Intrathecal administration of 4-aminopyridine in chronic spinal injured patients

Study design: Intrathecal administration of 4-aminopyridine (4-AP) in chron ic spinal cord injured (SCI) patients. Objective: To determine the safety and effects of intrathecal administratio n of 4-AP in a small population of chronic SCI patients. Setting: The post anesthesia care unit of a tertiary care hospital. Methods: Following animal mode studies to establish dosing safety, six subj ects with chronic SCI were examined. In each subject, an intrathecai cathet er was placed with the tip as close to the lesion level as possible. 4-AP w as infused at 5 mug/h for a period of 4-5 h. Vital signs were recorded and sensory-motor physical examinations and pain questionnaires were administer ed for 24 h. In two patients, samples of cerebrospinal fluid for analysis w ere drawn from a second intrathecal catheter. Results: No adverse systemic side effects were noted. One patient showed tr ansient improvement in sensory function; two showed transient increases in spasticity; three showed transient increases in cutaneomuscular reflexes an d two showed an apparent small increase in volitional motor control. The co ncentration of 4-aminopyridine in the cerebrospinal fluid reached a peak of 163 ng/ml at 4 h in one subject and 123 ng/ml at 5 h in the other subject examined. Conclusion: Intrathecal administration of 4-aminopyridine at a rate of 5 mu g/h does not appear to cause adverse effects and may modify spinal cord fun ction. This route of administration allows local cerebrospinal fluid concen trations equivalent to those produced by maximum tolerable systemic doses, which require 1000 times more drug substance to be delivered to the subject as a whole. Intrathecal administration offers the potential to focus thera peutic effects to the lesion site while minimizing systemic side effects.