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Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom.
Toxins (Basel). 2018 Nov 17; 10(11)T

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Authors+Show Affiliations

Ophirex, Inc., Corte Madera, CA 94925, USA. matt@ophirex.com. California Academy of Sciences, San Francisco, CA 94118, USA. matt@ophirex.com.Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA. l.gilliam@okstate.edu.Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA. john.gilliam@okstate.edu.California Academy of Sciences, San Francisco, CA 94118, USA. paulshania@yahoo.co.uk. Queen Elizabeth Hospital, Kings Lynn, Norfolk PE30 4ET, UK. paulshania@yahoo.co.uk.Ophirex, Inc., Corte Madera, CA 94925, USA. tommaso.bulfone@gmail.com. California Academy of Sciences, San Francisco, CA 94118, USA. tommaso.bulfone@gmail.com.Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA. bicklerp@anesthesia.ucsf.edu.Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José 11501-2060, Costa Rica. jose.gutierrez@ucr.ac.cr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30453607

Citation

Lewin, Matthew R., et al. "Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs From Lethal Doses of Micrurus Fulvius (Eastern Coral Snake) Venom." Toxins, vol. 10, no. 11, 2018.
Lewin MR, Gilliam LL, Gilliam J, et al. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins (Basel). 2018;10(11).
Lewin, M. R., Gilliam, L. L., Gilliam, J., Samuel, S. P., Bulfone, T. C., Bickler, P. E., & Gutiérrez, J. M. (2018). Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins, 10(11). https://doi.org/10.3390/toxins10110479
Lewin MR, et al. Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs From Lethal Doses of Micrurus Fulvius (Eastern Coral Snake) Venom. Toxins (Basel). 2018 Nov 17;10(11) PubMed PMID: 30453607.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. AU - Lewin,Matthew R, AU - Gilliam,Lyndi L, AU - Gilliam,John, AU - Samuel,Stephen P, AU - Bulfone,Tommaso C, AU - Bickler,Philip E, AU - Gutiérrez,José María, Y1 - 2018/11/17/ PY - 2018/11/01/received PY - 2018/11/14/revised PY - 2018/11/14/accepted PY - 2018/11/21/entrez PY - 2018/11/21/pubmed PY - 2019/9/13/medline KW - Micrurus fulvius KW - PLA2 KW - antidote KW - antivenom KW - coral snake KW - envenoming KW - inhibitor KW - neurotoxicity KW - phospholipase A2 KW - snakebite JF - Toxins JO - Toxins (Basel) VL - 10 IS - 11 N2 - OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 2072-6651 UR - https://www.unboundmedicine.com/medline/citation/30453607/Delayed_LY333013__Oral__and_LY315920__Intravenous__Reverse_Severe_Neurotoxicity_and_Rescue_Juvenile_Pigs_from_Lethal_Doses_of_Micrurus_fulvius__Eastern_Coral_Snake__Venom_ L2 - http://www.mdpi.com/resolver?pii=toxins10110479 DB - PRIME DP - Unbound Medicine ER -