Kimura I, Kawasaki M, Matsuda A, Kataoka M, Kokurba Y
Infusion Research Department, Hoechst Marion Roussel Ltd., Saitama, Japan.
Arzneimittelforschung. 1998 Dec;48(12):1163-7.
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.
5-[4-(2-羧乙基氨甲酰基)苯基偶氮]水杨酸二钠盐二水合物（CAS 80573-04-2，BX661A）被开发用作溃疡性结肠炎的治疗药物。为阐明BX661A的作用机制，研究了BX661A及其代谢产物5-氨基水杨酸（5-ASA）和4-氨基苯甲酰-β-丙氨酸（4-ABA）对多形核（PMN）白细胞趋化性以及PMN细胞产生活性氧（ROS）的影响，并与2-羟基-5-[[4-[(2-吡啶基氨基)磺酰基]苯基]偶氮]-苯甲酸（CAS 599-79-1，SASP）及其代谢产物4-氨基-N-2-吡啶基苯磺酰胺（CAS 144-83-2，SP）的作用进行比较。1. BX661A、SASP和SP浓度依赖性地抑制酵母聚糖激活血清诱导的豚鼠PMN细胞趋化性（IC50分别为1.39、2.17 mmol/l）以及N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（FMLP）诱导的趋化性，IC50值分别为0.55、0.06和0.66 mmol/l。5-ASA和4-ABA对酵母聚糖激活血清诱导的PMN细胞趋化性（IC50值均≥10 mmol/l）以及FMLP诱导的趋化性（IC50分别≥10和8.05 mmol/l）影响较弱。2. BX661A、SASP和SP浓度依赖性地抑制FMLP诱导的人PMN细胞趋化性，IC50值分别为0.68、0.05和2.68 mmol/l，但5-ASA和4-ABA的IC50值均＞10 mmol/l。3. BX661A、SASP、5-ASA、4-ABA和SP浓度依赖性地抑制FMLP刺激的大鼠PMN细胞产生ROS（IC50分别为58.4、27.5、0.61、1242和13.9 mmol/l）。4. BX661A、SASP、5-ASA、4-ABA和SP浓度依赖性地抑制FMLP刺激的人PMN细胞产生ROS（IC50分别为67.
