Intrathecal ketorolac in dogs and rats.
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 microl/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 microl/h), lumbar CSF concentrations of ketorolac were 3.8 and 52.7 microg/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 microl) 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.
Yaksh
Tony L
TL
University of California, San Diego, Department of Anesthesiology, Research Laboratory-0818, 9500 Gilman Drive, La Jolla, California 92093-0818, USA. tyaksh@ucsd.edu
Horais
Kjersti A
KA
Tozier
Nicolle
N
Rathbun
Michael
M
Richter
Phil
P
Rossi
Steve
S
Grafe
Marjorie
M
Tong
Chuanyao
C
Meschter
Carol
C
Cline
J Mark
JM
Eisenach
James
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D005260:Female; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007278:Injections, Spinal; D020910:Ketorolac / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007958:Leukocyte Count; D008297:Male; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply / Q000378:metabolism; D013117:Spinal Cord Compression / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020910:Ketorolac