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Damaging effects on the gastrointestinal tract of proglumetacin maleate (PGM), a new indomethacin (IND) derivative, were examined in comparison with those of IND. Gastric and small intestinal lesions were maximum 4 and 24 hr after a single oral administration of PGM, respectively. Ulcerogenic effects of PGM on the gastric mucosa were approximately 1/7 and 1/10 times as potent as those of IND on a molar ratio 4 hr after single oral dosing to fasting and feeding rats, respectively. PGM was also less active on the small intestinal mucosa 24 hr after single oral dosing. After repeated dosing for 7 days, ulcerogenic effects of PGM were about 1/3 and 1/2 times more potent than those of IND on the gastric and the small intestinal mucosa, respectively. The weak ulcerogenicity of PGM appears to be due to the fact that it has little direct action on the gastrointestinal mucosa. On the other hand, protective effects of PGM on diarrhea induced by arachidonic acid in mice were about 1/2 times as potent as those of IND in both 1 and 4 hr pretreatments. So PGM must have less inhibitory effects on prostaglandin biosynthesis in the intestine than IND. PGM is a safer drug than IND because it has less damaging effect on the gastrointestinal mucosa. Therefore, it may be much more useful for the treatment of chronic inflammatory disorders like rheumatoid arthritis.
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