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Toxins 2018, 10(11), 479; https://doi.org/10.3390/toxins10110479

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

1
Ophirex, Inc., Corte Madera, CA 94925, USA
2
California Academy of Sciences, San Francisco, CA 94118, USA
3
Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA
4
Queen Elizabeth Hospital, Kings Lynn, Norfolk PE30 4ET, UK
5
Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA
6
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José 11501-2060, Costa Rica
*
Author to whom correspondence should be addressed.
Received: 1 November 2018 / Revised: 14 November 2018 / Accepted: 14 November 2018 / Published: 17 November 2018
(This article belongs to the Section Animal Venoms)
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Abstract

There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom. View Full-Text
Keywords: snakebite; envenoming; antidote; inhibitor; coral snake; Micrurus fulvius; PLA2; phospholipase A2; neurotoxicity; antivenom snakebite; envenoming; antidote; inhibitor; coral snake; Micrurus fulvius; PLA2; phospholipase A2; neurotoxicity; antivenom
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Lewin, M.R.; Gilliam, L.L.; Gilliam, J.; Samuel, S.P.; Bulfone, T.C.; Bickler, P.E.; Gutiérrez, J.M. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins 2018, 10, 479.

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