No abstract

Study design: Intrathecal administration of 4-aminopyridine (4-AP) in chronic spinal cord injured (SCI) patients. Objective: To determine the safety and e ects of intrathecal administration 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 subjects with chronic SCI were examined. In each subject, an intrathecal catheter was placed with the tip as close to the lesion level as possible. 4-AP was infused at 5 mg/h for a period of 4 ± 5 h. Vital signs were recorded and sensory-motor physical examinations and pain questionnaires were administered for 24 h. In two patients, samples of cerebrospinal¯uid for analysis were drawn from a second intrathecal catheter. Results: No adverse systemic side e ects were noted. One patient showed transient improvement in sensory function; two showed transient increases in spasticity; three showed transient increases in cutaneomuscular re¯exes and two showed an apparent small increase in volitional motor control. The concentration of 4-aminopyridine in the cerebrospinal¯uid reached a peak of 163 ng/ml at 4 h in one subject and 122 ng/ml at 5 h in the other subject examined. Conclusion: Intrathecal administration of 4-aminopyridine at a rate of 5 mg/h does not appear to cause adverse e ects and may modify spinal cord function. This route of administration allows local cerebrospinal¯uid concentrations 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 o ers the potential to focus therapeutic e ects to the lesion site while minimizing systemic side e ects. Spinal Cord (2000) 12, 728 ± 732

Experimental compression injury of the spinal cord in guinea pigs results in delayed neurologic deficits that continue to increase in severity for several days following trauma, coincident with inflammatory responses, including invasion of the lesion by mononuclear phagocytes and increased levels of the neurotoxin quinolinic acid (QUIN). Inflammatory responses and QUIN elevation also occur following spinal cord contusion in rats, but maximal neurologic deficits develop immediately. In this study, somatosensory evoked potentials (SEP) and tissue, serum, and cerebrospinal fluid levels of QUIN were measured in guinea pigs and rats following similar compression injuries of the thoracic spinal cord. SEP changes differed between the species, consistent with other neurological changes. In guinea pigs, increases in QUIN levels at the lesion site began at 1 day postinjury, achieved maximal elevation (100-fold) by 12 days, then declined, but remained above serum levels at 25 days postinjury. A similar increase occurred in adjacent areas of the spinal cord, with lower peak levels. In rats, tissue QUIN at the center of the lesion remained below serum levels at all times, increasing moderately (<10-fold) up to 7 days, then decreasing between 7 and 25 days. These data demonstrate differences in the time course and magnitude of QUIN accumulation and neurological deficit between guinea pig and rat, which may relate to differences in secondary pathological mechanisms. Such profound differences may affect the use of these species for evaluation of experimental therapy in this and other inflammatory conditions of the central nervous system.