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Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom.
Toxins (Basel) 2018; 10(10)T

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.

Authors+Show Affiliations

Ophirex, Inc., Corte Madera, CA 94925, USA. mlewin@calacademy.org. California Academy of Sciences, San Francisco, CA 94118, USA. mlewin@calacademy.org.Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, an José 11501-2060, Costa Rica. jose.gutierrez@ucr.ac.cr.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.Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, an José 11501-2060, Costa Rica. maria.herrera_v@ucr.ac.cr.Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, an José 11501-2060, Costa Rica. wenjbq@gmail.com.Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, an José 11501-2060, Costa Rica. bruno.lomonte@ucr.ac.cr.Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94143, USA. philip.bickler@ucsf.edu.Ophirex, Inc., Corte Madera, CA 94925, USA. tommaso.bulfone@gmail.com. California Academy of Sciences, San Francisco, CA 94118, USA. tommaso.bulfone@gmail.com.Department of Pharmacology and Therapeutics, Australian Venom Research Unit, University of Melbourne, Parkville, VIC 3010, Australia. david.williams@unimelb.edu.au.

Pub Type(s)

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

Language

eng

PubMed ID

30241297

Citation

Lewin, Matthew R., et al. "Delayed Oral LY333013 Rescues Mice From Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus Scutellatus) Venom." Toxins, vol. 10, no. 10, 2018.
Lewin MR, Gutiérrez JM, Samuel SP, et al. Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins (Basel). 2018;10(10).
Lewin, M. R., Gutiérrez, J. M., Samuel, S. P., Herrera, M., Bryan-Quirós, W., Lomonte, B., ... Williams, D. J. (2018). Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins, 10(10), doi:10.3390/toxins10100380.
Lewin MR, et al. Delayed Oral LY333013 Rescues Mice From Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus Scutellatus) Venom. Toxins (Basel). 2018 09 20;10(10) PubMed PMID: 30241297.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. AU - Lewin,Matthew R, AU - Gutiérrez,José María, AU - Samuel,Stephen P, AU - Herrera,María, AU - Bryan-Quirós,Wendy, AU - Lomonte,Bruno, AU - Bickler,Philip E, AU - Bulfone,Tommaso C, AU - Williams,David J, Y1 - 2018/09/20/ PY - 2018/09/05/received PY - 2018/09/17/revised PY - 2018/09/17/accepted PY - 2018/9/23/entrez PY - 2018/9/23/pubmed PY - 2018/9/23/medline KW - PLA2 KW - antivenom KW - envenoming KW - field antidote KW - inhibitor KW - neglected tropical disease KW - neurotoxicity KW - phospholipase A2 KW - snakebite KW - taipan JF - Toxins JO - Toxins (Basel) VL - 10 IS - 10 N2 - 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. SN - 2072-6651 UR - https://www.unboundmedicine.com/medline/citation/30241297/Delayed_Oral_LY333013_Rescues_Mice_from_Highly_Neurotoxic,_Lethal_Doses_of_Papuan_Taipan_(Oxyuranus_scutellatus)_Venom L2 - http://www.mdpi.com/resolver?pii=toxins10100380 DB - PRIME DP - Unbound Medicine ER -