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

Life Sci. 2013 Apr 9;92(12):708-18. doi: 10.1016/j.lfs.2013.01.028. Epub 2013 Feb 8.

Abstract

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 agonist AGN205203 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 (100mg/kg) and budesonide (0.5mg/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 50mg/kg) dose-dependently reduced colitis with high efficacy on systemic inflammation. A combination of CsA 25mg/kg+olsalazine 100mg/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminosalicylic Acids / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Budesonide / therapeutic use*
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / pathology
  • Colon / drug effects
  • Colon / pathology
  • Cyclosporine / therapeutic use*
  • Dextran Sulfate
  • Drug Therapy, Combination
  • Female
  • Gastrointestinal Agents / therapeutic use
  • Humans
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / pathology
  • Mesalamine / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Prostaglandin E, EP4 Subtype / agonists
  • Thioguanine / therapeutic use*

Substances

  • Aminosalicylic Acids
  • Anti-Inflammatory Agents
  • Gastrointestinal Agents
  • Receptors, Prostaglandin E, EP4 Subtype
  • Mesalamine
  • Budesonide
  • Cyclosporine
  • Dextran Sulfate
  • Thioguanine
  • olsalazine