risen to 5.0 (3.7-6.0) (p less than 0.01) with morning dosage and 4.5 (3.0-5.6) (p less than 0.01) with evening dosage. This corresponded to a greater than 99% reduction in 24-h median hydrogen ion activity, with morning dosage having a greater effect (from 9 am to 8 pm) (p less than 0.01) than evening dosage. The relative bioavailability of omeprazole increased twofold from day 1 to day 5 of treatment with morning dosage (p less than 0.02) and threefold with evening dosage (p less than 0.02), suggesting that increased absorption of this acid-labile drug occurs with increasing inhibition of acid secretion. We conclude that this formulation of omeprazole presently being used in clinical trials is a highly potent antisecretory agent in humans, although its optimal effect may not be observed for several days.

Our aim was to construct an index that accurately predicts the degree of benefit or harm that prednisone therapy holds for patients with liver cirrhosis. The admission and survival data of 488 patients with cirrhosis who participated in a controlled clinical trial of prednisone in a dosage of 10-15 mg daily (251 patients) versus placebo (237 patients) and who were observed for up to 12 yr were analyzed using Cox's multiple regression model. Four variables each provided significant therapeutic information: antinuclear factor (p = 0.02) and large piecemeal necroses (p = 0.02) were associated with a beneficial effect, whereas ascites (p = 0.0004) and large regenerative nodules (p = 0.0007) were associated with a harmful effect of prednisone. From these four variables a therapeutic index was constructed. For a given patient the therapeutic index is a measure of how big the effect will be if prednisone is given. The gain in survival time obtained by administering prednisone according to the therapeutic index was estimated to be 349 yr, mainly confined to 217 patients with a significant positive (121) or negative (96) therapeutic index. The therapeutic index may prove useful for the optimal administration of prednisone treatment in new patients with cirrhosis.

Primary sclerosing cholangitis and primary biliary cirrhosis are chronic cholestatic syndromes that may be difficult to differentiate clinically. Destructive cholangitis occurs in both diseases and leads to similar clinical and biochemical abnormalities. Therefore, we compared the clinical, biochemical, immunologic, radiologic, and hepatic histologic features of these syndromes in two large groups of patients prospectively selected by predefined criteria. Primary biliary cirrhosis (n = 258) occurred predominantly in middle-aged women who were usually symptomatic with fatigue and pruritus, commonly had keratoconjunctivitis sicca, and often were hyperpigmented. Tests for antimitochondrial antibodies were always positive, usually in very high titer. Although the extrahepatic bile ducts were normal radiographically, smooth tapering and narrowing of the intrahepatic bile ducts was occasionally noted. Hepatic histology was diagnostic when a florid duct lesion was present. In contrast, primary sclerosing cholangitis (n = 60) occurred primarily in young men who were usually symptomatic with fatigue and pruritus and frequently had chronic ulcerative colitis. Tests for antimitochondrial antibodies were nearly always negative and cholangiography demonstrated abnormalities of the extrahepatic and intrahepatic bile ducts in all cases. Although hepatic histology was often compatible with the diagnosis, it was usually not diagnostic, and considerable overlap existed with the abnormalities seen in primary biliary cirrhosis. Likewise, biochemical tests of copper metabolism were similar in both syndromes. These results call attention to the differences and similarities in the clinicopathologic features of these two cholestatic syndromes and provide a basis for a rational diagnostic strategy.

This study was conducted to determine whether taurocholate alters human gastric function and structure at a neutral pH, when ionized, and to contrast this with its effect at an acid intraluminal pH, when pronated. Five fasted healthy subjects were studied on 4 days in random order. Net ion fluxes, mucosal damage (as quantitated endoscopically), and potential difference were measured. The control solution instilled into the stomach in the first, third, and fourth 15-min periods contained 200 ml of 100 mM HCl, 54 mM mannitol, and [14C]polyethylene glycol. Taurocholate (10 mM) was added to the control solution (pH 1.1) or citrate buffer (pH 7.0) during the second 15-min period. The effect of citrate buffer alone or control solution alone was also tested. Because hydrogen and sodium fluxes could not be quantitated at pH 7 in the presence of citrate buffer, the net ion fluxes during the 15 min immediately after exposure to the test agent were measured. At both pH 1.1 and 7.0 taurocholate produced similar and significant increases in net hydrogen ion flux (-1.7 +/- 0.4 and -1.8 +/- 0.3 mmol/15 min, respectively), net sodium ion flux (1.8 +/- 0.4 and 1.7 +/- 0.2 mmol/15 min, respectively), decreases in potential difference, and mucosal erosions. The net hydrogen ion fluxes were significantly greater than occurred after citrate buffer alone or the HCl control. The net sodium fluxes after taurocholate in citrate were significantly greater than the pH 1.1 acid control, but not citrate buffer alone. These findings indicate that pronated (pH 1.1) or ionized (pH 7.0) taurocholate significantly damaged the in vivo human gastric mucosa. Taurocholate at pH 7 could in part be responsible for the gastric mucosal injury that occurs in patients with bile reflux gastritis.

To determine the frequency and prognosis of histologic cirrhosis developing during or after corticosteroid therapy of hepatitis B surface antigen-negative chronic active hepatitis, we followed 83 patients for 90 +/- 5 mo after administration of corticosteroids. Thirty-three patients satisfied histologic criteria for cirrhosis after 30 +/- 5 mo. In 25 patients, cirrhosis developed during treatment; in 8 patients, cirrhosis eventuated after remission and cessation of therapy. The probability of developing histologic findings of cirrhosis was 59% if remission had not been achieved after 3 yr of continuous therapy. Longer requirements for treatment and deterioration during therapy characterized these patients. Once remission was achieved, the mean annual incidence of cirrhosis was only 2.6%. Patients who manifested evidence of cirrhosis in their biopsy specimens could not be distinguished by initial clinical, biochemical, or histologic findings. Ascites, encephalopathy, and esophageal varices developed infrequently; 5-yr survival after documentation of cirrhosis was 93%. We conclude that histologic features of cirrhosis develop commonly during therapy, especially if remission is not achieved quickly. After remission, cirrhosis develops infrequently. The development of histologic cirrhosis does not influence immediate morbidity and 5-yr life expectancy.

The addition of microbial beta-galactosidases directly to milk at mealtime represents a potential "enzyme replacement therapy" for primary lactase deficiency. We used the hydrogen breath test as the index of incomplete carbohydrate absorption to assess the efficacy of two enzymes--one from yeast, Kluyveromyces lactis (LactAid), and the other from the fungus Aspergillus niger (Lactase N)--to assist in the hydrolysis of 18 g of lactose in 360 ml (12 oz) of whole milk when consumed by an adult lactose malabsorber. Graded amounts of Lactase N produced, at best, a 53% relative reduction in breath hydrogen excretion, whereas quantitative elimination of excess hydrogen excretion was produced by 1 and 1.5 g of LactAid. A double-blind, controlled, crossover trial was subsequently performed in 50 healthy, unselected Mexican adults, to whom 360 ml of cow's milk was presented in the three forms in a randomized order: intact milk, prehydrolyzed milk, and milk to which 1 g of LactAid was added immediately before consumption. Among the 25 subjects with incomplete carbohydrate absorption with intact milk, adding enzyme 5-min before consumption produced a 62% reduction in breath hydrogen excretion, and symptoms of intolerance were significantly reduced. The feasibility of effective enzyme replacement therapy with a beta-galactosidase from K. lactis is demonstrated.