John W. Singleton

Development of a Crohn's Disease Activity Index: National Cooperative Crohn's Disease Study

Needing a single index of degree of illness in Crohns disease, the National Cooperative Crohns Disease Study group collected data prospectively from 187 visits of 112 patients with Crohns disease of the small bowel, colon, or both. Information on 18 predictor variables was gathered at each visit. In addition, the attending physician rated his over-all evaluation of how well the patient was doing and compared the patients status with that at the previous visit. A multiple regression computer program was utilized to derive an equation for prediction of the physicians over-all ratings from a subset of the predictor variables fulfilling a combination of constraints. This equation, numerically simplified and utilizing eight selected variables, is the Crohns Disease Activity Index. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease, and values above 450 are seen with extremely severe disease.

Double blind, placebo controlled trial of metronidazole in Crohn's disease.

A double blind study compared the efficacy of metronidazole in two doses (20 mg/kg, 10 mg/kg) with placebo in patients with Crohns disease. One hundred and five patients participated but only 56 completed the 16 week study -21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation. Significant improvement in disease activity as measured by the Crohns disease activity index (metronidazole 20 mg/kg, 97 units; metronidazole 10 mg/kg, 67 units; placebo -1 unit, p = 0.002) and serum orosomucoid (metronidazole 20 mg/kg/day, 49; 10 mg/kg/day, 38; placebo, -9, p = 0.001)) were detected. Changes in C reactive protein concentrations did not achieve significance when all three groups were considered but were significant when all metronidazole treated patients were grouped and compared with the placebo treated patients (0.8 v -0.9, p less than 0.05). Although patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day (difference 30 units (95% confidence intervals -27-87), the small sample size may have precluded the detection of statistical significance. Preliminary analysis suggests that metronidazole was more effective in patients with disease confined to the large intestine or affecting both small and large bowel than in those with small bowel disease only. There were no differences in remission rates between metronidazole and placebo treated patients. We conclude that metronidazole warrants further assessment in the treatment of patients with active Crohns disease.

Mesalamine capsules for the treatment of active Crohn's disease: Results of a 16-week trial

BACKGROUND Mesalamine is released from sulfasalazine in the colon and benefits colonic Crohns disease. The mesalamine used in this study releases the drug throughout the small bowel and colon. Therefore, this study was designed to detect benefit for Crohns disease involving the small bowel alone or both the colon and small bowel. METHODS This double-blind, randomized, multicenter prospective controlled trial compared placebo and three daily doses of mesalamine in 310 patients. The primary outcome criterion was change in the Crohns Disease Activity Index (CDAI) from baseline to final study visit. RESULTS Patients taking 4 g/day mesalamine experienced a decrease of 72 CDAI points compared with 21 points in the placebo group (P < 0.01). Remission occurred in 43% of the 4-g group and 18% of the placebo group. Patients with ileum-only disease showed a 93-point improvement on 4 g mesalamine, compared with a 2-point improvement in similar patients on placebo. Mesalamine in this trial was not associated with clinically significant toxicity. CONCLUSIONS This controlled-release mesalamine preparation is safe and effective at 4 g/day as a single agent in treatment of active Crohns disease of the ileum and colon.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease

BACKGROUND & AIMS Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohns disease and to explore the effects of dose and schedule on platelet count and Crohns disease activity. METHODS A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohns disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS Short-term treatment with rhIL-11 is well tolerated in patients with active Crohns disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohns disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Quality-of-life results of double-blind, placebo-controlled trial of mesalamine in patients with Crohn's disease.

Seven quality-of-life parameters were assessed in a trial of mesalamine in Crohns disease. The results with regard to efficacy and safety have been previously published. A total of 310 patients were enrolled in this double-blind, parallel trial and randomized to receive placebo, or 1, 2, or 4 g/day of mesalamine in controlled-release capsules for 16 weeks. Results revealed that mesalamine at the dose of 4 g/day resulted in significant (P<0.03) improvements from baseline in all quality-of-life parameters. A significant (P<0.02) linear trend between increasing doses of mesalamine and increasing response was also noted. The 1- and 2-g/day doses of mesalamine also resulted in an improvement in quality of life, however, with the exception of 2 g/day of mesalamine on the hobby and recreational activities parameter, these changes were not significantly different from placebo.

Humoral Effects of the Pancreas Upon the Gastrointestinal Tract

Pancreatic hormones have been found to have a variety of actions upon the motor and secretory functions of the gut. Insulin directly depresses both gastric secretion and motility while both glucagon and gastrin play an important role in the normal control of gastric secretion. It is postulated that the diarrhea hormone is a humoral product or products produced by certain islet-cell tumor causing diarrhea in the absence of gastric hypersecretion. It has also been suggested that the mechanism of action of the diarrhea hormone is an inhibition of transfer of fluid and electrolyte by the small intestine. A probable cause of diarrhea is prostaglandins the fatty acid derivatives which have the property of readily contracting smooth muscle. Prostaglandins have been found in the human stomach and have been shown to stimulate contractions by strips of human gastric muscle. In the dog they inhibit gastric secretion stimulated by either food or histamine. Further studies are needed to determine whether prostaglandins cause diarrhea and whether the diarrhea hormone may have an effect on intestinal transport of water and electrolyte.