Phase 1 Clinical Trial of 4-Aminopyridine Derivatives in Dogs with Chronic Myelopathies
4-Aminopyridine, a potassium channel blocker, has been shown to improve neurological function in chronic canine spinal cord injury and has recently received FDA approval for the treatment of multiple sclerosis. However, it also produces side effects such as tremors, anxiety and seizures. Carbamate derivatives of 4-AP were developed by a group at Purdue University and tested for their ability to restore conduction to the injured spinal cord in vitro. Effective drugs were then tested in an in vivo model of spinal cord injury in the guinea pig. Three derivatives compared favorably with 4-AP in these models and were shown to be safe in dogs. The aim of this study was to perform a phase 1 clinical trial of 4-AP derivatives in dogs with chronic myelopathies.
Dogs were recruited from the patient population of the NCSU College of Veterinary Medicine. Study participants had to have chronic, stable paraplegia due to an acute spinal cord injury, or to suffer from degenerative myelopathy. All cases underwent a full diagnostic workup and appropriate surgical treatment if indicated. In the first phase of the study the dogs were treated with 4-AP. The dose of 4-AP was titrated over a period of 4 days to determine the maximum, safe dose. Dogs were videotaped during a neurological examination and when walking on a non-slip surface each day of the dose titration. Once the safe dose was established, the dog was sent home on a placebo controlled, blinded trial with the owner for a period of 2 weeks; they received placebo for one week and 4-AP for the other week. The owners kept a daily log of neurological status and noted all changes in their dogs. At the end of the trial the owners were asked to identify which week the dog was on 4-AP. The trial was then repeated with one of the derivatives.
The methyl-carbamate (MC) and n-(4-pyridyl)-t-butyl-carbamate (t-BC) derivatives were evaluated. The MC derivative did not produce any discernable effect in two dogs in which it was tested. Both dogs showed a slight improvement with 4-AP but the owners were unable to detect an effect of MC during the blinded phase of the trial. The t-BC derivative appeared to produce a clear improvement in pelvic limb function in dogs with chronic paraplegia due to acute disc herniations during dose titration and all owners correctly identified the week during which the drug was being administered. In contrast, 4-AP did not produce a discernable effect in these dogs. The t-BC derivative was administered to one dog with degenerative myelopathy and no effect was noted. Several owners noted that their dogs had increased anxiety when receiving 4-AP but this complication was not reported with either of the derivatives. We conclude that the t-BC derivative may show promise as a safe drug for the therapy of chronic canine spinal cord injury. Recruitment of dogs to the phase 1 clinical trial is ongoing and if the results continue to show promise, larger phase 2 and 3 clinical trials should be undertaken.