We used an empirically selected venom dose ultimately corresponding to 12LD 50S, in order to model a severe envenoming. We administered LY333013 either immediately (within five min) or in one h (60 min) following the subcutaneous administration of venom. To begin answering this question, we tested the ability of LY333013 (10 mg/kg) when administered orally. The key unknown in this experiment was whether LY333013 would be effective in preventing neurotoxicity and lethality from Papuan taipan (Oxyuranus scutellatus) venom if given orally after venom injection, both immediately after envenoming and at a time when specific antivenom is no longer effective in preventing lethality. Papuan taipan venom was selected because its main toxicity relies on the action of a potent presynaptically-acting neurotoxic heterotrimeric PLA 2, taipoxin. As proof of a concept experiment, we sought to examine how these drugs might perform both alone and with antivenom in a scenario of lethal envenoming by Papuan taipan. Along with known safety profiles, LY315920 and LY333013 pharmacodynamics and pharmacokinetics in short-term use is well-understood, but unfortunately these potent sPLA2-blocking drugs were abandoned for lack of efficacy after more than 25 clinical trials they were never considered for use in the setting of snakebite. LY315920 and LY333013 were previously abandoned following Phase II and Phase III of human clinical trials for sepsis, rheumatoid arthritis, and cardiovascular disease, but could be repositioned at a low development cost for the initial treatment of snakebite. This work was recently replicated and extended when LY315920 preserved life and prevented haemorrhagic, myonecrotic, and neurological effects in mice injected with krait, cobra, or viper venoms from medically important species in China. LY315920 and its orally bioavailable prodrug, LY333013, have been found to have extremely potent, broad-spectrum activity against snake venom PLA 2S and have been proposed as a promising initial treatment for envenoming snakebite. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development efforts. These results suggest that sPLA 2 inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA 2S can be treated successfully, even after the window of therapeutic antivenom has closed. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. 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. The orally bioavailable, heat-stable, secretory phospholipase A 2 (sPLA 2) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment.
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