Article:
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
If you would like more information, please contact:
Mary Hardin Indiana University School of Medicine 1110 W.
Michigan, LO 401 Indianapolis, IN 46202 (317) 274-7722 mhardin@iupui.edu
**Statements contained herein
have not been evaluated by the Food and Drug Administration. These
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