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Novel way to treat snakebite

Snakebite is one of the world's biggest hidden health problems with up to 138,000 victims dying every year, and around 400,000 victims left with permanent physical disabilities or disfigurements. Those most affected live in some of the world's poorest communities in sub-Saharan Africa, Asia and Latin America and often rely on agricultural activities for their income. These activities put them at risk of snakebite by working in areas inhabited by venomous snakes, and the remoteness of many of these communities makes accessing appropriate healthcare problematic.

Snakebite victims in rural settings are therefore often greatly delayed in receiving treatment, because existing antivenom therapies have to be delivered in clinical settings due to their requirement to be given intravenously and because of their high risk of adverse reactions.

The Liverpool School of Tropical Medicine’s (LSTM) Dr Laura-Oana Albulescu and colleagues looked at various compounds that bind to metal ions as potential pre-hospital therapeutics for the treatment of snakebite.

Among the tested compounds, dimercaprol (also called British anti-Lewisite) and its derivative 2.3-dimercapto-1-propanesulfonic acid (DMPS) were found to inhibit the in vitro activity of snake venom enzymes that rely on zinc ions to function.

Using animal models mimicking a snakebite, the team then demonstrated that DMPS provided protection against the lethal effects of venom from saw-scaled vipers – a group of medically important snakes found widely distributed across parts of Africa and Asia.

Crucially, the oral administration of DMPS also provided protection against venom, and its effect was further enhanced when used in combination with much later doses of conventional antivenom.

The team's paper suggests that DMPS could be repurposed as an oral medicine for treating snakebite victims soon after a bite, and before they travel to a healthcare facility. While antivenom may still be needed once the patient arrives at a clinical setting, early treatment with DMPS has the potential to save lives and limbs in the world's poorest communities by removing treatment delays.

Professor Nicholas Casewell said: "The advantages of using a compound like DMPS is that it is already a licensed medicine that has been proven to be safe and affordable. That it can effectively neutralise saw-scaled viper venoms in models of envenoming highlights the promise of this drug as an early, pre-hospital, therapeutic intervention for life-threatening bites by snakes like the saw-scaled viper."

Albulescu added "Because DMPS is an oral drug, it could be easily administered in the community by trained volunteers immediately after a snakebite. This would be a tremendous advantage in helping to reduce the onset of pathology, as snakebite victims can currently take many hours to reach a healthcare facility."

Snakebite was recently classified as a 'priority NTD' by the World Health Organisation (WHO), who have since developed a strategy to halve the number of snakebite deaths and disabilities by the year 2030 by improving existing treatments, developing new therapeutics and empowering local communities to improve pre-hospital treatment. Utilising novel compounds, such as DMPS, which can be administered orally outside a healthcare facility, could save many thousands of lives in these rural settings.

Abstract
Snakebite envenoming causes 138,000 deaths annually, and ~400,000 victims are left with permanent disabilities. Envenoming by saw-scaled vipers (Viperidae: Echis) leads to systemic hemorrhage and coagulopathy and represents a major cause of snakebite mortality and morbidity in Africa and Asia. The only specific treatment for snakebite, antivenom, has poor specificity and low affordability and must be administered in clinical settings because of its intravenous delivery and high rates of adverse reactions. This requirement results in major treatment delays in resource-poor regions and substantially affects patient outcomes after envenoming. Here, we investigated the value of metal ion chelators as prehospital therapeutics for snakebite. Among the tested chelators, dimercaprol (British anti-Lewisite) and its derivative 2,3-dimercapto-1-propanesulfonic acid (DMPS) were found to potently antagonize the activity of Zn2+-dependent snake venom metalloproteinases in vitro.
Moreover, DMPS prolonged or conferred complete survival in murine preclinical models of envenoming against a variety of saw-scaled viper venoms. DMPS also considerably extended survival in a “challenge and treat” model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming. Last, the potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo. Our findings demonstrate that the safe and affordable repurposed metal chelator DMPS can effectively neutralize saw-scaled viper venoms in vitro and in vivo and highlight the promise of this drug as an early, prehospital, therapeutic intervention for hemotoxic snakebite envenoming.

Authors
Laura-Oana Albulescu, Melissa S Hale, Stuart Ainsworth, Jaffer Alsolaiss, Edouard Crittenden, Juan J Calvete, Chloe Evans, Mark C Wilkinson, Robert A Harrison, Jeroen Kool, Nicholas R Casewell

[link url="https://www.lstmed.ac.uk/news-events/news/researchers-at-lstm-demonstrate-a-novel-way-to-treat-snakebite"]Liverpool School of Tropical Medicine material[/link]

[link url="https://stm.sciencemag.org/content/12/542/eaay8314"]Science Translational Medicine abstract[/link]

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