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

Matthew Lewin,Philip Bickler,José Gutiérrez,Stephen Samuel,Lyndi Gilliam,Tommaso Bulfone,John Gilliam

doi:10.3390/toxins10110479

Abstract

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, LY315920, and its orally bioavailable prodrug, 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 (LY315920) and its prodrug (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 LY333013. 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or 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.

Highlights

Snakebite envenoming is a significant global health concern and has been recently included in the World Health Organization (WHO) list of Neglected Tropical Diseases [1]
There is a clear, unmet need for effective, heat stable, and economical broad-spectrum snakebite envenoming therapies based on drugs with a high volume of distribution that can be given rapidly and at the time of bite as well as an adjunct therapy to improve the efficacy of antivenoms [7,8]
Rescue experiments with a single-dose of LY315920 produced a significant improvement in survival times compared to controls, but after 10+ h from the time of envenoming the symptoms often reappeared, probably due to a delayed venom absorption from a depot in the tissue site where venom was injected

Summary

Introduction

Snakebite envenoming is a significant global health concern and has been recently included in the World Health Organization (WHO) list of Neglected Tropical Diseases [1]. Over 5 million people are affected every year by snakebites, and over 75% of the estimated 138,000 deaths occur outside of the hospital setting, where antivenom cannot be administered [2,3,4]. A disproportionate number of impoverished populations reside in hot-spots where there is a high risk of receiving a snakebite and are remote from hospital resources and antivenom [3]. Snakebite envenoming is an occupational risk to the majority of people working in manually dominated agricultural settings [5,6]. There is a clear, unmet need for effective, heat stable, and economical broad-spectrum snakebite envenoming therapies based on drugs with a high volume of distribution that can be given rapidly and at the time of bite as well as an adjunct therapy to improve the efficacy of antivenoms [7,8]

Methods

Results

Conclusion