X-Message-Number: 25012
From: "Basie" <>
Subject: Clot-buster can actually harm suspended patient
Date: Wed, 10 Nov 2004 15:56:19 -0500

Source:   University Of Rochester Medical Center

Date:   2004-11-09
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Scientists Pinpoint Flaw, Offer New Promise For Stroke Treatment
The best treatment doctors currently have for stroke can accelerate the
death of brain cells in addition to dissolving blood clots, researchers
report in the journal Nature Medicine. But they also found good news:
Another drug currently used to treat patients with severe sepsis counters
the harmful effects, offering the possibility that a combination of two
already-approved drugs might offer a powerful new stroke treatment that
would give doctors a bigger window of time to treat patients.

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The work is the result of a longstanding collaboration between scientists at
the University of Rochester Medical Center and counterparts at Scripps
Research Institute in La Jolla, Calif. The team found that the clot-buster
tPA (tissue plasminogen activator) can magnify the harmful effects of stroke
in mice and in human cells, and that a compound known as APC (activated
protein C) counters the harmful effects.

"TPA has been a great therapy for some patients, but right now it's
available to a tiny minority of patients. We hope to extend the window of
opportunity that tPA could be given, by protecting the brain against its
toxic effects," says Berislav Zlokovic, M.D., Ph.D., the Rochester
neuroscientist who led the research thanks to funding from the National
Heart, Lung and Blood Institute. "This holds great promise for stroke
therapy."

TPA is best known as a clot buster useful for patients who have the most
common type of stroke, where a blood clot blocks blood flow to a portion of
the brain, cutting off oxygen. The trauma causes more and more brain cells
to die as they try to cope with the damage. The result can be a devastating
brain injury that incapacitates the person for life.

TPA can prevent the damage by dissolving the clot and restoring the flow of
oxygen - but the drug must be given to patients within three hours of the
onset of stroke symptoms. That's a big reason why just a tiny fraction of
patients benefit from the drug: Zlokovic estimates that the drug reaches
only about three percent of patients who are eligible, and of those, not
everyone benefits.

The window of opportunity is so short largely because tPA is capable of
doing additional damage if not given immediately. While doctors know that
tPA can cause damage, the Rochester and Scripps team observed more extensive
damage than expected.

The team identified the specific molecular signals that enable tPA to
enhance the damage done by stroke. TPA kills neurons and endothelial cells,
the specialized cells that line our blood vessels, by accelerating a process
known as apoptosis or programmed cell death. In both human cells as well as
the brains of mice, the team showed that tPA activates an enzyme called
caspase-8, which goes on to activate caspase-3, which lays waste to a cell's
nucleus.

"This study sheds a lot of light on why tPA is not as effective as it could
be. TPA is tremendous at opening up blood vessels, but problems with
toxicity diminish the positive effects," says Zlokovic, who is professor in
the Department of Neurosurgery and director of the Frank P. Smith
Laboratories for Neuroscience and Neurosurgical Research at the University
of Rochester Medical Center. The study will be published in the December
issue of Nature Medicine and was published on-line November 1.

Most of the experiments outlined in the paper were done by research
assistant professors Dong Liu, Tong Cheng, and Huang Guo of the Department
of Neurosurgery - the three share credit as first authors of the paper. Also
contributing from Scripps were John Griffin, Ph.D., professor of molecular
and experimental medicine, an APC expert whose laboratory provided mouse APC
for the study, as well as staff member Jose Fernandez, M.D., Ph.D. of
Scripps, and technician Xiaomei Song of Rochester.

The team found that tPA not only causes bleeding by damaging the blood
vessel lining - increased bleeding is one of the main risks that limits tPA
use - but it also seeps out of the damaged blood vessels, breaking through
the blood-brain barrier and killing the brain's neurons directly. It's a
little bit like a powerful drain cleaner that not only clears out a clog in
a pipe but also eats through the pipe and then damages nearby structures.

"TPA is a two-edged sword capable of both beneficial and harmful effects
when given for ischemic stroke," says Griffin.

The administration of tPA boosted the percentage of cells that were marked
for death dramatically. In human brain blood-vessel cells subjected to
hypoxia or a shortage of oxygen, the stroke conditions alone killed 60
percent of cells, but when tPA was added, all the cells died. Similarly, in
mice, tPA nearly doubled the number of neurons marked for death from stroke
(from 32 to 60 percent) and more than tripled the number of cells in blood
vessels that were undergoing apoptosis (from 14 to 50 percent). The addition
of tPA also boosted the level of caspase-3, which chews up the insides of
cells, more than doubling in human brain cells and nearly doubling in mouse
neurons.

Then the researchers showed that APC counters the harmful effects of tPA
remarkably. In human brain cells in culture, APC reduced the number of cells
marked for death by 80 percent. Mice that received APC and tPA had 85
percent less brain damage from stroke as mice that received tPA but not APC,
and in mice APC completely countered the harmful effects of tPA, bringing
the level of "apoptotic" cells down to pre-tPA levels. The levels of the
harmful molecules caspase-3 and caspase-8 were also cut dramatically in mice
that received APC.

"This work combines two FDA-approved drugs in the setting of a major
challenge: ischemic stroke," says Griffin. "In the last 10 years, no other
drug has been approved for stroke, and in the last 15 years, no other drug
has been approved for severe sepsis. Perhaps these drugs could be
co-administered to give maximum beneficial effect to patients. It's
incredibly exciting."

The results are the latest in the team's research into the basic properties
of APC. Previously the researchers have shown that APC reduces inflammation
after stroke and protects neurons under stress.

Rochester neurologist Curtis Benesch, M.D., has received approval from the
U.S. Food & Drug Administration to test APC as a new investigational drug in
patients who have had a stroke and who are treated within six hours. If APC
is safe for patients and is effective, further tests are likely.

Related Link:

Outside The Strong Health Web Site: http://www.strokeassociation.org

Editor's Note: The original news release can be found here.

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