Invisible Wounds

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Daunting Questions: Part III

New pharmaceuticals may help block secondary brain damage.

We’ve only recently established the connection between brain injuries such as concussions and degenerative brain diseases like Alzheimer’s. We don’t fully understand yet why or how this is happening, and there’s not much we can do to prevent it now.

But help may well be on the way. There are three pharmaceuticals being tested that may reduce the amount of secondary brain damage that occurs right after the initial injury.

Potentially first out of the box is progesterone, with the results of its planned interim clinical study analysis expected sometime in 2013. Progesterone is best known as a reproductive hormone produced naturally in the body, but it’s also a powerful neurosteroid produced by the central nervous system. One study showed the glial cells naturally produced progesterone in the neurons of both men and women in the hours immediately after they had suffered severe traumatic brain injuries (TBIs).

In two Phase II studies, the mortality rate among patients receiving pharmaceutical progesterone was approximately half of another group receiving only a placebo. Its manufacturer, BHR Pharma LLC is currently conducting a double-blind, placebo-controlled Phase III clinical trial on 1,180 severe TBI patients at about 150 sites in 20 countries to demonstrate that this pharmaceutical is effective in reducing injuries to the brain.

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If the tests are successful, progesterone may “within a year or so, provide the basis for the first approved neuroprotective agent to treat severe TBI,” according to its manufacturer.

Not far behind is cyclosporine, which operates on the theory of the mitochondria, the tiny energy centers in the brain cells, are being destroyed by excess calcium. Cyclosporine has been used to prevent tissue rejection in organ-transplant recipients since the early 1980s, but a
Swedish firm, NeuroVive Pharma,  has been working for nearly two decades to prove that its medicine, called NeuroSTAT, can also protect mitochondria in brain injuries.

After an injury to the brain, a protein called cyclophilin D enables pores in the mitochondria’s membrane to open, through which water seeps. The mitochondria fill up, pop and die, ending cellular energy production and killing the brain cell. However, cyclosporine inhibits the cyclophilin D from helping open the pores, thus preserving the mitochondria, according to NeuroVive Pharma. “As mitochondria survive to produce energy for the brain cell, fewer brain cells die during the secondary (injury) stage,” it said. “Protecting brain cell mitochondria and energy production is the critical front line in the war against TBIs.”

Earlier mouse-model studies showed an 80 percent reduction in neural damage through the use of cyclosporine, the company said. Another mouse-model study by researchers at the University of Rochester, published this year in Nature magazine, showed that too much cyclophilin led to Alzheimer’s-like symptoms, but that “the administration  of cyclosporine inhibited cyclophilin’s actions and the Alzheimer’s symptoms were reversed,” according to the company. While NeuroVive is not targeting Alzheimer’s, the study shows the potential future importance of so-called cyclophilin inhibitors in treating many neurodegenerative diseases.

NeuroVive is conducting a Phase II/III trial in conjunction with the European Brain Injury Consortium and hopes to win regulatory approval in the United States and Europe within the next three to five years.  

Finally, Neuren Pharmaceuticals and the Department of Defense are developing their own drug to prevent brain injuries from progressing into degenerative brain diseases. Called NNZ-2566, it’s basically an anti-inflammatory.  “The drug is based on a very similar chemical that occurs naturally in the brain, but it has been altered in such a way that it stays in the body longer,” Neuren said. “NNZ-2566 was discovered by scientists at the University of Auckland in New Zealand who found that it had an ability to protect nerve cells from damage. Since 2004, scientists from the U.S. Army Walter Reed Army Institute of Research have been involved in research to show how NNZ-2566 reduces brain damage and seizures after TBI.”

It’s currently being tested in a 260-patient Phase II clinical trial at 13 hospitals in the United States, so it’s still several years out from approval. 

If approved at all…. While drugs from all three companies show promise, more than 30 once-promising TBI pharmaceuticals have reportedly failed to show benefit in human Phase III studies and not won FDA approval. No TBI pharmaceutical has ever received approval for use in humans, but these three are closest to being the first.   

 

Eric Newhouse is a Pulitzer Prize-winning journalist and the author of Alcohol: Cradle to Grave and Faces of Combat: PTSD and TBI.

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