Rapid Classification and Treatment of Battlefield Nerve Injuries: Drug Repurposing of 4-Aminopyridine
Abstract
There is no way to diagnose a severed nerve short of surgical exploration, and there is no way to treat a nerve that is not working due to traumatic injury. In contrast with injuries to bone or skin, peripheral nerve trauma is more difficult to diagnose. The critical question is whether the nerve has been severed or not -- because even mild nerve injuries often result in an insensate limb that does not move. Clinicians wait weeks or even months for a glimpse of diagnosis, causing muscle atrophy, which can be irreversible. Nonetheless, current teaching says to wait, and yet as we wait to figure out if a nerve is continuous, the patient with discontinuity is effectively sacrificed. In contrast, without the wait, surgical intervention in those with incomplete injuries that can eventually recover causes undue harm. In effect, two groups of patients exist, each with conflicting needs indistinguishable until long after injury. What benefits one patient harms the other. This is the current state-of-the-art in nerve injury diagnosis. We have discovered that a currently available, Food and Drug Administration-approved drug (4-aminopyridine, 4AP), has the previously unknown effect of awakening injured nerves in acute trauma. Prolonged treatment with 4AP also has lasting effects after the drug is no longer present. Prolonged treatment with 4AP accelerates recovery of muscle function elsewhere in the limb. We also made and tested a form of 4AP that can be applied at the site of injury and found it to be equally effective. We want to repurpose 4AP as a single-dose diagnostic agent to distinguish between permanent and recoverable nerve injuries in traumatized military Service personnel and treat our Wounded Warriors on the battlefield. The rationale for this proposal comes from the inability to distinguish limb injuries with severed nerves, which will not recover and need early surgical intervention, from those injuries that will benefit from the current care-standard of watchful waiting. This aligns with the rehabilitation focus area titled "secondary health effects" as 4AP tells us if the nerve is intact even if it is not functioning. Nerve continuity is the most critical predictor of outcome in severe limb injuries -- more than any systemic disease. The secondary health effect of severe limb injury to be identified is the hopelessly denervated limb destined to never recover -- a more critical distinction than any other in predicting outcome. The critical question is nerve continuity and it can be answered with 4AP. The military benefit of this proposal is the potential to diagnose and effectively treat recoverable severe limb injuries on or near the battlefield. The impact and clinical application of this work is the opportunity to distinguish recoverable injuries from those that absolutely require surgery. We believe that our preliminary work motivates the use of 4AP as a defined product, possibly locally applicable at the site of injury for military Service personnel with the most severe and often limb trauma. Can 4AP be repurposed to help our Wounded Warriors on the battlefield? We propose to answer this important question. This proposal is broken into two main aims geared towards answering the two questions needed to safely allow the use of 4AP in patients with limb injury of varying severity. First is the question of dosing. Applications of 4AP range from single doses given in or under the skin to sustained-release formulas, which can be applied directly to open wounds and in muscles and on nerves. Our first aim will tell us how to apply 4AP to patients. Our second aim will tell us which patients should be included in trials. The effects on other injured tissue are critically important. Even if 4AP were only effective on nerve, the implications would be vast. However, we have found 4AP treatment works on muscle -- whose only relation to the injury is a far-off nerve. The applications of this p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610725
Entities
People
- John C Elfar
Organizations
- United States Army
- University of Rochester