 |
 |
|
| Archive : Fall 2005 |
Reasons for Hope:
Vampire bats, cell-suicide preventers, free-radical scavengers, neuron revivers, improved logistics for better care faster.
Why Strokes Still Kill [page 2]
 By Cathryn M. Delude
|
|
|
Because the body sometimes needs clots—primarily to stop wounds from bleeding—the bloodstream contains other enzymes that counteract TPA. Normally, the coagulation system maintains a delicate balance, clotting only when necessary, but when that balance is disrupted—for example, when cholesterol builds up in arteries—dangerous clots accumulate. Natural levels of TPA can't clear them out, but administering extra TPA can dissolve the clots and restore blood flow.
The bloodstream isn't TPA's only home. Brain cells also make the enzyme, to promote the brain's key feature: plasticity, which enables new connections to form among neurons and allows the brain to formulate circuits dedicated to specific tasks—walking, talking or doing the times table. To make those connections, neurons have to send out long extensions, known as axons and dendrites, through a sugary extracellular matrix that cushions and supports brain cells and a network of tiny vessels called the microvasculature. As the brain constantly refines and prunes its neural circuits, TPA helps carve away space in the matrix.
During a stroke, TPA may first have a beneficial effect, dissolving clots. But within three hours, blood vessels in the brain become stressed and prone to leaking. After that, administering TPA intravenously further weakens those vulnerable vessels, allowing blood-borne TPA to seep out and make direct contact with brain tissue. The TPA also activates matrix metalloproteases (MMP), another family of protein-snipping molecules that fray the coating around blood vessels. A vicious cycle ensues as more TPA escapes the vessels to turn on more MMP. Still more TPA reaches the neurons, which it kills directly.
For the stroke treatments to improve, techniques are needed to circumvent or stem this chain of events. Many researchers are looking for combinations of drugs or technologies to extend the usefulness of TPA or other thrombolytics (clot busters), often by protecting neurons or exploiting the body's own therapeutic responses. For example, Berislav Zlokovic, working at the University of Rochester's Medical Center, has discovered that activated protein C (APC), a drug widely used to treat sepsis, shields neurons. In experiments described in Nature Medicine late last year, he found that APC turns on an antiapoptosis, or cell survival, pathway. When the two drugs are given together, APC effectively counters TPA's neurotoxicity in animals. Pending safety and efficacy studies in humans, a cocktail of the two might widen the treatment window for TPA with less collateral damage to the brain, Zlokovic suggests. Both TPA and APC are already FDA-approved drugs and well understood in clinical practice.
A more surprising boost to TPA could come from ultrasound. Several years ago nurses observed that when ultrasound was used to monitor stroke patients while administering TPA, patients did better, says Andrei Alexandrov, then associate professor of neurology at the University of Texas at Houston Medical School and now at Barrow Neurological Institute in Phoenix. Alexandrov suspected that the energy emitted from the ultrasound agitates the clot, allowing TPA to penetrate deeper. To test this hypothesis, he compared 126 patients randomly assigned to receive ultrasound or a placebo following intravenous TPA. The results, published in The New England Journal of Medicine in late 2004, showed 49% of ultrasound patients either having their arteries reopened or achieving dramatic clinical recovery within two hours, compared with 30% of the patients in the control group.
Desmoteplase, a recombinant drug derived from the saliva of vampire bats, is a thrombolytic that could serve as an alternative to TPA. (The bat secretes the compound to keep its victim's blood from clotting while it feeds.) Now entering final clinical trials, Desmoteplase acts like TPA in chewing up a fibrin clot. But it's more powerful and more selective, so it doesn't affect the rest of the coagulation system.
Also nearing the end of the pipeline is NXY-059, or Cerovive—not a thrombolytic but it could potentially be used alone or in combination with TPA. Developed by AstraZeneca, Cerovive is in Phase III clinical trials. Designed to protect neurons until blood flow can be restored, Cerovive is thought to scavenge up free radicals—highly reactive, unstable atoms released after a stroke that can worsen injury to affected areas or trigger programmed cell suicide (apoptosis).
|
Next page | Pages: 1 2 3
Photo: Creatas
|
|
|
|
