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 PGE2 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, PGE2 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 13646-13651 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 37 |
| DOIs | |
| State | Published - Sep 12 2006 |
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Keywords
- Arachidonic acid
- Cyclooxygenase
- Epoxygenase
- Linoleic acid
- Pain
ASJC Scopus subject areas
- Genetics
- General
Cite this
Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors. / Schmelzer, Kara R.; Inceoglu, Bora; Kubala, Lukas; Kim, In Hae; Jinks, Steven L.; Eiserich, Jason P.; Hammock, Bruce D.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 37, 12.09.2006, p. 13646-13651.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors
AU - Schmelzer, Kara R.
AU - Inceoglu, Bora
AU - Kubala, Lukas
AU - Kim, In Hae
AU - Jinks, Steven L.
AU - Eiserich, Jason P.
AU - Hammock, Bruce D.
PY - 2006/9/12
Y1 - 2006/9/12
N2 - 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 PGE2 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, PGE2 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.
AB - 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 PGE2 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, PGE2 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.
KW - Arachidonic acid
KW - Cyclooxygenase
KW - Epoxygenase
KW - Linoleic acid
KW - Pain
UR - http://www.scopus.com/inward/record.url?scp=33748797975&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33748797975&partnerID=8YFLogxK
U2 - 10.1073/pnas.0605908103
DO - 10.1073/pnas.0605908103
M3 - Article
C2 - 16950874
AN - SCOPUS:33748797975
VL - 103
SP - 13646
EP - 13651
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 37
ER -