BACKGROUND AND PURPOSE: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H(2)S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. KEY RESULTS: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). Treatment with ADT-OH, the H(2)S-releasing moiety of ATB-429, did not affect severity of colitis. CONCLUSIONS AND IMPLICATIONS: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H(2)S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.
BACKGROUND AND PURPOSE:Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H(2)S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. KEY RESULTS: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). Treatment with ADT-OH, the H(2)S-releasing moiety of ATB-429, did not affect severity of colitis. CONCLUSIONS AND IMPLICATIONS: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H(2)S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.
Authors: A Stallmach; B Wittig; T Giese; K Pfister; J C Hoffmann; S Bulfone-Paus; U Kunzendorf; S C Meuer; M Zeitz Journal: Gastroenterology Date: 1999-10 Impact factor: 22.682
Authors: Stefano Fiorucci; John L Wallace; Andrea Mencarelli; Eleonora Distrutti; Giovanni Rizzo; Silvana Farneti; Antonio Morelli; Jih-Lie Tseng; Babu Suramanyam; William J Guilford; John F Parkinson Journal: Proc Natl Acad Sci U S A Date: 2004-10-25 Impact factor: 11.205
Authors: Matthew Whiteman; Nam Sang Cheung; Yi-Zhun Zhu; Siew Hwa Chu; Jia Ling Siau; Boon Seng Wong; Jeffrey S Armstrong; Philip K Moore Journal: Biochem Biophys Res Commun Date: 2005-01-28 Impact factor: 3.575
Authors: J L Wallace; N Vergnolle; M N Muscará; S Asfaha; K Chapman; W McKnight; P Del Soldato; A Morelli; S Fiorucci Journal: Gastroenterology Date: 1999-09 Impact factor: 22.682
Authors: Stefano Fiorucci; Elisabetta Antonelli; Eleonora Distrutti; Giovanni Rizzo; Andrea Mencarelli; Stefano Orlandi; Renata Zanardo; Barbara Renga; Moses Di Sante; Antonio Morelli; Giuseppe Cirino; John L Wallace Journal: Gastroenterology Date: 2005-10 Impact factor: 22.682
Authors: Marika Collin; Farhana B M Anuar; Oliver Murch; Madhav Bhatia; Philip K Moore; Christoph Thiemermann Journal: Br J Pharmacol Date: 2005-10 Impact factor: 8.739