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.

Eighteen patients with irritable colon syndrome were treated with a new anticholinergic drug (prifinium bromide) and with a placebo in a 6-wk, randomized, double-blind cross-over study. The drug was orally administered in a daily dose of 90 mg before meals. Three manifestations (pain, flatulence, constipation, and/or diarrhea), scored weekly, were used as assessment criteria. Mean over-all ratings showed a difference in favor of the drug, and were statistically significant. Side effects were rare and mild. We have come to the conclusion that this anticholinergic drug may be of benefit to patients with pain-predominant forms of irritable colon syndrome.

Renal function is known to be abnormal in patients with cirrhosis. Diminished cortical blood flow due to active renal vasoconstriction is present. Renal prostaglandins, potent vasodilators, could be released by the kidney in an attempt to maintain renal blood flow. This possibility was investigated by measuring the effect of indomethacin, an inhibitor of prostaglandin synthetase, in patients with alcoholic liver disease. Administration of indomethacin reduced the effective renal plasma flow (ERPF) and creatinine clearance by 23% and 19%, respectively (P less than 0.001), and increased serum creatinine by 29% (P less than 0.001). The response to indomethacin was variable (fall in ERPF (+)7.8% to (-)67%), but was greatest in patients with ascites. Eighty percent of ascitic patients had a greater than 15% fall in ERPF after administration of indomethacin compared with 20% of nonascitic patients (P less than 0.025). An infusion of prostaglandin A1 in 13 patients corrected the decrease in ERPF and creatinine clearance that had followed the administration of indomethacin. The administration of indomethacin caused a significant fall in plasma renin activity, 8.2 +/- 2.5 to 3.6 +/- 1.4 ng/ml/hr (P less than 0.025). The fall in plasma renin activity occurred when ERPF was depressed maximally, suggesting that endogenous prostaglandins exert more control over renin release than does ERPF. Prostaglandins appear to be an important factor in maintaining renal blood flow in patients with cirrhosis and sodium retention.

In order to assess the efficacy of cimetidine in patients with endoscopically anastomotic ulcer after partial gastrectomy, 21 such patients entered a double-blind prospective clinical trial. At endoscopy after 4 wk of treatment, 8 of 12 patients treated with 1 g of cimetidine daily compared with 1 of 9 patients who received a placebo had healed ulcers (P less than 0.05). Evaluation of symptoms relief supported the efficacy of cimetidine compared with placebo. Healing rate after 1 mo of treatment with cimetidine was 67% and increased to 86% after 2 mo. During 1 year of maintenance therapy with 800 mg cimetidine daily, 3 of 19 patients relapsed. No serious side effects were observed. The results of this study demonstrate a beneficial effect of cimetidine on healing and symptoms of anastomotic ulcers.

A second randomized double-blind study to determine the efficacy of doxycycline, 100 mg daily, for the prevention of travelers' diarrhea was carried out among 50 Peace Corps Volunteers during their first 10 wk in Morocco. The volunteers took either doxycycline or placebo for 3 wk, and were observed for an additional 7 wk. Eleven of 24 taking the placebo and 2 of 26 taking doxycycline had travelers' diarrhea during the treatment period (P less than 0.01). One week after cessation of the doxycycline, however, persons in that group developed an increase in frequency of travelers' diarrhea (P less than 0.05) so that by 3 wk after the drug was stopped, there were no differences between groups. Enterotoxigenic E. coli, most of which were sensitive to doxycycline, were the most frequently isolated pathogens during the entire study. This study corroborates the effectiveness of doxycycline prophylaxis for travelers' diarrhea.

A randomized double-blind clinical comparison of bromocriptine, a new dopamine agonist, and placebo was performed on 7 cirrhotic patients with chronic portal systemic encephalopathy (PSE). Before given either medication, patients were stabilized with a standard treatment (neomycin and cathartics). Serial semiquantitative assessments were done, including mental state, asterixis, number connection test, electroencephalogram, and ammonia blood levels. Three patients developed signs of precoma while ingesting both placebo and bromocriptine. Two patients experienced precoma only with placebo, and another patient only while taking bromocriptine. One patient remained awake throughout the study. All patients responded initially to neomycin and cathartics. Bromocriptine proved not to be significantly superior to placebo and was always inferior to standard treatment. During treatment with bromocriptine, 3 patients experienced constipation. This may be partially responsible for the ineffectiveness in the treatment of PSE.

The effect of an infusion of natural motilin on the rate of gastric emptying of a standard breakfast was studied in 5 subjects using Caesium 129-tagged resin particles. Emptying rates were measured on 4 separate days. On 2 days, the subjects receive only saline (controls), while on the other 2 days a motilin infusion of 0.34 pmol/kg/min for 60 min, followed by 0.68 pmol/kg/min for 60 min, was given. All infusions were blind and given in random order. At the end of the low-dose motilin infusion 31 +/- 4% of the meal had emptied, compared with 17 +/- 2% with saline infusion (P less than 0.01). A similar effect was also seen with the high-dose infusion. Plasma motilin concentrations rose from a basal of 68 +/- 13 pmol/liter to 126 +/- 10 pmol/liter during low-dose motilin infusion and to 170 +/- 11 pmol/liter during the high dose. No significant change in basal or postprandial levels of glucose, gastrin, pancreatic glucagon, pancreatic polypeptide, gastric inhibitory peptide, enteroglucagon, or vasoactive intestinal peptide was noted, but postprandial insulin release was greater during motilin infusion.

Obese subjects are prone to supersaturated bile, which is maintained or increased during weight loss. In this report, two related studies were carried out on obese subjects to investigate effects of bile acid feeding on biliary lipid metabolism before and during weight reduction. In one study, chenodeoxycholic acid (CDCA), 750 mg/day, was given to 12 obese subjects during weight maintenance (1st mo) and during weight reduction (2nd mo). In the second study, effects of two bile acid preparations, CDCA and Bilron (containing mostly cholic acid and deoxycholic acid), randomly administered, were compared in another 12 obese subjects undergoing weight reduction. The results show that obese subjects had large pools of bile acids during weight maintenance which decreased on caloric restriction (1,000 kcal/day). CDCA increased pool size only modestly during weight maintenance, from 3,536 +/- 1,267 (SD) mg to 4,735 +/- 1,434 mg. Both CDCA and Bilron markedly reexpanded the contracted pool of bile acids in obese subjects on weight reduction. However, significantly reduced saturation of bile occurred only in those on CDCA and weight reductions, whereas supersaturation was unaltered when weight was maintained constant in these patients, or when Bilron was given. No significant side effects were noted during bile acid feeding for any of the subjects. Thus, CDCA given to obese subjects on weight reduction will reduce bile saturation and could protect against gallstones.

The effect of aluminum-magnesium hydroxide tablets (800 mg seven times per day) and that of sulpiride, a hypothalamic neurolaptic, were studied in 101 patients with duodenal ulcer in a double-blind controlled 4-wk trial. Significantly more of the patients treated with antacid, sulpiride, or antacid-sulpiride combination showed a greater than 50% reduction in ulcer size than did the patients treated with placebo. However, only in the antacid- and antacid-sulpiride-treated groups did the ulcer, with and without residual inflammation, disappear statistically more often than in the placebo-treated group. Furthermore, only in the antacid-sulpiride-treated group did complete healing, with no trace of inflammation, occur statistically more often than in the placebo-treated group. Disappearance of ulcer pain was likewise statistically more frequent in the antacid-sulpiride group than in the placebo-treated group. Antacid therapy with aluminum-magnesium hydroxide tablets appears to accelerate the rate of ulcer healing. Sulpiride appears to have a minor but definite synergism with antacids. Cigarette smoking affected ulcer healing adversely; on the other hand, factors favorable to healing were the early onset age of ulcer symptoms and acid hypersecretion. Male patients also healed more favorably than females.