Development of NSAIDs with lower gastric side effect

Tohru Mizushima

Research output: Chapter in Book/Report/Conference proceedingChapter


The anti-inflammatory action of nonsteroidal anti-inflammatory drugs (NSAIDs) is mediated through their inhibitory effects on cyclooxygenase (COX) activity. On the other hand, NSAIDs use is associated with gastrointestinal complications. The inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs. In this article, I review our recent work on the COXindependent mechanism involved in NSAID-induced gastric lesions. Using DNA microarray analysis, we found that NSAIDs affect expression of various genes in a COX-independent manner and found that membrane permeabilization activity of NSAIDs and resulting NSAID-induced apoptosis are involved in NSAID-induced gastric lesions. These results suggest that NSAIDs with lower membrane permeabilization activity would be safer on stomach tissue and we found that loxoprofen, a clinically used NSAID, has relatively lower membrane permeabilization activity than other NSAIDs. We synthesized derivatives of loxoprofen and found that fluoro-loxoprofen has lower membrane permeabilization activity and their oral administration produced fewer gastric lesions but showed an equivalent anti-inflammatory effect. These results suggest that fluoro-loxoprofen is likely to be therapeutically beneficial as safer NSAIDs.

Original languageEnglish
Title of host publicationCell/Tissue Injury and Cytoprotection/Organoprotection in the Gastrointestinal Tract
Subtitle of host publicationMechanisms, Prevention and Treatment
PublisherS. Karger AG
Number of pages8
ISBN (Electronic)9783318021844
ISBN (Print)9783318021837
Publication statusPublished - 2012 Jun 22

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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