Prevention of gastric ulcer relapse induced by indomethacin in rats by a mutein of basic fibroblast growth factor.
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.
Satoh
H
H
Pharmaceutical Research Laboratories, Takeda Chemical Ind., Ltd., Osaka, Japan.
Asano
S
S
Maeda
R
R
Murakami
I
I
Inada
I
I
Sato
F
F
Shino
A
A
D019342:Acetic Acid / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity*; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004347:Drug Interactions; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005744:Gastric Acid / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007213:Indomethacin / Q000008:administration & dosage / Q000633:toxicity*; D007279:Injections, Subcutaneous; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011899:Ranitidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012008:Recurrence; D013270:Stomach / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D014945:Wound Healing / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D006635:Histamine H2 Antagonists; D011994:Recombinant Proteins; C065198:protein CS23; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D002927:Cimetidine; D011899:Ranitidine; D009195:Peroxidase; D019342:Acetic Acid; D007213:Indomethacin