Potassium Channel Antagonists 4-Aminopyridine and the T-Butyl Carbamate Derivative of 4-Aminopyridine Improve Hind Limb Function in Chronically Non-Ambulatory Dogs; A Blinded, Placebo-Controlled Trial

Abstract

4-Aminopyridine (4-AP) blocks voltage gated potassium channels, restoring conduction to demyelinated axons and improving function in demyelinating conditions, but its use is associated with adverse effects and benefit in spinal cord injury is limited. Derivatives of 4-AP have been developed to improve clinical efficacy while reducing toxicity. We compared the therapeutic effects of orally administered 4-AP and its t-butyl carbamate derivative (t-butyl) with placebo in dogs that had suffered an acute spinal cord injury that left them chronically paralyzed. Nineteen dogs were entered into the trial, conducted in two-week treatment blocks starting with placebo, followed by random assignment to 4-AP or t-butyl, a washout and then the opposite medication followed by placebo. Investigators and owners were blinded to treatment group. Primary outcome measures included open field gait score (OFS), and treadmill based stepping score and regularity index, with additional secondary measures also considered. Thirteen of 19 dogs completed the protocol. Two were euthanized due to unrelated heath problems, two developed side effects and two were unable to complete for unrelated reasons. Dogs showed significant improvement in supported stepping score (from 17.39 to 37.24% with 4-AP; 16.85 to 29.18% with t-butyl p<0.0001) and OFS (from 3.63 to 4.73 with 4-AP; 3.78 to 4.45 with t-butyl, p = 0.005). Response was individually variable and most dramatic in three dogs that were able to walk without support with treatment. No significant difference was found between 4-AP and t-butyl. No adverse effects were reported with t-butyl but gastrointestinal upset and seizures were observed in two dogs with 4-AP. In conclusion, both 4-AP and t-butyl significantly improved supported stepping ability in dogs with chronic spinal cord injury with no adverse effects noted with t-butyl. Drug response varied widely between individuals, highlighting the need to understand the factors that influence canine and human patients' response to therapy.

Clinical presentation and outcome of dogs treated medically or surgically for thoracolumbar intervertebral disc protrusion

“…In a recent study the potassium channel antagonists 4-aminopyridine and the T-butyl carbamate derivative of 4-aminopyridine were found to improve hindlimb function in non-ambulatory dogs following intervertebral disc extrusion (Lim and others 2014). Their use in chronic spinal cord compression such as thoracolumbar IVDP requires investigation but may prove to be of therapeutic benefit, particularly if demyelination contributes to the pathology.…”

Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

“…Acute SCI is a trauma that may result in disability (2). One of the most important targets of early treatment for SCI is to prevent the secondary injury.…”

“…It frequently results in failure in limb sensation, motor function and automatic nervous function. The high disability and mortality rates of SCI often have a huge physiological and psychological effect on individuals, their families and society (2). However, there is no effective treatment due to the complicated pathophysiological mechanism of SCI, although numerous clinical and animal studies have been conducted (3,4).…”

Quantifying center of pressure variability in chondrodystrophoid dogs

“…In chondrodystrophoid breeds, the nucleus undergoes premature degeneration resulting in acute extrusion of calcified nuclear material, which causes compression and contusion of the overlying spinal cord (Hansen, 1952; Funkquist 1962). The high frequency and serious nature of this condition have heightened interest in developing novel ways to assess both mechanisms and extent of recovery from spinal cord injury in dogs (Borgens et al, 1999; Laverty et al, 2004; Baltzer et al, 2008; Granger et al, 2012; Levine et al, 2014; Lim et al, 2014; Olby et al, 2016). There are numerous measures of outcome in this population of dogs, with a heavy focus on ordinal scales of gait (Olby et al, 2001; Levine et al, 2009) that can be applied readily in a clinical setting.…”