title: Enhanced anti-inflammatory effects of a nitric oxide-releasing derivative of mesalamine in rats.
abstract: OBJECTIVE
  Nitric oxide (NO)-releasing derivatives of cyclooxygenase inhibitors exhibit enhanced anti-inflammatory activity and greatly reduced gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory activity.
  
  
  METHODS
  Effects of an NO-releasing derivative of mesalamine (NCX-456; NO-mesalamine) were compared with those of mesalamine itself and 2 other NO donors in a rat model of colitis. These drugs were compared for their ability to inhibit leukocyte adherence to the vascular endothelium in vivo, interleukin (IL)-1beta and interferon (IFN)-gamma release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon.
  
  
  RESULTS
  NO-mesalamine was significantly more effective than mesalamine in reducing the severity of colitis (damage and granulocyte infiltration). Unlike mesalamine, NO-mesalamine significantly suppressed leukocyte adherence to the vascular endothelium in vivo. NO-mesalamine inhibited IL-1beta and IFN-gamma release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon.
  
  
  CONCLUSIONS
  These studies show that an NO-releasing derivative of mesalamine has significantly enhanced anti-inflammatory activity, including improved efficacy in a rat model of colitis. The improved efficacy of this derivative is most likely caused by its enhanced ability to suppress leukocyte infiltration and possibly to scavenge peroxynitrite.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada. wallacej@ucalgary.ca
authors.forename: J L
authors.initials: JL
authors.lastname: Wallace
authors.forename: N
authors.initials: N
authors.lastname: Vergnolle
authors.forename: M N
authors.initials: MN
authors.lastname: Muscará
authors.forename: S
authors.initials: S
authors.lastname: Asfaha
authors.forename: K
authors.initials: K
authors.lastname: Chapman
authors.forename: W
authors.initials: W
authors.lastname: McKnight
authors.forename: P
authors.initials: P
authors.lastname: Del Soldato
authors.forename: A
authors.initials: A
authors.lastname: Morelli
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D020170:Caspase 1 / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D019804:Mesalamine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000032:analysis / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000276:immunology
chemical_list: D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D012333:RNA, Messenger; D009569:Nitric Oxide; D019804:Mesalamine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020170:Caspase 1