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Parkinson's and the pharmaceutical industry
Some possible future developments
Medicines in the pipeline Other experimental compounds are
being investigated, each with different properties. These
will help clarify some of the fundamental mechanisms underlying
Parkinson’s and, hopefully, will become second-generation
medicines with improved clinical properties. ABT-431
from Abbott is a modified form of another compound, but with
better chemical stability. It is interesting in that it stimulates
D1 receptors rather than the D2 type and counters the Parkinson’s-inducing
effects of MPTP. If it reaches the clinic, it will test the
theory that D1 receptors have a key role in Parkinson’s.
Pharmacia & Upjohn is also well advanced with pramipexole,
which binds to a sub-type of D2 receptor. Preliminary trials
in people in the early stages of Parkinson’s have been encouraging
and a trial to measure its effect on disease progression has
been suggested. Combined with levodopa, it permitted significant
dosage reduction, suggesting that it may have potential for
use alone or in combination. Pharmacia & Upjohn also has another
selective D2 agonist in early development, U-95667E.
Some evidence exists that another neurotransmitter called
glutamate may be involved in the progression of Parkinson’s
due to over-excitation, which may lead to the death of pigmented
cells in the brain. Hence, compounds which block the stimulation
of glutamate receptors (called NMDA receptors) may
be of value. To test this theory, Pfizer is developing CP-101606
(already in the clinic for head injury) and a related compound,
CP-283097, while Astra Charnwood has remacemide
in clinical trial. Rhône-Poulenc Rorer is developing riluzole
(already available for the treatment of Motor Neurone Disease)
and has collected experimental evidence that it protects nerves
from glutamate damage. It may slow the progression of Parkinson’s
and this is now about to be tested in the clinic. All three
compounds will provide new and important information on Parkinson’s.
Other compounds under investigation include brasofensine
from Bristol-Myers Squibb, an inhibitor of dopamine reuptake
by the nerves, and SL-34.0026 from Lorex-Synthélabo,
a novel MAO-B inhibitor in early development. Gensia and the
Japanese company Kyowa Hakko are exploring compounds that
affect yet another target called the adenosine receptor.
Eli Lilly is testing the value of olanzapine for the
treatment of psychotic symptoms in people with late-stage
Parkinson’s.
Evidence is mounting that an excess of certain toxic reactive
molecules which damage cells by a process called oxidative
stress may be one cause of neuronal loss in Parkinson’s. Lundbeck,
in association with Centaur Pharmaceuticals, is investigating
an agent which may neutralise or limit this damage, thereby
slowing the progress of the illness.
Very recently, the biotech company Amgen acquired the rights
to a novel class of compounds, neuroimmunophilins.
These promote nerve regeneration and repair, representing
a new approach to the treatment of Parkinson’s, and could
be of major importance in the treatment of several neurodegenerative
diseases.
Newer biological and biotech approaches
Future treatments, even possible cures, may emerge from research into tissue transplantation, the use of nerve growth factors and gene therapy.
Loss of nerve cells might be reversed if live dopamine-producing
cells could be introduced into the damaged regions of the
brain. This has already been done by injecting living cells
into the damaged region of the brain. This is done via a small
hole in the skull, using stereotactic surgery - a method first
employed more than 12 years ago. Two types of tissue have
been used: the patient’s own adrenal gland, because it can
produce dopamine and will not be rejected, and secondly, nerve
cells from a human foetus which hopefully have the potential
to re-establish new nerve connections. There have been good
responses, but also many failures, and the technique remains
highly experimental and as yet unproved.
Biological molecules called nerve cell growth factors can
now be produced outside the body by genetic engineering. These
factors have the ability to stimulate nerve cells to grow
and develop axons – the long filaments that carry the messages
around the body. One, called glial cell-derived neurotropic
factor (or GDNF) is being developed by Amgen. A trial
of this material in people with moderate to severe Parkinson’s
has begun and is expected to be completed in early 1998. The
interest in GDNF arises from the observations that it can
protect dopamine neurones from toxic damage, restore functional
activity to already damaged dopamine neurones and possibly
reverse the symptoms of Parkinson's. It will be given by direct
injection into the brain and has already been shown to reach
dopamine neurones when given in this way. This is exciting,
‘leading-edge’ research, but with any highly innovative approach
like this, success can only be hoped for, rather than assured.
A further possibility for the future is gene therapy. This
has been brought several steps nearer by the development of
special methods for introducing genes into non-dividing cells,
such as those in the brain. The technology for this (called
ProSavin™) has been developed by the biotech company, Oxford
Biomedica. It is carrying out research to see if it can introduce
the genes coding for the synthesis of beneficial proteins
into the brains of people with Parkinson’s, thus restoring
the brain’s capacity for dopamine production.
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