Skip Navigation

Publication Detail

Title: Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors.

Authors: Schmelzer, Kara R; Inceoglu, Bora; Kubala, Lukas; Kim, In-Hae; Jinks, Steven L; Eiserich, Jason P; Hammock, Bruce D

Published In Proc Natl Acad Sci U S A, (2006 Sep 12)

Abstract: Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed to evaluate the therapeutic potential of combination treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and previously undescribed soluble epoxide hydrolase inhibitors (sEHIs) in lipopolysaccharide (LPS)-challenged mice. NSAIDs inhibit cyclooxygenase (COX) enzymes and thereby decrease production of metabolites that lead to pain and inflammation. The sEHIs, such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), stabilize anti-inflammatory epoxy-eicosatrienoic acids, which indirectly reduce the expression of COX-2 protein. Here we demonstrate that the combination therapy of NSAIDs and sEHIs produces significantly beneficial effects that are additive for alleviating pain and enhanced effects in reducing COX-2 protein expression and shifting oxylipin metabolomic profiles. When administered alone, AUDA-BE decreased protein expression of COX-2 to 73 +/- 6% of control mice treated with LPS only without altering COX-1 expression and decreased PGE(2) levels to 52 +/- 8% compared with LPS-treated mice not receiving any therapeutic intervention. When AUDA-BE was used in combination with low doses of indomethacin, celecoxib, or rofecoxib, PGE(2) concentrations dropped to 51 +/- 7, 84 +/- 9, and 91 +/- 8%, respectively, versus LPS control, without disrupting prostacyclin and thromboxane levels. These data suggest that these drug combinations (NSAIDs and sEHIs) produce a valuable beneficial analgesic and anti-inflammatory effect while prospectively decreasing side effects such as cardiovascular toxicity.

PubMed ID: 16950874 Exiting the NIEHS site

MeSH Terms: Adamantane/administration & dosage; Adamantane/analogs & derivatives*; Adamantane/therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use*; Cyclooxygenase 1/metabolism; Cyclooxygenase 2/metabolism; Dinoprostone/blood; Down-Regulation; Drug Therapy, Combination; Enzyme Inhibitors/administration & dosage; Enzyme Inhibitors/therapeutic use*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Lipopolysaccharides/toxicity; Mice; Pain/drug therapy*; Urea/administration & dosage; Urea/analogs & derivatives*; Urea/therapeutic use

Back
to Top