COX Inhibition and NSAID-Induced Gastric Damage - Roles in Various Pathogenic Events

Author(s): K. Takeuchi, A. Tanaka, Y. Hayashi, A. Yokota.

Journal Name: Current Topics in Medicinal Chemistry

Volume 5 , Issue 5 , 2005

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Abstract:

This article reviews our recent studies on NSAID-induced gastric damage, focusing on the relation between COX inhibition and pathogenic events. Conventional NSAIDs such as indomethacin, at a dose that inhibits PG production, enhance gastric motility, resulting in an increase in mucosal permeability and MPO activity, and eventually, gastric lesions. The development of these lesions can be prevented by administering PGE2 or antisecretory drugs, and also via an atropine-sensitive mechanism, not related to any antisecretory action. The selective COX-2 inhibitor rofecoxib has no effect on PG production and does not induce damage in the stomach. The selective COX-1 inhibitor SC-560 also does not cause damage, despite evoking a decrease in the PGE2 level. The combined administration of SC-560 and rofecoxib, however, provokes the formation of gastric lesions. SC-560, but not rofecoxib, causes gastric hypermotility and an increase in mucosal permeability, although the level of MPO activity increases only when rofecoxib is co-administered. COX-2 mRNA is expressed in the stomach after administration of SC-560 and indomethacin but not rofecoxib. The upregulation of COX-2 expression in response to indomethacin is prevented by atropine at a dose that inhibits gastric hypermotility but not by omeprazole at an antisecretory dose. We conclude that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by the inhibition of COX-1 and require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 up-regulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition.

Keywords: nsaid, gastric damage, pathogenesis, pg deficiency, gastric hypermotility, selective cox and cox inhibitors

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Article Details

VOLUME: 5
ISSUE: 5
Year: 2005
Page: [475 - 486]
Pages: 12
DOI: 10.2174/1568026054201668
Price: $58

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