Wednesday, October 21, 2015

parkinson's: nilotinib, PP2A, AMPK, c-Abl tyrosine kinase inhibitors for parkinson's

Protocol to amplify nilotinib: take with 2 grapefruit, naringin, pepper/peperine, and curcumin, all to inhibit CYP3A enzyme that degrades it. Grapefruit by itself, about 30% more. The low pH (1.5) helps absorption, maybe 50%.  Take with food, about 50% more exposure. All in all, I might hope for a double or triple increase.  I need to take 50 mg twice a day to hopefully get 200 mg equivalent. Headache and nausea are most common symptoms.  Also maybe alcohol to increase capability of cells to remove a-Syn, along with other compounds that can remove a-Syn..

Posts to healthunlocked:

Concerning nilotinib in 12 PD patients: This work says they gave it at 1/5 to 1/3 normal doses, and in looking at the animal studies that led to this research, I see they were giving only 1/50 in human-equivalent doses. It looks like it should have noticeable benefit at only 15 mg instead of 150 mg.

Here's the work in mice:

They are saying not just Nilotinib (generic form of Tasigna) but also Bosutinib. 
The method of action is c-Abl inhibition. The connection with Parkinson's was discovered 5 years ago by John Hopkins. There have been 14 papers since then with on "c-Abl parkinson's" in the abstract or title, and none before.
Two years ago, this group tried this drug in mice. 
Any nutrient or drug capable of c-Abl inhibition probably works.
The two research groups that previously published on the c-Abl connection have jumped on this treatment, testing it in mice.  Here's their research papers:
The John Hopkins group was first to discover the c-Abl inhibition benefits:
The Japan group soon followed:
Then this group identified the existing drug that does it.
I'll be researching if any natural nutrients can also do it.  Yes, metacognito, there is a bioavailable form of fake-curcumin that does it.
These are the c-Abl inhibitors, most used for leukemia. Blocking c-Abl may help get rid of the bad a-syn, but c-Abl is also used for "neuronal plasticity, neurite outgrowth, and neurogenesis" and "required for optimal synaptic function"  so taking too much of it is not good for the brain.
 Keep in mind that lower doses are needed for PD, so the toxicity dangers are not as great as the ones I've pointed out.  
Switching from one to the other may be important as the body develops protection mechanisms against them.  So if you have 3 choices, you would try to alternate them every 3 months or something like that.

Nilotinib seems to be the one of choice due to less toxicity.  Price might be in the $100,000 a year range.  PD patients should not expect it to be less because the Pharmaceutical might require off-label use to charge 10x more even if you use 10x less.  They charge based on patient desperation and ability to pay, not based on cost to develop.  It does not matter if all their costs were paid by taxpayers through research grants.  Grapefruit "interferes" with it as it is a substrate of the protein CYP3A4 that grapefruit blocks.   I believe this means grapefruit will make a lower dose more powerful (more bioavailable for its benefits as well as its toxicity).  I did not know if the others are also affected by grapefruit.  There are "competing" pharmaceuticals, but it seems they all want $100,000 to take these drugs.  Be "thankful": I know a baby who had brain-damaging seizures and it was costing $50,000 a WEEK and was known to probably not work.  "Dude, get this $50,000 glass vial (1 teaspoon) out of my hand before I drop it. That's not funny putting something like that in my hand and then telling me what it is."

imatinib, the original, not as good as the others.  $100,000 a year for leukemia patients. Does not efficiently cross blood-brain barrier in humans.

Ponatinib (Ariad pharmaceuticals), works good, but was halted in U.S. due to toxicity (blood clots). Still available in U.K. to leukemia cancer patients.  Cost would have been about $100,000.

Bosutinib, may not be good because it stops the bad-protein removal mechanisms, even as it dissolves a-syn. Maybe at lower doses it is OK.  But it worked in mice when it was being compared to nilotinib.

Bafetinib (INNO-406) newer, looks good, may not be available.  Efficiently crosses blood brain barrier.  Molecular weight is 576.  Tested in PD mice:

Dasatinib (Bristol-Meyers).  looks good except can have several fluid on lung build up in 20% of patients on the high doses needed for leukemia. 15% lower molecular weight than bafetinib (488), so may cross blood-brain barrier. It has a lot of studies on it for PD, but I noticed one seems to claim it did not work as well as bafetinib.  U.S. gov is trying to stop indian manufacturers from making it in order to maintain Bristol-Meyers patent rights.  $133,000 a year for leukemia patients.  $1,500 a year in India if they are getting around the patents.  Same situation for rasagiline, $50 a year in india, several thousand here.   Almost all of Bristol-Meyers cost in developing it came from tax payers through NIH research grants and a 50% tax CREDIT (which can lead to tax REFUNDS). 
Green tea extract, olive oil, and fake-curcumins are so far the only compounds I can find that also inhibit c-Abl. 
If you've read my posts you know I believe there is a connection between PD and cancer.  Viruses and mitochondria dysfunction are two connections. This c-Abl connection is another:  "The c-Abl kinase protein is one of the most studied targets in the fight against cancer and is a hotspot for drug development because it participates in several solid tumors and is the hallmark of chronic myelogenous leukemia."
I keep repeating the lack of oxygen increases PD progression.  It turns out intermittent hypoxia (as may occur every night when we sleep) increases c-Abl.
Several of us use a stationary bicycle.  I have found that I need at least an hour a day of > 120 beats per minute heart rate to see improvement. At 30 minutes per day, it appears that I get worse.  At 1 hour per day I start getting better in every way.  My impression is that if I were able to do 2 hours per day, my PD symptoms would disappear and not return.  No exercise leads to a decline in everyway. 
Switching from 30 minutes to 1 hour has immediate benefits such as better mood and more energy, but then it is easy to digress back to zero exercise because skipping a day has no noticeable detriment.  Continuing with 1 hour per day for more than a few days becomes boring and I do not notice I feel better afterwards, but that is because I feel better BEFORE the exercise already because of the previous days' exercise.  After about 1 month of 1 hour per day, I suddenly realize I had not thought about PD for the past few days because no symptoms were bothering me.
Exercise increases AMPK which helps break down proteins like a-Syn.  Exercise also increases heat shock proteins that carry the broken pieces of the a-Syn out of the cell. 
Nilotinib also increases AMPK (also decreases PP2A which increases activity of AMPK and thereby slows cancers) and is almost assuredly how it appears to reverse symptoms. In other words, nilotinib may be a way to get the benefits of exercise (in regards to PD) without exercising, which is crucial in severe cases. 
EHT in coffee methylates PP2A which increases its activity and this appears to be why coffee reduces Alzheimer's and PD.  

So nilotinib decreases PP2A and coffee increases.  PP2A blocks nilotinib's effects on AMPK. So taking coffee with nilotinib may decrease its benefits.

So activation or deactivation of PP2A could help PD by stopping a-Syn aggregation.  This confusion was mentioned in wiki article on PP2A that referenced these articles

=========== from a patent forum:
As a physician and also a patient with advanced Parkinson disease (PD), I recognized the originality and merit of Dr. Charbel Moussa's proposal to treat PD with nilotinib, or a similar tyrosine kinase inhibitor (TKI), by employing low-level cellular autophagy to clear out the accumulated toxic alpha-synuclein (ASN) protein which is the pathological cause of death in affected neurons. Dr. Moussa published a paper in 2013 which related his theories regarding the therapeutic potential of TKI's in PD and similar neurodegenerative diseases, and which documented dramatic reversal of PD in mice he treated with nilotinib. This paper was not his first on this topic, but it was the first time I was aware of his work and it convinced me that, if he could repeat those results in humans, he would be the first scientist to reverse the underlying course of PD in humans. This development, when fully proven in humans, will be one of the most significant advances in medical history and will certainly be awarded the Nobel prize in medicine. I would probably be taking nilotinib now, off label and self-prescribed based on Dr. Moussa's work, were it not for a rare but often fatal side-effect of nilotinib known as torsade de pointes (or just torsade), a cardiac arrhythmia that can strike suddenly and with little symptomatic warning.
Torsade, though, is predictably associated with a finding on the patient's electrocardiogram (ECG) called QT interval prolongation. Drugs that increase the risk of torsade do so by prolonging the QT interval, in a dose-dependent manner. Dr. Moussa addressed this concern by stating in his paper that the dose of nilotinib required to stimulate therapeutic autophagy in the brain of a PD patient would be substantially lower than the dose used to treat cancer patients, and that even at the full anti-cancer dose, torsade was a rare event. However, PD is known to cause the loss of autonomic sympathetic innervation to the heart, which contributes to the dangerous drops in blood pressure in advanced PD. Loss of sympathetic innervation might, in turn, result in the increased production of catecholamine receptors in denervated cardiac myocytes, thus potentially increasing their susceptibility to torsade, triggered by circulating catecholamines.
So, my specific question regarding patent WO2013166295A1 is this: what is the effect of nilotinib treatment on the QT interval (and thus, the likelihood of torsade) in PD patients treated with the reduced dose? The answer can be found by calculating the change in the QT interval in advanced PD patients treated with nilotinib. This calculation consists simply of subtracting the measured QT interval before administration of nilotinib from the measured QT interval during steady-state therapeutic dosing for each patient treated for advanced PD. The larger this increase in the QT interval, the greater the increased risk of torsade. Ideally, there would be no increase in the QT interval, but if so, the patient can be monitored more carefully and treated with medications to reduce the risk of torsade, such supplemental magnesium, potassium and beta-blockers if indicated.
Thank you for the opportunity to post this question, and I wish much continued success to Dr. Moussa and his research group at Georgetown University.

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