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

Matthew R Lewin, José María Gutiérrez, Stephen P Samuel, María Herrera, Wendy Bryan-Quirós, Bruno Lomonte, Philip E Bickler, Tommaso C Bulfone, David J Williams, Matthew R Lewin, José María Gutiérrez, Stephen P Samuel, María Herrera, Wendy Bryan-Quirós, Bruno Lomonte, Philip E Bickler, Tommaso C Bulfone, David J Williams

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.

Conflict of interest statement

M.R.L. is employed by Ophirex, Inc. and has stock; S.P.S., T.C.B. and P.B. have consulted for Ophirex, Inc. for compensation. Author contributions from the study sponsor are detailed, above. Ophirex, Inc. is a Public Benefit Corporation. J.M.G., W.B.-Q., B.L., M.H., D.J.W. and P.E.B. have no competing interests.

Figures

Figure 1
Figure 1
A single oral dose of LY333013 restores the effect of antivenom even after an otherwise fatal delay in antivenom administration. A single oral dose of LY333013 (10 mg/kg) or intravenous taipan specific antivenom (5 mL/kg) administered urgently (within 5 min) following subcutaneous injection of 12 × LD50O. scutellatus venom resulted in survival of all tested mice. A single dose of oral LY333013 administered with a 60 min delay following the 12 × LD50 resulted in survival of seven out of nine mice, whereas only one out of five mice receiving antivenom with a 60 min delay survived. The combination of LY333013 and antivenom at this same 60 min time resulted in survival for all mice.

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Source: PubMed

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