RESEARCH - A strategy for development of NSAIDs with lower risk for side effects

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Yakugaku Zasshi. 2008 Feb;128(2):255-61.

A strategy for development of NSAIDs with lower risk for side effects

Mizushima T.

Graduate School of Medical and Pharmaceutical Sciences, Research

Institute for Drug Discovery, Kumamoto University, Japan.

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most

frequently used classes of medicines worldwide. The major clinical

problem encountered with the use of NSAIDs is gastrointestinal

complications. In the USA, about 16,500 people per year die as a

result of NSAID-associated gastrointestinal complications.

COX-2-specific NSAIDs have been developed as safer for the

gastrointestinal tract, although the risk of cardiovascular thrombotic

disease has recently been noted with the use of COX-2-specific NSAIDs.

To find the strategy for the development of gastrointestinally safe

NSAIDs other than COX-2-specific NSAIDs, we examined the molecular

mechanism for NSAID-induced gastric ulcer formation. We found that

NSAIDs induce gastric mucosal cell death in a manner independent of

COX inhibition and that this cytotoxic effect is due to their membrane

permeabilization activity, which is not required for the

antiinflammatory activity of NSAIDs. Furthermore, we showed that in

addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is

required for NSAID-induced gastric ulcer formation. These results

suggest that NSAIDs that have neither membrane permeabilization

activity nor COX-2 specificity would be safe for both the

gastrointestinal tract and cardiovascular system and we are now

chemically synthesizing such NSAIDs.

PMID: 18239373

http://www.ncbi.nlm.nih.gov/pubmed/18239373

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