Snake Venom: The Pain and Potential of Poison

by Ed Ferrer

Reprinted from The Monitor, the Newsletter of the Hoosier Herpetological Society, Vol.12, No.2, February 2001.

Snake venom is one of the most amazing and unique adaptions of animal evolution. Venomous serpents have developed one of the most effective and efficient weapon systems of the animal kingdom. What is snake venom and how does it work? Venom is a prey-immobilizing substance in snakes that is used secondarily as a defense system. Venom is not composed of a single substance, but is a toxic saliva consisting of a complex mixture of chemicals called enzymes. Almost all venoms are composed of approximately 90% proteins. Two general types of toxins are known, neurotoxins and hemotoxins. Neurotoxic venom attacks the victim's central nervous system and usually result in heart failure and/or breathing difficulties. Cobras, mambas, sea snakes, kraits and coral snakes are examples of snakes that contain mainly neurotoxic venom. Hemotoxic venom attacks the circulatory system and muscle tissue causing excessive scarring, gangrene, permanent disuse of motor skills, and sometimes leads to amputation of the affected area. The Viperidae family such as rattlesnakes, copperheads, and cottomouths are good examples of snakes that employ mostly hemotoxic venom. Some snakes contain venom that contains combinations of both neurotoxins and hemotoxins.

There are approximately 20 types of toxic enzymes found in snake poisons throughout the world known to man. Although no venomous snake has all of these toxins, most snakes employ between six to twelve of these enzymes in their venom. Each of these enzymes has its own special function. Some aid in the digestive process, while others specialize in paralizing the prey. Scientists believe they have identified the following chemicals from snake venom and the specific purpose of each as follows:

• cholinesterase; attacks the nervous system, relaxing muscles to the point where the victim has very little control.
• amino acid oxidase; plays a part in digestion and the triggering of other enzymes, (is responsible for venom's characteristic light yellowish coloring.)
• hyaluronidase; causes other enzymes to be absorbed more rapidly by the victim.
• proteinase; plays a large part in the digestive process, breaking down tissues at an accelerated rate. (causes extensive tissue damage in human victims)
• adenosine triphosphatase; believed to be one of the central agents resulting in the shock of the victim and immobilizing smaller prey. (probably present in most snakes.)
• phosphodiesterase; accounts for the negative cardiac reactions in victims, most notably a rapid drop in blood pressure.

These are only a few of the enzymes found in the chemistry of snake venom known today. Other enzymes have been isolated and identified but their purpose is still largely a mystery to science.

Now that you probably feel that you have just taken a crash course in organic chemistry, you probably want to know if science has made any progress in finding within this new-found knowledge of venom any benefits for humans. Although the danger of snake venom to humans has been well documented, mankind also benefits from increased research of snake venom. The most obvious benefit to man is the snake venom's role in producing "antivenom" (also known as "antivenin") to help counteract the effects of snake bites. The most well-known method of producing antivenom is a technique referred to by many as the "horse serum" method. Venom is injected into the horse, slowly increasing the amount as the horse builds up antibodies to the venom. Blood is then taken from the animal and the serum containing the antibodies is then separated. Unfortunately about one-third of all recipients have allergic reactions to horse serum. Standard procedure calls for a test for serum sensitivity before giving antivenom to patients. Although certain "polyvalent" antivenoms can be utilized for certain "groups" of snakes, usually each type of snake has its own specific antivenom.

Besides the obvious benefits of snake venom to produce antivenom, have there been any other breakthroughs in medical research? There have been many early results from research that gives promise on many medical fronts. In France, an enzyme derived from copperhead venom may hold an answer to treatment for breast cancer. Ingredients from the venom of a Malayan pit viper has shown promise in breaking blood clots that would be very beneficial in treating stroke victims. Enzymes from cobra venom may hold the keys to finding cures for Parkinson's disease and Alzheimer's disease. Some viper venom seems to hold the secrets to curing osteoporosis and promoting tumor reduction. Several venom extracts have shown possibilities that could lead to the production of anticoagulants that would be helpful in treating heart disease. Proteins from certain rattlesnakes has produced blood pressure medicine. Ingredients from the red-necked spitting cobra has provided clues to breaking down cell membranes that would provide treatment for leukemia and cancer. It is obvious that these very complex enzymes derived from snake venom could produce potentially huge medical benefits for mankind. Besides protecting these unique creatures as part of a responsible effort to preserve our natural heritage, it seems increasingly clear that protecting venomous snakes is in our own best medical and health interest.

References:
Venomous Snakes of the World. 1995, W. P. Mara
Venomous Reptiles of North America. 1992, Carl H. Ernst
Conversation with Jim Harrison, Kentucky Reptile Zoo, Slade, Kentucky

Contact: Karen Richardson
krchrdsn@wfubmc.edu
336-716-4453
Wake Forest University Baptist Medical Center

Snake venom reveals clues about heart drug

WINSTON-SALEM, N.C. – With the help of snake venom and sophisticated laboratory testing, scientists believe they've uncovered the reason why a group of new heart medications were doing some patients more harm than good. Researchers from Wake Forest University Baptist Medical Center and colleagues report the findings in the current on-line issue of The Journal of Molecular Biology.

"Our findings suggest that drug developers should take a different approach," said Roy Hantgan, Ph.D., principal investigator, "and we've also developed a way to test drugs for these harmful effects before they are given to patients."

Hantgan, an associate professor of biochemistry, and colleagues studied a group of drugs called integrin antagonists that are designed to prevent blood clots from forming and causing a heart attack during angioplasty, a procedure that uses a balloon-like device to clear narrowed heart arteries.

Intravenous forms of the drug, including ReoPro®, proved very effective at minimizing complications of angioplasty in most patients. Drug manufacturers then worked to make oral forms, so the benefits could be extended after patients left the hospital. But research trials for three different oral drugs were stopped after early results showed a 33 percent increase in patient deaths – with no clear cause. Researchers were unsure what caused the disparity – the intravenous drug was beneficial, while the oral form could be deadly.

Integrin antagonists are designed to block a natural clotting mechanism. They target a protein on blood platelets called an integrin. Integrins, which have been described as the "glue of life," are essential for clotting. The process begins when integrin receptors combine with fibrinogen, a protein in the fluid part of blood. The platelets then congregate at the site of an injury to stem blood loss.

During angioplasty, however, this clotting mechanism can result in a heart attack. When a piece of plaque buildup breaks off in an artery, or when the angioplasty balloon crushes plaque buildup, integrin receptors are activated, which can cause a blood clot to block the artery. Integrin antagonists were designed to prevent this response – the drugs combine with the integrin receptors so that fibrinogen isn't able to.

In trying to solve the mystery of why one type of integrin antagonists works better than another, Hantgan and colleagues decided to enlist the help of a protein found in snake venom that binds to the integrin and blocks fibrinogen. This causes rapid bleeding in the snake's prey.

"We wanted to look at a natural protein to see how the synthetic drugs might work," Hantgan said.

Using the electron microscope and laboratory tests that measure the size and shape of very small proteins, the team discovered that the snake venom protein blocks the receptors, just as the drugs do. But after the protein is withdrawn, some of the receptors remain activated, creating the potential for clotting.

"Likewise, the drugs are effective at blocking the receptor, but some of the newer drugs also cause the receptor to remain activated," said Hantgan. "The beneficial effects of these drugs seem to be inseparable from their side effects."

The team tested several integrin antagonists and found that all, including the newer, oral medications, had the response in varying degrees. Hantgan speculated that dips in patients' drug levels that can occur with oral medications could leave them especially vulnerable to the integrin-activating effects.

"This result suggests that no matter how good a drug you develop, you're going to have this problem in some patients," said Hantgan. "We believe that drugs that are designed to bind to integrin receptors inside the platelet, rather than on the surface, might have a better chance of working."

Hantgan's co-researchers are Mary Stahle, B.A., John Connor, Ph.D., Douglas Lyles, Ph.D., David Horita, Ph.D., all at Wake Forest University School of Medicine, Mattia Rocco, Ph.D., at the IST in Genova, Italy, Chandrasekaran Nagaswami, B.S., John Weisel, Ph.D., at the University of Pennsylvania, and Mary Ann McLane, Ph.D., at the University of Delaware. His research is supported by the American Heart Association, Mid-Atlantic Affiliate.

Contacts: Karen Richardson, krchrdsn@wfubmc.edu; Shannon Koontz, shkoontz@wfubmc.edu; at 336-716-4587.

About Wake Forest University Baptist Medical Center: Wake Forest Baptist is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. The system comprises 1,282 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.

Deadly Snake Hunted for Lifesaving Venom Brian Handwerk for National Geographic News March 10, 2003 Snake Photo Gallery >> Which snake has the longest fangs? Click here to find out >> In Australia, life-threatening poisonous animals have always posed a hazard to humans. But some of the most dangerous also act as lifesavers. Such is the case with the notorious death adder, a snake that's essential to the production of lifesaving snakebite antivenins. The National Geographic Channel tags along with snake wranglers from the Australian Reptile Park in Somersby, New South Wales, as they hunt death adders for their valuable and deadly venom. Death Adder Duet is an installment in the Snake Wranglers series, which brings viewers face-to-fang with the planet's most compelling snakes. For more than 50 years, the staff of the Australian Reptile Park has raised and milked hundreds of venomous spiders and snakes—including the death adder—for their poisonous venom in order to create life-saving medicines. The park's venom-milking program is the only supplier of venom to Melbourne's Commonwealth Serum Laboratories—makers of antivenins crucial to treating snakebite victims.

Craig and Jackie Adams with an Olive python Photograph copyright David Wright Watch Death Adder Duet, is part of a Snake Wranglers series on the National Geographic Channel. Watch this installment tonight, March 10, 2003, in the United States. The program profiles Craig and Jackie Adams-Maher of the Australian Reptile Park as they search for one of Australia's deadliest snakes—the death adder. The program is being aired as part of the Channel's Five Days of Snakes, airing each night this week. Learn more >>

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The work is time-consuming and not without hazard. Hundreds of milkings are necessary to create a single dose of antivenin. It's a difficult job, but one that pays tremendous dividends for public health. As John Weigel, director of the Australian Reptile Park, notes, the program helps save hundreds of lives each year. "Producing the venom that's used to make the antivenin, that's part of the soul of us, part of our heritage and what we do," Weigel told National Geographic News. "We've done it for 55 years and it saves perhaps 280 to 300 lives a year. That's something we feel really good about." From Deadly Venom to Healing Medicine Thanks to the widespread availability of effective antivenins, snakebite fatalities in Australia have become rare in recent decades. The nation's antivenin program suffered a setback two years, however, after a devastating fire raged through the Australian Reptile Park. The blaze gutted much of the park and killed most of its captive animals—including snakes used in the venom-milking program. Since the catastrophe, staff members have traveled Australia to collect venomous snakes in order to rebuild the program. Death adder venom remains in particularly short supply. Snake wranglers are combing Australia for the reclusive reptiles. "We need something like 50 to 60 death adders to milk every two weeks in order to provide a sufficient quantity of venom," Weigel estimated. Like that of other snakes, death adder venom, is a form of saliva. When a venomous snake bites, it injects venom into its victim through hollow fangs—though this does not happen with every bite. In the milking process, a snake is prompted to bite through a latex membrane stretched over a glass beaker. Venom is collected in the beaker then later dried, weighed, and packaged by staff members wearing protective masks. Dried venom is sent to the Commonwealth Serum Laboratories, in Melbourne, Victoria. Over long periods of time, some 250 huge Percheron horses are injected with tiny but increasing amounts of venom (the animals are unharmed). The horses produce natural antibodies to counteract the small amounts of poison in their systems. After about a year, blood plasma is extracted from the horses in a process as simple a human blood donation—plasma rich with antibodies that can neutralize snake venom. Death Adders Hunted For Potent Venom Capturing a death adder is difficult and dangerous. The snakes grow up to 75 centimeters (29.5 inches) long and are rather reclusive. They hunt by ambush—sometimes partially buried in sand, soil, or leaves—waiting for lizards, birds, or other small animals beneath low bushes and shrubs. The camouflaged snake uses the thin tip of its brightly-colored tail as a lure before striking its prey with large fangs six to eight millimeters (0.2 to 0.3 inches) long. The several species of death adders are often ranked among the world's most deadly snakes—although their reputation may be a bit misleading. "These popular listings are often based on the potency of the snake's venom— the quantity of reconstituted dried venom it would take to kill a laboratory mouse or a human." Weigel explained. While death adder venom is highly potent, such rankings often overlook important mitigating factors when determining how likely a human is to survive an encounter with the snake. Factors include the amount of venom typically injected during a bite, the likelihood of a death adder to strike and bite, and even the odds of encountering the snake in the wild. So while death adders rank among the most deadly snakes, the risks they pose to humans are not quite so high. This tempered threat is due to the high success rate of antivenin treatment and also decreased instances of human-snake encounters as the death adder's population has declined. Nonetheless, hunting the snakes is dangerous. If left untreated, the death adder's bite is deadly. "It's one of those snakes that, if it bites and envenomates you, you can certainly die," said Weigel. The snake's venom contains neurotoxins that can cause major respiratory paralysis within 6 hours of receiving a bite. "An untreated bite has a high death rate," Weigel explained. "In New Guinea, where we don't have much antivenin, the death rate remains something like 50-50."

Offer applies to U.S. and Canadian addresses only. Savings based on annual U.S. newsstand price of .40. Canadian price (C), including GST. Sales tax will be added where applicable. Allow 4-6 weeks for delivery. While all dues support National Geographic's mission of expanding geographic knowledge, 90 percent is designated for the magazine subscription, and no portion should be considered a charitable contribution. Snake Bites From Vincent Iannelli, M.D., Your Guide to Pediatrics. FREE Newsletter. Sign Up Now! Treatment and Prevention They fascinate. They repel. Some pose a danger. Others are harmless. And whether they are seen as slimy creatures or colorful curiosities, snakes play important environmental roles in the fragile ecosystems of the nation's wildlife areas. People who frequent these wilderness spots, as well as those who camp, hike, picnic, or live in snake-inhabited areas, should be aware of potential dangers posed by venomous snakes. Every state but Maine, Alaska and Hawaii is home to at least one of 20 domestic poisonous snake species. A bite from one of these, in which the snake may inject varying degrees of toxic venom, should always be considered a medical emergency, says the American Red Cross. About 8,000 people a year receive venomous bites in the United States; nine to 15 victims die. Some experts say that because victims can't always positively identify a snake, they should seek prompt care for any bite, though they may think the snake is nonpoisonous. Even a bite from a so-called "harmless" snake can cause an infection or allergic reaction in some people. Medical professionals sometimes disagree about the best way to manage poisonous snakebites. Some physicians hold off on immediate treatment, opting for observation of the patient to gauge a bite's seriousness. Procedures such as fasciotomy, a surgical treatment of tissue around the bite, have some supporters. But most often, doctors turn to the antidote to snake venom--antivenin--as a reliable treatment for serious snakebites. Antivenin is derived from antibodies created in a horse's blood serum when the animal is injected with snake venom. In humans, antivenin is administered either through the veins or injected into muscle and works by neutralizing snake venom that has entered the body. Because antivenin is obtained from horses, snakebite victims sensitive to horse products must be carefully managed. The danger is that they could develop an adverse reaction or even a potentially fatal allergic condition called anaphylactic shock. The Food and Drug Administration regulates antivenins as part of its oversight of biological products. The agency requires certain criteria to be met before these materials are sold, including standards for purification, packaging and potency. FDA also regulates antivenin labeling, ensuring that data on potential side effects and other pertinent information are available. The agency also periodically inspects antivenin production facilities to ensure compliance with regulations.   Remember Red touch black friend of Jack(no venom) Red touch yellow kill a fellow(has venom).