RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis

• Published in: Inflammation research 2002-11, Vol.51 (11), p.522-531
• Main Authors: Murthy, S, Flanigan, A, Coppola, D, Buelow, R
• Format: Article
• Language: English
• Subjects: Animals; Biological Availability; Chronic Disease; Colitis, Ulcerative - chemically induced; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - pathology; Colon - pathology; Dextran Sulfate; Dogs; Feces - cytology; Female; Macaca mulatta; Mice; Occult Blood; Peptides - pharmacokinetics; Peptides - therapeutic use; Peptides - toxicity; Tissue Distribution; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/PL00012423

RDP58 is a novel anti-inflammatory peptide that inhibits TNF synthesis and upregulates heme oxygenase-1. RDP58 therapy was evaluated in the dextran sodium sulphate (DSS) model of chronic colitis. Colitis was induced by giving DSS to mice (n = 8 animals/group). Toxicity studies were done in Rhesus monkeys (n = 5), dogs (n = 3) and mice (n = 10). In colitis, mice were treated with p.o. vehicle (saline), RDP58 (5 and 10 mg/kg/day) or 5-ASA (50 mg/kg/day). Disease activity index (DAI) was used as the endpoint of efficacy. RDP58 therapy significantly reduced DAI and histological scores in all animals. DAI scores in RDP58 treated animals declined faster than 5-ASA. RDP58 at 5 or 10 mg/ kg/day significantly reduced DAI compared to 5-ASA. RDP58 significantly reduced acute, chronic and total inflammation scores. It enhanced re-epithelialization by reducing crypt scores. RDP58 was not bioavailable and was well tolerated. Therapeutic efficacy of RDP58 combined with a lack of bioavailibility and toxicity suggest that RDP58 may be a promising new therapeutic for IBD.