The Effects of 4-Aminopyridine on Neurological Deficits in Chronic Cases of Traumatic Spinal Cord Injury in Dogs: A Phase I Clinical Trial

Abstract

A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77%) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36%) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis.

Effect of 4-aminopyridine and single-dose methylprednisolone on functional recovery after a chronic spinal cord injury

“…Nevertheless, 4-AP is a compound with toxic e ects such as promoting neurotransmitter release and enhancement of neuronal excitability, inducing spontaneous synchronous activity which provokes seizures. 1,15 In fact, our experimental rats treated with 6 mg/kg of 4-AP developed generalized seizures immediately after the initial 4-AP administration.…”

“…No statistically signi®cant di erence was observed at any time between the groups AP to ensure capturing possible transient improvements, as reported by others. 15 The neurological scores obtained at day 49 post-injury was not signi®cantly better than the non-treated control animals. This negative ®nding could be due to (a) lack of significant number of demyelinated axons which contribute to Figure 4 Higher magni®cation of a lesion proximal to an area of malacia demonstrates partial preservation of axons, as well as areas of axonal loss, Sevier-Munger stain.…”

“…16 In dogs, 4-AP administration has produced adverse reactions such as anxiety, nervousness and seizures. 15 The objective of the present study was to determine if a long term (4 weeks) administration of the 4-AP would improve functional recovery in chronic model of SCI in rats. An additional group of animals treated with single dose of methylprednisolone was included in the study for comparison with a more traditional therapy.…”

“…This functional recovery occurred within 15 ± 45 min of the drug administration but it fully reversed within a few hours. 15 The initial clinical trial for application of 4-AP in patients with SCI was an open, unblinded study using 2 mg every 20 min up to 24 mg of the compound. 1 This treatment did not bene®t patients with complete SCI.…”

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy

“…58 Notably, investigators at Purdue University investigated the effects of 4-AP and electromagnetic stimulation on severely injured canine spinal cord, 59,60 paving the way for human clinical trials; the recent publication of a study of the effects of intravenous PEG has reiterated the value of canine SCI in testing putative neuroprotective agents. 61 In this review, we have focused specifically on the use of clinical SCI in dogs as a model in which to investigate the efficacy of intraspinal cell transplantation, which has hitherto not been explored.…”