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

摘要: Combination therapies have long been used to treat inflammation while reducing side effects. The present study was designed 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 thereby decrease production metabolites that lead pain inflammation. sEHIs, such as 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE), stabilize epoxy-eicosatrienoic acids, which indirectly reduce expression COX-2 protein. Here we demonstrate therapy sEHIs produces significantly beneficial effects are additive for alleviating enhanced protein shifting oxylipin metabolomic profiles. When administered alone, AUDA-BE decreased 73 ± 6% control mice treated LPS only without altering COX-1 PGE2 levels 52 8% compared LPS-treated not receiving any intervention. low doses indomethacin, celecoxib, or rofecoxib, concentrations dropped 51 7, 84 9, 91 8%, respectively, versus control, disrupting prostacyclin thromboxane levels. These data suggest these drug combinations (NSAIDs sEHIs) produce a valuable analgesic effect prospectively decreasing cardiovascular toxicity.