Hiroshi Satoh (1), Shoichi Asano (1), Rika Maeda (1), Izumi Murakami
(1), Ikuko Inada (1), Fumihiko Sato (1) and Akio Shino (2)
(1) Pharmaceutical Research Laboratories, Pharmaceutical Research Division and (2) Drug Safety Research Laboratories, Pharmaceutical Development Division, Takeda Chemical Ind., Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532, Japan
Abstract: We found indomethacin aggravates healed gastric ulcers (ulcer relapse) in rats. In the present study, we examined the effects of human basic fibroblast growth factor (bFGF) mutein CS23 (TGP-580) and histamine H2-receptor antagonists (H2-RAs) on ulcer relapse in this model. In male SD rats, gastric ulcers were induced in the antrum by injection of acetic acid. Indomethacin (1 mg/kg/day) given s.c. for 2 weeks starting 4 weeks after the operation aggravated the healed ulcer; the areas with and without indomethacin were 4.8+/-1.4 and 0.4+/-0.3 mm2, respectively. Drugs were given orally once daily for 4 weeks starting 2 days after the operation or for the 2-week indomethacin administration period. Treatment with ranitidine (100 mg/kg), cimetidine (100 mg/kg) and TGP-580 (0.1 mg/kg) for 4 weeks accelerated the healing. The aggravation by indomethacin was significantly inhibited by pretreatment with TGP-580 and mildly inhibited by cimetidine but not ranitidine. When the drugs were co-administered with indomethacin for 2 weeks, the aggravation was significantly prevented by ranitidine and mildly inhibited by cimetidine and TGP-580. Both TGP-580 and H2-RAs can prevent the ulcer relapse induced by indomethacin but via different modes of action: TGP-580 inhibits relapse mainly by acting on the process of healing, while H2-RAs act mainly on the process of aggravation.
Keywords: Gastric ulcer relapse, Basic fibroblast growth factor (bFGF), bFGF mutein CS23, TGP-580, Histamine H2-receptor antagonist