Supplement for Lou Gehrig's 

Full-Length Doctor's Interview In this full-length doctor's interview, Bob Pascuzzi, M.D., explains how creatine may help people with Lou Gehrig's Disease.

Interview with Bob Pascuzzi, M.D., Neurologist Indiana University School of Medicine, Indianapolis, Indiana

Topic: Supplement for Lou Gehrig's

What is creatine? How does it affect the body?

Dr. Pascuzzi: Creatine is an amino acid. It is a health food supplement, and the body normally makes it in the liver. It's stored largely in muscle, but is present in other tissues in the body also. Its role seems to be largely that of energy for cells and for many years, people have used creatine as a health food supplement. The feeling is that this form of supplement may improve muscle bulk and possibly muscle strength and muscle endurance -- that's why physical fitness people around the country and the world have for many years been looking to creatine as one of a number of supplements that might help improve performance in muscle. It's an interesting substance in that, while it's normally made in the body, because it is involved with energy metabolism, it's been a focus of interest in diseases where energy may be limited or suspect, and that includes a number of neurological conditions. Not just one, but a number of them that have been targets of a therapeutic strategy for creatine because a lot of neurological problems involve cells that fail either in the brain, spinal cord, nerves, or muscles. Part of that failure involves the energy processing of the cells. If you can think of a way to help improve the energy function, deliver them more energy, help protect them from degrading and if you have a safe way of doing that, it offers some logical strategy for treating a whole host of neurological problems. That's really the basis for its consideration as a treatment option for not muscle diseases but brain and spinal cord diseases, which is what ALS is.

I know some of the research has been done with mice. How has creatine shown to be effective against ALS in those mice?

Dr. Pascuzzi: Well, there is a mouse version of ALS. It is a genetically based version, so it's an animal model. The importance of having a model is it allows research to be done in a lot more thorough and controlled and methodical way. It allows research to be done a lot faster than what could be done in just studying the course of an illness in humans. Those studies would suggest that mice with this genetically determined form of ALS live longer, they survive longer, if they take creatine than those who don't take creatine. It's a difference that is sufficient to make people interested in going the next step, which would be to treat patients, humans, who have ALS with creatine supplements and see if a similar benefit can be found in those folks.

That's what the ongoing study is now with patients? Can you explain a little about how the study is working?

Dr. Pascuzzi: Here at Indiana, we're in a network of medical centers around the country that has an interest in a variety of neurologic diseases and one of those that we have focused on is ALS. In many medical centers around the country, in fact around the world, there are individuals really focused on trying to deal with treatment of ALS. We work closely together whenever possible to pool our resources, including trying to perform multi-center studies of new treatment options for people with serious neurological problems including ALS. We're one of, I would guess, 15 or so centers around the country involved with a specific protocol testing creatine to see if it is beneficial for people who have ALS or not and also to establish that if it is beneficial, how beneficial is it? Also to establish, is it safe? We always like to think that the things we expose our patients to are safe, but a formal trial like this is an excellent way of trying to make sure we're doing the right thing and that the patients are not put at risk from the treatment. So, we're trying to establish whether or not there's reason to think it's an important therapy for ALS patients to take, does it offer them some meaningful benefit or not, and is it a safe form of treatment? It is a multi-center study that's going on at many fine medical centers around the country and we just happen to be fortunate to be one of those that has this to offer to patients in the Midwest.

Are there any preliminary results, or have you seen any difference?

Dr. Pascuzzi: We have patients here that are seen periodically according to our protocol. It's a six-month protocol where patients are followed meticulously, acidulously, methodically for six months, very carefully both for any evidence of benefit and any evidence of a safety problem. We're in the midst of that follow-up now. What we need to do is wait until the study is completed. Then we will pool all of the data from the 15 sites around the country and compare those patients that took creatine supplements with those who took a placebo. The way these studies are set up, the patients don't know whether they were on the real drug or the placebo, and we the clinicians don't know that either -- that is so that we aren't too biased in thinking that we see what we want to see. We want at the end of the day to be sure that we give patients and physicians and everyone else correct information, real information that they can use. Does this form of treatment work or not, does it work well or not, is it safe or not? So we do these in what's called a blinded fashion.

Everything is rolling along smoothly but I don't have any results to share with you. You'll have to come back in six months. The way these studies work, and this is fairly typical, where some of the patients are randomly assigned to the active drug, the real drug, and some are assigned to a placebo. At the end of the study period, which in this case is six months, all the patients are offered the real drug for real following that. That's the standard protocol for studies of ALS and other similar serious neurological problems.

Can you talk a little about ALS and how if affects patients?

Dr. Pascuzzi: ALS is a brain and spinal cord disease that shows up by making the muscles malfunction. Your muscles work only because the brain and spinal cord talk to them and while there are many diseases that affect muscle primarily, like muscular dystrophy for example, ALS is a bit different. ALS is a problem with the motor nerves that are located in the brain and in the spinal cord. These motor nerves send wires -- called axons -- from the spinal cord out to the muscle. If these wires fail, the muscles don't work well. The problem in ALS is the motor nerves located in the brain and spinal cord malfunction prematurely, and over the course of several years, patients lose function.

The disease may initially show up with some very subtle loss of function in an arm, maybe some loss of muscle in a hand or arm, some muscles cramps or twitches. Everybody gets cramps and twitches now and again, but these patients may get more. It may start with some trouble walking, like a foot drop. It may start with some malfunction of the muscles in the face or throat, so slurred speech or something like that could be the initial symptom, but it's a very gradual thing. The onset is difficult to place because it doesn't come on overnight, it doesn't come on abruptly like a stroke. It's a very gradual indolent onset. Wherever it starts, it typically then spreads slowly, so if it starts in an arm, it will spread into the other limbs and eventually usually spread up into the speech and swallowing and breathing area. So, it slowly creeps along.

There is an old name for this disease that's very appropriate and gives people a good sense of what the disease really does and that's creeping paralysis. Typically most patients run a course of two to five years where the paralysis creeps along. At the end of that point in time, if their breathing muscles become too severely affected, that's what limits their survival -- that's what really threatens their long-term survival -- unless they then go on a breathing machine or unless they have a slower course, then we have a real problem with their survival.

Some patients have a rapidly progressive course and may not survive for a year, but most people have a two to five year course. I think Lou Gehrig, after whom the disease is named in this country, probably had a two or three year course of illness.

Another important issue is that not all patients are within this two to five year window. We have about 20 percent of patients, about one in five, that have a course that runs longer than five years and about 1 in 10, 10 percent, longer than 10 years. We have some people who are on year 15, year 19, year 21, and they come back and see us and they said, 'well, you told me that this was going to run two to five years and I'm still here' and they're correct. There is a group of patients where it creeps along even more slowly. It's just a gradual progressive condition. It doesn't come and go; it continues to run on a slope, if you will. You can have a steep slope or a real, real gentle slope, but whatever slope you're on is the slope you stay on.

The idea behind a treatment is to try to ideally get the slope to turn around and get it stronger. If we can't do that, get a treatment that will let the slope level off so it plateaus so people don't lose more ground, kind of arrest the disease. Then if we can't do that, if we can get treatments that will change the slope so that people won't progress as rapidly, that would also be hugely important for a disease like this.

Is the theory behind this study that creatine could help change that slope?

Dr. Pascuzzi: Correct.

When you think creatine, many people think body builders or performance and health. Why is it so important for ALS patients to increase that performance or strength?

Dr. Pascuzzi: The interesting thing about creatine and ALS is that, although most people out there taking creatine for bodybuilding and its effect on muscle, the ALS patient is probably taking it for effect on brain and spinal cord function. Those cells that are malfunctioning, the motor nerves, are the ones where the creatine is intended to be playing a role to help save them, to help provide those cells with more energy, to help keep them from braking down, to help protect them. I think that's the theory behind using creatine in ALS. Now, in the patient, the idea is that if you can preserve or protect some function in your hand, it means you can mow your grass longer and you can button buttons longer, you can open jars longer, and you can turn the keys in the ignition. That's function, and the bottom line is it doesn't really matter what your grip strength is, its function. Can you use your hand for things? If your arms, shoulders, are too weak to lift things above your head, then there are a whole set of functions you can't do during the day. You can't put the dishes away, you can't do your hair, so if we can preserve some function and keep it from dropping off, then for a longer period of time, for more months or more years, the patient will be able to do more things. If somebody's function is limited in the legs where they can't walk, if we can have a treatment that keeps them walking longer, that's a function that would mean a lot to them. And the same with speech, the longer we can keep speaking with just a limited Hoosier drawl, probably the more function we get and our quality of life is better.

I think the idea is if you can preserve some function, even if it's not perfect, if you can keep it reasonable so that the patient can do more, then their quality of life is affected in a favorable way and the quality of their family life, their friends, their work and colleagues is affected in a positive way also.

With the creatine, I know your research it still early to say, but my understanding is there has been other research here that has shown some positive effects. That's why you moved into phase II. Is that correct?

Dr. Pascuzzi: Yes. In fact, there are a variety of neuromuscular conditions in humans and there are investigators in North America, in particular, who have looked at creatine supplementation in a whole variety of nerve and muscular diseases with some positive results, some beneficial effects noted, and a good safety profile as well, which has actually added to the interest in pursuing this for the treatment of ALS.

I think at this point in time, it's fair to say the jury is still out until a trial like this is completed and we really see for sure over an extended period of six months of treatment comparing two groups -- one that took the supplement, one that took a blank -- patients that have been studied very, very carefully. I think that's what it's going to take to really answer the question: Is there something meaningful there for our patients? I would think that if this study were to suggest that there is something substantially beneficial then there will be an even larger study that will really try to fine tune how useful is the drug, how well does it work, and in what patients does it work best.

Have you seen any side effects with your patients?

Dr. Pascuzzi: Not really. I think our patients, just like those athletes around town that use it, tolerate it very well. Although it has been pointed out by a number of observers over the years that safety information on creatine is limited and there are occasional patients that have been reported with some kidney trouble from taking a lot of creatine, it's in the doses being used. I think it is, in my view, a very safe program, so I'm not uneasy about our patients in the protocol. In the protocol, they are being followed for safety very carefully, so if there's one good thing about a trial like this, it offers everybody else interested in creatine an opportunity to really be certain about what its safety profile really is. Beyond that, people in the community, athletes taking creatine, I think that it's a relatively safe form of supplement. That's my honest view of the thing.

We have a number of other experimental options for treating patients with ALS and it's important to realize that it's not as though creatine is going to be the only one out there that might make us or break us in having a good treatment for ALS. We have trials of other neuroprotective drugs, we have trials of what are called nerve growth factors, which are like fertilizers for motor nerves, and the important point is that we, like the other major medical centers around the country, try to work as closely together as possible in exploring what are logical, reasonable strategies for treating the disease. If we get to the point where a clinical trial in humans is appropriate, then we try to work together and collectively get answers as effectively as possible and as safely as possible.

Is the dosage any different than what an athlete takes?

Dr. Pascuzzi: Not really. The dose of creatine that is being used in this trial is actually very consistent with the common doses that the typical athlete or fitness individual would be very similar.

How did the idea come up in the first place to try creatine?

Dr. Pascuzzi: Creatine has been of interest in a variety of neurological diseases. It's not the case that ALS is the only one that it's been considered. Even more specific brain diseases like Huntington's disease have been the subject of considerable interest for creatine therapy because it's something that's involved with energy metabolism. A lot of these neurological diseases involve the failure at some point in the series of events of energy to cells and for nerve cells, that's real important because once a nerve cell dies, for the most part, it doesn't get remade. It's not like skin and can just be rebuilt. You have to protect them. It's a drug that's been considered for a whole host of neurological diseases for good reason because of its involvement with energy metabolism.

END OF INTERVIEW
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