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.
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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.