Intrathecal ketorolac in dogs and rats

Tony L. Yaksh, Kjersti A. Horais, Nicolle Tozier, Michael Rathbun, Phil Richter, Steve Rossi, Marjorie Grafe, Chuanyao Tong, Carol Meschter, J. Mark Cline, James Eisenach

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45 Scopus citations

Abstract

This study was conducted to assess spinal safety of the cyclooxygenase inhibitor ketorolac in dogs and rats. Beagle dogs were prepared with lumbar intrathecal catheters and received continuous spinal infusions of 5 mg/ml ketorolac (N = 6), 0.5 mg/ml ketorolac (N = 8), or saline vehicle (N = 6) at 50 μl/h (1.2 ml/day) for 28 days. No systematic drug or dose-related changes were observed in motor function, heart rate, or blood pressure. Histological examination revealed a mild pericatheter reaction in all groups with no drug or dose related effect upon spinal pathology at the lumbar site of highest drug concentration. Cisternal CSF protein was elevated for all treatment groups at necropsy, and cisternal glucose was within normal range for all treatment groups, though three dogs displayed decreases in cisternal glucose. Significant reductions in hematocrit were noted, and increased incidence of gastric bleeding at necropsy was observed in animals receiving ketorolac. Intrathecal ketorolac kinetics revealed a biphasic clearance: t1/2s = 10.3 and 53 min, respectively. After initiation of infusion (0.5 mg and 5 mg/ml/50 μl/h), lumbar CSF concentrations of ketorolac were 3.8 and 52.7 μg/ml, respectively. Bolus and continuous infusion of intrathecal ketorolac resulted in significant reduction of lumbar CSF PGE2 concentrations. In rats, with intrathecal catheters, four daily bolus deliveries of saline or ketorolac (5 mg/ml/10 μl) had no effect upon spinal histology or upon spinal cord blood flow. These data indicate that intrathecal ketorolac in two species at the dose/concentrations employed does not induce evident spinal pathology but diminishes spinal prostaglandin release.

Original languageEnglish (US)
Pages (from-to)322-334
Number of pages13
JournalToxicological Sciences
Volume80
Issue number2
DOIs
StatePublished - Aug 1 2004

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Keywords

  • COX
  • Cyclo-oxygenase
  • Nonsteroidal anti-inflammatory drug (NSAID)
  • Prostaglandin
  • Spinal

ASJC Scopus subject areas

  • Toxicology

Cite this

Yaksh, T. L., Horais, K. A., Tozier, N., Rathbun, M., Richter, P., Rossi, S., Grafe, M., Tong, C., Meschter, C., Cline, J. M., & Eisenach, J. (2004). Intrathecal ketorolac in dogs and rats. Toxicological Sciences, 80(2), 322-334. https://doi.org/10.1093/toxsci/kfh168