A sheep model for continuous intrathecal infusion of test substances.

Pharmaceutical research and new drug development rely extensively on animal research. The development of novel agents for intrathecal administration requires preclinical studies of toxic effects in an animal model. We have developed a nonrodent animal model for this purpose. Our sheep model: 1 Is an animal whose neural axis is similar to the human 2 Allows for the percutaneous placement of intrathecal catheters 3 Has minimal possibilities of infection because the infusion system is totally implanted 4 Provides continuous infusion of the test agent 5 Generates behavioral, motor, neurological and histopathological information so that safety guidelines can be established prior to preclinical studies.

Preclinical toxicity study of intrathecal administration of the pain relievers dextrorphan, dextromethorphan, and memantine in the sheep model.

Objectives To determine the toxicity window for the continuous intrathecal administration of dextrorphan, dextromethorphan, and memantine via an implanted delivery pump. Materials and Methods Using 48 sheep with programmable continuous intrathecal infusion systems we determined the behavioral, motor, neurological, and histopathological changes produced by a 43-day continuous infusion study of dextrorphan, dextromethorphan, and memantine dissolved in 0.9% NaCl. Daily doses of each N-methyl-D-aspartate (NMDA) antagonist were 0.013, 0.051, 0.203, 0.510, 0.811, and 2.533 mg/kg/day, flow rates ranged from 13.25 ml/day to 0.051 ml/day at a concentration of 10 mg/ml. Control animals received saline in the range of 7.9985 ml/day to 1 ml/day. Conclusions Infusion of saline in the control animals produced no behavioral or motor changes. However, infusion of dextrorphan, dextromethorphan, and memantine at the higher doses (> 0.051 mg/kg/day) produced dose-dependent negative behavioral, motor, and histopathologic changes as indicated by a series of nonparametric statistical analyses. The minimal toxic doses were dextrorphan dose 3, dextromethorphan dose 1 and memantine dose 1. This study suggests that continuous intrathecal infusion of dextrorphan, dextromethorphan, and memantine via an implantable pump system can cause significant toxicities at the higher doses studied.

Cerebrospinal fluid distribution of opioids after intraventricular & lumbar subarachnoid administration in sheep.

The study of opioid distribution in blood and cerebrospinal fluid (CSF) is required to understand pharmacokinetic-pharmacodynamic relationships following lumbar intrathecal (it) and intracerebroventicular (i.c.v.) administration, and to investigate the contributions of spinal or supraspinal sites of action. The sheep model developed for pharmacokinetic study of analgesics allows atraumatic sampling of plasma and CSF after drug administration by the intravenous (i.v.), i.c.v., and it routes in an unanesthetized animal. Five adult female sheep were prepared with femoral vascular catheters, lumbar it and epidural cannulae, i.c.v. cannulae, and cisterna magna cannulae. Hydromorphone, methadone, naloxone, and [14C] sucrose were injected and collected by two methods: 1) injection into the i.c.v. cannula with lumbar CSF samples collected via the lumbar cannula and 2) injection into the lumbar cannula and cisternal CSF samples collected via ventriculocisternal cannula. Hydromorphone, morphine, and [14C] sucrose were detected at 90-105 min in lumbar CSF after i.c.v. injection. Hydromorphone and [14C] sucrose were detected in i.c.v. cerebrospinal fluid at 50 min after lumbar i.t. injection. Methadone was not detected in i.c.v. cerebrospinal fluid after i.t. injection, nor was methadone significantly detected in lumbar CSF after i.c.v. injection. These data indicate that i.c.v. and i.t. administration of lipophilic opioids produces CSF distributions different from those of hydrophilic opioids. This suggests that lipophilic opioids such as methadone or naloxone exert their effects predominantly on tissues near the site of injection. The study of i.t. and i.c.v. opiate administration and CSF pharmacokinetics may therefore have direct clinical implications.