CPI-1189 Protects Against Dextran Sulfate Sodium-induced Colitis in Mice

Karl R Tyler,Beverley Greenwood-V Meerveld

doi:10.3844/ajptsp.2006.54.59

Abstract

Nitrone-related therapeutics (NRTs) represent a new class of small molecules potentially effective in the treatment of inflammatory bowel disease (IBD) by protecting cells from damage caused by excess inflammation and/or oxidative stress. The goal of this study was to determine the efficacy and potency of CPI-1189, a novel therapeutic agent, in dextran sulfate sodium (DSS)-induced colitis in mice. Mice received oral doses of either CPI-1189 (3, 10, or 30 mg kg?1) or the methyl cellulose vehicle along with 3% dextran sulfate in their drinking water. Assessment of colitis was by calculation of a disease activity index (DAI) and by histological observations. Signs of colitis in vehicle-treated mice were evident by day 3 using the DAI and with histological confirmation on day 7. In mice given CPI-1189, there was a significant and dose-dependent improvement in all signs of colitis with an overall protection of approximately 50%. These observations suggest that CPI-1189 is a novel, orally active, therapeutic agent that could be developed for the treatment of crohn’s disease and ulcerative colitis in humans.

Highlights

Inflammatory bowel disease (IBD) is a blanket term for the chronic, inflammatory condition experienced by individuals with either Crohn’s disease or ulcerative colitis
The poor sideeffect profile of corticosteroids restricts their use to treating acute and serious episodes of disease, while products based on 5-aminosalicylic acid (5-ASA) as the active agent show frequent drug intolerance, limited efficacy and can only be used in mild to moderate cases
Treatment with monoclonal antibodies to TNF-α is a recently introduced, novel therapeutic approach to the treatment of patients with IBD[5,6,7]

Summary

Introduction

Inflammatory bowel disease (IBD) is a blanket term for the chronic, inflammatory condition experienced by individuals with either Crohn’s disease or ulcerative colitis. The current treatment options for patients with either Crohn’s disease or colitis are limited[3,4]. The poor sideeffect profile of corticosteroids restricts their use to treating acute and serious episodes of disease, while products based on 5-aminosalicylic acid (5-ASA) as the active agent show frequent drug intolerance, limited efficacy and can only be used in mild to moderate cases. Treatment with monoclonal antibodies to TNF-α is a recently introduced, novel therapeutic approach to the treatment of patients with IBD[5,6,7]. Antibodies like those to TNF-α are not active following oral administration and the potential longterm toxic effects of these potentially immunogenic proteins remain to be determined. The lack of a safe and effective pharmacological agent to treat IBD often leads to surgery, in severe cases, to remove the affected region of the small or large bowel[8]

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Results