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ToxSci Advance Access originally published online on May 12, 2004
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Toxicological Sciences 80, 322-334 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.

Intrathecal Ketorolac in Dogs and Rats

Tony L. Yaksh*,1, Kjersti A. Horais*, Nicolle Tozier*, Michael Rathbun*, Phil Richter*, Steve Rossi*, Marjorie Grafe{dagger}, Chuanyao Tong{ddagger}, Carol Meschter§, J. Mark Cline{ddagger} and James Eisenach{ddagger}

* University of California, San Diego, Department of Anesthesiology, Research Laboratory-0818, 9500 Gilman Drive, La Jolla, California 92093-0818; {dagger} Oregon Health and Science University, Department of Pathology, Portland, Oregon 97239; {ddagger} Wake Forest University School of Medicine, Department of Anesthesiology, Winston-Salem, North Carolina 27157; and § Comparative Biosciences, Inc., 2672 Bayshore Parkway, Suite 515, Mountain View, California 94043

Received February 13, 2004; accepted May 2, 2004

This study was conducted to assess spinal safety of the cyclo-oxygenase 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: t1/2 s = 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.

Key Words: nonsteroidal anti-inflammatory drug (NSAID); spinal; cyclo-oxygenase; COX; prostaglandin.


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