Application of anti-inflammatory drugs with less damage to the gastrointestinal mucosa
Authors: Ikeda Issei , Masuda Yuya , Otsuka Yuuki , Yamakawa Naoki , Mizushima Tohru , Amagase Kikuko 
Published: May 2023

Background & Aim: A nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory effects by inhibiting cyclooxygenase (COX), thereby reducing prostaglandin (PG) levels. However, PGs play a number of roles in the gastrointestinal tract, including regulating mucus and gastric acid secretion and maintaining homeostasis. Loxoprofen (LOX), a NSAID, is widely used for clinical treatment in Asia, but its gastrointestinal toxicity is still a problem. Fluoroloxoprofen (F-LOX), a derivative of LOX, has been reported to be an NSAID with similar anti-inflammatory activity as LOX, but with less effect on the gastric mucosa. If F-LOX shows lower damage to the small intestinal mucosa than LOX, it can be proposed as a safer NSAID. In this study, we investigated the effect of F-LOX, a newly synthesized anti-inflammatory drug, on the small intestinal mucosa. Materials & Methods: Male SD rats were orally administered LOX and F-LOX, dissected 24 hours later, and lesion area was measured under a dissecting microscope. Histopathological observation was performed by hematoxylin-eosin staining. Myeloperoxidase (MPO) activity was measured by the o-dianisidine method as an indicator of intestinal mucosal inflammation. Three or 6 hours after oral administration of LOX and F-LOX, the PGE2 production or cAMP concentration of the small intestinal mucosa was measured by an enzyme immunoassay. The amount of mucus was quantified by Periodic Acid Schiff (PAS) staining. Results: After 24 hours of LOX administration, hemorrhagic injury was observed in the jejunum and ileum under a dissecting microscope, hemorrhagic injury was also observed in the F-LOX group, but the area of injury was smaller and the depth of injury was shallow compared to the LOX group. Compared to the LOX-treated group, a weaker of epithelial cell damage was observed histopathologically in the F-LOX-treated group. Although MPO activity tended to increase 24 hours after LOX administration, almost no difference was observed in the F-LOX-treated group compared to the solvent group. Compared to the vehicle treated group, PGE2 production in the small intestinal mucosa 3 hours after LOX administration was significantly reduced, and was reduced to the same extent in the F-LOX group. Small Intestinal mucosa PAS-positive mucus was reduced at 6 hours after LOX and F-LOX administration, but the reduction was smaller in the F-LOX group. The cAMP concentration in the small intestinal tissue was lower in the LOX group and was higher in the F-LOX group than in the LOX group, and was the same as that of the vehicle treated group in the F-LOX group. Conclusion: F-LOX was demonstrated to be an NSAID with similar anti-inflammatory effects as LOX, but with less injurious effects on the small intestinal mucosa. Furthermore, although F-LOX inhibited PGE2 production in the small intestinal mucosa, it did not markedly decrease mucus volume, which we speculate is partially due to increased cAMP levels. Institution This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.