ABSTRACT-Effectsof KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5 200 mg/kg inhibited water-immersion stress and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicat ing that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5 -100 mg/kg, also inhibited ethanol-induced gas tric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB 5492 was 3 times more potent than teprenone, whereas cimetidine produced no ob vious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-in duced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.It is generally accepted that peptic ulcers are caused by a disruption in the balance of aggressive factors (gastric acid and pepsin) and mucosal defensive factors (blood flow, mucus, HC03 secretion, etc.) (1). Anti-ulcer agents have therefore been used either for suppres sing aggressive factors or for enhancing mucosal defensive factors. However, in recent years, it has been considered that different anti-ulcer agents should be used for gastric and duodenal ulcers, because of the patho physiological differences between the two ulcer types. That is, as gastric acid secretion is generally greater in duodenal ulcer patients than in normal subjects (2-4), agents such as H2-receptor antagonists or proton pump in hibitors, which strongly inhibit gastric acid secretion, show prominent effects on duodenal ulcers. In contrast, since gastric acid secretion is usually normal or below normal in gastric ulcer patients, gastric ulcers are presumed to be caused by weaknesses in gastric mucosal re sistance (4, 5). Therefore, agents which en hance mucosal defensive factors would be ex pected to show desirable effects against gastric ulcers. Although various agents in this catego ry have already been developed so far, they have not been particularly effective, so anti secretory agents are used preferably, even in the treatment of gastric ulcers.Seeking a novel agent which would enhance mucosal defensive factors more potently than existing agents, we developed 4-methoxy phenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate m...

Summary The expression of Group-TI phospholipase A2 (M-PLA2) was analysed immunohistochemically in malignant, non-malignant (including atrophic, hyperplastic, pseudopyloric metaplastic and intestinal metaplastic) and normal human gastric mucosae. M-PLA2 was consistently detected in the stem cell lineage, pseudopyloric metaplasia and the generative cells of hyperplastic foveolar epithelium and intestinal metaplasia (IM). In IM, the appearance of Phospholipase A2 (PLA2) catalyses the specific hydrolysis of a fatty acyl ester bond at the sn-2 position of glycerophospholipids. In addition, a calcium-dependent PLA2 is thought to be one of the most important enzymes regulating the release of arachidonic acid from membrane phospholipids (Lands, 1968; Van den Bosh, 1980). Until recently, two genetically distinct isoenzymes, exocrine PLA2 (secreted in pancreatic juice) and intracellular PLA2 (contained in the cytosol and membrane-associated fraction), have been recognised in humans (Vadas & Pruzanski, 1986;Nakaguchi et al., 1986). In the membrane fraction of human spleen cells the existence of a PLA2, which does not react with anti-human P-PLA2 antibody, has been demonstrated (Nakaguchi et al., 1986). Further purification and subsequent sequencing of this enzyme revealed that it belongs to the Group-I1 PLA2 (Kanda et al., 1989). Group-II PLA2 has been thought to play an important regulatory role in several metabolic pathways (Nakano et al., 1990a;Nakano et al., 1990b). And recently, the distribution of this Group-II-PLA2 in human organs has been published (Kiyohara et al., 1992).The product of this enzyme's action, free arachidonate (which serves as a substrate for the cyclo-oxygenase route and lipoxygenase route) (Van den Bosh, 1980) is the first and rate-limiting precursor in the biosynthes of prostaglandins (PG), leukotriene and HETE (Lands, 1979; Van den Bosh, 1980). Among these products, PG is abundant in gastrointestinal mucosa (Robert et al., 1979), and especially PGE2, has potent cytoprotective effects, e.g. inhibition of gastric secretion, prevention of ulcer formation, and acceleration of the healing of mucosal damage (Robert et al., 1979;Wilson et al., 1971;Robert et al., 1976). Nevertheless, the biological significance and function of PLA2 in the human stomach is still unknown. In the rat gastric mucosa, PLA2 which is structurally identical to the rat pancreatic type PLA2 (P-PLA2, Group-I PLA2) (Tojo et al., 1988;Okamoto et al., 1985) was immunocytochemically detected in chief cells (Tatsumi et al., 1990). Knowledge of the distribution of this enzyme in human gastric mucosa might provide useful insight into the function of PLA2 in gastric mucosa.In this study, the immunohistochemical expression of M-PLA2 was examined by using a monoclonal antibody (MoAb) against the recently described human splenic Group-II PLA2 (M-PLA2) in a variety of human gastric mucosae, such as normal, atrophic, hyperplastic, pseudopyloric metaplastic and intestinal metaplastic mucosae, as well as cancerous lesions. Moreover, the po...

ABSTRACT-The effect of KB-5492, a new anti-ulcer agent with a selective affinity for the sigma-receptor, on aspirin-induced disruption of the gastric mucosal barrier was studied in rats. Intragastric instillation of aspirin at 200 mg/kg rapidly decreased the gastric transmucosal potential difference (PD) in anesthetized rats. The PD recovered gradually following the removal of aspirin from the instillation solution. Aspirin, ad ministered orally at 200 mg/kg, also reduced the amount of gastric covering mucus and induced a decrease in gastric H+ concentration and an increase in gastric Na+ concentration in pylorus-ligated rats. KB-5492, administered intraduodenally at 200 mg/kg, significantly prevented the aspirin-induced decrease in PD and accelerated the recovery of PD. In addition, KB-5492 at 200 mg/kg significantly prevented the reduction of gastric covering mucus, the decrease in gastric H+ concentration and the increase in gastric Na+ concentra tion induced by aspirin. These effects were similar to those of 0.01 mg/kg of 16,16-dimethyl prostaglandin E2 (dmPGE2). Teprenone at 200 mg/kg did not show any effect except for the inhibitory effects on the changes in gastric H+ and Na+ concentration. In the histological study, marked reduction of PAS-positive epithelial mucus and the exfoliation of surface epithelial cells were observed in the gastric mucosa exposed to aspirin. KB-5492 and dmPGE2 almost completely prevented the former, whereas both drugs prevented the latter incompletely. These findings indicate that KB-5492 protects the gastric mucosal barrier against the disruption by aspirin, which may be mainly exerted by retention of the gastric covering mucus.

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