Nonsteroidal antiinflammatory drugs (NSAID) induce the formation of bleeding gastric and intestinal ulcers in experimental animals. The damage can be prevented by prior local administration of prostaglandins, indicating that prostaglandins have protective properties on the gastrointestinal mucosa. The protective effect was studied in humans by measuring the fecal blood loss during indomethacin treatment of 18 patients with rheumatic diseases with and without concomitant oral supplementation with 1 mg prostaglandin E2 three times daily. The study had a randomized double-blind crossover design using 51Cr-labeled erythrocytes as marker of gastrointestinal bleeding. Indomethacin increased the daily fecal blood loss from 1.0 +/- 0.3 to 2.8 +/- 0.6 ml (P less than 0.005). When oral PGE2 was taken concomitantly, the blood loss was reduced to 1.1 +/- 0.2 ml daily (P less than 0.01), i.e., to the control level. Side effects of prostaglandin E2 were negligible, and the beneficial effect of indomethacin on joint status and symptoms was not interfered with. No changes were recorded in repeated blood tests except for a slightly reduced hemoglobin and a small but statistically significant reduction of serum-calcium during indomethacin treatment, an effect hitherto not described in normocalcemic human subjects. A protective effect on the gastrointestinal mucosa by oral prostaglandin E2 has by the present study been demonstrated also in humans. The protection is unrelated to the gastric acid secretion, which is not inhibited by oral prostaglandin E2. The finding may have clinical application, as gastrointestinal side effects and bleeding are common reasons for discontinuation of NSAID in patients with rheumatic diseases.

Fifteen patients with chronic diarrhea and fecal incontinence were admitted to a clinical research center and treated for 3 days with either placebo or diphenoxylate with atropine (Lomotil). The patients were then crossed over to the alternate medication. Lomotil had no effect on rectal or anal sphincter pressure or on continence for saline that had been infused into the rectum. However, Lomotil therapy reduced average stool frequency (from 4.9 to 2.6 times/day) and average stool weight (from 460 to 256 g/day). These results suggest that temporary or intermittent therapy with Lomotil and related drugs might benefit patients with chronic diarrhea and fecal incontinence. They should do this by virtue of a reduction in stool frequency and stool volume, without a deleterious effect on the defense mechanisms against incontinence.

The cholelitholytic action of ursodeoxycholic acid (UDCA) was investigated by a double-blind clinical trial. The trial started with 151 subjects all confirmed by radiographic examination as having radiolucent gallstones in a functioning gallbladder. The subjects were divided into three groups receiving 600 mg/day of UDCA, 150 mg/day of UDCA, and placebo (lactose) per day, respectively. Seventy-nine cases were classed as dropouts or were excluded due to incomplete follow-up or inadequate patient selection, and the data on the remaining 72 cases were analyzed. After 6--12 mo of treatment, dissolution of decrease in size or number of stones occurred in 10 of the 29 cases in the 600 mg/day group (34.5%), 4 of 23 cases in the 150 mg/day group (17.4%), and 1 of 20 cases in the control group (5.0%). For those cases with noncalcified, less than 15 mm in diameter, and floating stones, efficacy increased to 83.3% in the 600 mg/day group. Lithogenic index of bile defined by Thomas and Hofmann became unsaturated after treatment in the 600 mg/day group. Neither diarrhea nor hepatic toxicity was noted. The results indicate that UDCA is a safe and effective litholytic agent.

Twenty-eight patients entered a double-blind controlled trial to evaluate the efficacy of prednisolone treatment in severe acute alcoholic hepatitis accompanied by encephalopathy. Fifty-three percent (8 of 15) given prednisolone and 54% (7 of 13) given placebo died during the study. The mean duration of hospitalization was 66 days for the prednisolone-treated group and 56 days for those treated with placebo. Prednisolone treatment produced no important beneficial effect on any of the hepatic biochemical tests. The outcome in any particular case was directly related to the development of specific lethal complications (renal failure, injection, and gastrointestinal bleeding) rather than to the treatment employed. We were unable to show any beneficial effect of prednisolone treatment on morbidity or mortality in patients with severe acute alcoholic hepatitis and encephalopathy.

Two comparative studies of six staining techniques in detection of Entamoeba histolytica in rectal biopsies were performed. The techniques evaluated were direct and indirect fluorescent antibody technique, and four conventional stains: PAS, H & E, Trichrome, and PTAH). On ethanol-fixed tissue, the direct fluorescent antibody technique was the most sensitive, detecting amoebas in 84% of rectal biopsies from 19 aspirate-positive dysentery patients. PAS staining was specific, almost as sensitive, and amoebas could be rapidly detected. The other three conventional methods, however, detected amoebas in only 53--58% of the aspirate-positive patients and required considerable efforts to find the amoebas. The indirect fluorescent antibody technique performed on ethanol-fixed tissues was comparable to the direct technique. The same technique used on formalin-fixed tissues had high background staining, but amoebas could still be detected more efficiently than with conventional staining. Following 20 hr or more treatment with metronidazole, no patient had amoebas detectable in their rectal biopsies by any technique used. Patients with amoebic dysentery and necrotic ulcers on protoscopy had amoebas detected more frequently in rectal biopsy than did patients with mild disease as determined by proctoscopy. Entamoeba histolytica in rectal biopsies can be detected most easily in ethanol-fixed tissue stained with either a fluorescent antibody or with PAS. If amoebas are not detected in the rectal biopsy, amoebic colitis cannot be excluded.

Gastroparesis is a relatively uncommon but clinically troublesome disorder that develops in some patients with diabetes mellitus or after gastric operations. Its pathogenesis remains obscure. We used a manometric technique to record pressure changes in fasting patients in the gastric fundus, distal stomach, and adjacent small bowel of patients with severe gastroparesis, asymptomatic diabetic patients, asymptomatic postsurgical patients, and healthy controls. Patients with gastroparesis had normal interdigestive motor cycles (phase III) in the intestine but not in the stomach. Sporadic motor activity in the stomach (phase II) also was markedly reduced. Metoclopramide and bethanecol significantly increased gastric motor activity in these patients, often triggering an intense burst of motor activity in the stomach, similar to phase III. These observations suggest that gastroparesis is a potentially reversible disorder and should encourage further attmpts for pharmacologic control of the syndrome.

A prospective study of the clinical pattern and course of primary biliary cirrhosis based on the data of 236 patients (211 females, 25 males) in an international randomized trial has been performed mainly using life-table technique. The median follow-up period has been 18 mo. After the entry into the study, at which time the median duration of symptoms was 2.1 yr, the estimated 5-yr increase in the cumulative percentage of patients was for pruritus from 75% to 95%, jaundice 59% to 82%, hepatomegaly 54% to 86%, pigmentation 54% to 85%, xanthomas 27% to 50%, GI bleeding 17% to 46%, ascites 7% to 49%, and vertebral collapse 3% to 20%. The frequency of cirrhosis increased from 30% to 82% in 4 yr. The mitochondrial antibody titer showed a high rate of progression with time. In analysis of subgroups, age, histologic stage, and particularly the serum bilirubin level were important prognostic factors. Sex, duration of symptoms, and character of first symptom or sign had no independent prognostic influence. The most important indication of seriously progressive course was rapid development of severe cholestasis independent of the histologic stage.

One of the potential complications of bile acid therapy for gallstone disease is the promotion of intestinal absorption of cholesterol, thereby increasing the influx of cholesterol in body pools. To determine whether bile acid feeding is associated with an increased absorption of intestinal cholesterol, absorption measurements were made in 8 obese subjects given chenodeoxycholic acid (CCDA) or Bilron (750 mg/day). The bile acids were given in random order, separated by control periods, in patients undergoing weight reduction. Absorption of cholesterol (mass and percent) and of bile acids were determined by a technique of combined measurements of biliary lipid secretion and fecal steroid excretion. Our data showed that during treatment with either bile acid, a marked increase in pool size and hepatic secretion of bile acids occurred. However, despite an increased flux of bile acids through the intestinal tract, there was no significant increase in cholesterol absorption as compared to control periods. Absorption rates during administration of the two bile acids were approximately the same. Furthermore, plasma cholesterol concentrations were stable throughout both control and treatment periods. Bile acid absorption remained highly efficient (greater than 96%) during all periods, even with administration of exogenous bile acids.

Among 569 patients with Crohn's disease, 24% had a history of at least one extraintestinal manifestation and 36% had a history of perianal disease before randomization. Multiple extraintestinal manifestations occurred in the same patient more frequently than would be expected by chance. Seventy-six percent of patients with ileocolitis had perianal disease, extraintestinal manifestations, or both. This was significantly greater than the 58% incidence in patients with disease confined to the small bowel. Perianal complications alone were significantly more common in patients with colitis or ileocolitis than in those with disease of only the small bowel. This was true also of internal fistulization. There was a significant positive association between perianal disease and the presence of extraintestinal features. Perianal abscess appeared to respond to sulfasalazine and anal fissure to prednisone or azathioprine. These results require confirmation in larger series of patients.

Records of 1084 patients entered into the National Cooperative Crohn's Disease Study were analyzed to gather information concerning the natural history and clinical features of Crohn's disease. The age of onset reached a single peak between the second and fourth decade and was evenly distributed in both sexes. There was an average interval of 35 mo from onset of symptoms to diagnosis. Involvement of both colon and terminal ileum was the most frequent pattern and was present in 55% of patients. The disease was confined to the terminal ileum, other areas of the small intestine, or colon-only in 14%, 3%, and 15% of patients, respectively. Sigmoidoscopic abnormalities were seen in 34% of all patients and 51% of patients with Crohn's colitis. Diarrhea, abdominal pain, weight loss, and fever were present in the majority of the patients. Lower GI bleeding, fever, and perianal complications characterized patients with colon-only involvement. The frequency of extra intestinal manifestations was similar in all groups. Among patients who were randomized to placebo, 32% achieved a spontaneous remission by the end of 17 wk, and 53% of these were still in remission at the end of 24 mo. Clinical remission was associated with an improvement in barium x-rays in 18% of the patients. The predicted factors associated with favorable outcome in placebo-treated patients were: previous surgical removal of all observable disease, absence of perianal disease, and Crohn's Disease Activity Index value under 200.

The effectiveness of cimetidine vs. antacid in the treatment of patients with scleroderma and symptomatic reflux esophagitis was studied in a double-blind cross-over controlled trial. Fifteen patients were initially randomized to either cimetidine (300 mg four times daily) with placebo antacid, or placebo tablet (1 four times daily) with Mylanta II (30 ml four times daily and PRN). After 8 wk of therapy on the initial regimen, each patient was crossed over to the alternate regimen for an additional 8 wk of therapy. The severity of symptoms during each treatment period was estimated by patient interviews and changes in esophagitis were evaluated endoscopically. Cimetidine gave significantly greater relief of heartburn than antacid regardless of the initial randomization. Cimetidine also resulted in significant endoscopic improvement of the esophageal mucosa whereas antacid was without effect. Neither cimetidine nor antacid produced any improvement in esophageal stricture size or lower esophageal sphincter pressure. Cimetidine was without toxicity whereas antacid therapy frequently produced diarrhea.

A double-blind study was made of the comparative effectiveness of cimetidine in the treatment of acute alcoholic pancreatitis. The study group was composed of 27 patients with acute episodes of alcoholic pancreatitis of mild to moderate severity. The patients were randomized into 2 groups, either receiving cimetidine, 300 mg four times daily or a placebo. Both groups were given intravenous fluids and meperidine hydrochloride (Demerol) as needed. There were no significant differences between the 2 groups as measured by a variety of clinical and laboratory parameters. The mean value of the daily serum amylase in the placebo group declined steadily to normal; hyperamylasemia in this group persisted for 52 +/- 11 hr (mean +/- SE). By contrast, serum amylase in the cimetidine group peaked at 24 hr after the start of treatment and remained abnormal slightly longer; the duration of hyperamylasemia in the group was 69 +/- 10 hr. It is concluded that: (1) cimetidine is not superior to a placebo in the management of mild to moderately severe acute alcoholic pancreatitis and (2) serum amylase activity in patients with acute alcoholic pancreatitis given cimetidine tends to be greater and hyperamylasemia is of somewhat longer duration than in those treated with a placebo.

Peripheral blood leukocyte counts, percentages of lymphocytes and granulocytes, serum albumin levels, and results of skin tests with five antigens were examined in patients randomized in the National Cooperative Crohn's Disease Study. Inspection for differences from normal and correlations with a variety of variables showed no unusual characteristics except for a high incidence of anergy (31%) at randomization, and ranging up to 47.5% after treatment.

The effect of the combination of sulfasalazine and prednisone has been compared with that of prednisone and placebo in 89 actively symptomatic patients with Crohn's disease in a double-blind, randomized, multicenter controlled trial. The combination was less effective than prednisone alone in treatment of active symptomatic disease. The probability of obtaining this result, if sulfasalazine truly has a clinically useful effect equal to or greater than that specified in the calculation, is less than 1%. Patients who were in remission at the end of 8 wk were rerandomized to receive either the two drugs together or prednisone plus placebo while repeated systematic attempts to withdraw prednisone were made over the next 6 mo. Sulfasalazine showed no prednisone-sparing effect as judged either by outcome ranking or total dose of prednisone consmed by the two treatment groups. However, in this comparison the probability is greater than 5% that, given the results observed, a clinically useful effect of sulfasalazine of specified minimum degree truly exists. It was possible to withdraw prednisone from 25% of patients at the first attempt and ultimately in 37%.

Pancreatitis developed in 6 patients in the National Cooperative Crohn's Disease Study. In five of these the diagnosis was confirmed by elevated levels of seum amylase or lipase. All cases were in the 113 patients who received azathioprine and occurred within the first 21 days of treatment. This incidence of pancreatitis was significantly greater than in the patients treated with sulfasalazine, prednisone, or placebo (P less than 0.01).

Adverse reactions to the drugs employed in the National Cooperative Crohn's Disease Study were sought prospectively at each patient visit and by retrospective review of all patient charts. Prednisone caused evident side effects in over 50% of patients on high-dose suppressive therapy and in approximately one-third of patients on prophylactic dose. Thirty-two percent of patients on high-dose, and 26% on prophylactic-dose prednisone required dose reduction or withdrawal because of side effects. Comparable figures for sulfasalazine were 14% and 12%, and for azathioprine 32% and 20%. The incidence of nausea, vomiting, or anorexia among patients taking sulfasalazine was 46% and 34%, on high and low dose respectively; however, this incidence was no different than that observed among patients taking placebo. These symptoms occasioned withdrawal from the study of only 4% and 3% of patients on high and low doses of sulfasalazine, respectively. Azathioprine produced leukopenia at a dose of 2.5 mg/kg body weight in 15% of patients and the mean white cell count, lymphocyte count, granulocyte count, and hematocrit all fell significantly in patients on this dose. Pancreatitis occurred in 5% of patients taking azathioprine but in no other patients. Sulfasalazine proved to be the safest effective suppressive drug for Crohn's disease. Prednisone toxicity, though substantial, is acceptable in view of its demonstrated suppressive efficacy. Azathioprine was approximately as toxic as prednisone but no more effective than placebo in suppressing active disease. None of the drugs was effective prophylactically, and all showed appreciable long-term toxicity.

The response of active and quiescent Crohn's disease to prednisone, sulfasalazine, or azathioprine has been studied in 569 patients in a placebo-controlled, randomized, multicenter cooperative trial. The response of active symptomatic disease to prednisone or sulfasalazine was significantly better than to placebo. Response to azathioprine was better than to placebo, but the difference did not reach conventional levels of statistical significance. Patients with colonic involvement were especially responsive to sulfasalazine, and those with small bowel involvement were especially responsive to prednisone. Patients' drug therapy immediately before entry to the study significantly affected subsequent response. For patients with quiescent disease, none of the drugs was superior to placebo in prophylaxis against flare-up or recurrence. There is less than a 5% risk that a clinically significant prophylactic effect of any of the drug regimens was missed.

The design and execution of the National Cooperative Crohn's Disease Study are described in this paper. The Study incorporated several noteworthy features developed to meet specific demands of the disease and its therapy. A standard clinical grading system, the Crohn's Disease Activity Index (CDAI) was developed to allow uniform decentralized clinical evaluation and decision-making throughout the 5 yr of the study. All three drugs in widespread clinical use in Crohn's disease were studied both for suppressive and prophylactic efficacy and for toxicity. The study employed a scheme for double-blind evaluation of patient progress which allowed adjustment of prednisone dose according to the degree of illness and ensured continuous monitoring for serious toxicity of any study drug. Results were analyzed primarily by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. Outcome was also analyzed by life-table methods. Eleven hundred nineteen patients were entered and 604 patients were randomized at 14 study centers during the 5-yr duration of the study. Twenty patients were eliminated from analysis as not meeting diagnostic criteria for Crohn's disease, and another 15 patients were eliminated as not meeting other preestablished criteria for analysis. Nine percent of randomized patients, equally distributed in the four treatment groups, withdrew as noncompliant. Ninety percent of patients completed all or all but one protocol-specified visits, and 95% completed the final radiologic and sigmoidoscopic evaluation.

As part of a double-blind, randomized, controlled trial to evaluate the effect of colchicine on liver cirrhosis, 43 cirrhotic patients were assigned to either a placebo (20 patients) or a colchicine (23 patients) treatment group. Colchicine 1 mg and an indistinguishable placebo were administered orally on a daily dose 5 days a week. In the colchicine group, 12 were males and 11 females, while in the control group 13 were males and 7 females. The time elapsed between diagnosis and inclusion in the study was 14.1 mo for the controls and 14.5 mo for the patients on colchicine. Mortality related to the liver disease occurred in 4 patients on colchicine and 8 patients on placebo. Although the probability of surviving in the colchicine group was greater than that of the placebo, the difference did not reach statistically significant levels. Of the colchicine-treated patients, in three a remarkable decrease in liver fibrosis was observed in serial biopsies. In two other patients, carcinoma of the liver developed. Six of the survivors on colchicine have improved clinically, noticing disappearance of ascites and edema, as well as a decrease in the size of the spleen. All the survivors on placebo continue to show clinical deterioration. In contrast to the usual drop of serum albumin seen in the cirrhotic patients, those receiving colchicine increased and maintained their serum albumin levels throughout the study. Serum proline values were elevated only in the alcohol cirrhotic patients. Serum alkaline phosphatase increased only in those patients receiving colchicine. The results indicate that in some cases, liver fibrosis could be modified by treatment with antifibrotic drugs. The use of colchicine at present should remain within controlled studies.

Infusions of intraarterial vasopressin (IAV) into the superior mesenteric artery have been shown to be effective in controlling hemorrhage from esophagogastric varices. Intravenous infusions of vasopressin (IVV), which can be initiated rapidly and require less sophisticated equipment and personnel, have also been reported to control variceal hemorrhage. We undertook a controlled clinical trial to compare these two routes of administration. Twenty-two cirrhotic patients with massive hemorrhage from varices were randomized to receive either IVV or IAV. Intraarterial vasopressin was begun at 0.1 U/min and increased progressively as needed to 0.2, 0.3, 0.4, and 0.5 U/min. Intravenous vasopressin was begun at 0.3 U/min and increased progressively as needed to 0.6, 0.9, 1.2, and 1.5 U/min. Hemorrhage was controlled in 5 of 10 episodes (50%) with IVV and in 6 of 12 episodes (50%) with IAV. Seven of the ten episodes treated with IVV (70%) ended fatally compared with 9 of 12 treated with IAV (75%). Side-effects and complications occurred with similar frequency in the two groups. The two routes of administration are equal in effects, side-effects, and complications. We recommend that IVV, which can be administered more easily, be given a brief therapeutic trial early in the management of hemorrhage from varices.