After old age–associated causes, colic is the leading cause of death in horses.1,2 Many of these deaths are attributable to the results of increased intestinal absorption of endotoxin through a compromised intestinal epithelial barrier.3 Many of the systemic effects and clinical signs of endotoxemia are mediated by PGs, which are elaborated from arachidonic acid by the constitutively expressed COX-1 and inducible COX-2 enzymes. Therefore, NSAIDs such as flunixin meglumine are frequently administered to horses with colic to inhibit COX and ameliorate the detrimental effects of PGs. However, PGs are critical for recovery of barrier function in ischemia-injured intestine.4,5 Treatment of ischemia-injured equine jejunum with the nonselective COX inhibitor flunixin meglumine retards recovery of intestinal barrier function.6-8 Previous evaluations of the COX-2 selective inhibitors deracoxib and etodolac in horses have not resulted in identification of an alternative NSAID to flunixin meglumine that is practical to use in clinical cases of colic in horses.6,8
Meloxicam is a preferential COX-2 inhibitor in the enolic acid class of NSAIDs and has a favorable gastrointestinal adverse effect profile in humans, compared with the adverse effect profile of nonselective COX inhibitors.9 The European Agency for the Evaluation of Medicinal Products recently approved meloxicam for oral and IV use in horses at a dose of 0.6 mg/kg every 24 hours.a
The purpose of the study reported here was to determine and compare the effects of meloxicam and flunixin meglumine on recovery of ischemia-injured equine jejunum. Our hypothesis was that administration of the preferential COX-2 inhibitor meloxicam to horses that underwent jejunal ischemia would permit sufficient local PG production to facilitate recovery of intestinal barrier function, while ameliorating clinical signs of pain and endotoxemia attributable to the detrimental systemic effects of PGs. Furthermore, we speculated that the NSAIDs flunixin meglumine and meloxicam would affect expression or activity of other proteins associated with the inflammatory response to ischemia-reperfusion, given the emerging interest in COX-independent actions of COX inhibitors on MAPKs and PPARγ.10
Nonsteroidal anti-inflammatory drug
Mitogen-activated protein kinase
Peroxisome proliferator-activated receptor gamma
Spontaneous potential difference
Transepithelial electrical resistance
Lipopolysaccharide from Escherichia coli serotype O111:B4 labeled with fluorescein isothiocyanate
High-pressure liquid chromatography
p38 mitogen-activated protein kinase
Phosphorylated p38 mitogen-activated protein kinase
The European Agency for the Evaluation of Medicinal Products. Available at: www.emea.eu.int/vetdocs/PDFs/EPAR/metacam/032397en2.pdf. Accessed Feb 28, 2006.
Metacam (20 mg/mL) solution for injection, Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany.
Sigma Chemical Co, St Louis, Mo.
Agilent 1100 series, Agilent Technologies, Wilmington, Del.
Zorbax RX-C18, Agilent Technologies, Wilmington, Del.
Oasis HLB cartridges (1 mL), Waters Corp, Milford, Mass.
WinNonlin, version 4.0, Pharsight Corp, Mountain View, Calif.
Bio-Rad Laboratories, Hercules, Calif.
Hybond ECL, Amersham Life Science, Birmingham, England.
Santa Cruz Biotechnology Inc, Santa Cruz, Calif.
Abcam, Cambridge, Mass.
Cell Signaling Technology Inc, Danvers, Mass.
Amersham Biosciences Corp, Piscataway, NJ.
IP gel, Scanalytics, Fairfax, Va.
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Dupouy VM, Ferre PJ, Uro-Coste E, et al. Time course of COX-1 and COX-2 expression during ischemia-reperfusion in rat skeletal muscle. J Appl Physiol 2006;100:233–239.
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Behavioral pain scoring system used to assess signs of pain in horses that were treated with saline (0.9% NaCl) solution, flunixin meglumine, or meloxicam before and at intervals after a 2-hour period of surgically induced jejunal ischemia Scores from each category are added to give a total subjective pain score (modified from Pritchett et al 12)
|Behavioral category||Behavioral score|
|Gross signs of pain||None||NA||Occasional|
|Head position||Above withers*||NA||At withers*|
|Ear position||Forward; frequent movement||NA||Slightly back; little movement|
|Location||At door, watching environment||Standing in middle of stall, facing front||Standing in middle of stall, facing side|
|Spontaneous locomotion||Moves freely||Occasional steps||NA|
|Response to another horse||Ears forward; head up; moves to door||Ears forward; head up; no movement to door||Ear flicks; no movement to door|
|Response to open door||Moves to door||Looks at door||NA|
|Response to approach||Moves to observer; ear forward||Looks at observer; ear forward||Moves away|
|Lifting feet||Freely when prompted||After mild encouragement||NA|
Highest point of vertebral column between scapulae.
NA= Not applicable.