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 dihydrate (CAS 80573-04-2, BX661A) is being developed as a therapeutic drug for ulcerative colitis. To determine the active therapeutic moiety of BX661A, the therapeutic effects with single and combined administration of 5-aminosalicylic acid (5-ASA), 4-aminobenzoyl-beta-alanine (4-ABA) and 4-amino-N-2-pyridinyl-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 decreased the erosion area (mm2) 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. Salazosulfapyridine (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%, respectively, but did not improve the shortening of the large intestine. However, at a dose of 300 mg/kg (p.o.) SASP, the % inhibition value of the erosion area in the large intestine was reduced. 2. A single intrarectal administration of 5-ASA (105 mg/kg, i.r.) significantly decreased the erosion area (mm2) in the large intestine, but a single administration of 4-ABA or SP did not show any significant effect on the erosion 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 large intestine with a % inhibition value of 63.8%. On the other hand, the efficacy of 5-ASA disappeared with combined administration with SP (% inhibition value of 7.3%). These results suggest that 5-ASA is the active moiety for the therapeutic effects of BX661A and indicate that the efficacy of 5-ASA disappears with the 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 with ulcerative colitis.
Kimura
I
I
Infusion Research Department, Hoechst Marion Roussel Ltd., Saitama, Japan.
Kawasaki
M
M
Nagahama
S
S
Matsuda
A
A
Kataoka
M
M
Kokuba
Y
Y
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000636:Aminosalicylic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004347:Drug Interactions; D008297:Male; D019804:Mesalamine / Q000494:pharmacology; D010659:Phenylhydrazines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013427:Sulfapyridine / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology
C116574:4-aminobenzoyl-alanine; D000636:Aminosalicylic Acids; D000897:Anti-Ulcer Agents; D010659:Phenylhydrazines; D012460:Sulfasalazine; D019804:Mesalamine; D016264:Dextran Sulfate; D000409:Alanine; C038637:balsalazide; D013427:Sulfapyridine