An Exciting New Use for Gleevec.

[Guest guest]

http://www.medpagetoday.com/Neurology/Strokes/tb/9882##

ANN ARBOR, Mich., June 23 -- In an unexpected finding, the kinase inhibitor

imatinib (Gleevec) has shown promise in a mouse model as a means to extend

the three-hour thrombolytic therapeutic window for ischemic stroke.

Imatinib, approved for chronic myelogenous leukemia and gastrointestinal

stromal tumors, reduced the edema associated with ischemic stroke and also

improved response to tissue plasminogen activator, according to

Lawrence, Ph.D., of the University of Michigan School of Medicine and

colleagues in Sweden.

Imatinib reduced the blood-brain barrier permeability associated with tPA

and also expanded the window in which it can be used, Dr. Lawrence and

colleagues said online in Nature Medicine.

Action Points

_____

* Explain to interested patients that tissue

plasminogen activator (tPA) -- whose main job is to break down a blood clot

that has caused a stroke -- is also associated with increased permeability

of the blood-brain barrier, which can have adverse consequences.

* Note that this study identifies the mechanism that

causes the increased permeability and also shows that imatinib (Gleevec) can

block the process and also improve response to tPA.

* Caution that the study took place in animals and more

research is needed to see if the drug will benefit humans.

" Our findings may have immediate clinical relevance, and could be applied to

find new treatments that will benefit stroke patients, " Dr. Lawrence said.

" It was a completely unexpected result but we are very excited about it, " he

said.

But he and colleagues cautioned that the use of imatinib in stroke still

needs to be tested in clinical trials. Members of the research team at the

Karolinska Institute in Sweden are currently planning a human trial, Dr.

Lawrence said.

Mice were treated with imatinib an hour after the middle cerebral artery

occlusion and then given tPA four hours later -- a total of five hours.

Analysis found that imatinib significantly (P<0.05) decreased hemorrhage,

reducing the amount of hemoglobin associated with the ischemic hemisphere by

50% compared to untreated mice.

That last finding may have important potential for clinical practice, Dr.

Lawrence said. Currently, only about 3% of patients who could benefit from

tPA get the drug, because delays in treatment put them outside the

three-hour window.

In addition to the three-hour therapeutic window limitation, tPA can cause

hemorrhagic complications. The current finding is based on the discovery

that tPA -- aside from breaking down clots -- also causes the activation of

a molecule called platelet-derived growth factor receptor-alpha

(PDGFR-alpha).

That, in turn, leads to the increased permeability of the blood-brain

barrier, Dr. Lawrence said.

In non-ischemic mice, the researchers first showed that injecting tPA into

the cerebrospinal fluid leads to increased permeability, something that

wasn't seen when the drug was given intravenously.

When the activation of PDGFR-alpha was blocked, the tPA-induced permeability

was reduced significantly at P<0.01, the researchers found.

Because imatinib is an inhibitor of PDGFR-alpha, the researchers tested its

effects as a preventive agent in a mouse model of ischemic stroke.

The animals were given a middle cerebral artery occlusion and then treated

with imatinib an hour later, leading to a 33% reduction in leakage across

the blood-brain barrier, compared with control mice (P<0.05).

Because controlling blood-brain barrier dysfunction may affect infarct

expansion, the researchers looked at infarct volume after 72 hours. They

found that imatinib-treated mice had a 34% reduction in lesion volume on

average, compared to the control mice, a difference that was significant at

P<0.05.

Finally, they examined imatinib's ability to reduce the hemorrhagic

complications of late treatment with tPA -- five hours instead of three. The

strategy significantly (P<0.05) decreased hemorrhage, reducing the amount of

hemoglobin associated with the ischemic hemisphere by 50% compared to

untreated mice.

But imatinib may also be valuable in treating patients not eligible for tPA

because it appears to reduce damage on its own, he said.

The study was supported by the NIH, the Karolinska Institute, the Novo

Nordisk Foundation, the Swedish Research Council, the Swedish Cancer

Foundation, the LeDucq Foundation, and the IngaBritt and Arne Lundberg

Foundation. The authors did not report any potential conflicts.

Primary source: Nature Medicine

Su EJ, et al

<http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm1787.html> " Activation

of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier

integrity during ischemic stroke " Nature Medicine 2008.

Zavie (age 70)

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INF OCT/99 to FEB/00, CHF

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Gleevec since MAR/27/01 (400 mg)

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