The Rise and Fall of Tacrine Cognex

As the largely negative clinical trials with choline, lecithin, and acetyl-l-carnitine demonstrate, promemory effects in rats or mice are not easy to replicate in people. Improving cognition in the primitive rodent brain is a lot simpler than boosting it in the ultracomplex human brain.

As a matter of fact, by the mid 1980s, research with a variety of cholinergic compounds—lecithin, choline, phosphatidylcholine, acetyl-l-carnitine, and physostigmine—had run into a dead end, despite the investment of over a billion dollars by a number of drug companies in the United States, Europe, and Japan. Then came a report by William Koopmans Summers describing strong efficacy for a cholinesterase inhibitor named tetrahydroaminoacridine or tacrine (THA, Cognex) in seventeen patients with Alzheimer's disease. A tortuous road ensued for tacrine, with many ups and downs and the U.S. Congress getting involved in supporting research and development of this Warner Lambert drug. Eventually, the FDA approved it as a treatment for Alzheimer's disease, because high doses of the medication showed a significant, though small, advantage over placebo in cognitive performance.

But after tacrine was approved by the FDA, it fell by the wayside because of its liver toxicity. This risk was so high that after tacrine was approved for clinical use, none of the neurologists and psychiatrists in my group at Columbia University, including myself, were willing to prescribe the medication for our Alzheimer's patients, with rare exceptions. This situation changed dramatically with the development of the next FDA-approved cholinesterase inhibitor, donepezil (Aricept).

Donepezil (Aricept): A Rare Instance of Japan-U.S. Collaboration

Esai Pharmaceuticals, a Japanese company, did the basic research and initial clinical trials to develop donepezil (Aricept). Since they did not have a major presence in the United States, they cut a deal with Pfizer to conduct the required studies to obtain FDA approval and then to jointly market the medication in the United States and Europe. As one might expect, this Japan-U.S. collaboration has had its ups and downs, but both sides have learned a great deal in this process. Cross-border research and marketing will become increasingly important as drug development becomes more and more international, particularly if the byzantine regulations in different countries become more uniform.

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