691 replies to this topic

[Library]

Nicotine --- not 3A4.
Its 1A2.


https://www.ncbi.nlm...?report=classic

---Library

[MarcB]

This study seems to bee the most promising.

 

A study by Prothena Corporation, in collaboration with Roche, of a monoclonal antibody, PRX002, also known as RG7935, which, from the phase 1b trial, as reported Nov, 9, 2016, DUBLIN, IRELAND GLOBE NEWSWIRE, “…reduction in levels of free serum alpha-synuclein of up to 97%...within one hour… after a single dose.”

 

http://alanhobbes.bl...prx002-and.html

 

http://ir.prothena.c...eleaseid=998603

 

[Library]

CYP 450 enzymes and Nilotinib


Why you need to check out all your prescription meds before you take Nilotinib
http://www.straighth...e-p450-3a4.html

Medications that are inhibitors of CYP 3A4
turn off the enzymes that get Nilotinib out of your body, so it accumulates to an overdose. Do not mix! Discontinue two weeks to a month before starting Nilotinib.

Medications that are substrates of CYP 3A4
compete with Nilotinib for the necessary enzymes and use them up, causing a shortage of them, so that Nilotinib also accumulates to an overdose. Do not mix! Discontinue two weeks to a month before starting Nilotinib.

***Unfortunately, more prescription medications require CYP 3A4 than any other enzyme.***


Introduction to CYP 3A4
http://www.pharmacyt...09/2008-09-8687

CYP 450 enzymes - Rx list
https://ctep.cancer....docs/cyp3a4.doc

CYP 450 enzymes - Searchable data base
http://bioinformatic...ite=drug_search



herbal supplements


While prescription drugs must determine their enzyme requirements prior to market,
nobody owns or is responsible to determine the requirements for supplements.

So, with hundreds of chemical components per each and their enzyme requirements unknown, nobody knows if any of the supplements' components are inhibitors or substrates of CYP 3A4 or not.
Therefore, any could be dangerous. This is why doctors (quite reasonably) have such a strong negative reaction to them.


Here are the enzymes for a very few:

https://www.hindawi....am/2015/736431/


----Library

[Library]

Has anyone heard of any interaction with rasagiline and N? I did notice that in the original Georgetown trial rasagiline was allowed, but the latest one (https://clinicaltria...how/NCT02954978) says " No mono-amine oxidase (MAO)-B inhibitors (Selegeline or rasagiline) are allowed at least 6 weeks before enrollment".

- splib

[Library]

https://www.research...iver_Microsomes


1. MAO-B inhibitors keep L Dopa and others around longer. Nilotinib reduces the need for L Dopa and the higher levels of L Dopa that results is neurologically toxic.
2. Metabolites of Selegiline (the body changes Selegiline to a different chemical) require CYP 3A4 to get rid of, so taking it with Nilotinib causes accumulation, overdose. 6-weeks is the wash-out requirement.

Rasagiline
Ther Clin Risk Manag. 2007 Jun; 3(3):467-474

Unlike Selegiline, Rasagiline is not metabolized to potentially toxic amphetamine metabolites and requires CYP 1A2 (like Nicotine) instead of 3A4. However, as Nilotinib increases dopamine levels, dose reduction of Rasagiline would be needed as therapy proceeds.

---Library

[bossmanglb]

I have ~19.8g of Nilotinib from Group Buy #3 that I am willing to sell. Please PM

[Logic]

I never finished my last post?:

... wouldnt count on it.

Its great for stripping away the lipid layer = virus's disguise as a ...nutrient IIRC, exposing virii, and bacteria with similar tricks, to the immune system however.

Considering the many papers on links between dementias and pathogens its something thats worth having around...

 

Thx for all the info Library.

 

Interesting link MarcB.
I hope Resveratrol Guy chips in here.  IIRC he's done a lot of research in this area.

 
 

[centralFloridaMan]

I have 80 grams of nilotinib that i have decided not to use for now.  I will sell the lot for $5 per gram. please pm me.

[MarcB]

I never finished my last post?:

... wouldnt count on it.

Its great for stripping away the lipid layer = virus's disguise as a ...nutrient IIRC, exposing virii, and bacteria with similar tricks, to the immune system however.

Considering the many papers on links between dementias and pathogens its something thats worth having around...

 

Thx for all the info Library.

 

Interesting link MarcB.
I hope Resveratrol Guy chips in here.  IIRC he's done a lot of research in this area.

 
 

 

A PD neurologist, who is not involved in the trial, but who works at one of the trial locations with those who are involved, told one of his pwp patients (who told me) that if the data holds up, this will be FDA approved and on the market in two years.  I, of course, don't know.  I'm just passing what I was told, but the person who told me pressed his doctor and says the doctor believed it.  HOPE LIVES.  

[centralFloridaMan]

I believe that MarcB is referring to me.  The neurologist mentioned is in charge of the study at his location and is very excited about the results, not just safety but improvements they saw in the participants.  He did indicate to me that he anticipated fast track status for prx002.  Of course as marcb pointed out nothing is for sure.  However, it looks very hopeful.   Incidentally i posted this info some months ago and got no reaction form the members of the forum.

[splib]

Thanks for the information Library!

 

[togl]

Hi, question about the straight healthcare listing of drug interactions - nilotinib is not listed as a substrate, but as a weak inhibitor... Is this an oversight or does it mean it is metabolized in some other way? Thanks!

[richard hnry]

I believe that MarcB is referring to me.  The neurologist mentioned is in charge of the study at his location and is very excited about the results, not just safety but improvements they saw in the participants.  He did indicate to me that he anticipated fast track status for prx002.  Of course as marcb pointed out nothing is for sure.  However, it looks very hopeful.   Incidentally i posted this info some months ago and got no reaction form the members of the forum.

 

Godspeed prx002.  It looks really good.  I bet if one could clean out 97% of the alpha synuclein it would suffice for a long time and provide relief.  What I mean is we would not need to go through the process of administering the prx002 and go through the side effects over and over again.  It should work for an extended term unlike Nilotnib which needs to be taken daily.  I wonder how much alpha synuclein Nilotnib removes per weekly dose for example?  That would be an interesting piece of information.

[centralFloridaMan]

It is encouraging that prx002 does such a good job removing alpha synuclein from the brain and, indeed, seems to target the same culprit that it appears causes neuron cell death as nilotinib.  While there are good signs that there is a link between alpha synuclein and disease modification, there is no conclusive evidence that the link exists.  Nonetheless it appears that there is a lot of reason for hope.  I just wish that they would hurry  up!!!!!

[Library]

Hi, question about the straight healthcare listing of drug interactions - nilotinib is not listed as a substrate, but as a weak inhibitor... Is this an oversight or does it mean it is metabolized in some other way? Thanks!

[Library]

Nilotinib is both inhibitor and substrate for 3A4.

There are 2 plug-in places on the enzyme.


Inhibition: One molecule of Nilotinib plugs up one part of the 3A4 enzyme so the substrate place doesn't work.
Substrate: So another molecule needs to find an un-plugged one so it can plug into the substrate place to get processed.
This cuts down on enzyme availability and slows down getting it out of the body.

Nilotinib already has a very long half-life (~17 hr.)

With Nilotinib's inhibition+substrate problem, any other drugs competing with it for 3A4 will make the slow-down even worse, Nilotinib will accumulate and sudden death from its side effect of prolonging the QT interval becomes increasingly likely.

This is why it is so life-or-death important that you don't take any drugs,* herbs, nutraceuticals, foods that compete with Nilotinib for 3A4. Its already competing with itself so any additional completion endangers your life.

*Half of all Rx drugs will compete for 3A4.


---Library

[togl]

Thanks for the great info, library.

[togl]

Thanks for the great info, Library.

[Library]

MORE...."Before you take Nilotinib......"




I. Interaction checker

https://www.drugs.co...x.html?filter=3

940 drugs that interact
5376 brand names and generic names of drugs
203 major interactions

II. CYP enzymes

Inhibitors:

3A4 (MOST IMPORTANT)

Others:

2C8
2C9
2D6

Inducers:

2B6

III. Other Considerations:

1. No proton pump inhibitors at all. None.
(affects Nilotinib solubility)

2. No antacids 10 hr before taking Nilotinib.

3. Food makes Nilotinib more bioavailable, increasing
the QT interval and therefore odds of sudden death.
Take ONLY on an empty stomach.

4. Nilotinib has a black box warning. It has caused sudden death (heart attack).

After taking it for 7 days, get an EKG to be sure the interval has not been increased.
If it has become longer than 480 milliseconds, STOP Nilotinib.
Do not resume, even if the interval has shortened to 480 milliseconds and even at a greatly reduced dose-- without 1. a work-up from a Cardiologist AND 2. the supervision of an Oncologist.

5. Many drugs ALSO prolong the QT interval, so check out every Rx. The effect of a second drug that also prolongs the interval (in addition to Nilotinib) is additive. Danger! Avoid !!! (See the last reference below).


IV. Advanced Information on Nilotinib metabolism


(The more you know about it, the more you understand why your doctor hits the ceiling when you tell them you plan to take Nilotinib unsupervised.)


1. Explains the 4 kinds of inhibition

http://what-when-how...abolism-part-1/


2. The influence of 3A4 inhibition

https://www.research...b5923000000.pdf


3. Drug interactions of Tyrosine Kinase Inhibitors (Nilotinib)


Includes some drugs that prolong the QT interval (avoid!!)


http://www.gistespañ...uala-e75-87.pdf


-----Library

[MarcB]

 

I believe that MarcB is referring to me.  The neurologist mentioned is in charge of the study at his location and is very excited about the results, not just safety but improvements they saw in the participants.  He did indicate to me that he anticipated fast track status for prx002.  Of course as marcb pointed out nothing is for sure.  However, it looks very hopeful.   Incidentally i posted this info some months ago and got no reaction form the members of the forum.

 

Godspeed prx002.  It looks really good.  I bet if one could clean out 97% of the alpha synuclein it would suffice for a long time and provide relief.  What I mean is we would not need to go through the process of administering the prx002 and go through the side effects over and over again.  It should work for an extended term unlike Nilotnib which needs to be taken daily.  I wonder how much alpha synuclein Nilotnib removes per weekly dose for example?  That would be an interesting piece of information.

 

 

The half life is 18 days, so he dose is expected to be once every 28 days
 

[Linda Gray]

Is prx002 currently being prescribed for anything else?

[MarcB]

Is prx002 currently being prescribed for anything else?

 

I don't know, but from what I've read so far, it sounds like it   was developed for PD.  If it is already on the market, it would be under a different name.

 

About PRX002 (RG7935)

 

PRX002 is a monoclonal antibody under development for the potential treatment of Parkinson's disease. PRX002 targets alpha-synuclein and is designed to slow the progressive neurodegeneration associated with alpha-synuclein misfolding and/or the cell-to-cell transmission of the aggregated pathogenic forms of alpha-synuclein found in Parkinson's disease and other synucleinopathies. Prior to initiating clinical trials, Prothena demonstrated the efficacy of PRX002 in various cellular and animal models of alpha-synuclein-related disease. In multiple transgenic mouse models of Parkinson's disease, passive immunization with 9E4, the murine version of PRX002, reduced the appearance of alpha-synuclein pathology, protected synapses and improved performance in behavioral testing. In December 2013 Prothena and Roche entered into a worldwide collaboration to develop and commercialize antibodies that target alpha-synuclein, including PRX002. Prothena has an option to co-promote PRX002 in the U.S., where the companies share all development and commercialization costs, as well as profits, on a 30/70 basis (30 percent Prothena, 70 percent Roche). Outside the U.S., Roche will have sole responsibility for developing and commercializing PRX002 and will pay Prothena up to double-digit royalties on net sales. A Phase 2 clinical study of PRX002 in patients with Parkinson's disease is expected to begin in 2017.

 

http://ir.prothena.c...eleaseid=998603

 

Here's a good, comprehensive link.

 

http://alanhobbes.bl...prx002-and.html

 

 

 

 

Is prx002 currently being prescribed for anything else?

 

I don't know, but from what I've read so far, it sounds like it   was developed for PD.  If it is already on the market, it would be under a different name.

 

About PRX002 (RG7935)

 

PRX002 is a monoclonal antibody under development for the potential treatment of Parkinson's disease. PRX002 targets alpha-synuclein and is designed to slow the progressive neurodegeneration associated with alpha-synuclein misfolding and/or the cell-to-cell transmission of the aggregated pathogenic forms of alpha-synuclein found in Parkinson's disease and other synucleinopathies. Prior to initiating clinical trials, Prothena demonstrated the efficacy of PRX002 in various cellular and animal models of alpha-synuclein-related disease. In multiple transgenic mouse models of Parkinson's disease, passive immunization with 9E4, the murine version of PRX002, reduced the appearance of alpha-synuclein pathology, protected synapses and improved performance in behavioral testing. In December 2013 Prothena and Roche entered into a worldwide collaboration to develop and commercialize antibodies that target alpha-synuclein, including PRX002. Prothena has an option to co-promote PRX002 in the U.S., where the companies share all development and commercialization costs, as well as profits, on a 30/70 basis (30 percent Prothena, 70 percent Roche). Outside the U.S., Roche will have sole responsibility for developing and commercializing PRX002 and will pay Prothena up to double-digit royalties on net sales. A Phase 2 clinical study of PRX002 in patients with Parkinson's disease is expected to begin in 2017.

 

http://ir.prothena.c...eleaseid=998603

 

Here's a good, comprehensive link.

 

http://alanhobbes.bl...prx002-and.html

 

 

Edited by MarcB, 22 December 2016 - 05:18 PM.

[richard hnry]

It is encouraging that prx002 does such a good job removing alpha synuclein from the brain and, indeed, seems to target the same culprit that it appears causes neuron cell death as nilotinib.  While there are good signs that there is a link between alpha synuclein and disease modification, there is no conclusive evidence that the link exists.  Nonetheless it appears that there is a lot of reason for hope.  I just wish that they would hurry  up!!!!!

 

So do I.  I think they are on to something for the first time.
 

[mlsirkis]

http://www.medicalne...cles/314786.php
Yes they are figuring it out.

[richard hnry]

Great article.  I hope we can buy this PREP enzyme blocker and get the same results the mice had.  It is giving me hope.

http://www.medicalne...cles/314786.php
Yes they are figuring it out.

 

[Rawin]

It looks promising, I hope we can buy some of this enzime to do research.

[45rpm]

Speaking of PREP enzyme blockers and inhibitors, Wikipedia lists several others, some of which are familiar to many of us on this site.

 

• Pramiracetam
• Baicalin
• JTP-4819
• KYP-2047
• S-17092
• Berberine

 

 

[45rpm]

A couple years ago, I gave my mother one of the above substances for a month and didn't see any improvement,

 

I gave her Baicalin, also known as Chinese Skullcap.

 

But it does look like a promising agent to prevent Parkinson's and Alzheimers.

 

 

"In a rat model, Baicalein has been shown to prevent the build up of amyloid beta peptide (Abeta), which is known to generate free radical damage to brain cells and participate to a significant degree in the development and progression of Alzheimer’s disease.  Additionally, chronic inflammation occurs in Alzheimer’s pathogenesis and Baicalein was shown to inhibit the 12- lipoxygenase enzyme responsible for brain inflammation, to a large degree.  When tested against other known 12-lipoxygenase inhibitor agents, only Baicalein was able to attenuate both nerve cell death (apoptosis) and over-expression of Abeta production.  As such, Baicalein may help to prevent or forestall the development of Alzheimer’s disease by reducing the build up of the toxic brain protein, Abeta and inflammatory mediators, and preventing brain cell death, which has been shown to be triggered by the accumulation of Abeta in affected brain cells.³⁸  In studies using human neuroblastoma cells, the antioxidant properties of Baicalein were shown to inhibit free radical damage to these nerve cells induced by treatment with hydrogen peroxide (a powerful free radical generating agent).  The researchers argue that oxidative  (free radical) stress plays an important role in the development of neurodegenerative diseases (e.g. Alzheimer’s disease, Multiple Sclerosis, Parkinson’s disease) and that antioxidants such as Baicalein and Quercetin (also a flavonoid) may be useful bioactive agents in the prevention and/or management of these conditions, pending further studies.  Both of these flavonoids have shown impressive protective effects under experimental conditions.^"

 

http://www.meschinoh...ancer_Treatment

 

[richard hnry]

It looks promising, I hope we can buy some of this enzime to do research.

It looks like the original work was done in 2012 https://www.ncbi.nlm...pubmed/22233220  I was under the impression that this was new but it is about 4 years old.  

I hope they have continued to develop it so it can be used for therapy.

[khalidnt]

 

Speaking of PREP enzyme blockers and inhibitors, Wikipedia lists several others, some of which are familiar to many of us on this site.

 

• Pramiracetam
• Baicalin
• JTP-4819
• KYP-2047
• S-17092
• Berberine

 

 

Great information 45rpm,  I will try "Baicalin" I just place in-order in Amazon.com.

 

For "Berberine" it has bad side effect. May Allah help us to find a cure.