TOLEDO BLADE (Ohio) 19 December 05 Taking a bite out of stroke - Drug with viper venom may help dissolve blood clots (Jenni Laidman)
Stroke treatment can be a deadly game of Beat the Clock, but researchers hope that the bite of a venomous viper will help slow down the ticking.
Toledo Hospital and the Medical University of Ohio are among 15 medical centers around the country testing Viprinex, a drug created from the poisonous bite of the Malayan pit viper.
Researchers hope Viprinex can extend the time people can receive treatment by helping dissolve blood clots that can cause a stroke. If it proves effective at extending the window of time that a patient can be treated, it could have a far-reaching impact.
Stroke, which occurs when a blood vessel in the brain either becomes blocked or bursts, is the nation’s third-leading cause of death and No. 1 cause of disability, according to the American Stroke Association. Each year 700,000 Americans have a stroke and 168,000 die.
Today, it’s a rare stroke patient who arrives at the hospital soon enough to receive the best medication available — a drug called tPA (shorthand for tissue plasminogen activator). When tPA is administered within three hours of the onset of stroke, it breaks up the clot blocking the brain’s circulation, thereby reducing the amount of permanent damage to the brain. The administration of tPA can be the difference between full recovery and permanent disability or death.
But time is the enemy with this promising drug, and few are quick enough.
“Five percent get in on time to receive tPA,’’ said Dr. James Sander, chief of neurology at Toledo Hospital and principal investigator for the hospital’s Viprinex trial.
“The problem is, people just aren’t educated. Or they’ll wake up with a stroke, and you don’t have a start time. It could have been there for God-knows-how-long. Hours. Or, if they think they’re having a stroke, they don’t come in because of denial.’’
It’s a problem around the country.
“Recruitment of patients for early treatment is not what it should be. Some could call it dismal,’’ said Dr. Gregory Del Zappo, an expert on stroke at the Scripps Research Institute in La Jolla, Calif.
“It’s not the fault of the medicine,’’ Dr. Del Zappo said. “If there’s a fault, it’s the rapid evolution of injury in the brain.’’
After the three-hour tPA treatment window closes, administration of the drug could pose a greater health risk to patients by increasing the chance of serious hemorrhage inside the brain.
At least one trial has suggested Viprinex may pry open the treatment window a little further. In that U.S. study — in which MUO participated — Viprinex reduced serious stroke symptoms and increased survival when administered up to six hours after stroke onset.
Among the study’s 500 patients, 42 percent of the 248 people receiving Virpinex — also called Ancrod — returned to full-functioning or nearly so, compared to 34 percent of the 252 people in the placebo group. The placebo group also had a higher rate of disability, with nearly 20 percent of the placebo group severely disabled, compared to about 12 percent of the treatment group.
Still, the drug carries risk. A trial of the drug in Europe had to be terminated early because of an increased number of deaths among patients given Ancrod/Viprinex.
In the U.S. trial, the Viprinex group had a slightly higher rate of “symptomatic” intracranial hemorrhages, 5 percent compared to 2 percent; and a large increase in asymptomatic hemorrhages — 19 percent vs. almost 11 percent.
Dr. David Levy, vice president of clinical development for Neurobiological Technologies Inc., which purchased Ancrod from Abbott Laboratories, said today’s Viprinex trial has been designed to avoid an increase in brain bleeds. “I think we understand why these hemorrhages occurred,’’ Dr. Levy said.
Drug dosing in the earlier studies was based on how Viprinex is used in Europe to treat narrowed and blocked arteries in the legs, Dr. Levy said. Patients treated for peripheral circulation problems receive a high dose of medicine intravenously initially, and additional infusions in days following.
The goal of that treatment pattern is maintaining reduced levels of a substance called fibrinogen in the blood. Virpinex breaks down fibrinogen, a protein involved in blood clotting.
While study data suggest it is necessary to reduce fibrinogen levels quickly after a stroke, Dr. Levy said it is not necessary to keep them low. The new drug trial will include only a single infusion of Viprinex, and none of the follow-up doses that seemed to cause problems in earlier studies.
Dr. Levy said the treatment regimen in the new study should improve both efficacy and safety at the same time.
“At the end of the day it’s going to be safer than tPA,’’ Dr. Levy said.
Viprinex is just one of the drugs under investigation to increase the amount of time patients can be treated for the acute effects of stroke.
In 2003, MUO participated in a small study of a drug called Desmoteplase, a compound based on a substance found in the saliva of vampire bats.
The study has not been published, but results presented in February at the International Stroke Conference revealed improvement in 60 percent of the 15 patients to receive a higher dose of Desmoteplase. Twenty-eight percent of the 14 patients in the low-dose group improved, while 25 percent of eight patients given a placebo improved.
Another Desmoteplase study, published in the journal Stroke in January, looked at results of treatment in 104 patients in Europe, Australia, and Asia. It also showed benefits among patients treated up to nine hours after symptom onset.
But the bat-saliva drug ran into some of the same problems the snake-bite medicine caused. Among patients receiving higher doses in the European trial, there was an “excessive rate” of brain bleeds compared to placebo.
It’s not easy to figure out which stroke drug will work best, Dr. Del Zappo said. A basic problem is stroke patients differ significantly in both the severity of their injury, and their overall health at the time of the stroke. People with worse damage and poor circulation are going to fare worse on any drug. Younger people with less severe stroke and better circulation will do better.
Another strategy for stroke treatment under investigation is the use of drugs that protect the neurons, said Dr. Del Zappo. One such drug, Aptiganel, looked promising in animal studies, reducing stroke damage by up to 70 percent. But a human trial of the drug was halted when it appeared Aptiganel increased death rates and provided no benefit over a placebo at high or low dose, a report showed.
Researchers also tried a drug that prevented the binding of blood platelets to fibrinogen, preventing platelet-dependent clots. “This is another example of forcing an idea onto biology without a lot of experimental evidence,’’ Dr. Del Zappo said.
A trial of this drug was stopped in October because of a high rate of brain hemorrhage, according to a report on the Internet Stroke Center. Still, stroke researchers are hopeful these and other drug trials will eventually pay off.
“The development of injury in stroke is still a black box,’’ Dr. Del Zappo said. “But we know more than we did 10 or 15 years ago.”
Pharmazooticals
A single Malayan pit viper can provide some 1,000 to 1,500 treatments of the stroke therapy Viprinex every month, estimates Dr. David Levy, vice president of clinical development for Neurobiological Technologies.
Dr. Levy declines to reveal where the company has its snakes stashed today, or where it will eventually establish its snake farm, but explorations into Mother Nature’s drug store may eventually prompt other pharmaceutical companies to house a sizeable collection of reptiles, amphibians, and even insects.
Here are some other candidate animal contributors to human medicine:
Poison-dart frog
This Ecuadorian tree frog is just one of an array of amphibians doing its bit for modern medicine. A biochemist from the National Institutes of Health found a pain killer some 200-times stronger than morphine in the skin of the frog. The drug, epibatidine, is under investigation.
Thailand cobra
The venom of this snake garnered a lot of attention a few years ago as a potential treatment for multiple sclerosis. But thus far, it failed to prove effective for a condition called Adrenomyeloneuropathy — which, like multiple sclerosis, is a disease in which nerves lose their protective myelen covering. The venom also showed no benefit for sufferers of amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.
Southern Copperhead
The venom of this amphibian shows promise in the treatment of metastatic cancers. Contortrostatin has been shown effective in animal models against glioma, a type of brain tumor, and in laboratory studies of ovarian and breast cancer.
Gila monster
Clinical trials are under way for a drug modeled on the venom of this lizard. The drug stimulates insulin production and could be useful in the treatment of diabetes.
Brazilian arrowhead viper
A class of drugs used to treat high blood pressure and heart failure got its start in studies of the viper’s venom. Chemicals isolated from the poison led to the development of the angiotensin-converting enzyme (ACE) inhibitors captopril and enalapril.
Sea snakes and more
The venom of a variety of vipers, along with cobras, coral snakes, and sea snakes are being investigated as a source of natural antibiotics.
Southeastern pygmy rattlesnake
Studies of the venom of the pygmy rattlesnake led to the development of the anticoagulant Integrilin, which is used to treat severe cardiovascular disease.
African saw-scaled viper
The creation of another anticoagulant, Aggrastat, was based on the venom of the African viper. It keeps blood clots from growing when administered with aspirin and the blood-thinner Heparin.
Giant Israeli scorpion
Researchers at the University of Alabama discovered a chemical in the venom of this scorpion, called chlorotoxin, could be a weapon in the fight against gliomas — tumors of the brain’s supporting cells, the glial cells.
Chilean pink tarantula
The neurotoxic venom from this spider could play a role as a pain medication.
Drug with viper venom may help dissolve blood clots

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