This article is so confusing it's funny, but I think they are answering my probing question about AD and PD taking cholinesterase inhibitors.
I think this article says that when anti-cholinesterase drugs [Aricept] are given to a person with a cholinesterase deficiency [polymorphism? gene?] it can cause it to overexpress the enzyme, resulting in pools of extra enzyme.

Researchers who are multi lingual and speak this language feel free to add.

http://hmg.oxfordjournals.org/cgi/content/full/9/9/1273

One of the last sentences says,

"To conclude, this polymorphism, identifies a new HNF3-binding enhancer domain important for AChE expression. Heterozygosity for the deletion is manifested as constitutive overproduction of AChE;

such overproduction, which increases the susceptibility to acute anti-AChE exposures in mice, [ surely this increases acetylcholine?] is likely to be the cause of the hypersensitivity of proband I to pyridostigmine.

pyridostigmine is anticholinesterase [like Aricept]

The proposed link between this mutation and the hypersensitivity points to carriers of this allele [gene?]as individuals at risk of developing adverse responses under treatment with or exposure to anti-AChEs, which is important in view of the increasing use of anti-AChEs as Alzheimer’s disease drugs (11).

Moreover, stress- or anti-AChE-induced increases in AChE levels (17) may cause acquired anti-AChE sensitivity, putting at risk a considerably wider group of individuals (7).

This type of chemical hypersensitivity therefore emerges from our study as a complex trait, perhaps involving both early modulators such as transcription factors and downstream responding genes."

So messing with the enzyme can ruin its function,which can cause permanent sensitivity problems and dysfunction. It's an overproduction of the enzyme, but rather than flowing freely it collects, but i'm left with the same question:

Is the result of this an increase in acetycholine? Is the bottom line still too much acetylcholine? or does the trouble stop at the pool of enzyme spillage? i doubt the latter. Does anyone know?


It isn't as cut and dry as i thought when starting this research but now i know more about what leads to a similar reaction as mine when trying aricept. From what I can tell, the results are delivering the same message. It's risky to take this type of drugs if you have alzheimers or pd. It interferes and interrupts the break down of acetylcholine, which is toxic if givven too large a quantity. These drugs whose purpose is to provide greater quantities of acetylcholine for cognition cause overexpression of the enzyme inhibitor AChE which collects in pools. Collecting in pools sounds ominous.

thanks!
paula

pyridostigmine - cholinesterase iinhibitor like aricept.

Proband I, a 30-year-old woman of Ashkenazi Jewish origin and no significant history of adverse drug responses, received a single oral dose of 30 mg pyridostigmine, a dose considered safe, which is given prophylactically under anticipation of chemical warfare (12).

Within 1 h, peripheral blood AChE fell to an almost undetectable level, increasingly severe muscle fasciculations developed, accompanied by intense headache, rhinnorea, lacrimation and frequent urination. These acute symptoms continued for 3 days, and resolved into a 5-day period of extreme fatigue, muscle weakness and general malaise.

I hear ya!
Been there,
paula

http://hmg.oxfordjournals.org/cgi/content/full/9/9/1273

ahhhha, It's stress triggerring changes in the epigenome which controls the expression of the gene which controls ACHe levels, resulting in increased ACHe levels....
I am certain the answer is not that linear...nonetheless

For what it's worth, we are very careful about any drug or supplement which impacts the acetylcholine system for my husband--he reacts in a definite adverse way.

and wasn't able to manage it but found this site which might help some of the mind-boggled (like me) among us!! browsing around it helped a little.

http://www.brainexplorer.org/neurolo...smitters.shtml

Thanks for this Paula, I am dimly understanding some of what it is about, keep it coming

Paula,

Laughing at the ominous collecting in pools comment; you are funny. I think of a new sort of West Side Story with our neurotransmitters in primary roles!

Speaking of ominous...I ran across this disturbing, but highy detailed and nicely formatted governmental site that has multiple pages explaining the function of acetylcholine, the peptide (AcHe), and the main types of receptors: the nicitinic and the muscarinic. The CDC site on environmental toxins explores something called cholinergic toxicity and its symptoms, etc....interestingly enough this toxic buildup can result from toxic exposure to insecticides or chemical warfare nerve agents. Yikes, interesting to see a pesticide link though.

http://www.atsdr.cdc.gov/csem/cholin...nhibitors.html

What is more alarming, but not at all surprising, is that abrupt withdrawal from an anti-cholinergic can cause what is called "cholinergic rebound" with some serious symptoms. When we end up with too much acetylcholine we can get a "cholinergic toxidrome".

I find the research on how the receptors (muscarinic) are implicated in demential and that they are different again for PD and AD.

Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases.
Aubert I, Araujo DM, Cécyre D, Robitaille Y, Gauthier S, Quirion R.

Department of Neurology, McGill University, Montreal, Quebec, Canada.

Interesting to pursue and may post more later...

Anyone know if too much a-choline causes a focal dystonia (like my darn foot) or a general dystonia?

Laura

Laura, thanks for this. I am on an anti-cholinergic patch which is working ok, except......I seem to have developed a rash, so need to change it. Trying to come off is not good, I'll need another clinic appointment to address this problem, I had no idea till I tried that it would be so bad.

Suppose that is one of the reasons I am following Paula's research, even though I am way in over my head with the science.

In the meantime I itch all over...........

About foot dystonia - While on the patch I have had nocturnal foot cramps ......and an increase in jaw dystonia when sinemet wears off......

Is Benadryl an anticholinergic?

It seems to help my dystonia.

Yep, it is considered in the same drug family as the anticholinergics. Benadryl was used early on in PD treatment before our standard drugs were in play.

i'm going to think out loud and lindy i don't have it down either. This is not to be taken as fact.

the article says they give it to people when a chemical weapon is expected for protection. they give them the enzyme inhibitor - which blocks the AChE - then- what right here is what i am trying to learn.

why would they want the enzyme to stop breaking down acetylcholine? They are giving people meds to stop cholinergic activity during chemical warfare.

we know that acetylcholine is used in chemical warfare, so would the enzyme prevent the acetylcholine from a chemical attack from getting processed? it is offering some kind of protection that we haven't learned about yet, it seems. This is a contradiction to me so I need help with it.

next, lindy says she is getting dystonia when off since she started taking an anticholinergic. So your patch's job is to assist in keeping acetylcholine regulated as the enzyme does that breaks it down - namely it helps AChE which is cholinesterase. Acetylcholine needs to be kept low.

So lindy's patch is causing dystonia when off. Did you not have dystonia before this lindy or did it get worse? my dystonia is quite bad when i'm off and it sounds like this could be the imbalance of acetylcholine and dopamine and i 'm wondering if the type of dystonia we are talking about is from acetylcholine levels being too high when we are off.

But the anti-cholinergic activity from the patch should keep you from getting dystonia because it should balance the transmitters. it should be enabling the enzyme to break it down and keep the levels low. Nortriptyline has reduced the length and severity of my morning dystonia.

Therefore, I don't understand why lindy would be getting increased dystonia with an anti-cholinergic patch. Were you on an anticholinergic pill before you started the patch? Did you have a reduction in the dosage by going on the patch? is this an experimental med?

exelon has the patch.but it is not anticholinergic. it's anti-acetylcholinesterase, a cholinesterase inhibitor, an alzheimer med. and if so it's raising your aceptylcholine and that causes cramping and i think it causes the dystonia. So if your patch is exelon or any cholinesterase inhibitor and it is giving you dystonia, you have proven my point. this is not for people with pd unless they have a deficiency like franny. But even with the psuedo AChE deficiency franny felt the best with nortriptyline, which is not a cholinesterase inhibitor- but rather an anti-cholinergic to help lower acetylcholine. if you are on exelon and getting more dystonia, you have validated what i'm thinking based on my own experience. if not, i'm still confused.

donw -Benadryl quite a few pwp take benadryl and say it helps. it helps to keep acetylcholine low [as it should be]

i asked my pharmacist about giving pwp alzheimers medicines and mentioned acetycholine- asked him if i was speaking his language. he said they wouldn't do that or shouldn't or who would do that? something like that. i told him it was FDA approved for pd and they gave it to me and it made me very sick. he thought i meant sick to my stomach but i was getting the feeling that he didn't want to go against my neuro as he changed and said, 'well i guess it's an individual thing...have to try it and see." he also added, well it makes sense to give it to pwp. i didn't walk away with the matter cleared up at all. There were two people waiting so i gave it up.

my question remains the same. is the problem with using cholinesterase inhibitors too much acetylcholine? This is a deadly poison in access.

thanks for helping with your comments. it's very important. i'm confused about whether the sensitivity and polymorphism talked about in this article which is soooo technical is the same genetic deficiency as the one franny has? pseudoAChE deficiency? yet it sounds like it can be a result of the alzheimer-like meds.

keep the info coming - lindy i'm very curious about your patch.

paula

Paula,

From all I've read, a cholinisterase inhibitor is an enzyme which inhibits the breakdown of acetylcholine. In other words, our bodies naturally produce this enzyme and drugs like Aricept interfere with the enzyme either blocking it or dampening it, so acetylcholine does not break down. In PD, we already have too much of it, so in essence using something like Aricept leave us with even more which could result in more dystonia! Is this what you are wondering?

To your question...

we know that acetylcholine is used in chemical warfare, so would the enzyme prevent the acetylcholine from a chemical attack from getting processed? it is offering some kind of protection that we haven't learned about yet, it seems. This is a contradiction to me so I need help with it.

The drug or chemical warfare blocks the enzyme from breaking down acetylcholine; it does the opposite, it allows the acetyl-ch to proliferate unchecked. The enzyme is like a bouncer at a bar keeping things in check, by giving the bouncer the night off (the cholinesterase inhibitor), the bar is over run with too much drunken acetyl choline- I'm bad with analogies, but you get it. In war we end up with cholinergic toxidrome or toxicity (too much acetyl choline) which can result in death.

This info and research I put together is buried in another post; I am going to copy/paste it here. Also, the common sense idea about this aggravating our symptoms has been corraborated by a pharmacist and by research. Next, I ask, do our doctors have any common sense?

From my other post:

Fairly recently, it has become in vogue for neuros to prescribe cholinesterase inhibitors used routinely for Alzheimer's to treat cognitive impairment for PD. However, you should ask your neuro many questions before doing so because they directly counteract the effect of any other PD drugs we may take and further screw with what little neurotransmitters we have left. We have dissected this in another recent long thread, but this is the gist of it all:

-PD results in loss of dopamine and a subsequent increase in acetylcholine; the latter is what causes our motor symptoms: bradykinesia, tremor, and rigidity.

-Taking a cholinesterase inhibitor actually raises our levels of acetylcholine when we already have too much. Common sense would tell us that this will exacerbate our Parkinson's symptoms. Sure enough, there are studies to substantiate this:

From PubMed:

Cholinesterase inhibitors: tremor and exacerbation of Parkinson's disease.

[No authors listed] Prescrire Intl

(1) Three cholinesterase inhibitors are marketed in France for the treatment of Alzheimer's disease: donepezil, galantamine and rivastigmine. Tremor and dystonia are known adverse effects of cholinesterase inhibitors. (2) In patients with Parkinson's disease who have cognitive disorders, or in patients with Lewy body dementia, exacerbations of parkinsonism and tremor have been observed during treatment with cholinesterase inhibitors at normal doses. The disorders were reversible on withdrawal of the cholinesterase inhibitor. (3) Withdrawal of cholinesterase inhibitors should be considered if gait disorders, falls or parkinsonism occur or worsen during treatment.


-To further confound our treatment, neuros do this when we are already taking anticholinergics like Amantadine to lower the acetylcholine levels. Why would they give us another drug that then increases it? Doesn't this seem counterintuitive?

-Finally, from the DSM IV:

e. Mild cognitive impairment

The term "mild cognitive impairment" describes a heterogeneous group of individuals, with some patients in the earliest stages of Alzheimer's disease and others suffering from other conditions. There are no FDA-approved medications for the treatment of mild cognitive impairment at this time. Clinical trials of cholinesterase inhibitors for mild cognitive impairment have enrolled a narrower and better defined population of patients with mild cognitive impairment than most clinicians actually treat in practice, but even with these well-defined patients the evidence from clinical trials supporting use of cholinesterase inhibitors is weak (172, 173). Given the inconclusive data, the potential safety concerns that exist with this class of medications in this patient population, and the lack of FDA approval for this indication (reviewed in Sections V.B.1.a.4 and II.C.5.a.1.a), no specific recommendation can be made in favor of routine use of cholinesterase inhibitors in patients with mild cognitive impairment at this time. Nonetheless, individual patients may benefit from their use.

Not sure about Lindy' s patch; I'd like to know too. Hope I'm not thread-jacking...trying to help

Laura