Posts tagged tPA

A drug that blocks the action of the enzyme Cdk5 could substantially reduce brain damage if administered shortly after a stroke, UT Southwestern Medical Center research suggests.

The findings, reported in the June 11 issue of the Journal of Neuroscience, determined in rodent models that aberrant Cdk5 activity causes nerve cell death during stroke.

“If you inhibit Cdk5, then the vast majority of brain tissue stays alive without oxygen for up to one hour,” said Dr. James Bibb, Associate Professor of Psychiatry and Neurology and Neurotherapeutics at UT Southwestern and senior author of the study. “This result tells us that Cdk5 is a central player in nerve cell death.”

More importantly, development of a Cdk5 inhibitor as an acute neuroprotective therapy has the potential to reduce stroke injury.

“If we could block Cdk5 in patients who have just suffered a stroke, we may be able to reduce the number of patients in our hospitals who become disabled or die from stroke. Doing so would have a major impact on health care,” Dr. Bibb said.

While several pharmaceutical companies worked to develop Cdk5 inhibitors years ago, these efforts were largely abandoned since research indicated blocking Cdk5 long-term could have detrimental effects. At the time, many scientists thought aberrant Cdk5 activity played a major role in the development of Alzheimer’s disease and that Cdk5 inhibition might be beneficial as a treatment.

Based on Dr. Bibb’s research and that of others, Cdk5 has both good and bad effects. When working normally, Cdk5 adds phosphates to other proteins that are important to healthy brain function. On the flip side, researchers have found that aberrant Cdk5 activity contributes to nerve cell death following brain injury and can lead to cancer.

“Cdk5 regulates communication between nerve cells and is essential for proper brain function. Therefore, blocking Cdk5 long-term may not be beneficial,” Dr. Bibb said. “Until now, the connection between Cdk5 and stroke injury was unknown, as was the potential benefit of acute Cdk5 inhibition as a therapy.”

In this study, researchers administered a Cdk5 inhibitor directly into dissected brain slices after adult rodents suffered a stroke, in addition to measuring the post-stroke effects in Cdk5 knockout mice. 

“We are not yet at a point where this new treatment can be given for stroke. Nevertheless, this research brings us a step closer to developing the right kinds of drugs,” Dr. Bibb said. “We first need to know what mechanisms underlie the disease before targeted treatments can be developed that will be effective. As no Cdk5 blocker exists that works in a pill form, the next step will be to develop a systemic drug that could be used to confirm the study’s results and lead to a clinical trial at later stages.”

Currently, there is only one FDA-approved drug for acute treatment of stroke, the clot-busting drug tPA. Other treatment options include neurosurgical procedures to help minimize brain damage.

(Source: utsouthwestern.edu)

Ischemic strokes, caused by blood clots that can develop in the brain and cut off blood flow, make up more than 80 percent of strokes suffered in the U.S. annually. To date, the most effective treatment is the clot-dissolving thrombolysis drug tissue plasminogen activator, tPA. But tPA is a far-from-perfect solution, says Andrew Barreto, a neurologist at the University of Texas Health Science Center in Houston. “IV-tPA will help about 30 of 100 patients who receive it within the first 4.5 hours after stroke symptom onset,” Barreto says. “But, many patients are still disabled, so we need better treatments.”

Barreto and some of his colleagues think that ultrasound could be one of those treatments. Ultrasound has been a valuable tool for diagnosing and tracking strokes in the brain for years. Now, a wide variety of new technologies are making it possible for neurosurgeons to use ultrasound waves, which travel at frequencies too high for the human ear to pick up, to not only identify the signs of stroke such as blood clots in the brain but also to help treat them.

Barreto was a principal researcher in the recent study of the Clotbust device, a headband-like piece of equipment placed on a patient’s head that aims to use ultrasound directed to increase tPA’s effectiveness in breaking up clots in the brain. A preliminary test of the device, which fires 2-MHz pulses of ultrasound from a series of 18 transducers at 5-second intervals, found that it was safe to use in stroke patients. Now, the device is in the midst of effectiveness testing on a group of 830 stroke patients worldwide.

One of the sites involved in testing the device is Swedish Neuroscience Center in Seattle, where chief of neuroscience David Newell notes that preliminary results from the trial were promising. In safety trials, the Clotbust device combined with the thrombolysis drug tPA cleared 40 percent of clots in ischemic strokes in the first two hours after being used. That’s twice as effective as the 20 percent clearance rate usually achieved by tPA alone.

Clotbust isn’t the only tool of its kind being tested at Swedish. Newell and his colleagues are involved in testing three different types of ultrasound technologies for a variety of neurological ailments. Those include one technique devised by. Newell in collaboration with EKOS corporation, a Seattle-area company specializing in ultrasound-emitting catheters, which are designed to travel up a blood vessel and transmit ultrasound from an emitter at its tip, to help loosen blood clots. Newell and his colleagues have been testing a modified version of the EkoSonic catheter, which can more easily be placed directly in the brain and used to detect a different type of stroke known as intracerebral hemorrhage (ICH).

Caused by bleeding from ruptured blood vessels deep in the brain, ICH strokes are much harder to treat because of their location. They are also particularly deadly, with a mortality rate north of 50 percent. Even those who survive are likely to be left disabled or with long roads to recovery. The tPA may be effective in treating these strokes as well, breaking up the clots in the brain that form around the bleed and allowing fluid to be drained off before it can do lasting harm.

While the effectiveness of tPA in treating ICH is still being studied, Newell and his team used the repurposed EkoSonic catheter to improve delivery of clot-busting drugs to bleed sites deep in the brain, and their early results are promising. In an introductory round of tests on nine patients at Swedish, Newell and his colleagues found that clots accompanying hemorrhagic strokes were cleared three times faster by a combination of ultrasound and tPA than they were by drugs alone. By combining the two techniques, Newell said, he and his team could clear clots from most patients in the first day of treatment. He’s now working with the company that developed the technology on creating a new type of catheter, designed specifically for use within the brain, that combines drug delivery, ultrasound emission, and drainage in one tool.

Neither Clotbust nor the EkoSonic catheter uses ultrasound to physically destroy clots. Instead, the blasts of high-frequency sound produce “a micromechnical action that makes the lytic effect of tPA a lot more effective,” by improving the efficiency with which it is delivered. “Injecting tPA is like putting an ice cube in a drink and waiting for it to melt,” says Newell. “With ultrasound, it’s more akin to creating a snow flurry. The drug binds to more binding sites, and it does so a lot faster.”

That’s not the case in the third ultrasound device being tested at Swedish. The ExAblate Neuro device developed by Israeli company InsighTec uses thousands of beams of ultrasound focused on one spot to create intense heat at a targeted point in the brain. The ExAblate Neuro mimics the effects of a tool used in neurosurgery for years, the gamma knife, which uses highly focused radiation energy to cut out material like tumors or to create lesions that can lessen the effects of diseases like Parkinson’s or epilepsy. In the case of stroke, the Neuro could potentially superheat solidified clots, turning them to more easily cleared liquid.

Since it uses focused ultrasound rather than the dangerous radiation associated with the gamma knife, says Newell, ExAblate has the potential to perform similar surgeries that are more easily repeatable. Current gamma knife surgeries have to get it right the first time, as exposing patients to powerful radiation over and over again can be dangerous. Since ultrasound energy doesn’t carry the same exposure dangers, doctors could potentially do the same sort of treatments in smaller steps without raising concerns over patient health.

All three of these new methods are still in their experimental phases, but each one has the potential to transform—and improve—the way strokes and other ailments in the brain are treated. And that may be only the beginning of the potential for the techniques. “Ultrasound technology represents almost a whole new field in neurosurgery,” said Newell.

(Source: popularmechanics.com)

Ever since its introduction in the 1990s, the “clot-busting” drug tPA has been considered a “double-edged sword” for people experiencing a stroke. It can help restore blood flow to the brain, but it also can increase the likelihood of deadly hemorrhage. In fact, many people experiencing a stroke do not receive tPA because the window for giving the drug is limited to the first few hours after a stroke’s onset.

But Emory neurologist Manuel Yepes may have found a way to open that window. Even when its clot-dissolving powers are removed, tPA can still protect brain cells in animals from the loss of oxygen and glucose induced by a stroke, Yepes’ team reported in the Journal of Neuroscience (July 2012).

"We may have been giving the right medication, for the wrong reason," Yepes says. "tPA is more than a clot-busting drug. It functions naturally as a neuroprotectant."

The finding suggests that a modified version of the drug could provide benefits to patients who have experienced a stroke, without increasing the risk of bleeding.

"This would be a major breakthrough in the care of patients with stroke, if it could be developed," says Michael Frankel, director of the Marcus Stroke and Neuroscience Center at Grady Memorial Hospital.

tPA is a protein produced by the body and has several functions. One is to activate the enzyme plasmin, which breaks down clots. But Yepes’ team has discovered that the protein has additional functions. For example, in cultured neurons, it appears to protect neurons in the brain, turning on a set of genes that help cells deal with a lack of oxygen and glucose. This result contradicts previous reports that the protein acts as a neurotoxin in the nervous system.

Tweaking tPA so that it is unable to activate plasmin—while keeping intact the rest of its functions—allowed the researchers to preserve its protective effect on neurons in culture. This modified tPA also reduced the size of the damaged area of the brain after simulated stroke in mice, with an effect comparable in strength to regular tPA. The next step is to test the modified version of tPA in a pilot clinical trial.

The possibility that tPA may be working as a neuroprotectant may explain why, in large clinical studies, tPA’s benefits sometimes go unobserved until several weeks after treatment, Yepes says. “If it was just a matter of the clot, getting rid of the clot should make the patient better quickly,” he says. “It’s been difficult to explain why you should have to wait three months to see a benefit.”

(Source: emoryhealthmagazine.emory.edu)