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| Neurones Involved in Alzheimer's Disease |
Considering
the ageing nature of world populations, and the fact that diseases of the
central nervous system constitute 38.35% of the global economic health burden,
investment in this area of medicine currently appears to be inadequate. A major
reason for this is the excessive time needed to conduct clinical trials of new
drugs in this field, the subjective and unpredictable effects of psychological
medications and the difficulty in developing treatments that cross the
blood-brain barrier.
Moreover, the
stigma and lack of informed knowledge associated with psychological disorders
such as depression and schizophrenia have further hindered investment in the
development of new medications for these particular disorders. The following
question therefore arises: should commercial considerations or ethical ones
drive pharmaceutical companies?
The Withdrawal of Big Pharma Investment
In February,
2011, GlaxoSmithKline (GSK) announced it would no longer fund the development
of psychiatric medicine, while pharmaceutical giant Pfizer is reducing its
investment in this area by two billion dollars in the next two years.
AstraZeneca (AZ), known for its antipsychotic drug Quetiapine, will also be
ending its involvement in the development of future mental health medications.
According to
Andrew Witty, CEO of GlaxoSmithKlein, ‘Pain, depression, and anxiety are areas
where we believe the probability of success is relatively low, and we think the
cost of attaining success is disproportionately high.’ This reflects a general
predicament in CNS drug development, where there is an average wait of 13 years
between drug discovery and market approval, around two years longer than for
other drugs. In addition, only 8.2 percent of potential CNS drugs that begin
human testing will reach the marketplace, compared with 15 percent for drugs
overall.
Reasons for Uncertainties in CNS Drug Development
In March,
2011, the European College of Neuropsychopharmacology (ECNP) acknowledged these
issues, and warned that this poses a particular threat to sufferers of
depression, anxiety and addiction. Whereas drugs for other diseases are now
being discovered with the help of protein biomarkers, the ECNP points out that
there are few current biomarkers for psychiatric disorders. Drugs in this field
have instead often been discovered by chance, a luxury few companies are now
willing to accommodate.
This problem
is exacerbated by the relatively low priority given to mental health by society
in general, and the reluctance of industry to recognize, at the very least, the
need for newer, improved versions of existing treatments. Moreover, the recent
increase in regulatory measures such as the requirement for placebo controlled
trials in children and double data entry has made the development of some
psychiatric indications almost impossible.
Some success
has been achieved in the bid to relax such prohibitive regulations. Pfizer and
Johnson and Johnson, for instance, have been successful in convincing U.S.
regulators to ease some of the safety restrictions required in clinical trials
of their Alzheimer’s drugs. The F.D.A. has also formed the ‘Critical Path
Initiative’, which re-assesses how medical products are being developed.
Psychiatric
drugs do have one advantage over other CNS medications. While most medications
treating mental illnesses such as schizophrenia and depression are
small-molecule, lipid soluble compounds capable of crossing the blood-brain
barrier, other CNS treatments currently cannot do this.
While
scientists have discovered the genes responsible for many of these disorders,
including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease,
there is currently no way large enzymes can be delivered to the brain using
gene therapy. In the case of Parkinson’s disease, L-Dopa, used to alleviate
symptoms, can enter the brain, but provides only temporary relief.
Potential Solutions to the Blood- Brain Barrier Problem
William M.
Pardridge has highlighted several areas where researchers are
attempting to foil the barrier between the blood and the epithelial cells of
the brain. One of these techniques, ‘trans-cranial’ drug delivery, involves the
medication being injected or inserted into the brain itself. Problems with this
have arisen, however, because diffusion rates from the site of delivery are not
rapid enough.
Another
possible solution is ‘blood-brain barrier disruption’, where solutes such as
mannitol are used to shrink the brain’s endothelial cells, allowing various
molecules to pass into the cerebral tissue. Trials to date, however, have
revealed serious side effects associated with this treatment.
‘Trans- nasal’
drug delivery to the brain via the nasal cavity has also been considered, but
it has been found that this only works for certain small molecules and in
limited quantities. Another method, involving the use of molecules such as
monoclonal antibodies to act as molecular ‘Trojan horses’, may help to carry
genes and large proteins across the blood-brain barrier.
Limited
success with this technique has occurred in trials on rats with experimental
Parkinson’s disease. In these trials, plasmids containing dopamine-producing
genes were first encapsulated in liposomes and then attached to monoclonal
antibodies, which transported the genes into the brain. Similar ‘Trojan horse’
molecules are also being tested with nanocapsules
containing glial growth factors or neurotransmitters. If successful, these
treatments may help to repair damaged nerve cells in the brain and spinal cord.
Possible Answers to Funding and Trial Issues
In terms of
the issues associated with CNS research and development, the ‘Coalition Against
Major Diseases’ has been formed in the U.S. from drug companies, government
agencies and other related organizations as a way of developing new guidelines
for clinical trials. In addition, organizations such as the International
Society for CNS Clinical Trials and Methodology (ISCTM) has recently convened
to discuss the path forward in CNS drug development, with particular reference
to recent results in Alzheimer trials.
The 2010 U.S.
Health reform Act also provides for the funding of a Patient-Centered Outcomes
Research Institute, aimed at improving the effectiveness of drug research,
while the 'Critical Path Initiative', mentioned above, is also focussing on
streamlining drug trial regulations. Organizations such as these are obviously
vital in the light of recent developments in CNS drug research, which suggest
that the major priority of pharmaceutical companies will always be their profit
margins.
References
•
Goodwin, G. and Nutt, D., ‘ECNP Summit on the future of CNS drug
research in Europe 2011’, ecnp.eu
•
Kaitlin, K., and Milne, P., 2011, ‘A Dearth of New Meds’,
scientificamerican.com
•
Nierenberg, A., 2010, cnsspectrums.com, ‘The Perfect Storm: CNS Drug
Development in Trouble’
•
Pardridge, W., ‘The Blood-Brain Barrier: Bottleneck in Brain Drug
Development’, nih.gov
•
Ritter, A., 2011, ‘The Future of CNS DrugDevelopment’, pharmtech.com
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