Effects of BX661A, a new therapeutic agent for ulcerative colitis, on chemotaxis and reactive oxygen species production in polymorphonuclear leukocytes in comparison with salazosulfapyridine and its metabolite sulfapyridine.
5-[4-(2-Carboxyethylcarbamoyl)phenylazo]salicylic acid disodium salt dihydrate (CAS 80573-04-2, BX661A) is developed as a therapeutic agent for ulcerative colitis. To clarify the mechanisms of action of BX661A, the effects of BX661A and its metabolites 5-aminosalicylic acid (5-ASA) and 4-aminobenzoyl-beta-aline (4-ABA) on polymorphonuclear (PMN) leukocyte chemotaxis and production of reactive oxygen species (ROS) from PMN cells were investigated and compared with the effects of 2-hydroxy-5-[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]-benzoic acid (CAS 599-79-1, SASP) and its metabolite 4-amino-N-2-pyridinyl-benzenesulfonamide (CAS 144-83-2, SP). 1. BX661A, SASP and SP concentration-dependently inhibited guinea pig PMN cell chemotaxis induced by zymosan-activated serum (IC50 = 1.39, 2.17 mmol/l, respectively) and by N-formyl-methionyl-leucyl-phenylalanine (FMLP) with IC50 values of 0.55, 0.06 and 0.66 mmol/l, respectively. 5-ASA and 4-ABA weakly affected the PMN cell chemotaxis induced by zymosan-activated serum (both IC50 values > or = 10 mmol/l) and by FMLP (IC50 > or = 10 and 8.05 mmol/l, respectively). 2. BX661A, SASP and SP concentration-dependently inhibited human PMN cell chemotaxis induced by FMLP with IC50 values of 0.68, 0.05 and 2.68 mmol/l, respectively, but both IC50 values of 5-ASA and 4-ABA were > 10 mmol/l. 3. BX661A, SASP, 5-ASA, 4-ABA and SP inhibited ROS production from rat PMN cells stimulated by FMLP in a concentration-dependent manner (IC50 = 58.4, 27.5, 0.61, 1242 and 13.9 mmol/l, respectively). 4. BX661A, SASP, 5-ASA, 4-ABA and SP inhibited ROS production from human PMN cells stimulated by FMLP in a concentration-dependent manner (IC50 = 67.4, 46.1, 0.69, 748 and 8.31 mumol/l, respectively). These results suggest that BX661A itself has inhibitory effects against PMN cell chemotaxis and ROS production from PMNs and that 5-ASA, which is the active moiety of BX661A, has a potent inhibitory effect against ROS production from PMNs. Therefore, these effects may be partially involved in the therapeutic effects of BX661A on ulcerative colitis.
Kimura
I
I
Infusion Research Department, Hoechst Marion Roussel Ltd., Saitama, Japan.
Kawasaki
M
M
Matsuda
A
A
Kataoka
M
M
Kokurba
Y
Y
D000636:Aminosalicylic Acids / Q000627:therapeutic use*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D019804:Mesalamine; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010659:Phenylhydrazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology
D000636:Aminosalicylic Acids; D000897:Anti-Ulcer Agents; D010659:Phenylhydrazines; D017382:Reactive Oxygen Species; D012460:Sulfasalazine; D019804:Mesalamine; C038637:balsalazide; D013427:Sulfapyridine