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Gastroenterology. 1998 Jul;115(1):101-9.

Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity.

Author information

1
Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada. wallacej@ucalgary.ca

Abstract

BACKGROUND & AIMS:

Selective inhibitors of cyclooxygenase (COX)-2 are being developed as gastrointestinal-sparing anti-inflammatory drugs based on the premise that this isoform is solely responsible for prostaglandin synthesis at sites of inflammation, whereas COX-1 produces prostaglandins important for maintenance of mucosal integrity. We investigated the relationship between suppression of inflammation by COX-2 inhibitors (NS-398, nimesulide, DuP697, and etodolac) and their effects on gastric prostaglandin synthesis.

METHODS:

Effects of pretreatment of rats with drugs with a range of in vitro selectivity for COX-2 vs. COX-1 on carrageenan-induced paw inflammation were assessed, along with extent of suppression of COX-1 and COX-2. The role of COX-1 in inflammation was also assessed in COX-2-deficient mice.

RESULTS:

Significant anti-inflammatory effects were only observed at doses of the drugs that inhibited COX-1. At these doses, the drugs also significantly suppressed gastric prostaglandin synthesis and elicited gastric mucosal erosions. The degree of suppression of prostaglandin synthesis at the site of inflammation correlated significantly with inhibition of COX-1 but not COX-2.

CONCLUSIONS:

COX-1 makes an important contribution to inflammatory responses. To achieve desirable anti-inflammatory effects, COX-2 inhibitors needed to be given at doses in which selectivity was lost, leading to suppression of gastric prostaglandin synthesis and to mucosal injury.

PMID:
9649464
DOI:
10.1016/s0016-5085(98)70370-1
[Indexed for MEDLINE]

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