Acute toxicology of an enkephalinase inhibitor (SCH 32615) given intrathecally in the ewe.
Intrathecal application of the enkephalinase inhibitor, SCH 32615, yields antinociception in animal paradigms. Our purpose was to identify possible acute behavioral effects, neurotoxicity, or systemic toxicity of intrathecal SCH 32615 administration during 9 days in the ewe. Seventeen ewes were implanted with lumbar silicone intrathecal catheters and subcutaneous access ports for repeated injection. Baseline and serial daily behavioral assessments were made during 9 days of 2-mL intrathecal injection twice daily of either normal saline (SAL group) or a 20 mg/mL isotonic sterile solution of SCH 32615 (SCH group). Data were analyzed by treatment group (SCH versus SAL) by taking the group means of individual ewe cumulative scores during 9 days. At 15-18 h after the last injection, the ewes were euthanized and the spinal cords and leptomeninges were grossly examined and prepared for histological assessment. Histological evaluation of the lumbar (at catheter entrance site and catheter tip), thoracic, and cervical sections of all animals was performed by two neuropathologists. Several mild, reversible, and apparently nonprogressive behaviors (Stepping/Placing and Hindlimb Stretching/Splaying) were observed almost exclusively in SCH-treated ewes. These behaviors were interpreted as mild temporary irritative effects, without significant neuropathological sequelae. Pathological findings primarily consisted of mild, focal dural thickening and white matter compression. These changes were distributed equally between drug-treated and control groups and were attributable to catheter implantation and local compressive effects. There were no pathological bases identified in this study to preclude the clinical study of SCH 32615 within the dose range studied.
Coombs
D W
DW
Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756.
Colburn
R W
RW
DeLeo
J A
JA
Hoopes
P J
PJ
Rhodes
C H
CH
Twitchell
B B
BB
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005684:Gait / Q000187:drug effects*; D007278:Injections, Spinal; D009043:Motor Activity / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012756:Sheep; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D004151:Dipeptides; C062344:SCH 32615; D015260:Neprilysin