Abstract
Background: AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord.
Results: 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. AYX1 dose-response profile shows that efficacy rapidly increases from a minimum effective dose of ∼ 0.5 mg to a peak maximum effective dose of ∼ 1 mg. With further dose escalation, the efficacy paradoxically appears to decrease by ∼ 30% and then returns to full efficacy at the maximum feasible dose of ∼ 4 mg. The reduction of efficacy is associated to doses triggering a near-saturation of AYX1 metabolism by nucleases in the cerebrospinal fluid and a paradoxical reduction of AYX1 exposure during the period of early growth response protein 1 induction. This effect is overcome at higher doses that compensate for the effect of metabolism.
Discussion: AYX1 is a competitive antagonist of early growth response protein 1, which is consistent with the overall increased efficacy observed as dose-levels initially escalate. Chemically, AYX1 is unprotected against degradation by nucleases. The sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose-response curve.
Conclusions: These findings point to the importance of the nuclease environment of the cerebrospinal fluid to the research and development of AYX1 and other intrathecal nucleotide-based therapeutics.
Document Type
Article
Publication Date
4-10-2017
Digital Object Identifier (DOI)
https://doi.org/10.1177/1744806917703112
Funding Information
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by Adynxx, Inc.
Repository Citation
Mamet, Julien; Harris, Scott; Klukinov, Michael; Yeomans, David C.; Donahue, Renee R.; Taylor, Bradley K.; Eddinger, Kelly; Yaksh, Tony; and Manning, Donald C., "Pharmacology, Pharmacokinetics, and Metabolism of the DNA-Decoy AYX1 for the Prevention of Acute and Chronic Post-Surgical Pain" (2017). Physiology Faculty Publications. 103.
https://uknowledge.uky.edu/physiology_facpub/103
Included in
Anesthesiology Commons, Pharmacology Commons, Physiology Commons, Surgery Commons, Trauma Commons
Notes/Citation Information
Published in Molecular Pain, v. 13, p. 1-16.
© The Author(s) 2017
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).