Efficacy of drugs used in the treatment of IBD and combinations thereof in acute DSS-induced colitis in mice

Aims: Although acute dextran sodium sulphate (DSS)-induced colitis in mice is frequently used as a preclinical model for testing drugs involved in inflammatory bowel disease (IBD), only limited data is available that compares the efficacy of established drug treatments and combinations employed in IBD. We have therefore compared the efficacy of aminosalicylates (mesalazine, olsalazine), corticosteroids (budesonide), thiopurines (6-thioguanine (6-TG)) and cyclosporine A (CsA) and combinations thereof as well as the EP4 agonistAGN205203 in the acute DSS-colitis model. Main methods: Female BALB/c mice were challenged with 4% DSS in drinking water for 7 days to induce colitis and treated daily with different drugs/combinations orally. Disease scores (diarrhoea, bleeding, disease activity index), systemic (body weight loss, serum amyloid A levels) and colonic (myeloperoxidase activity, length and histopathology) inflammation parameters were analysed. Key findings: Mesalazine, olsalazine (100 mg/kg) and budesonide (0.5 mg/kg) were only weakly active or even worsened colitis. 6-TG dose-dependently reduced systemic and colonic inflammation parameters with estimated ED50 values between 0.5-4 mg/kg. CsA (10, 25 and 50 mg/kg) dose-dependently reduced colitis with high efficacy on systemic inflammation. A combination of CsA 25 mg/kg + olsalazine 100 mg/kg produced a more pronounced anti-inflammatory effect than the compounds given alone. AGN205203 (3, 10 and 30 mg/kg BID) was the most efficacious compound and almost completely inhibited colitis. Significance: 6-TG and CsA are suitable reference compounds in the DSS mouse model. CsA+ olsalazine, as a combination, was more efficacious than the compounds given alone, supporting combination treatments in IBD. (C) 2013 Elsevier Inc. All rights reserved.