What is the problem/background?

Every year 94,000 people die following a snakebite.  In Kilifi County Hospital alone, there have been 1,500 snakebites requiring hospital admission since 2007. The only treatment available (antivenom – a product made by repeatedly exposing mammals, such as horses, to sub-lethal doses of venom) is expensive and can cause allergic reactions. Many snake venoms require zinc to function. Drugs that stick to and remove zinc (‘chelators’, including unithiol) have been shown to deactivate these snake venoms in laboratory experiments.

Unithiol is a treatment for heavy metal poisoning (such as arsenic or mercury poisoning) and has been in use as an established therapy for a number of decades. It is known to bind to zinc. This drug is available as an oral capsule as well as a solution for intravenous injection into the blood-stream. As far as we are aware, unithiol is not routinely available in Kenya, and it is not registered with the pharmacy and poisons board (PPB). For many years, safety data has been collected for unithiol elsewhere and overall it is a safe drug with minimal risk of serious side effects. When unithiol is used as a treatment for snakebite, laboratory experiments suggest that higher doses may be needed, compared to doses normally used for treating heavy metal poisoning.

Unlike antivenom, unithiol is available as a capsule and could be stocked in rural clinics, which would reduce delays to accessing snakebite treatment. Unithiol has been used for the treatment of metal poisoning for many years and there is a reasonable amount of reassuring safety data.

In this study, groups of healthy Kenyan people were given increasing amounts of unithiol and closely monitored to check if this is safe.

What questions did we answer?

1) Can higher oral doses of unithiol be safely given to healthy adult Kenyan voluneteers?

2) What are the drug levels of unithiol and how long are drug levels maintained after each dose?

3) Can a new method of measuring the activity of unithiol in blood samples, to inhibit the actions of venom, produce reliable results?

What did this study tell us?

1) Increased oral doses of unithiol were well tolerated and safe in this small group of healthy adult Kenyan volunteers.

2) Drug levels in the blood stream were were proportionally higher as the oral dose of unithiol was increased. At a higher dose (above 1,200 mg), the rate of gut absorption seemed to prevent blood levels from increasing any further, therefore, doses above this level are not recommended.

3) It was not possible to develop a reliable new method of measuring the activity of unithiol in blood to inhibit the actions of venom. Future studies to assess whether unithiol provides benefit in individuals with snakebite are a priority.

What will happen next?

Future studies are being planned to test the increased oral dose developed in this study in people with snakebite. If unithiol were to demonstrate clinical benefit (such as reducing the risk of abnormal bleeding in snakebite patients) then it may be developed as a treatment that can routinely be given in community settings. This could reduce the time to treatment, reduce our reliance on antivenom, and ultimately reduce the burden of death and disability caused by snakebite.

Snakebite affects over 5 million people each year, and over 100,000 per year die as a result. Children and young people bear the greatest burden, and the majority of bites occur in remote rural settings with limited access to medical services. The only available treatment is antivenom, an animal product produced through a process of exposing large mammals to repeated sublethal doses of snake venom. Antivenom has many shortcomings, including high cost, intravenous administration, high risk of adverse events and narrow species specificity. The venom of vipers predominantly consists of Snake Venom Metalloproteinases (SVMPs), which are zinc dependent enzymes. SVMPs cause blood vessel breakdown, consumption coagulopathy and skin necrosis. Pre-clinical research, including use of the same in vivo experiments that are the gold standard for assessing antivenom, have shown that metal chelators can potently inhibit the activity of viper venom, by deactivating SVMPs. Through systematic screening of a range of chelating agents, unithiol has been identified as the most promising chelating agent and needs further evaluation in clinical trials. As well as preventing skin damage and death in vivo, unithiol is a safe and well tolerated drug that has been is use as a treatment for heavy metal poisoning for many decades. We propose a phase I clinical trial to assess unithiol as a treatment for snakebite.

The primary outcome will be to determine safety and tolerability of a dosing regimen that is relevant to snakebite. The pharmacokinetic and pharmacodynamic profile of unithiol will also be described. Healthy Kenyan volunteers will be invited to enroll from Kilili County. Volunteers will be randomized into dosing cohorts of 8. The first dosing cohort will receive 300 mg of oral unithiol, which is the dose normally used for heavy metal poisoning. With review of safety, single ascending dose escalations will be made with the aim of giving a maximum dose of 1,500 mg oral. A minimum of two further cohorts will receive intravenous doses of unithiol, as this route may be useful for rapidly achieving therapeutic levels. Following review of the emerging data, two cohorts will receive multiple doses of unithiol for up to 72 hours, which will be the anticipated regimen for snakebite treatment.Pharmacokinetic analysis will be undertaken to calculate the half-life, Cmax and to define the elimination of unithiol in the urine. Pharmacodynamic analysis will include application of a novel ex vivo assay for quantifying the inhibition of SVMP associated pathology.