Just a small fraction of patients who have a stroke receive the only drug – TPA – available to treat the condition. Now doctors and scientists at the University of Rochester Medical Center have developed a potential new treatment that will reach a milestone in the next few months, when the experimental treatment is tested for the first time in people who have suffered a stroke or "brain attack."
The team has approval from the U.S. Food and Drug Administration and $3.4 million in funding from the National Heart Lung and Blood Institute to test the treatment in 72 patients in four communities around the nation, including Rochester. It's an effort to break the frustrating impasse at which doctors who treat stroke patients find themselves: It's been more than a decade since a drug was approved to treat acute stroke, and the only drug available is rarely used and itself can cause harmful side effects.
The experimental treatment is actually a form of a medication, Activated Protein C or Xigris, that doctors now use to treat sepsis. In a series of scientific achievements over the last decade, Berislav Zlokovic, M.D., Ph.D., professor of Neurosurgery and Neurology, has shown that the compound offers promise for stroke patients as well.
"It's tremendously exciting to bring the work from the laboratory to patients," said Zlokovic, who is director of the Frank P. Smith Laboratory for Neuroscience and Neurosurgery Research. "This is why we do research, to ultimately develop a new treatment that could improve the lives of many, many people. That's why I've devoted my life to research like this."
Neurologist Curtis Benesch, M.D., M.P.H., director of the Strong Stroke Center, will lead the study of APC for stroke. During the next five years he will work together with doctors at the University of California at Irvine, Washington University in St. Louis, Mt. Sinai Hospital in New York City, and Rochester General Hospital to enroll 72 people in the study. Participants will be people who have had a stroke within six hours but who decline the use of TPA.
The study moves forward just a week after a major pharmaceutical company, AstraZeneca, announced that a drug the company had hoped could protect the brain from stroke had failed. That's the latest disappointment in a field where more than 100 treatments have been tested – and failed – since TPA was approved in 1996. That leaves TPA as the only choice for just a few of the 700,000 Americans who have a stroke each year. Partly because of the shortage of good treatments, stroke is the most common cause of long-term disability in the nation.
"There's a great need for new treatments as well as to educate people to recognize the symptoms of stroke more quickly than they do," said Benesch. "Dozens of drugs have been tested in the last decade, but currently there are no other approved medications available besides TPA to help doctors treat acute stroke. While it's been very disappointing, we're excited about testing APC; the pre-clinical work has been very favorable."
Benesch says TPA is not used widely for a variety of reasons. Currently, patients must receive the drug within three hours of the onset of symptoms, and it's rare for patients to get to the hospital on time and to receive the tests necessary for doctors to move ahead with treatment. In addition, the drug carries with it risks such as increased brain bleeding or hemorrhage. Overall, the drug is used in fewer than 3 percent of patients who might benefit from it, and it helps the patient about one-third of the time.
APC offers a potential way to temper the side effects of TPA and to increase the treatment "window" beyond three hours. Zlokovic and colleagues have demonstrated that APC protects brain cells that are under siege in multiple ways. When a stroke happens, part of the brain is immediately shut off from oxygen and other vital nutrients, and a wave of destruction sweeps across a section of the brain. The body's immune system rushes in to try to fix the damage but often makes things worse by causing inflammation. Molecular signals telling damaged brain cells to kill themselves abound, and more and more brain cells die off as the body tries to cope with the damage.
In the laboratory, Zlokovic and colleagues have shown that APC counters a great deal of this damage, saving most of the brain cells that otherwise die and reducing the impact of stroke by 70 percent. His team first showed that TPA itself can kill neurons and amplify a stroke, then demonstrated that APC protects brain cells from the toxic effects of TPA and slows down the cascade of signals that causes more brain cells to die. They've also shown that APC helps quell inflammation.
Now, in a paper published in the November issue of Nature Medicine, Zlokovic and colleagues show that the protective effect of APC extends even further than has been thought. TPA can cause harmful bleeding in the brain, by breaking down the barrier of cells that line the arteries and veins that act as a gatekeeper. TPA works like a corrosive that is too strong on the insides of the body's "pipes" – arteries and veins – damaging the gatekeeper cells which then mistakenly allow blood to seep out of the blood vessels and into brain tissue, where it causes serious injury. In the Nature Medicine paper, Zlokovic's research team showed that APC blocks the cascade of chemical signaling that enables TPA to disable the blood-brain barrier.
"It's generally known that there are some risks with TPA, but overall the benefits outweigh the drawbacks," said Benesch. "But the medication's shortcomings have fueled the search for other agents to use when treating stroke. We're looking for a medication that does not increase the risk of bleeding, that does not kill brain cells, and that can be used for a period of time longer than just a few hours after stroke. We're hopeful that APC fits those criteria."
Scientists are cautiously optimistic about APC partly because it's already been shown to be safe and is currently used in patients with sepsis. The new study will focus on the safety of the drug when used to treat stroke patients. In this study, a patient who has just had a stroke will receive the drug more quickly than do sepsis patients: half the dose will be given immediately, and the other half will be given by IV over the next hour. In addition to monitoring patients' safety, doctors will do preliminary analysis of how well the drug works, using brain scans and neurological exams to gauge participants' status during the first three months after the stroke.
"This is a wonderful opportunity for Rochester and the University," said Benesch. "We've conducted several studies of drugs designed to help stroke patients, but this is the first study of a potential treatment that our researchers have actually developed. It's a great example of scientists and clinicians working together to try to improve the health of people not only here but around the globe. This has been a very fruitful collaboration."
The first authors on the Nature Medicine paper are Tong Cheng, former research assistant professor, and medical student Anthony Petraglia. Other University authors besides Zlokovic are Meenakshisundaram Thiyagarajan, Zhihui Zhong, Zhenhua Wu, Dong Liu, Sanjay Maggirwar, Rashid Deane, Jose Fernandez, and Barbra LaRue. Other authors include John Griffin of Scripps Research Institute in San Diego, and Zhang Li and Michael Chopp of the Henry Ford Health Sciences Center in Detroit. The new clinical study of APC and Zlokovic's ongoing research have been funded by NHLBI's Thrombosis and Hemostasis Program.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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