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[NEW DELHI] With some 50,000 citizens dying annually from snakebites, India is compelled to explore a range of effective methods to deal with the problem, which the WHO characterises as a neglected tropical disease.

India accounts for about half of all global snakebite deaths. The difficulty of treating snakebites starts with identifying the biting reptile. This is vital, since venom composition differs vastly between snake species. India has around 60 different species of poisonous snakes but most fatalities are caused by the ‘Big Four’ — the spectacled cobra (Naja naja), the common krait (Bungarus caerulus), the saw-scaled viper (Echis carinatus) and Russel’s viper (Daboia russelii).

Of the 300,000 snakebites reported in India there is no envenomation in 70 per cent of cases. This does not make it any easier for doctors who must decide within a rapidly closing window on whether to administer the standard polyvalent antivenom, which carries the risk of severe allergic reaction, says Nishigandha Naik, director of the state-run Haffkine Institute, established in Mumbai in 1899 to conduct research in medical biotechnology.

Identifying the biting snake is not easy as the animal typically slithers away, leaving the victim dazed and in pain. But, it is possible for doctors to determine the species by considering the symptoms and the geographical location of the incident.

“Ecological and environmental factors, gender, age, temperature, and prey/predators govern snake venom composition and activity.”

Kartik Sunager, Indian Institute of Science in Bangalore

The bite of a krait or cobra leads to local swelling and blisters, ultimately causing a symptom called wet gangrene, where the affected body part is closed off from the blood stream and begins to rot. The venom acts of the nervous system, resulting in paralysis of the face, eyes, tongue, and neck. Death often comes from respiratory failure.

Viper venom, on the other hand, affects the blood vessels directly and causes dry gangrene,  where tissue dries up and often falls off. The venom also results in kidney failure, leading to death if not treated rapidly. The quantity of venom delivered into the body also differs with species — the krait injects about 20 milligrams of venom, while the Indian cobra is capable of pumping in thrice that amount.


The where and how of antivenom


India is one of the few countries with the capacity to both extract venom and process it to make antivenom. This is fortunate, because across the world manufacturers are ceasing production, due to a global lack of demand. This has made antivenom costly for poor countries. According to the WHO, antivenom availability has declined significantly or even disappeared in many countries, opening the market for inappropriate, untested or even fake antivenom. This, in turn, undermines confidence in the only mode of therapy available for snakebites.

Antivenom production starts with milking the snake by squeezing its head and allowing the venom to ooze out of the fangs and into a vessel. The venom is freeze-dried and diluted with sterile water before being injected into horses (the dosage is calculated to ensure the horse stays alive). This elicits an immune response in the animal, which creates antibodies. The horse is then bled, and the antibodies are processed to make antivenom. India produces polyvalent antivenom — a combination treatment for different snake bites — by immunising horses with venom from the Big Four. 

About 85 per cent of the venom needed for producing antivenom in India is extracted by the Irula Snake-catchers Industrial Cooperative Society in Chennai, South India. But there are issues with the venom collected there. The antivenom produced by using the local snakes is relatively ineffective in North India, as the composition of venom of a single species can vary greatly according to location and the snake’s habitat.

“Ecological and environmental factors, gender, age, temperature, and prey/predators govern snake venom composition and activity,” explains Kartik Sunager, a scientist at the venom research centre of the Indian Institute of Science in Bangalore.

“Collecting venom regionally and producing antivenom for that particular region could be done to make treatment more effective,” says Priyanka Kadam, founder of the Snakebite Healing and Education Society. “Although efforts are being made in this direction, permission needs to be obtained from the different provincial forest departments, and they are generally hesitant to grant permission to private players.”

Polyvalent antivenom produced in the country also fails when it comes to poisonous species other than the Big Four. It does not, for example, work against the bite of the hump-nosed pit viper (Hypnale hypnale), a medically important species in southwestern India and Sri Lanka. Treatment with polyvalent antivenom is also associated with a high incidence of adverse reactions.

Snakebite - Efficacy of peptides 1

As for the Big Four, better availability of antivenoms aimed at specific species would reduce the dose requirement and increase the chances of patient survival and recovery, says Himmat Bawasker, a toxicologist in private practice who specialises in scorpion and snake venom. “Antivenom should be given only for venomous snakebite, but doctors routinely administer it for every snakebite case.”

“Most government doctors are not adequately trained in when and how to use anti-snake venom and the patient is transferred to private hospitals, where charges for treatment can be unaffordable for patients who typically live in the rural areas,” Bawasker says.
Snakebite - Efficacy of peptides 2

On the trail of the Big Four  


The Big Four Mapping project started in May 2017 as part of the Indian Snakebite Initiative, a national programme to tackle the problem. The mapping effort aims to geographically identify spots favoured by particular species and the nearest treatment centres. “We realised that there was no information regarding the distribution of snakes and hospitals that treat snakebite,” says Jose Louies, who heads the wildlife litigation department at the Wildlife Trust of India, a non-profit organisation.

Using a mobile app, volunteers upload a picture and the location of every snake they spot. This kind of geographic mapping has shattered myths such as the one that says snakes prefer rural habitats. “We found that urban areas harbour snakes, 70 per cent of them Indian cobras,” Louies says. “If you have a house with rodents and hiding places suitable for snakes then the chances are that you have a snake staying with you.”

Beginning January 2019, the app will map hospitals that can help victims quickly. “You can add your location and the app will tell you the nearest hospital that treats snakebite, saving precious time. Users can provide feedback if a particular district hospital does not stock antivenom, and this information can be communicated to the health secretary or state minister,” Louies explains.

Better data on the frequency and type of snakebite can also help the government estimate requirements and draw up distribution policies, which manufacturers can follow. This is expected to build confidence in the ability of the healthcare system to deal with snakebite and prevent victims from turning to traditional healers and quacks — thought to be one reason for the large number of snakebite-related deaths in India.

Kyntox Biotech India Private Limited, a start-up in Bangalore, has developed a point-of-care diagnostic kit that helps determine the snake behind the bite. “The kit can detect picogram [one trillionth of a gram] levels of venom from the Big Four in blood, urine, or local bitten area and identify the snake in less than two minutes,” Gopi Kadilaya, director of Kyntox Biotech, tells SciDev.Net.

That is a huge advantage over existing kits, which are often unreliable and may misdiagnose a cobra bite as that of a krait. With funding and support from the government’s Biotechnology Industry Research Assistance Council (BIRAC), the kit is expected to be commercially available in the next 4-5 months.


A multi-fanged approach


But efforts are also underway to increase the potency of the standard antivenom, especially by collecting it locally and generating region-specific antivenoms. “Haffkine recently received funding from BIRAC to collect venom from at least four different states,” Naik says. “We have written to almost all states and union territories to give us permission to hunt and milk snakes. We already have licence for Maharashtra state and have initiated venom collection in a district-wise manner. Categorising venom from different places will help if we need to change the venom content or pool venom from different regions to increase effectiveness.” As part of the BIRAC project, the Haffkine Institute also plans to assess anti-snake venom produced by different manufacturers to standardise dosages and potency across India, Naik adds. This would help, because existing regulation to control the manufacture and stocking of appropriate antivenoms is poor. Complaints against Indian antivenom products have included misleading and ambiguous recommendations on dosing, as well as erroneous or missing instructions in the event of adverse reactions.


Nature’s cure


But nature itself might hold some clues. Opossums, for example, are immune against rattlesnake bites. In 2015, scientist isolated several proteins that controlled this immunity. Interestingly, all these proteins ended with a similar peptide — a chain of amino acids.

When researchers from the Indian Institute of Technology-Delhi (IIT-Delhi) chemically synthesised the peptide and injected it into mice, along with a lethal dose of rattlesnake venom, the peptide neutralised the toxins. The group hopes to demonstrate that synthetic molecules have a broader range than standard polyvalent antivenom, and that they will even work against the hump-nosed pit viper.

“The peptide neutralises quite a few proteases [enzymes that separate out the peptide, so it can bind the dangerous venom], which raises the hope that it will work against most, if not all, venom,” Anurag Rathore, a scientist at IIT-Delhi, tells SciDev.Net. The group has already shown that it is possible to produce large quantities of purified peptide in a cost-effective manner (US$1 per dose), using recombinant DNA technology.

Vishwanathan Hebbi, a graduate student in Rathore’s lab, adds: “The limitation is getting enough data from preclinical studies. It will be possible to commercialise the product within 2—5 years.”
  
This piece was produced by SciDev.Net’s Global desk.

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