Tags

Type your tag names separated by a space and hit enter

Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation.
Toxins (Basel). 2016 08 25; 8(9)T

Abstract

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

Authors+Show Affiliations

Research and Development, Ophirex, Inc., Corte Madera, CA 94925, USA. matt@ophirex.com. Center for Exploration and Travel Health, California Academy of Sciences, San Francisco, CA 94118, USA. matt@ophirex.com.General Medicine, Queen Elizabeth Hospital, King's Lynn, Norfolk PE30 4ET, UK. paulshania@yahoo.co.uk.Yale Center for Molecular Discovery, Yale University, West Haven, CT 06516, USA. janie.merkel@yale.edu.Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA. bicklerp@anesthesia.ucsf.edu.

Pub Type(s)

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

Language

eng

PubMed ID

27571102

Citation

Lewin, Matthew, et al. "Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation." Toxins, vol. 8, no. 9, 2016.
Lewin M, Samuel S, Merkel J, et al. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins (Basel). 2016;8(9).
Lewin, M., Samuel, S., Merkel, J., & Bickler, P. (2016). Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins, 8(9). https://doi.org/10.3390/toxins8090248
Lewin M, et al. Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins (Basel). 2016 08 25;8(9) PubMed PMID: 27571102.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. AU - Lewin,Matthew, AU - Samuel,Stephen, AU - Merkel,Janie, AU - Bickler,Philip, Y1 - 2016/08/25/ PY - 2016/06/17/received PY - 2016/08/11/revised PY - 2016/08/15/accepted PY - 2016/8/30/entrez PY - 2016/8/30/pubmed PY - 2017/11/9/medline KW - LY315920 KW - LY333013 KW - antidote KW - envenomation KW - field treatment KW - inhibitor KW - methyl-varespladib KW - pre-referral KW - snakebite KW - varespladib JF - Toxins JO - Toxins (Basel) VL - 8 IS - 9 N2 - Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite. SN - 2072-6651 UR - https://www.unboundmedicine.com/medline/citation/27571102/Varespladib__LY315920__Appears_to_Be_a_Potent_Broad_Spectrum_Inhibitor_of_Snake_Venom_Phospholipase_A2_and_a_Possible_Pre_Referral_Treatment_for_Envenomation_ L2 - http://www.mdpi.com/resolver?pii=toxins8090248 DB - PRIME DP - Unbound Medicine ER -