David Wright, M.D., Director of Emergency Neurosciences at Emory University School of Medicine in Atlanta, Ga., explains why progesterone is promising treatment for traumatic brain injury.
What’s the current challenge with traumatic brain injury, as far as treatment?
Dr. David Wright: The challenge is that there is actually no treatment available. No drug has been developed over the past 30 to 40 years that has been shown to improve outcome. What we do when a traumatic brain injury comes in is we stabilize a patient, we provide supportive care, we try to prevent the brain from swelling with a variety of options, but we don’t have anything that we can give that really saves neurons, that protects the brain, and that improves the outcome in the long run.
How is the progesterone administered?
Dr. Wright: The progesterone is administered as an infusion over a four day period. We give a bolus dose and then it is administered intravenously over three days, and then we do a fourth day as a taper.
How quickly does the intervention have to occur after a patient arrives to the emergency department?
Dr. Wright: We know now that time is brain. All the research shows that if you don’t get the drug in early that you’re already sort of behind the eight ball, as we say. The earlier we give the drug, the better chance we have that it’s going to work. We’re trying to get the drug in in less than four hours, with our goal actually being as soon as two hours after injury.
What does progesterone do when it gets inside the brain specific to a traumatic brain injury?
Dr. Wright: Traumatic brain injury is a very complex disease. We used to think it was just the initial injury. You had a ripping or a tearing or a shirring of the brain and that was pretty much it, and that damage that was done at that time was the damage that you had. The reality is that that is a really small part of the injury. Most of the injury actually occurs after the initial event. A whole host of what we call neurotoxic or cytotoxic cascade occurs, and it just continues to grow the size of the injury, killing neurons that really are potentially survivable.
Progesterone gets in there, coats and protects the brain. A number of the ways that it does it is that it decreases the inflammation that causes the swelling in the brain. It prevents the neurons that are injured from going on and dying. There’s a process called apoptosis, which means cell suicide. This is the natural part of the way the body gets rid of injured cells, but in the brain, that causes a lot of significant damage because the brain is like a very delicate circuit board. When you have indiscriminate death of neurons and circuits, then all of a sudden, those memories that you had, your thinking process, all of those things are impaired. That’s different than say, you were injured on your elbow or you were injured in your heart, whatever, you have extra tissue that can make up for that, but in the delicate pathways of the brain, it’s critical to preserve as much as you can.
That’s what the progesterone does?
Dr. Wright: That’s what we believe progesterone does, yes. It’s something we call pleiotropic, so it works in multiple different aspects of the injury. It’s one of the things that’s different from the historical clinical trials. Up to this point, over 50 trials have been done in traumatic brain injury and they’ve all failed miserably. One of the reasons for that is that these have been very targeted therapies, so a single cell receptor, a single pathway.
As I said, traumatic brain injury is extraordinarily complex and there are multiple bad things going on at the same time. It’s sort of like having a dyke with multiple holes in it. If you just put one finger and block up one hole, it’s going to leak out of all the other holes, so you really need something, kind of a drug cocktail, per se, to stop all of these different pathways, and progesterone seems to do that.
Why progesterone?
Dr. Wright: It almost sounds like it’s too good to be true to be able to use something right under our noses. Progesterone classically has been called a female hormone, but the reality is that it’s actually a neurosteroid. It’s made in the brain, by the brain, for the brain. It’s actually in equal amounts in males and females in their brain and there’s an equal amount of receptors in the brain for this drug.
It’s interesting, if you look at progesterone, now that we know more about it and we look back, progesterone goes very high during pregnancy. We think part of the reason for that is to protect the fetus, and during the neuronal development, the brain development of the fetus. Another little hint in nature is those scientists who do research on neurons – when they grow their neurons, you have to have progesterone in a growth medium or the neurons won’t grow right. It has some critical role in neuronal development and neuron protection that we just didn’t understand before. I think if it was discovered in the brain first, we wouldn’t call it a female hormone, we would call it a neurosteroid that happens to be used in the female system.
When you’re talking about hormone replacement therapy, there have been some concerns raised about progesterone and whether it’s safe in other applications. What have you determined as far as the safety of this?
Dr. Wright: It’s a great question because the hormone replacement therapy trials showed some concern for early stroke and some other problems, and that’s exactly what they were trying to treat. The problem with taking that information and applying it to progesterone is that the drug they used – medroxyprogesterone acetate – is a synthetic. Many of these synthetic compounds are actually quite different than the natural progesterone, and the drug that was used in those trials is extraordinarily different than progesterone.
We’ve done a side to side animal experiment with the drug that they used in those trials against natural progesterone and showed that indeed, the progestins, the synthetics don’t work. They don’t improve behavior in the animals after a head injury, whereas the natural progesterone does.
What kind of progesterone are we dealing with here, and how significant is it in terms of not being the kind that’s caused the issues?
Dr. Wright: It’s the natural progesterone that the body makes, and it actually is in nature as well – it’s in plants. The progesterone that is typically bought from the chemical companies and that we use for our drug comes from yams. It has a high amount of progesterone in yams, so it’s a vegetable form and an animal form. The synthetics are made in the laboratory. They have different properties, and they have different receptors, so they cause all sorts of different side effects.
Can this vegetable form work in the human brain?
Dr. Wright: It’s exactly the same. It is chemically identical to the animal form, yes, and works in the brain. It crosses the blood/brain barrier and gets in quickly.
How excited are you at this point, and how hopeful are you that you found something that’s really going to finally make a difference for these TBI patients?
Dr. Wright: We are extremely excited. For the first time – really since recorded history from NIH, we may have a drug that will work for traumatic brain injury. The graveyard is full of patients with TBI and it’s full of clinical trials trying to find something. To really be on the verge of having a drug that might work is extraordinarily exciting. It could change the way we practice.
How close to reality is this in terms of being an actual viable treatment?
Dr. Wright: This has been a long process. The first discovery by Dr. Donald Stein in the laboratory was over 27 years ago. He noticed the difference between the male and the female rats and that the female rats were recovering better than the male rats, so that set him off 17 years of research to discover what the difference was. It turned out that it was progesterone. Ten years ago, after his 17 year exploration, we got together and started creating the trial to take it into humans. Now, we’re set finally to do an efficacy Phase III clinical trial to prove whether or not it works.
What does your gut tell you?
Dr. Wright: My gut tells me it’s going to work, and I’ll tell you why. We conducted the first in human use from 2001 to 2005. It was a pilot study – 100 patients at Grady Memorial Hospital here in Atlanta. In that study, we found a 50 percent reduction in death and an improvement in outcome in the moderate group. Since we’ve published that study, another study was conducted in China, unbeknownst to us, that essentially duplicated this, that in a 157 patients they found an improvement in outcome at both three months and six months. Now, we have two independent Phase II clinical trials that seem to show that it actually is going to work in humans, and that you add on top of the over 100 positive publications from preclinical work in animals, it’s some of the best data we’ve ever seen.
Is this a cure?
Dr. Wright: Not a cure. No. This is an improvement in outcome. The only cure for traumatic brain injury is to not have the injury.
What does the progesterone treatment mean for patients like Mark?
Dr. Wright: I think it provides him the ability to have a normal, functional life. Mark was severely injured when he came in. In fact, if you talk to his family, they say they actually came to the hospital to say good-bye, and his recovery has been remarkable. I will couch that and say that patients who aren’t treated with progesterone do recover and some of them recover remarkably, so until we do this Phase III clinical trial we can’t say for sure that it was progesterone, but we’re certainly excited about it.
Do you remember how bad his brain was when they brought him in?
Dr. Wright: I think he had a Glasgow coma scale of 6. The Glasgow coma scale is the score that we use to determine severity of injury in the brain, and it goes from 3 to 15 – a 15 being normal, a 3 being absolutely no response, so a 6 is considered very severe. Anything lower than an 8 is a severe injury.
How safe is the treatment?
Dr. Wright: In the Phase II clinical trial that we conducted, we saw no serious side effects of the drug infusion that we gave, which is essentially the same infusion we’re going to be using in Phase III clinical trial. The China study also found no serious adverse events or even significant adverse events related to the study drug.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
What’s the current challenge with traumatic brain injury, as far as treatment?
Dr. David Wright: The challenge is that there is actually no treatment available. No drug has been developed over the past 30 to 40 years that has been shown to improve outcome. What we do when a traumatic brain injury comes in is we stabilize a patient, we provide supportive care, we try to prevent the brain from swelling with a variety of options, but we don’t have anything that we can give that really saves neurons, that protects the brain, and that improves the outcome in the long run.
How is the progesterone administered?
Dr. Wright: The progesterone is administered as an infusion over a four day period. We give a bolus dose and then it is administered intravenously over three days, and then we do a fourth day as a taper.
How quickly does the intervention have to occur after a patient arrives to the emergency department?
Dr. Wright: We know now that time is brain. All the research shows that if you don’t get the drug in early that you’re already sort of behind the eight ball, as we say. The earlier we give the drug, the better chance we have that it’s going to work. We’re trying to get the drug in in less than four hours, with our goal actually being as soon as two hours after injury.
What does progesterone do when it gets inside the brain specific to a traumatic brain injury?
Dr. Wright: Traumatic brain injury is a very complex disease. We used to think it was just the initial injury. You had a ripping or a tearing or a shirring of the brain and that was pretty much it, and that damage that was done at that time was the damage that you had. The reality is that that is a really small part of the injury. Most of the injury actually occurs after the initial event. A whole host of what we call neurotoxic or cytotoxic cascade occurs, and it just continues to grow the size of the injury, killing neurons that really are potentially survivable.
Progesterone gets in there, coats and protects the brain. A number of the ways that it does it is that it decreases the inflammation that causes the swelling in the brain. It prevents the neurons that are injured from going on and dying. There’s a process called apoptosis, which means cell suicide. This is the natural part of the way the body gets rid of injured cells, but in the brain, that causes a lot of significant damage because the brain is like a very delicate circuit board. When you have indiscriminate death of neurons and circuits, then all of a sudden, those memories that you had, your thinking process, all of those things are impaired. That’s different than say, you were injured on your elbow or you were injured in your heart, whatever, you have extra tissue that can make up for that, but in the delicate pathways of the brain, it’s critical to preserve as much as you can.
That’s what the progesterone does?
Dr. Wright: That’s what we believe progesterone does, yes. It’s something we call pleiotropic, so it works in multiple different aspects of the injury. It’s one of the things that’s different from the historical clinical trials. Up to this point, over 50 trials have been done in traumatic brain injury and they’ve all failed miserably. One of the reasons for that is that these have been very targeted therapies, so a single cell receptor, a single pathway.
As I said, traumatic brain injury is extraordinarily complex and there are multiple bad things going on at the same time. It’s sort of like having a dyke with multiple holes in it. If you just put one finger and block up one hole, it’s going to leak out of all the other holes, so you really need something, kind of a drug cocktail, per se, to stop all of these different pathways, and progesterone seems to do that.
Why progesterone?
Dr. Wright: It almost sounds like it’s too good to be true to be able to use something right under our noses. Progesterone classically has been called a female hormone, but the reality is that it’s actually a neurosteroid. It’s made in the brain, by the brain, for the brain. It’s actually in equal amounts in males and females in their brain and there’s an equal amount of receptors in the brain for this drug.
It’s interesting, if you look at progesterone, now that we know more about it and we look back, progesterone goes very high during pregnancy. We think part of the reason for that is to protect the fetus, and during the neuronal development, the brain development of the fetus. Another little hint in nature is those scientists who do research on neurons – when they grow their neurons, you have to have progesterone in a growth medium or the neurons won’t grow right. It has some critical role in neuronal development and neuron protection that we just didn’t understand before. I think if it was discovered in the brain first, we wouldn’t call it a female hormone, we would call it a neurosteroid that happens to be used in the female system.
When you’re talking about hormone replacement therapy, there have been some concerns raised about progesterone and whether it’s safe in other applications. What have you determined as far as the safety of this?
Dr. Wright: It’s a great question because the hormone replacement therapy trials showed some concern for early stroke and some other problems, and that’s exactly what they were trying to treat. The problem with taking that information and applying it to progesterone is that the drug they used – medroxyprogesterone acetate – is a synthetic. Many of these synthetic compounds are actually quite different than the natural progesterone, and the drug that was used in those trials is extraordinarily different than progesterone.
We’ve done a side to side animal experiment with the drug that they used in those trials against natural progesterone and showed that indeed, the progestins, the synthetics don’t work. They don’t improve behavior in the animals after a head injury, whereas the natural progesterone does.
What kind of progesterone are we dealing with here, and how significant is it in terms of not being the kind that’s caused the issues?
Dr. Wright: It’s the natural progesterone that the body makes, and it actually is in nature as well – it’s in plants. The progesterone that is typically bought from the chemical companies and that we use for our drug comes from yams. It has a high amount of progesterone in yams, so it’s a vegetable form and an animal form. The synthetics are made in the laboratory. They have different properties, and they have different receptors, so they cause all sorts of different side effects.
Can this vegetable form work in the human brain?
Dr. Wright: It’s exactly the same. It is chemically identical to the animal form, yes, and works in the brain. It crosses the blood/brain barrier and gets in quickly.
How excited are you at this point, and how hopeful are you that you found something that’s really going to finally make a difference for these TBI patients?
Dr. Wright: We are extremely excited. For the first time – really since recorded history from NIH, we may have a drug that will work for traumatic brain injury. The graveyard is full of patients with TBI and it’s full of clinical trials trying to find something. To really be on the verge of having a drug that might work is extraordinarily exciting. It could change the way we practice.
How close to reality is this in terms of being an actual viable treatment?
Dr. Wright: This has been a long process. The first discovery by Dr. Donald Stein in the laboratory was over 27 years ago. He noticed the difference between the male and the female rats and that the female rats were recovering better than the male rats, so that set him off 17 years of research to discover what the difference was. It turned out that it was progesterone. Ten years ago, after his 17 year exploration, we got together and started creating the trial to take it into humans. Now, we’re set finally to do an efficacy Phase III clinical trial to prove whether or not it works.
What does your gut tell you?
Dr. Wright: My gut tells me it’s going to work, and I’ll tell you why. We conducted the first in human use from 2001 to 2005. It was a pilot study – 100 patients at Grady Memorial Hospital here in Atlanta. In that study, we found a 50 percent reduction in death and an improvement in outcome in the moderate group. Since we’ve published that study, another study was conducted in China, unbeknownst to us, that essentially duplicated this, that in a 157 patients they found an improvement in outcome at both three months and six months. Now, we have two independent Phase II clinical trials that seem to show that it actually is going to work in humans, and that you add on top of the over 100 positive publications from preclinical work in animals, it’s some of the best data we’ve ever seen.
Is this a cure?
Dr. Wright: Not a cure. No. This is an improvement in outcome. The only cure for traumatic brain injury is to not have the injury.
What does the progesterone treatment mean for patients like Mark?
Dr. Wright: I think it provides him the ability to have a normal, functional life. Mark was severely injured when he came in. In fact, if you talk to his family, they say they actually came to the hospital to say good-bye, and his recovery has been remarkable. I will couch that and say that patients who aren’t treated with progesterone do recover and some of them recover remarkably, so until we do this Phase III clinical trial we can’t say for sure that it was progesterone, but we’re certainly excited about it.
Do you remember how bad his brain was when they brought him in?
Dr. Wright: I think he had a Glasgow coma scale of 6. The Glasgow coma scale is the score that we use to determine severity of injury in the brain, and it goes from 3 to 15 – a 15 being normal, a 3 being absolutely no response, so a 6 is considered very severe. Anything lower than an 8 is a severe injury.
How safe is the treatment?
Dr. Wright: In the Phase II clinical trial that we conducted, we saw no serious side effects of the drug infusion that we gave, which is essentially the same infusion we’re going to be using in Phase III clinical trial. The China study also found no serious adverse events or even significant adverse events related to the study drug.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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