Plasma and cerebrospinal fluid concentrations of 4-aminopyridine following intravenous injection and metered intrathecal delivery in canines.

Abstract

Potassium channel blockade by 4-aminopyridine (4-AP) has been shown to initiate modest levels of functional recovery in spinal-injured dogs and people following intravenous administration; however, the relevant central nervous system (CNS) concentration mediating these effects is not known. We have determined the concentrations of 4-aminopyridine in plasma and cerebrospinal fluid following intravenous administration (0.5 mg/kg) in large (> 22 kg) dogs, using liquid column chromatography. Plasma levels are initially high (> 1 microgram/mL) and fall rapidly to levels less than 100 ng/mL by about 2 h postinjection. A characteristic secondary peak in plasma 4-AP is observed at about 1 h postinjection. Corresponding concentrations of 4-AP in CSF were relatively stable for nearly 2 h, never exceeding (as a mean) 50 ng/mL within the first 2 h postinjection. We suggest behavioral recovery in clinical cases of spinal cord injury in both dogs and humans is mediated by such low (< 50 ng/mL) concentrations of 4-AP bathing the lesion. Since the adverse side effects that accompany IV administration of the drug limit its potential clinical usefulness, we have evaluated the feasibility of an alternate route of administration, continuous metered delivery of 4-AP into the spinal cord's subarachnoid space. This is accomplished by using a surgically implantable pump and delivery catheter. The pump itself can be interrogated, and is fully programmable, by noninvasive telemetry. Intrathecal delivery rates of between 1 and 60 micrograms of 4-AP per hour never produced detectable levels of the drug in plasma or cervically sampled CSF in dogs independent of the amount or duration of infusion (hours to days). The levels of 4-AP in lumbar samples of CSF near the lumbar delivery site suggest a very steep gradient of the drug, with local concentrations easily reaching 1 microgram/mL or higher (10- to 20-fold higher than can be safely produced by IV administration). The most frequent adverse reaction to intrathecal 4-AP delivery was a mild hindlimb tremor, fully reversible following reduction in the rate of drug delivery or termination of delivery. This route of drug administration relative to clinical spinal cord injury is discussed.