7 replies to this topic

[Pantheon]

Ninotinib (sold as Tasigna by Novartis) is a type of biological therapy called a tyrosine kinase inhibitor (TKI).  Nilotinib blocks a tyrosine kinase protein called Bcr-Abl. The protein is made by chronic myeloid leukaemia cells that have an abnormal chromosome called the Philadelphia chromosome. Blocking this protein stops the leukaemia cells growing.

 

A study conducted at Georgetown (published July 11, 2016 in the Journal of Parkinson’s Disease) providing molecular evidence that nilotinib significantly increased brain dopamine (the chemical lost as a result of neuronal destruction) and reduced toxic proteins linked to disease progression in Parkinson’s disease or dementia with Lewy bodies.

http://content.iospr...sease/jpd160867

 

Currently Nilotinib is not prescribed for Parkinson’s or any other Neurodegenerative disease. The clinical trial is in phase II, designed to evaluate the safety and tolerability of low doses of nilotinib, the efficacy on disease biomarkers, and clinical outcomes in people with mid-stage Parkinson’s disease.  

https://gumc.georget...kinsons-disease

 

The question remains whether patients with Parkinson’s, MSA, or other synucleinopathies and neurodegenerative diseases can benefit from NATURAL BCR-ABL TKI ALTERNATIVES which may delay the progression of their disease.

 

Some of the natural candidates based on current studies are the following:

 

1) Xanthohumol (Flavonoid  from hops)

 

Antileukemia effects of Xanthohumol in BCR/ABL-transformed cells involve nuclear factor-kappaB and p53 modulation.
https://www.ncbi.nlm...pubmed/18790751

 

2) Curcumin 
(possibly in the form of Longvida Curcumin, as it can cross the BBB)

 

Curcumin inhibits proliferation and induces apoptosis of leukemic cells expressing wild-type or T315I-BCR-ABL and prolongs survival of mice with acute lymphoblastic leukemia

https://www.ncbi.nlm...pubmed/19055861

 

3) Genistein (Isoflavone from Soy)

 

Genistein exerts anti-leukemic effects on genetically different acute myeloid leukemia cell lines by inhibiting protein synthesis and cell proliferation while inducing apoptosis

https://www.ncbi.nlm...les/PMC4381704/

 

Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic myelogenous leukemia patients after in vitro treatment with the tyrosine kinase inhibitor genistein.

https://www.ncbi.nlm.../pubmed/8874208

 

4) Pterostilbene

 

Pterostilbene and 3'-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells.
https://www.ncbi.nlm...pubmed/15878840

 

5) Galangin (Flavonoid)

 

Galangin increases the cytotoxic activity of imatinib mesylate in imatinib-sensitive and imatinib-resistant BCR-ABL expressing leukemia cells.

https://www.ncbi.nlm...pubmed/18374481

 

6) EGCG

 

A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia
https://www.ncbi.nlm...pubmed/25825203

 

7) Oleic Acid

 

Oleic acid is the active component in the mushroom Daedalea gibbosa inhibiting BCR-ABL kinase autophosphorylation activity.
https://www.ncbi.nlm...pubmed/21273596

 

Certain other Flavonoids & Polyphenols like Myricetin, Apigenin, Nobiletin (Tangerine) may influence the bcr-abl overexpression or provide other benefits via their antioxidant, anti-inflammatory and possibly neuroprotective abilities.

 

Large scale human studies may provide further evidence whether any of those natural compounds and nutrients can synergistically or alone act as natural alternatives for the treatment of currently untreated neurodegenerative diseases at far less cost than promising patented synthetic drugs like Nilotinib and with probably less side effects.

 

Edited by Pantheon, 05 June 2017 - 05:31 PM.

[MarcB]

Thank you for this.  a lot to digest.  Do you have any thoughts or experience with any of these?  The only one I've previously researched is Curumin.

[Pantheon]

A possible synergistic action of certain flavonoids and other potent natural compounds may be more effective treatment against potent neurodegenerative diseases. Unfortunately many of the current studies are limited to animal models and the few human studies usually involve a small number of subjects. After all inexpensive and possibly safer Natural compounds are not a multi-billion industry for pharmaceuticals if they cannot be patented.

 

There is some compelling evidence however backed by current research data that certain natural compounds and Tyrosine Kinase Inhibitors (TKI), like  Nobiletin (not the same as Nilotinib) and Tangeretin , polymethoxylated flavonoids found in citrus fruit peel, can exhibit biological activities including antioxidant, anti-inflammation and anticancer properties.

https://www.ncbi.nlm...les/PMC5059563/

 

Nobiletin (C₂₁H₂₂O₈) and Tangeretin (C₂₀H₂₀O₇) are natural citrus flavonoids with potent biological activities. These small molecules are referenced in over 400 articles and studies on Pubmed.

 

Neuroprotective Effects of Citrus Fruit-Derived Flavonoids, Nobiletin and Tangeretin in Alzheimer's and Parkinson`s disease.

https://www.ncbi.nlm...pubmed/28474543

 

Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease.

https://www.ncbi.nlm...pubmed/25325362

 

Nobiletin treatment (10 mg/kg bw, rat model), significantly protected DA neurons in the substantia nigra (SN) of MPP(+)-treated rats. In parallel to the neuroprotection, Nobiletin treatment at 10 mg/kg inhibited microglial activation and preserved the expression of the glial cell line-derived neurotrophic factor, which is a therapeutic agent against PD, in the SN

 

Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

https://www.ncbi.nlm...pubmed/24316474

 

Nobiletin administration (50mg/kg i.p., mouse model) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal.  MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1.

 

Bioavailability of Citrus Polymethoxylated Flavones (Nobiletin & Tangeretin) and the Role in Metabolic Syndrome and Hyperlipidemia (Human Study)

http://cdn.intechope.../pdfs/35687.pdf

 

So how natural compounds compare to chemical compounds like Nilotinib?

 

Nilotinib (C₂₈H₂₂F₃N₇O) is a selective Bcr-Abl kinase inhibitor mainly designed for the treatment of resistant chronic myelogenous leukemia (CML).  A clinical Trial will examine the impact of Nilotinib as a PD repurposed drug on the Safety, Tolerability, Pharmacokinetics and Biomarkers in Parkinson's disease. The estimated study completion date is July 2020.

https://clinicaltria...udy/NCT02954978

 

The Abl Kinase Hypothesis & PD:

 

It was hypothesized in the first clinical trial of Nilotinib  that "Nilotinib enters the brain and inhibits Abl in PD and DLB patients, leading to reduction of oxidative stress and protection of DA neurons".

 

If this hypothesis proves to be correct in the second phase of the clinical trial, then it is highly possible that a synergy of potent Natural compounds, capable of targeting the Abl Kinase directly or through multiple signaling pathways, can exhibit similar or superior biological effects in neurodegenerative diseases, such as Parkinson's, with less or no side effects compared to existing synthetic drugs.

 

A growing list of inexpensive Natural compounds such as Flavonoids, Alkaloids, Terpenoids, Polyketides, Lignans, Saponins, Peptides and plant extracts have exhibited potent anti-CM leukemia activity in addition to their anti-inflammation and antioxidant action.

 

If Nilotinib, an expensive drug used for the treatment of chronic myelogenous leukemia, proved to be effective in the treatment of PD and other neurodegenerative diseases, then it is possible  that certain natural compounds with potent anti-CM leukemia properties may exhibit comparable biological activities and should be studied as safer and inexpensive natural alternatives.

 

The following article describes many of those potent Natural compounds, including the IC50 levels of each compound, a measure of how effective a compound is (the lower the better), and their possible mechanism of action:

 

Natural Products for Treatment of Chronic Myeloid Leukemia

https://www.intechop...yeloid-leukemia

 

 

 

 

Edited by Pantheon, 26 July 2017 - 10:37 PM.

[khalidnt]

Hello Pantheon,

 

Interesting topic, if Nobiletin a novel substance why there is no Clinical Trial!   

 

I did more research regarding Nobiletin and Tangeretin. The challenge there is no link between Nobiletin and PD inhibitors. Nobiletin can cross BB to improve the memory.

 

I requested both for testing@

 

Regards,

 

 

[Ibbz]

Does anyone happen to have heard how the Studies are progressing for Ninotinib ?

[khalidnt]

Does anyone happen to have heard how the Studies are progressing for Ninotinib ?

 

Phase I has been completed and now they started Phase II. Please check my post.

[Ibbz]

 

Does anyone happen to have heard how the Studies are progressing for Ninotinib ?

 

Phase I has been completed and now they started Phase II. Please check my post.

 

 

I know that phase 1 has been completed - I actually inquired about being included in phase 2 trials over a year ago. (Not for myself, for a family member)

 

I was wanting to know whether anyone had heard either any anecdotal stories from the trial, or whether anyone had any contact with the researchers. I have read some people reports from using it off label that it did have positive results.

[MarcB]

FYI, there are many PWP REPORTING REDUCTION OF SYMPTOMS WITH HIGH DOSE OF tHIAMINE   HCL 

 

 

 

 

 

 

https://healthunlock...180304/thiamine

 

http://www.blogtalkr...kinsons-disease