Snakebite is a major, but neglected disease, says S.Ananthanarayanan.

If the number of persons who succumb to malaria is a cause for worldwide concern, the number that succumb to snakebites, which is a fourth of that number, should be of concern too.

Managing snakebite, however, has not received proportionate attention of the global health community, says a paper in the journal, Nature Communications, while proposing an alternate preparation that could be more effective, easier to administer and more readily available. Laura-Oana Albulescu, Chunfang Xie, Stuart Ainsworth, Jaffer Alsolaiss, Edouard Crittenden, Charlotte A. Dawson, Rowan Softley, Keirah E. Bartlett, Robert A. Harrison, Jeroen Kool and Nicholas R. Casewell, from the Liverpool School of Tropical Medicine, Vrije Universiteit, Amsterdam and Centre for Analytical Sciences, Amsterdam describe a combination of just two preparations, which can be orally administered, and is effective against the venom of most of the medically-important vipers of Africa, South Asia and Central America.

In the contest between health workers and the community of snakes, of saving or immobilising victims of snakebite, snakes have the advantage of millions of years of evolution of highly effective venoms, and instruments of delivery. Snakes administer their cocktails of chemically complex venoms through perfectly adapted needle-like fangs, and the venom quickly spreads through the victim’s body through the bloodstream. For centuries, humans had no inkling of how the venom acted and the only recourse was to tourniquets and amputation.

It was after the late 1800s that scientists observed that it was possible to people to get immunity to snake or insect bites if they trained with low doses of the same poison that they feared. The notion that the body generates an antidote was followed through and methods were found to culture the antibodies against important venoms by injecting the venoms into the bodies of animals. The process was successful and there are now several farms, or labs, all over the world, that produce doses of antivenin, as the substance is called, against a variety of snakes, spiders, and so on. As each antivenin is almost solely effective against the venom of a small group of species, the appropriate antivenin needs to be near at hand, to be administered fairly soon and it often needs refrigeration to stay effective. And again, as the antivenin is produced in the body of an animal, there is often reaction when used with humans. Hence, both for administration, by injection, and then to deal with possible reactions, there is the need for trained personnel. These features limit the value of the line of treatment. However, is almost the only recourse in case of a poisonous snakebite. And antivenin does save thousands of lives each year.

Snake venom is now understood to consist of proteins and enzymes, or substances that promote or retard body processes. Venom has evolved to contain those agents that lead to tissue damage, or that affect the nervous system – leading to paralysis, or that affect the clotting of the blood, either by creating clots or by preventing clotting. Although the discovery of the constituents of the substances the immune system of the animal produces is daunting, we now have the possibility of analysing what snake or other venom consists of and devising synthetic agents to neutralise the active portion of the venom.

One approach, the paper says, has been the use of ‘small molecule’ inhibitors, as an alternative to the products of the immune system. The ‘small molecule’, which is what most of the drugs that we use consist of, are units that act by attaching to cells or other molecules, to block or facilitate the cell action. While acting in a way not different from the enzymes in snake venoms, the advantage with small molecules is that they can be administered orally, unlike large molecule drugs, which need to be administered intravenously.

The authors of the paper in Nature Communications note that the viper family of snakes, which consists of hundreds of varieties, including the rattlesnake, the adders, pit vipers, bush vipers, the Russel’s viper, the saw scaled viper, is responsible for the majority of the snake poisoning incidents over the Americas, Africa and Asia. While treatment of snakebite needs to take care of several classes of toxins, across species, it is found that there are three specific kinds that account for more than 60% of the toxins found. These three, which are substances that cause the breakdown of proteins, are found to be the main cause of (i) destruction of tissue, (ii) decay of cell membrane, with leakage of fluids and (iii) breakdown of the clotting mechanism, leading to haemorrhage.

The authors draw attention to a known preparation, varespladib, which inhibits the action of enzymes that break up proteins, and was considered for treatment of some cardiac disease. While this application did not progress, varespladib showed promise as antivenin, as it could block the action of a category of components of the venom and another group, which includes the cobra. In addition, the authors say, there were other substances in use to inhibit other groups of enzymes, which also proved effective against venom induced haemorrhage and tissue death. The also cite a licensed oral medicine, used to treat cases of poisoning by heavy metals (mercury, arsenic), which worked against the venom of the saw-scaled viper.

The authors hence proposed that a selection such small molecule specifics could be combined, to act as ‘broad spectrum’ treatment to take care of the venom of several species of snakes. And in this effort, “to rationally select and preclinically validate a therapeutic small molecule mixture capable of neutralizing distinct pathogenic toxins found in the venoms of geographically diverse, medically important, hemotoxic (toxic to blood) vipers,” the authors, say, they have succeeded.

They prepared a mixture of just two small molecule substances. One is marimastat, which was tried out for its ability to suppress the action of some enzymes, in the immune system, instance. The other is varespladib, which we have spoken of. The paper describes how this combination, administered to experimental mice, a fixed time after controlled doses of different venoms were administered, showed that the combination was successful in overcoming the main viper venoms that are encountered.

About a year ago, a group from the University of California, writing in the journal of the American Chemical Society, described a nano-particle based ‘long molecule’, which was easier to handle and had similar ‘broad spectrum’ application. The present, small molecule solution, however, has the great advantage that it can be administered orally, or need not be injected. The concept that has been demonstrated could hence lead to an antivenin dose that a person could carry with her when she ventures into the wild. If she should be bitten, she could just swallow a first-aid dose which would keep her well till she reached medical attention!

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