title: Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors.
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.
authors.affiliation: Departments of *Entomology, Internal Medicine, Anesthesiology and Pain Medicine, and Physiology and Membrane Biology and Cancer Research Center, University of California, Davis, CA 95616.
authors.forename: Kara R
authors.initials: KR
authors.lastname: Schmelzer
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Steven L
authors.initials: SL
authors.lastname: Jinks
authors.forename: Jason P
authors.initials: JP
authors.lastname: Eiserich
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C503560:1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea; C503559:12-(3-adamantan-1-ylureido)dodecanoic acid butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014508:Urea; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004851:Epoxide Hydrolases; D015232:Dinoprostone; D000218:Adamantane