Scientific programme

eP65  E-POSTER - 6-9 SEPTEMBER 2017
PAIN TREATMENT (CONSERVATIVE): NOVEL THERAPEUTIC AGENTS

06-Sep-2017 11:30 20:00
 
 
Abstract:
RELATION BETWEEN THE PHARMACOLOGY AND PHARMACOKINETICS OF THE EGR1 DECOY AYX1 FOR THE PREVENTION OF POST-SURGICAL PAIN

Aims: AYX1 is a DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose preoperatively. AYX1 inhibits EGR1, a transcription factor that, at the time of an injury, initiates gene regulations required for the initiation and maintenance of long-term sensitization and pain. This work characterizes the AYX1 dose response in rats and the link to AYX1 pharmacokinetics in the cerebrospinal fluid (CSF), dorsal root ganglia and spinal cord.

Methods: The effects of ascending dose-levels of AYX1 on mechanical hypersensitivity were measured in the spared nerve injury model of chronic pain and in a plantar incision model of acute post-surgical pain using repetitive von Frey probe application. AYX1 was detected using Capillary Gel Electrophoresis-Hybridization.

Results: AYX1 dose response shows increasing efficacy from a minimum effective dose of ~ 0.5 mg to a maximum effective dose of ~ 1mg. With higher doses, the efficacy paradoxically decreases by ~ 30 % and then returns to full efficacy at the maximum feasible dose of ~ 4mg. The reduction of efficacy is associated with doses triggering a near-saturation of AYX1 metabolism by nucleases in the CSF and a paradoxical reduction of AYX1 exposure over time. This effect is overcome at higher doses that compensate for the effect of metabolism.

Conclusions: AYX1 is a competitive antagonist of EGR1, consistent with the overall increased efficacy observed as dose-levels initially escalate. AYX1 sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose response curve. 

 
Co-authors
J. Mamet 1, S. Harris 1, M. Klukinov 2, D. Yeomans 2, R. Donahue 3, B. Taylor 3, K. Eddinger 4, T. Yaksh 4, D. Manning 1
1Adynxx- Inc, N/A, San Francisco, USA
2Stanford University, Anesthesia, Stanford, USA
3University of Kentucky, Physiology, Lexington, USA
4University of California- San Diego, Anesthesiology, San Diego, USA