Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

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, {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920, and its orally bioavailable prodrug, {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient ({"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920) and its prodrug ({"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}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 {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}LY333013. 14 of 14 animals (100%) receiving either {"type":"entrez-nucleotide","attrs":{"text":"LY315920","term_id":"1257380081","term_text":"LY315920"}}LY315920 (intravenous) and/or {"type":"entrez-nucleotide","attrs":{"text":"LY333013","term_id":"1258032558","term_text":"LY333013"}}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. 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.