Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation

Abstract

Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.

Acetaminophen Use and Risk of Myocardial Infarction and Stroke in a Hypertensive Cohort

“…Recent data suggest that this may also occur after acetaminophen use. 16 There are numerous differences between our study and the previous analysis from the Women's Health Study. 8 That study included only women, aged 30 to 55 years, from a particular professional group (nurses).…”

“…by guest on May 12, 2018 http://hyper.ahajournals.org/ Downloaded from low, medium, or high-frequency users on unadjusted analysis (online-only Data Supplement). The risk of any cardiovascular event was lower after adjustment in medium-frequency acetaminophen users compared with the reference group (HR, 0.75; 95% CI, 0.59-0.95).…”

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

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