From: Rafal Smigrodzki (rms2g@virginia.edu)
Date: Mon Jan 27 2003 - 16:59:32 MST
owner-extropians@extropy.org wrote:
> Hal Finney says:
>
>> this drug (sold under the name Aricept) often
>> shows decreased effectiveness after a while. This may be due to the
>> progressive nature of Alzheimer's, or it might be that the
>> enhancement of the cholinergic system becomes less effective as the
>> brain adjusts to its new chemistry.
>
> I suspect that the endogenous levels of most neurohumoral systems
> might drop off if the natural supply is continuously enhanced for
> long enough, and indeed that their vesicles might be resorbed,
> perhaps in ways that make it hard for the brain to rebuild them. I'd
> be very scared of using enhancers that routinely shovel in unusual
> quantities of neurotransmitters. With Alzheimer patients levels are
> already depleted, and the patients usually elderly, so perhaps
> there's not much to lose. For the rest of us--brrrr.
>
### I reviewed the following article: Doody RS. Geldmacher DS. Gordon B.
Perdomo CA. Pratt RD. Donepezil Study Group. Open-label, multicenter, phase
3 extension study of the safety and efficacy of donepezil in patients with
Alzheimer disease. Archives of Neurology. 58(3):427-33, 2001, which to my
knowledge is the longest trial of efficacy and safety of an AChE inhibitor.
The very long course of the cognitive decline on donepezil, which closely
parallels natural course of the disease, makes it unlikely that induction of
changes in neurotransmitter synthesis could be the cause. Most neurochemical
responses to drugs take place over hours to weeks, here we have a steady
decline over a period of two years. The rate of decline is essentially
identical for treated and placebo groups in the shorter double-blind
studies, and not substantially different from natural progression of the
disease in historical controls (this is a very weak datapoint).
The most likely explanation is that donepezil (and other AChE inhibitors,
like galantamine, and rivastigmine) do not affect the underlying disease
process and provide strictly symptomatic relief.
This said, I would not recommend sustained use of AChE inhibitors in healthy
persons, except on a temporary basis. Their safety has not been tested in
long-term studies on healthy volunteers. If there are adventurous spirits
willing to expose their brains to some (probably small) risk for the sake of
clearer thinking, I wish we could track their progress over a few years.
Rafal
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