title: Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative.
abstract: S-diclofenac (2-[(2,6-dichlorophenyl)amino]benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester; ACS 15) is a novel molecule comprising a hydrogen sulfide (H2S)-releasing dithiol-thione moiety attached by an ester linkage to diclofenac. S-diclofenac administration inhibited lipopolysaccharide-induced inflammation (as evidenced by reduced lung and liver myeloperoxidase activity) and caused significantly less gastric toxicity than diclofenac. S-diclofenac did not affect blood pressure or heart rate of the anesthetized rat. S-diclofenac administration downregulated expression of genes encoding enzymes which synthesize nitric oxide, prostanoids, and H2S; reduced plasma IL-1beta/TNF-alpha; and elevated plasma IL-10. Reduced liver NF-kappaB p65 and AP-1/c-fos DNA-binding activity was also observed. These effects were mimicked in large part by a combination of diclofenac plus an H2S-releasing moiety (ADT-OH). Incubation of S-diclofenac (100 microM) with rat plasma or liver homogenate caused a time-dependent release of H2S, which was inhibited by sodium fluoride (10 mM). Administration of S-diclofenac (47.2 micromol/kg, i.p.) to conscious rats significantly increased plasma H2S concentration (at 45 min and 6 h). We propose that H2S release from S-diclofenac in vivo contributes to the observed effects.
authors.affiliation: Cardiovascular Biology Research Group, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 18 Medical Drive, Singapore 117597.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossoni
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Lin Chiou
authors.initials: LC
authors.lastname: Lee
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Philip Keith
authors.initials: PK
authors.lastname: Moore
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004008:Diclofenac / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D041981:Gastrointestinal Tract / Q000187:drug effects*; D008070:Lipopolysaccharides; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000139:chemically induced / Q000517:prevention & control; D013871:Thiones / Q000494:pharmacology
chemical_list: C520611:2-((2,6-dichlorophenyl)amino)benzeneacetic acid 4-(3H-1,2-dithiol-3-thione-5-yl)phenyl ester; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D013871:Thiones; D004008:Diclofenac