Serotonin Antagonists As Therapy For Alzheimer Disease

haidut

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As I posted in another thread, over 90% of the drugs tested for Alzheimer during the last 10 years have veen utter and abject failure. This is a pretty solid indication that the theory of Alzheimer's pathology and proposed beneficial pathways on which these drugs were based is solidly wrong.
Since 2002, 99%+ of Alzheimer Disease trials have failed

Aside from the failure of all of these drugs, it is quite common to treat Alzheimer patients with SSRI drugs to "improve" their mood and claims have been made that SSRI would even improve cognition. Nothing short of abomination, considering something as simple as aspirin can probably cure the condition.
salicylate for alzheimers (Aspirin)
Aspirin Effective For Alzheimer, Parkinson And Huntington
Chronic Aspirin Ingestion Improves Spatial Learning In Adult And Aged Rats


As the saying goes, "no matter how beautiful the theory, you have to acknowledge reality sometimes", and so it seems that finally Big Pharma is embarking on the right path. Of course, none of this publicly acknowledged and officially new drugs that act in ways opposite to SSRI or the cholinergic poisons used for the last 20 years, are presented as "modulators" rather than as antagonists. Be that as it may, the latest trial used the drug idalopirdine that is a very specific and direct serotonin antagonist, and was found beneficial for people with Alzheimer's. While the PR articles dances carefully around the issue of serotonin "modulation" the study authors state directly that serotonin antagonism can be a viable therapy for Alzheimer's. No wonder cyproheptadine disappeared from the pharmacies of Europe and USA. It won't be long before we see it sold as off-label treatment for the low cost of $9,899/month.

Idalopirdine - Wikipedia, the free encyclopedia
Cognition Enhancer Promising in Alzheimer's

"...A drug targeting the 5HT-6 serotonin receptor, when added to donepezil (Aricept) in patients with moderate Alzheimer's disease, significantly slowed cognitive decline compared with donepezil alone, a researcher reported here. Patients receiving idalopirdine plus donepezil for 24 weeks in a phase II trial showed a 0.77-point improvement from baseline in ADAS-Cog scores, compared with a 1.38-point worsening in scores among patients taking donepezil plus placebo, reported Alireza Atri, MD, PhD, of California Pacific Medical Center in San Francisco."

"...Idalopirdine is not intended to be a disease-modifying agent, he explained. Preclinical evidence had suggested that the 5HT-6 receptor modulates a variety of neurotransmitter systems involved in cognition -- including glutamatergic and GABAergic pathways -- such that a selective antagonist could improve cognitive function with a different mechanism than current drugs such as memantine (Namenda) and acetylcholinesterase inhibitors. As such, idalopirdine could serve as an add-on drug to current agents as well as future disease-modifying drugs, Atri said."
 

Drareg

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Their saying the larger trial will be getting a lower dose? Do they want it to have less of an effect so they can label it not effective.

I tried vitamin E and niaciniamide for an Alzheimer's patient that has an aspirin allergy, they didn't have the effect that theanine did, I was curious if they nine was so how moderating the 3 Different ssri's they give her.

Would the consultant prescribe those meds right now do you know? The ssri's they gave her are potent anti psychotics, one is causing a side effect of Parkinson's, he told the family this is normal and her symptoms are not that bad but definitely Parkinson's ,incredible.
He was asked about measuring serotonin levels, we don't normally do that was his resposne.
Paid hundreds of euro per hour.
 

jaguar43

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Remember, if it works well they probably won't even sell it.

But assuming that the receptors 5-ht6 seems to be one of the last fully to be discovered ( therefore last to be studied) it seems that only recently have any legit research been done on it. Just by a quick wikipedia search regarding the 5-ht6 receptor seems to have anti-obesity, pro-memory and anti-depression effects.

Unfortunately the pro-economic ideology, the 5-ht6 will probably soon be divided into smaller subgroups like 5-ht1 and the other beginning neurotransmitters. I think the overall effects of each receptor maybe better than their divided counterparts.

I think the most important discoveries for this receptor will be around this time before they become divided into small sub unites.
 

haidut

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Their saying the larger trial will be getting a lower dose? Do they want it to have less of an effect so they can label it not effective.

I tried vitamin E and niaciniamide for an Alzheimer's patient that has an aspirin allergy, they didn't have the effect that theanine did, I was curious if they nine was so how moderating the 3 Different ssri's they give her.

Would the consultant prescribe those meds right now do you know? The ssri's they gave her are potent anti psychotics, one is causing a side effect of Parkinson's, he told the family this is normal and her symptoms are not that bad but definitely Parkinson's ,incredible.
He was asked about measuring serotonin levels, we don't normally do that was his resposne.
Paid hundreds of euro per hour.

Since it is research chemical and not a drug yet, you can buy it from some chemical vendors like Sigma. I don't see why other serotonin antagonists like cypro and ondansetron won't have similar/same effects given the many studies showing they improve memory and even showed benefit specifically for Alzheimer in some tests.
 

High_Prob

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As I posted in another thread, over 90% of the drugs tested for Alzheimer during the last 10 years have veen utter and abject failure. This is a pretty solid indication that the theory of Alzheimer's pathology and proposed beneficial pathways on which these drugs were based is solidly wrong.
Since 2002, 99%+ of Alzheimer Disease trials have failed

Aside from the failure of all of these drugs, it is quite common to treat Alzheimer patients with SSRI drugs to "improve" their mood and claims have been made that SSRI would even improve cognition. Nothing short of abomination, considering something as simple as aspirin can probably cure the condition.
salicylate for alzheimers (Aspirin)
Aspirin Effective For Alzheimer, Parkinson And Huntington
Chronic Aspirin Ingestion Improves Spatial Learning In Adult And Aged Rats


As the saying goes, "no matter how beautiful the theory, you have to acknowledge reality sometimes", and so it seems that finally Big Pharma is embarking on the right path. Of course, none of this publicly acknowledged and officially new drugs that act in ways opposite to SSRI or the cholinergic poisons used for the last 20 years, are presented as "modulators" rather than as antagonists. Be that as it may, the latest trial used the drug idalopirdine that is a very specific and direct serotonin antagonist, and was found beneficial for people with Alzheimer's. While the PR articles dances carefully around the issue of serotonin "modulation" the study authors state directly that serotonin antagonism can be a viable therapy for Alzheimer's. No wonder cyproheptadine disappeared from the pharmacies of Europe and USA. It won't be long before we see it sold as off-label treatment for the low cost of $9,899/month.

Idalopirdine - Wikipedia, the free encyclopedia
Cognition Enhancer Promising in Alzheimer's

"...A drug targeting the 5HT-6 serotonin receptor, when added to donepezil (Aricept) in patients with moderate Alzheimer's disease, significantly slowed cognitive decline compared with donepezil alone, a researcher reported here. Patients receiving idalopirdine plus donepezil for 24 weeks in a phase II trial showed a 0.77-point improvement from baseline in ADAS-Cog scores, compared with a 1.38-point worsening in scores among patients taking donepezil plus placebo, reported Alireza Atri, MD, PhD, of California Pacific Medical Center in San Francisco."

"...Idalopirdine is not intended to be a disease-modifying agent, he explained. Preclinical evidence had suggested that the 5HT-6 receptor modulates a variety of neurotransmitter systems involved in cognition -- including glutamatergic and GABAergic pathways -- such that a selective antagonist could improve cognitive function with a different mechanism than current drugs such as memantine (Namenda) and acetylcholinesterase inhibitors. As such, idalopirdine could serve as an add-on drug to current agents as well as future disease-modifying drugs, Atri said."


Interperdine is another 5ht6 receptor antagonist that is in phase 3 studies for alzheimers and phase 2 studies for demenia with lewy bodies....
 

haidut

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Interperdine just announced as a failure in Phase 3 studies: Roivant receives bad news — and so does SoftBank

As I said in the other thread - could be dose-related. Pfizer continues to run a few other AD trials with idalopirdine and latrepirdine, which are due to report in early 2018. All of these drugs passed phase II, so it is strange that they will fail phase III. Could still be beneficial for a subset of the population as that is what phase II actually amounts to.
 

jyb

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Patent EP0214557A2 - Use of serotonin antagonists, particularly cyproheptadine, in the treatment of cancer, Alzheimer's disease, AIDS and multiple sclerosis

But it seems like people are not keen as they worry about anticholinergic substances. Typical opinion:
Cognitive impairment and dementia in older adults have been linked to anticholinergic drugs, which block the neurotransmitter acetylcholine, in an increasing number of studies over the last decade. Some popular antihistamines, antidepressants, and anti-nausea meds used as migraine drugs have anticholinergic effects.
from Some Migraine Drugs Linked to Cognitive Impairment, Dementia in Older Adults

I wonder where this association comes from.
 
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haidut

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The anticholinergic drugs are actually useful for treating dementia like AD. The currently approved drug memantine is anticholinergic. I would like to see a trial on that as opposed to epidemiological study. No known mechanism exists for anticholinergic drugs directly causing dementia.
 

Mito

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The anticholinergic drugs are actually useful for treating dementia like AD. The currently approved drug memantine is anticholinergic. I would like to see a trial on that as opposed to epidemiological study. No known mechanism exists for anticholinergic drugs directly causing dementia.

Original Investigation
June 24, 2019
Anticholinergic Drug Exposure and the Risk of Dementia

Conclusions and Relevance
Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.
 

haidut

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Original Investigation
June 24, 2019
Anticholinergic Drug Exposure and the Risk of Dementia

Conclusions and Relevance
Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

Yes, I saw that. It is an observational study and the fat that both memantine and amantadine (which are approved for AD) are anticholinergics suggests the dementia link is likely due to some other factor the observational study could not control for.
 

Experienced

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Yes, I saw that. It is an observational study and the fat that both memantine and amantadine (which are approved for AD) are anticholinergics suggests the dementia link is likely due to some other factor the observational study could not control for.
Hey @haidut my grandma is in her early dementia :( what am I able to give her I've bought some ginkgo and she is prescribed with donepezil + memantin . What about Lion's mane or L-Theanine? What do you or know recommending me?
 

haidut

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Hey @haidut my grandma is in her early dementia :( what am I able to give her I've bought some ginkgo and she is prescribed with donepezil + memantin . What about Lion's mane or L-Theanine? What do you or know recommending me?

There are human trials with methylene blue and even aspirin for AD. So, that's what I would try first. Anti-serotonin chemicals have also been tried on humans with some success so adding cyproheptadine or another similar chemical may help too. Of course, ask a doctor before you engage into any of this.
 
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