Determination of the active moiety of BX661A, a new therapeutic agent for ulcerative colitis, by studying its therapeutic effects on ulcerative colitis induced by dextran sulfate sodium in rats

5-[4-(2-Carboxyethylcarbamoyl)phenylazo]salicylic acid disodium salt dihydr ate (CAS 80573-04-2, BX661A) is being developed as a therapeutic drug for u lcerative colitis. To determine the active therapeutic moiety of BX661A, th e therapeutic effects with single and combined administration of 5-aminosal icylic acid (5-ASA), 4-aminobenzoyl-beta-alanine (4-ABA) and 4-amino-N-2-py ridinyl-benzenesulfonamide (CAS 144-83-2, sulfapyridine, SP) on ulcerative colitis induced by dextran sulfate sodium (DSS) in rats were investigated, and the following results were obtained. 1. BX661A at doses of 30, 100 and 300 mg/kg (p.o.) dose-dependently decreas ed the erosion area (mm(2)) in the large intestine with % inhibition values of 28.7, 49.1 and 61.6 %, and the shortening of the large intestine with % inhibition values of 17.1, 25.7 and 48.6 %, respectively. Salazosulfapyrid ine (SASP) at doses of 30 and 100 mg/kg (p.o.) decreased the erosion area ( mm2) in the large intestine with % inhibition values of 30.7 and 45.3 %, re spectively, but did not improve the shortening of the large intestine. Howe ver, at a dose of 300 mg/kg (p.o.) SASP, the % inhibition value of the eros ion area in the large intestine was reduced. 2. A single intrarectal administration of 5-ASA (105 mg/kg, i.r) significan tly decreased the erosion area (mm2) in the large intestine, but a single a dministration of 4-ABA or SP did not show any significant effects on the er osion area. Combined administration with 5-ASA (105 mg/kg, i.r.) and 4-ABA (142.8 mg/kg, i.r.) significantly decreased the erosion area (mm2) in the l arge intestine with a % inhibition value of 63.8 %. On the other hand, the efficacy of 5-ASA disappeared with combined administration with SP (% inhib ition value of 7.3 %). These results suggest that 5-ASA is the active moiety for the therapeutic e ffects of BX661A and indicate that the efficacy of 5-ASA disappears with th e combined use of SP, but not of 4-ABA. Therefore, it seems that BX661A is clinically safe and more effective than SASP in the treatment of patients w ith ulcerative colitis.