Abstract-Antiulcer effects of geranylgeranylacetone (GGA) on aspirin induced gastric ulcers in rats were studied, comparing them with those of gefarnate. The oral administration of GGA prevented the development of gastric ulcer induced by a single or repeated oral administration (5 consecutive days) of aspirin. The effects of GGA were more potent and more definite than those of gefarnate. The intraduodenal administration of GGA, but not the intragastrical administration, also inhibited the ulceration induced by aspirin in pylorus-ligated rats, while the intraduodenal adminis tration of gefarnate did not. GGA prevented the reduction of the H+ concentration and the increment of Na+ concentration in the gastric juice induced by aspirin. In addition, the decrease of hexosamine content in the gastric mucosa induced by aspirin was restored to a normal level by GGA, but not by gefarnate. From these results, it was concluded that the protective actions of GGA on aspirin-induced gastric ulcers might be due to its pro tection from the weakening of gastric mucosal resistances.
As part of our search for novel antiinflammatory drug candidates, we have designed and synthesized a series of 3-pyridylmethyl-substituted 2-amino-6- hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl group into the 2-amino group (type-A) or the benzene ring (type-B) of 2-amino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by glycogen-induced peritoneal cells of rat (in vitro) of leukotriene B4 (LTB4) and thromboxane A2 (TXA2), while not significantly inhibiting that of prostaglandin E2 (PGE2). The observed inhibition of the former two arachidonic acid metabolites was indicated to be the result of a direct action on 5-lipoxygenase and TXA2 synthetase by a cell-free in vitro assay. On the other hand, the inhibitory activities against PGE2 production were for most compounds very weak, indicating that they did not inhibit cyclooxygenase. Structure-activity relationship studies concerning the position of the 3-pyridylmethyl group revealed that type-B compounds generally showed about 10-fold stronger inhibitory activity against TXA2 synthetase than type-A compounds. The position of the 3-pyridylmethyl group played an important role in TXA2 synthetase inhibition. When some of these compounds (8, 13a, 26a (E3040), 26b, 27b, and 28b) were orally administered in the rat TNB/ethanol-induced chronic colitis model (100 mg/kg), the production of both LTB4 and TXB2 in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (26a), demonstrated a therapeutic effect at treatments of 100 mg/kg po once daily for 11 days and showed almost comparable activity to sulfasalazine at a dose of 500 mg/kg, the reference drug for inflammatory bowel diseases, in this in vivo model.
Abstract-The effects of aspirin and treatment with geranylgeranylacetone (GGA), an antiulcer drug, on the content of gastric glycoproteins were investigated in pylorus ligated rats. In normal rats, the amount of gastric glycoproteins in the mucous layer was about 1.5 times higher than that in the gastric mucosa, indicating that the glycoproteins were distributed in the mucous layer as a highly concentrated state. Aspirin (100 mg/kg, p.o.) decreased the content of gastric glycoproteins both in the mucous layer and in the gastric mucosa. The amount of the macromolecular fraction in the gastric juice, which corresponded to the gastric glycoproteins on the basis of molecular size, was not affected by aspirin. GGA (300 mg/kg, i.d.) could prevent the decreases of the total amount of gastric glycoproteins in the mucous layer plus gastric mucosa. These results indicated that the glycoproteins coating the surface of the gastric mucosa may play a role as a defensive mechanism and that GGA exerted an antiulcer effect on aspirin induced mucosal damage through preventing the decreases in gastric glycoproteins.
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