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A platform stratifying a sequestering agent and a pharmacological antagonist as a means to negate botulinum neurotoxicity

Academic Article
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Overview

authors

  • Harris, T. L.
  • Lowery, Colin
  • Hixon, M. S.
  • Janda, Kim

publication date

  • 2014

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • Botulinum neurotoxicity is characterized by peripheral neuromuscular blockade/flaccid paralysis that can lead to respiratory failure and ultimately death. Current therapeutic options provide relief in a pre-exposure scenario, but there are no clinically approved postexposure medical countermeasures. Here, we introduce a platform that utilizes a combination of a toxin sequestering agent and a pharmacological antagonist to ablate botulinum neurotoxicity in a well-defined mouse lethality assay. The platform was constructed to allow for ready exchange of sequestering agent and/or pharmacological antagonist for therapeutic optimization. As such, we attempted to improve upon the pharmacological antagonist, a potassium channel blocker, 3,4-diaminopyridine, through a prodrug approach; thus, a complete kinetic decomposition pathway is described. These experiments provide the first proof-of-principle that a synergistic combination strategy can be used to reduce toxin burden in the peripheral using a sequestering antibody, while restoring muscle action via a pharmacological small molecule antagonist.

subject areas

  • 4-Aminopyridine
  • Animals
  • Botulinum Antitoxin
  • Botulinum Toxins
  • Drug Therapy, Combination
  • Female
  • Kinetics
  • Mice
  • Neurotoxicity Syndromes
  • Potassium Channel Blockers
  • Sequestering Agents
  • Survival Analysis
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Research

keywords

  • Botulinum neurotoxin
  • K+ channel blocker
  • antibody
  • drug combination
  • prodrug
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Identity

PubMed Central ID

  • PMC4140587

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/cn500135h

PubMed ID

  • 25000171
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Additional Document Info

start page

  • 632

end page

  • 636

volume

  • 5

issue

  • 8

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