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CSRO
MAGAZINE BACK ISSUES
Development
of 4-AP
For Chronic Spinal Cord Injury
Andrew Blight, Ph.D., University of North Carolina,
Chapel Hill
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Several clinical studies of the drug 4-Aminopyridine (4-AP) (now
also known by its "adopted name" of Fampridine) have been carried
out over the last 5 years in small groups of people with chronic
spinal cord injury. The first of these studies were initiated and
supported by CSRO, and the organization remains fully engaged in
further developing the drug. The studies performed to date have been
positive enough to convince many of the scientists, clinicians, and
patient subjects involved in the study that the drug is useful. One-third
of the people with "incomplete" spinal cord injuries have experienced
an improvement in their quality of life in a variety of ways. In
some people with a significant preservation of motor function the
types of benefits include reduced "central" pain, spasticity and
muscle stiffness, increased or more normal sensation, and some improvement
in motor function, such as hand grip or walking efficiency. There
are also consistent indications of improvements in bladder control
and male sexual function. It should be stressed at this point that
many of these reports come from small trials, where "placebo effects" may
play some role in perceived benefits, and none of these beneficial
effects of the drug have been proven to anyone's full satisfaction.
The problem now is to obtain substantial proof of efficacy and safety,
in order to apply for government approval of the drug, so that it
will be freely available for physicians to prescribe. Starting in
1992, CSRO began the process of obtaining patent rights for the use
of fampridine in the treatment of pain and spasticity in spinal cord
injury, and the process culminated into the issuance of a patent
in 1996. This was an important step to provide a limited amount of
commercial protection for the product that would allow a company
to invest the substantial effort and funds necessary to bring the
drug to market and approve government approval. Without some protection
of this kind, promising pharmaceuticals for uncommon conditions are
left undeveloped, because there is no economic justification in the
free market for the kinds of investments required. In 1995, CSRO
licensed the patent rights to Acorda Therapeudics, a New York based
biotechnology company dedicated to developing treatments for spinal
cord injury.
The process of further development and approval is likely to require
at least another 2-3 years of concentrated effort. Many people will
be eager to be included in the intervening trials as a rapid way
of finding out if they can be helped personally by the drug, or simply
to help out in the process. In fact, participation in these trials
will depend primarily on location within the "catchment area" of
one of the participating centres within Canada or the USA. Potential
subjects can keep abreast of developments through the CSRO. Acorda
and its research have a full schedule as they push the fampridine
process forward and simultaneosly pursue a number of other potential
treatment strategies that are in the pipeline but are presently at
earlier stages of development.
Quick
Tips For Fitness
By: Michelle Kinsey, BPHE, CFA/PFLC
Rehab. Assistant/Fitness Appraiser
Lyndhurst Hospital |
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Where possible, choose a wheeling activity such as wheel chair basketball
or free-wheeling over arm cranking. In general, for the same workload,
the heart and lungs work harder during wheeling than during arm cranking
exercises, and wheeling is a more specific exercise which improves
aerobic capacity and works the muscles in the activity you have to
perform most.
Damage to the nervous system following a spinal cord injury alters
the effectiveness of the body to maintain core body temperature.
During exercise, heat is produced by exercising muscles. Therefore,
to provide thermoregulation during exercise, drink plenty of liquids,
cool the skin by the use of a fan and/or water mist, and avoid heavy
exercise especially during hot humid weather.
People with spinal cord injuries are more prone to repetitive strain
injuries to the upper-limb. To prevent injuries; warm-up, stretch,
maintain good upper limb strength and endurance, progress exercise
programs slowly, and heed signs of overload and overuse such as pain
and/or tenderness.
Choose exercise programs you enjoy, as you are more likely to enjoy
them.
Enteric
Neuron Transplantation
By: Michel P. Rathbone, Ph.D., McMaster University |
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Spinal cord injury triggers a complex series of cellular events.
Some nerve cells at the site of the injury are killed. Also some
of the long nerve cell processes which run up and down the spinal
cord are damaged and no longer conduct nerve impulses. Many of the
remaining nerve processes only conduct impulses poorly resulting
in pain and even less motor strength than one might have. Moreover,
the inflammation and swelling which take place as a result of the
injury cause further damage which causes a further loss of nerve
cells and nerve cell processes. There is obviously no "quick fix" for
all of this damage. The problem must be tackled bit-by-bit in several
ways. We are working on two related problems; loss of the nerve cells
and reduction in the long term damage.
It has been thought that the nerve cells which are lost do not regenerate.
Recent experiments have demonstrated that primitive precursor cells
in the spinal cord and brain can, under certain circumstances, grow
and differentiate into new nerve cells. But this is not sufficient
to result in a significant regeneration with restoration of function.
So a number of groups have attempted to replace the lost nerve cells
from, for example, the adrenal glands or from embryos. The use of
embryonic tissue is fraught not only with moral problems but also
with technical ones. The cells in the adrenal gland are limited in
number and do not represent the varied types of cells present in
the spinal cord or brain.
Another potential source of nerve cells is the intestine, which is
a very large organ running from the mouth to the anus. Perhaps surprisingly,
the intestine has a rich nervous system, the "enteric" nervous system.
Yes, we do indeed have "gut feelings"! The enteric nervous system,
like the spinal cord, contains many different kinds of nerve cells.
We have been removing the layer which contains most of the nerve
cells from a part of the intestine and have begun to grow the nerve
cells in tissue culture. We are finding out what types of nerve cells
we have isolated. Next we are preparing to place these cells into
injured spinal cords to see whether they survive and make new connections.
We believe that they will indeed do so and thus may replace some
of the nerve cells lost during spinal injury.
While we were undertaking these experiments, our colleague Dr. Richard
Borgens at Purdue University (supported by the CSRO), found that
when mixed tissue from the gut was implanted into an injured spinal
cord, the cord did not undergo the usual progressive inflammatory
changes and progressive damage over the following weeks and months
which it normally did following injury. This was interesting because
it seemed that the cells responsible for preventing the further degeneration
of the spinal cord were not nerve cells, but rather supporting cells
called glia. These cells are found in the central nervous system,
including the spinal cord. In fact they outnumber the nerve cells
by a ratio of 10:1! The important thing is that they resemble one
of the most important types of glia in the spinal cord called astrocytes.
Even of more interest was the observation that nerve cell processes
which were damaged in the spinal injury started to re-grow up and
down the spinal cord but then, when they reached the implanted graft,
turned towards it and entered it. This indicated that the implanted
graft tissue made some substances which attracted certain regenerating
nerve fibres and repelled others. This suggested that the glial cells
may be able to enhance the regeneration of nerve cells after spinal
injury.
Therefore we set about learning both how the glia reduced the progressive
degeneration after spinal cord injury and how they also enhanced
the outgrowth of regenerating nerve cell processes. We first extracted
and purified glia from the intestine, grew them in culture until
we had large numbers and implanted them into the spinal cord. At
first the glia grew very fast and formed tumors. We prevented the
implanted glia from growing out of control by treating them with
various chemicals, similar to those used to prevent growth of cancer
cells, before we implanted them into the spinal cords. This worked
well.
However we then discovered another problem. After the glial cells
were implanted into the spinal cord they became very mobile; they
moved from the site where they were implanted up and down the spinal
cord. We are currently investigating how we can stop the implanted
glial cells from dividing or moving. We may have found a solution
to the problem; a chemical extracted from plants, called colcicine,
prevents, both cell division and stops the glia from moving, for
a few days. We are adding colcicine to the glia in the cell culture.
We anticipate that within a few months we will be able to implant
glia into the spinal cord and observe precisely their effects on
both the growth of nerve processes in the spinal cord after injury
and also how they prevent the ongoing progressive degeneration of
the spinal cord after injury.
The work on glia is being done at the same time as the work on implantation
of nerve cells into the spinal cord. This should be even more exciting
and important than the simultaneously implantation of either glia.
The glia should enhance the survival of the nerve cells and stimulate
them to extend processes and contact other nerve cells similar to
the regeneration processes of spinal nerve cells. At the same time
the glia should prevent the further degeneration of the spinal cord,
thus reducing the amount of long term injury.
At the Canadian Spinal Research Organization, we have implemented
a planned giving program that allows us to honour those who have
supported us financially by providing them with special benefits
unavailable for other types of donations.
If you would like more information about our planned giving program,
please email us with your request.
For Centuries, physicians have taken special pains to dash the hopes
of people who have suffered spinal cord injury.
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