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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.

Donepezil (Aricept) to Treat Alzheimer's Disease

In the double-blind study that provided the basis for obtaining FDA approval, outpatients with mild
to moderate Alzheimer's disease were randomized to receive 10 mg donepezil daily (157 patients), 5
mg donepezil daily (154 patients), and placebo (162 patients). Both the 5 mg and 10 mg donepezil
groups showed an average 3 to 8 percent advantage over placebo on cognitive performance and
global clinical improvement. The peak effect occurred after six weeks on medication, and by six
months the effect had begun to wear off. Nonetheless, throughout this period, patients on donepezil
retained an advantage over patients who continued on placebo. In other words, the progress of
Alzheimer's disease was not dramatically changed, but being on donepezil meant that the patient's
worsening was delayed, unlike people on placebo, who deteriorated steadily over time.

From the original series of donepezil study participants, 133 Alzheimer's patients were followed
for an average of two years. Donepezil treatment did not completely halt long-term decline, but it
was associated with less deterioration than what was expected over time in these Alzhemier's
patients.