Saturday, May 21, 2005

Another Long Strange Trip:
What PCP Teaches Us About Science Policy

In the category of Things Found While Looking For Other Things, I noticed that one of my former pharmacology professors, Ed Domino, has published a book: Sixty-One Years of University of Michigan Pharmacology, 1942-2003. (HPP Books, 2004.)  As you can tell from the title, he now is an emeritus professor.

I have not read his book, but I did poke around a bit on the 'net, looking into the history of pharmacological research.  There is an interesting story about Dr. Domino's research that teaches an important lesson for policymakers. 

Dr. Domino established his reputation in the mid-twentieth century through his involvement in the discovery of phencyclidine.  At the time, phencyclidine was thought to have promise as an anesthetic agent, and was patented by Parke Davis in 1958.  It was withdrawn from the market in 1978.  Since then, Parke Davis has undergone phagocytosis, and now is a pseudopodium of Pfizer.  Phencyclidine, meanwhile, has become notorious as a street drug, more commonly known as PCP, or angel dust.  PCP has caused untold suffering across the country, and across the decades since (see Dangerous Angel, by Sol Snyder).  Perhaps in atonement, Dr. Domino later became involved in research at the University of Michigan Substance Abuse Research Center (UMSARC). 

A derivative of phencyclidine, ketamine, attained limited commercial success as an anesthetic, but it too is abused sometimes.

In the 1950's it was not known how or why PCP and ketamine affect the brain the way they do.  It has been learned, since then, that the brain has a widespread network of neurons that act by release of glutamate.  Glutamate, in fact, is the most abundant neurotransmitter in the human brain.  It stimulates activity via three kinds of receptor: the NMDA, AMPA, and kainate receptors.  Both PCP and ketamine block (antagonize) the NMDA (N-methyl-D-aspartate) receptor.  Subsequently, it has been proposed that blockade of the NMDA receptor may mimic schizophrenia in some important respects. 

Although the history of PCP and ketamine is tainted by the illicit use of those substances, the research (1 2) on their mechanism of action since then has been more auspicious.  Two drugs the modify glutamate transmission have been marketed recently. 

Riluzole (Rilutek®) inhibits release of glutamate, and has demonstrated clinical utility in slowing the progression of amyotrophic lateral sclerosis (ALS).  This may be due to the fact that excessive glutamate release leads to neuronal cell death.  Preliminary studies indicate that riluzole may have a role in the treatment of depression as well.  A single case study showed benefit for a patient with obsessive-compulsive disorder. 

Memantine (Namenda®) acts by blocking NMDA receptors, and has some use in treatment of Alzheimer disease (AD).  It binds weakly to the NMDA receptor, thus it modifies -- but does not prevent -- the normal physiological function of glutamate that is released by the presynaptic neuron. Like riluzole, it is thought to help prevent cell death. 

In addition to the utility in treatment of Alzheimer disease, there is some evidence that memantine could reduce binge eating.  Such an application might be expected to generate some excitement in the general public.  The reference was electronically published ahead of the print publication on May 7 of this year.  I will be curious to see if the mainstream media pick up on it. 

However, there is reason for caution.  There is one case report of subtle psychotic symptoms caused by memantine.  Such an adverse effect may be acceptable in the treatment of a dreadful illness such as AD.  It would not be acceptable to expose patients with binge eating problems (binge eating disorder) to such an adverse effect, if the frequency of the problem is appreciable.  On the other hand, it is possible that further research on the role of glutamate and the NMDA receptor in the regulation of appetite will lead to something that is clinically useful, with an acceptable risk-benefit ratio. 

Recall that glutamate has effects on receptors other than the NMDA receptors.  AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, in particular, have been items of interest for pharmacologists.  A class of compounds knows as ampakines has been developed; some of these may turn out to be clinically useful.  CX717, in particular, is under development in phase I as a wakefulness-promoting drug.  Org24448 and CX516 are in phase II trials, in hope of finding something to improve cognition in patients with AD, schizophrenia, fragile X syndrome, and autism. 

The kainate receptor also has generated some interest.  NGX424, which is an AMPA/Kainate antagonist, is under development as a analgesic.  There is preclinical interest in the kainate receptor subunit GluR7 as a possible target for development of a new class of antidepressants.  Similarly, there is preclinical interest in the glutamate transporter.

What this story shows is that the earliest research into drugs that modulate glutamate activity resulted in a terrible drug, PCP, before anything was known about the fundamental pharmacology of the system.  As our understanding of the basic science improved, it became possible to develop some drugs that are safe and at least a little bit effective for some serious illnesses.  As our knowledge increases, the opportunities for development of new drugs improve even more. 

This long strange trip has implications for policymakers.  There is a trend in our government to increase the proportion of funding that goes to applied research and development for pharmaceuticals. 
FDA plans praised, criticized
AAMC says that return on research investment should not be measured only by drug approvals
By Paula Park

The Food and Drug Administration's (FDA) proposal to reform the drug development process have been met with criticism from the Association of American Medical Colleges (AAMC), but with praise from other groups, including the Pharmaceutical Research and Manufacturers Association (PhRMA).

The AAMC charges that the FDA plans begin with a faulty premise: that the federal biomedical investment should translate directly to new treatments. David Korn, senior vice president of Biomedical and Health Science Research at AAMC, also warned that any attempt to involve the National Institutes of Health (NIH) in drug-related research could dilute funding for "curiosity driven" investigations that have, in the end, contributed to new therapies. [...]
The proponents of realignment of funding priorities complain that the funding for drug development has not kept up with the explosion of knowledge in basic sciences.  The counterpoint is illustrated by this post: basic science should be ahead of applied science.  It is dangerous to fumble around in the dark.  We need more memantines and riluzoles, not more phencyclidines.

(Note: The Rest of the Story/Corpus Callosum has moved. Visit the new site here.)
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