Studies with the cholinesterase inhibitor physostigmine in small numbers of Alzheimer's patients, some of which were conducted by my colleagues Drs. Yaakov Stern and Richard Mayeux, showed superior memory test performance compared to placebo. The size of the improvement was comparable to what would be shown years later with tacrine and donepezil, but physostigmine never succeeded in the same fashion for two main reasons: the very short duration of action meant that pills needed to be given five to six times daily, and it frequently caused nausea and other side effects. Given these difficulties, using physostigmine to prevent age-related memory loss was never even entertained as a concept. A long-acting physostigmine compound with single daily dosing was developed, but this did not prove to be very effective, and physostigmine is now consigned to the dust heap of history. I feel that this is unfortunate, because several of the Alzheimer's patients who participated in the clinical trials at our center did show some benefit.

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