13 replies to this topic

[ozone]

I've never heard what the hard-core users of this forum have to say about the following (I value everyone's opinion, but I'd like to hear what LifeMirage and others have to say about this).

From Wikipedia:

An anticholinesterase is a chemical that inhibits a cholinesterase enzyme from breaking down acetylcholine, so increasing both the level and duration of action of the neurotransmitter acetylcholine.

A cholinesterase inhibitor (or "anticholinesterase") suppresses the action of the enzyme. Because of its essential function, chemicals that interfere with the action of cholinesterase are potent neurotoxins, causing excessive salivation and eye watering in low doses, followed by muscle spasms and ultimately death (examples are snake venom, sarin and VX).

That definition would justify the following:
Reminyl (i.e., AChE) Deaths Prompt Warning

New Precaution Added to Label of Alzheimer's Disease Drug

By Daniel DeNoon
WebMD Medical News Reviewed By Brunilda Nazario, MD
on Tuesday, April 05, 2005

April 5, 2005 -- The deaths of 13 elderly patients taking the Alzheimer's drug Reminyl during a study has prompted a change to the drug's label.

News of the voluntary label change was announced in a "Dear Healthcare Professional" letter from Reminyl maker Ortho-McNeil, a subsidiary of Johnson & Johnson.

Information about the deaths will be added to the "Precautions" section of Reminyl's label. There is no change in the dosage of the drug or the indications for its use.

Reminyl is approved only for the treatment of mild-to-moderate Alzheimer's disease. The studies were exploring the use of the drug for mild cognitive impairment. Mild cognitive impairment is memory loss less severe than Alzheimer's disease but more severe than would be expected based on a person's age.

In the two studies, 1,026 patients received Reminyl and 1,022 patients received a placebo. There were 13 deaths in the Reminyl group but only one death in the placebo group.

The deaths, according to the Ortho-McNeil letter, "were due to various causes, which could be expected in an elderly population." About half were due to heart attack, stroke, and sudden death.

It's not clear why there were more deaths in the Reminyl group. The letter notes that during the first six months of the two-year trials, there were no deaths in the placebo group -- "a highly unexpected finding in this population," the letter states.

Studies of patients with Alzheimer's disease do not show increased deaths among patients treated with Reminyl.

For more information about Reminyl, contact Ortho-McNeil Neurologics at (800) 526-7736.

So... with lots of folks advocating AChE inhibitors, what is everyone's thoughts on this? My own opinion? Well I'm not nearly educated enough on this topic, but if I had to take a wild stab, I'd say that because lots of people take this supplement on this forum and have yet to die then death must not be immediate. And, if only 10 more people died out of 1,026 patients than the placebo group, death must not occur in everyone. Also, the study doesn't tell what dose of the AChE's the people were taking. And we all know that for studies the doctors like to exceed the recommended dose often to get a response. So my "wild stab" would be that at certain doses, AChE supplements shouldn't be harmful... but at higher doses, they can cause death.

Thoughts?

[LifeMirage]

A cholinesterase inhibitor (or "anticholinesterase") suppresses the action of the enzyme. Because of its essential function, chemicals that interfere with the action of cholinesterase are potent neurotoxins, causing excessive salivation and eye watering in low doses, followed by muscle spasms and ultimately death (examples are snake venom, sarin and VX).

In clinically studied doses the AChE inhibitors Huperzine A and Galantamine are highly neuroprotective...if you were to take greater than 10 times the highest human dose that would not be a great idea.

So... with lots of folks advocating AChE inhibitors, what is everyone's thoughts on this? My own opinion? Well I'm not nearly educated enough on this topic, but if I had to take a wild stab, I'd say that because lots of people take this supplement on this forum and have yet to die then death must not be immediate. And, if only 10 more people died out of 1,026 patients than the placebo group, death must not occur in everyone. Also, the study doesn't tell what dose of the AChE's the people were taking. And we all know that for studies the doctors like to exceed the recommended dose often to get a response. So my "wild stab" would be that at certain doses, AChE supplements shouldn't be harmful... but at higher doses, they can cause death.

Thoughts?

Both Huperzine A and Galantamine are not toxic in both recommended doses...in regards to the study it is unusual considering the previous 100's of studies shown no increase in death..even the authors of the study stated this was unclear.

[exigentsky]

I had a similar question and it was forwarded to Prof. Dr. Munem Daoud. Unfortunately, it was not addressed to me directly and so it may be hardet to follow. But here is what the resposne was:

Dear Warren

It seems that this person is not familiar with pharmacology otherwise he would not ask such questions. The sites he referred to are talking in general terms (not in real scientific evidence with approved clinical trials).

In any case the levels and possible function of several neurotransmitters can be influenced by the supply of their dietary precursors. The neurotransmitters include serotonin, dopamine, noradrenaline, histamine, acetylcholine and glycine, which are formed from tryptophan, tyrosine, histidine, choline and threonine.

When such dietary precursors enter the human tissues they will metabolize according to the availability of other nutrients/enzymes/co-enzymes/co-factors/physiological processes…etc. so, if there is any extra or overdose of such precursors either the body will not use the entire amount and get rid of these extra precursors unless the body/cells require the same precursor/s in another metabolic pathway OR a sign of overdose will affect the tissues (or cells) leading to develop a side effect/s all due to the precursor/s only.

Acetylcholinesterase and butyrylcholinesterase are two closely related enzymes important in the metabolism of acetylcholine so any inhibition of acetylcholinesterase (if this is really the case) then the other enzyme is still active and always there is a balance between the acetylcholine level in the body and the effect of such inhibitors. Most of the ingredients he listed are what we call (facilitated) are acting on increasing Choline in the brain and the body can take up to four grams of choline per day without any side effect/s (for years).  Why… because choline is a water soluble vitamin and is never stored in the body.

In case of Phosphorylation process due to nerve gas this is a complete damage to almost all nervous system enzymes including acetylcholinesterase and butyrylcholinesterase. There are many clinical examples of direct solanaceous glycoalkaloids toxicity due to cholinesterase inhibition, example the potato (when the skin of potato tern to green colour), a less potent alkaloid presented in Huperzine A. Published data indicate human serum Huperzine A concentrations at least ten-fold lower than required to inhibit acetylcholinesterase and butyrylcholinesterase in vitro.

The Huperzine A amount [250 mcg] is within the minimum dose that can give a safe result within a long period of time according to all references talking about high doses of such alkaloids. Also most of these literatures concentrated on Bis-huperzine B (highly potent and selective acetylcholinesterase inhibitors). One final important note: Huperzine A are used to protect and treatment the individuals from nerve gas poisoning (example the nerve gas Soman) over 300 publications in this field. This is because in many ways, Huperzine A is neuroprotective.


Regards,

    Dr. Munem Daoud

I wish I had the source e-mail I sent since it would make everything more readable, but unfortunately, I dissapoint in that regard. However, I hope this is helpful anyway.

[exigentsky]

Also, I am interested in knowing how Galantamine compares to Huperzine A. Which is more selective? How do they compare in terms of side effects and efficacy? Which is "BETTER" :-p ?

[REGIMEN]

I think Galantamine is "better". Wicked "better".

[exigentsky]

LOL, a little more details would be appreciated. :-)

[virago]

I trust the research that supports AChE inhibitors' neuroprotective attributes and safety, but is it possible for them to become toxic with extended continuous use, or should you cycle off them every once in a while?

Also, is taking a choline booster such as Centro along with Galantamine or Huperzine A redundant, and can it be harmful? If it is possible to take both, what are optimal does?

Thanks,
Vira

[johnmk]

I think a little of each wouldn't be too bad of an idea, but a lot of each of course might be contraindicated. Just see how you feel. Feeling rotten? Try less of each. No change? Try none of each. Etc., figure it out through experiment. And of course, advice obtained here.

[LifeMirage]

I trust the research that supports AChE inhibitors' neuroprotective attributes and safety, but is it possible for them to become toxic with extended continuous use, or should you cycle off them every once in a while?

Based on the research & how they work.. no they can not become toxic if taken at the recommend doses...cycling any nootropic is a good idea.

Also, is taking a choline booster such as Centro along with Galantamine or Huperzine A redundant, and can it be harmful?

Because centrophenoxine or other acetylcholine precursors work quite differently no... but you can take a lower dose of both as they work together. Both are not harmful in the sense it causes damage (or is toxic), unless you purposely took a massive suicidal dose.

If it is possible to take both, what are optimal does?

It varies per person and the doses I recommend depend on what you are hoping to achieve. For Huperzine A people take anywhere from 100 mcg - 400 mcg daily or every other day (up to 990 mcg can be taken at one time without serious side effects).

For Galantamine 4-24 mg daily is taken daily or every other day (avoid if you have bronchial asthma, bradycardia, angina pectoris, heart failure, epilepsy, hyperkinetic dyskinesia, or serious liver damage). Nausea can be a common side effect if you start too high of a dose.

[xanadu]

LifeMirage wrote:

"...cycling any nootropic is a good idea"

Could you amplify on that a little? What ill effects might one notice from not cycling noots? Would they become less effective or might there be bad side effects? Are there any in particular that need to be cycled? By cycling, do you mean going from piracetam to another racetam or should one get off all noots altogether for a while? And, how long should one stay off them or how often should one switch them?

A lot of questions I know but no doubt others will find the answers interesting. BTW, thanks for posting your personal stack. While I doubt I'll ever take all of those, it gives me a good starting point of what's good and how much to take. Right now I'm just taking baby steps trying out a few things.

[LifeMirage]

Could you amplify on that a little?

Sure, I don't think its a bad idea to give the brain a rest from nootropics every once in a while.

What ill effects might one notice from not cycling noots?

None.

Would they become less effective or might there be bad side effects?

No, there are never serious side effects to taken nootropics...unless you had an extremely rare reaction.

Are there any in particular that need to be cycled?

No.

By cycling, do you mean going from piracetam to another racetam or should one get off all noots altogether for a while?

Going off all or most for afew days of the month or so.

And, how long should one stay off them or how often should one switch them?

Anywhere from a few days each week or a few days each month.

[xanadu]

Thanks, LifeMirage.

Have you noticed any positive effects from laying off them for a few days now and then? It seems intuitive that laying off what is basicly a drug now and then would be a good thing to do to recover from any mild side effects that might exist, or for other reasons I might not be aware of. I was just wondering if you had seen anything quantifiable or had heard of studies that showed this?