Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom

Toxins (Basel). 2018 Sep 20;10(10):380. doi: 10.3390/toxins10100380.

Abstract

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A₂ (sPLA₂) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA₂ inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts.

Keywords: PLA2; antivenom; envenoming; field antidote; inhibitor; neglected tropical disease; neurotoxicity; phospholipase A2; snakebite; taipan.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetates / therapeutic use*
  • Administration, Oral
  • Animals
  • Antivenins / therapeutic use*
  • Elapid Venoms / toxicity*
  • Elapidae
  • Female
  • Indoles / therapeutic use*
  • Keto Acids
  • Male
  • Mice
  • Neurotoxins / toxicity*
  • Phospholipase A2 Inhibitors / therapeutic use*

Substances

  • Acetates
  • Antivenins
  • Elapid Venoms
  • Indoles
  • Keto Acids
  • Neurotoxins
  • Phospholipase A2 Inhibitors
  • varespladib methyl