Snakebite, a scourge in the tropical world, accounts for up to five million bites and 100,000 deaths annually.
Dr. Matthew Lewin. Photo by Kathryn Whitney, California Academy of Sciences
SAN FRANCISCO (March 11, 2016) — A team of independent researchers led by Dr. Matthew Lewin, Director for the Center for Exploration and Travel Health at the California Academy of Sciences and founder of Ophirex, Inc., has taken a promising step towards the development of a broad-spectrum field antidote for snakebite. Snakebite is one of the most neglected of all tropical diseases, with nearly five million people bitten by snakes each year. Mortality from snakebite is currently estimated to be as high as 100,000 annually, with hundreds of thousands of limb injuries and untold economic and psychological cost to their victims. Today, Lewin announces his team’s promising antidote tests with two off-patent drug compounds at Venom Week V, a meeting of the North American Association of Toxinology, held at East Carolina University.
"In addition to being an occupational hazard for field scientists, snakebite is a leading cause of accidental death in the developing world, especially among otherwise healthy young people,” says Lewin. “We continue to try to change the way people think about this ancient scourge and persistent modern tragedy by developing an inexpensive, heat-stable, easy-to-use treatment that will at least buy people enough time to get to the hospital for further treatment."
It has been estimated that more than 75% of deaths from snakebite occur before the victims reach a hospital, largely because there is no easy way to treat them in the field. Life-saving antivenoms are expensive, require refrigeration, and demand significant expertise to administer and manage, and for these reasons, are rarely available in areas far from population centers where bites often occur. And their use often requires that the snake species responsible is correctly identified and that the antivenom even exists and is available in the first place.
Recently, Lewin branched out from his original idea of a nasal spray for snakebite, repurposing off-patent drugs originally tested by other researchers as anti-inflammatory medications for severe illnesses such as pancreatitis, sepsis and coronary disease. These drugs—varespladib and methylvarespladib—are potent inhibitors of certain enzymes (called secretory phospholipase A2 [sPLA2]) in humans. In a surprising turn of events, Lewin's research has shown them to be even more potent against snake venom PLA2s.
Lewin’s team tested the drugs in test tubes against the sPLA2s of more than 25 medically important snake species from six continents, including black mamba, several cobras, Russell’s viper, death adder, tiger snake, taipan, sea snake, rattlesnake, and coral snake, among others. Early examples of confirmatory experiments conducted by Dr. Janie Merkel of Yale University’s Center for Molecular Discovery were presented at this year’s Venom Week in Greenville, North Carolina.
“Recent shortages of good quality antivenom make the concept of an easy to administer, inexpensive, heat-stable bridge to survival particularly appealing,” says Lewin. Earlier today at Venom Week, Lewin pointed to heartening proof-of-concept animal studies in which animals were administered with 100% lethal doses of adder (Vipera berus) or coral snake (Micrurus fulvius) venom at an IUPAC certified contract laboratory. All of the animals given a single dose of intravenous varespladib between one and five minutes after receiving the venom went on to survive 24 hours, though long-term survival was not assessed. The model does not perfectly mimic a field treatment, but it suggests that the concept is viable and worth pursuing aggressively.
Lewin's team, including Dr. Stephen Samuel of the UK and Dr. Philip Bickler (who, like Lewin, is a Fellow of the California Academy of Sciences), emphasized only findings that have been replicated in other labs. Ophirex has also tested the drug alone and in combinations with other drugs against rattlesnake and Russell’s viper with promising, but not yet independently replicated results.
“The two compounds we’ve focused on have already been tested in humans for other uses but never went all the way to FDA approval,” says Lewin. “They could be developed rapidly and at lower cost than a completely new chemical entity. It’s too early to suggest that small molecules could eventually result in a complete antivenom replacement, but that is certainly our long-term goal.”
A snakebite antidote also has promising implications for the global landscape of human health and economics. “Snakebite is typically treated with very costly antivenom and critical supportive care, resulting in catastrophic expenses to the world’s poorest populations,” says Benjamin Herzel, a global health researcher at UCSF, former Master’s student of Lewin’s in UCSF’s Global Health Sciences, and winner of its John L. Ziegler Outstanding Capstone Award in 2015. Herzel used mathematical models to suggest that any new snakebite intervention improving outcomes or preventing as few as 3% of serious cases could be cost effective, “even if the amount of antivenom administered is unchanged. This shows how much room remains for improvement in the field. It’s staggering.”
Data from both abstracts have been submitted for peer review.
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