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Posted 26 December 2015 - 06:10 PM
Base on the current study on Nilotinib on Parkinson and it's cost, I have decided start a group buy. This is the first group buy I have done, so any recommendation of manufactures and labs to do an analysis is are welcome.
The first manufacture I contacted was a Chineses lab and they gave me a quote of 1 kg for USD 4,200. 1kg is enough for ~3333 doses @ 300mg/day -which will be $1.26/mg. Anyone interested please let us know.
Posted 26 December 2015 - 06:41 PM
Looks like we need at least 10 people to commit to a year's supply each, or perhaps a shorter period of time if we can find enough interest.
Count me in for 100 g. A friend of mine has Parkinson's and can't wait for FDA BS.
Again, we need HPLC or MS verification, which might add 20 or 30% to the cost. But looking at the study results, I can't say it's not worth it.
Posted 29 December 2015 - 03:04 PM
Looks like we need at least 10 people to commit to a year's supply each, or perhaps a shorter period of time if we can find enough interest.
Count me in for 100 g. A friend of mine has Parkinson's and can't wait for FDA BS.
Again, we need HPLC or MS verification, which might add 20 or 30% to the cost. But looking at the study results, I can't say it's not worth it.
I agree we need to verify this stuff, do you know of a good lab that does this and how many grams do you think the lab will need?
Posted 02 January 2016 - 05:12 AM
I have friends here who need help with their Parkinson. Let me know how this works out. I am wondering if a lab like the Health Ranger, Mike Adams, who has an ICP-MS, in house and is up on this type of data and testing. I would like to start out with 100 grams (+-$500). Do you you know how many daily doses are required to see results? Thanks.
Posted 05 January 2016 - 11:33 AM
I have been looking into getting the group bought Nilotinib tested.
A very important consideration when buying from China.
The cost should be added the the group buy cost, with payment for product done through an escrow account, after testing.
For a mass spectrometry test you need a spec in your database for the compound, or it won't tell you anything.
Without one; you need a reference sample, to test 1st, to compare to the sample in question.
So can anyone get hold of 1 pill of the original Novartis Nilotinib?
Edited by Logic, 05 January 2016 - 11:35 AM.
Posted 05 January 2016 - 12:06 PM
Some notable quotes from Georgetown University, that did the Parkinson's study:
Alan Hoffman, a professor emeritus of social science education at Georgia State University, was diagnosed with Parkinson’s disease in 1997. He says he participated in several clinical trials with no benefit until he enrolled in Pagan’s study.
“Before the nilotinib, I did almost nothing around the house,” he says. “Now, I empty the garbage, unload the dishwasher, load the washer and the dryer, set the table, even take responsibility for grilling.”
In the three weeks prior to enrolling in the study, Hoffman says he fell eight times, but he only fell once during six months on the study. His speech has improved, as has his thinking.
“My wife says it’s life-changing for her and for my children and grandchildren,” Hoffman says. “To say that nilotinib has made a change in our lives is a huge understatement.”
Hoffman and other patients in the clinical trial can continue taking nilotinib as part of an expanded access study.
https://www.georgeto...sons-study.html
https://gumc.georget...e-in-Parkinsons
Studies:
"...induce[s] autophagic protein clearance and modulate brain and peripheral immunity..."
https://neurology.ge....edu/moussa_lab
Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance
Alzheimer's disease (AD) is a neurodegenerative disorder associated with amyloid accumulation and autophagic changes. Parkin is an E3 ubiquitin ligase involved in proteasomal and autophagic clearance. We previously demonstrated decreased parkin solubility and interaction with the key autophagy enzyme beclin-1 in AD, but tyrosine kinase inhibition restored parkin-beclin-1 interaction.
In the current studies, we determined the mechanisms of nilotinib-induced parkin-beclin-1 interaction, which leads to amyloid clearance. Nilotinib increased endogenous parkin levels and ubiquitination, which may enhance parkin recycling via the proteasome, leading to increased activity and interaction with beclin-1. Parkin solubility was decreased and autophagy was altered in amyloid expressing mice, suggesting that amyloid stress affects parkin stability, leading to failure of protein clearance via the lysosome. Isolation of autophagic vacuoles revealed amyloid and parkin accumulation in autophagic compartments but nilotinib decreased insoluble parkin levels and facilitated amyloid deposition into lysosomes in wild type, but not parkin mice, further underscoring an essential role for endogenous parkin in amyloid clearance.
These results suggest that nilotinib boosts the autophagic machinery, leading to increased level of endogenous parkin that undergoes ubiquitination and interacts with beclin-1 to facilitate amyloid clearance. These data suggest that nilotinib-mediated autophagic changes may trigger parkin response via increased protein levels, providing a therapeutic strategy to reduce Aβ and Tau in AD.
http://connection.eb...yloid-clearance
Increasing Parkin also increases mitophagy: The clearance of old, 'sick' mitochondria:
Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan
http://www.pnas.org/...1/8638.abstract
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
http://journals.plos...al.pbio.1000298
Mitochondrial Quality Control: Decommissioning Power Plants in Neurodegenerative Diseases
http://www.hindawi.c...wj/2013/180759/
Posted 05 January 2016 - 01:04 PM
Here is a news report video of the clinical trial of Nilotinib in parksinon's.
https://www.youtube....h?v=Rifa6LPy60A
I have been looking into getting the group bought Nilotinib tested.
A very important consideration when buying from China.
The cost should be added the the group buy cost, with payment for product done through an escrow account, after testing.
For a mass spectrometry test you need a spec in your database for the compound, or it won't tell you anything.
Without one; you need a reference sample, to test 1st, to compare to the sample in question.
So can anyone get hold of 1 pill of the original Novartis Nilotinib?
I'm can get a box -of 28 pills- of Nilotinib for around USD 1,300 from Mexico, but that's still a bit high. Since Nilotinib is only sold by request, I most first pay half of money before the pharmacy place an order.
The dose in the study was 150mg/d to 300mg/d. I wonder if healthy people could take some to get an antiaging effect, since it suppose to remove some of the garbage that cause cells to die in parkinson patients.
I made a mistake when I first contacted the Chines manufacture & ask for Nilotinib in base form not the HCL form which is what the pill is. However, Logic mention of know a manufacture and I already contacted an other manufacture -which I'm waiting for a quote on. I'll be looking for a 3rd one just to allow us to have multiple source from where to choose one, as a group.
Now to end in an up note, it seems is to be possible to cut Nilotinib dose in half by using grapefruit juice.
Look at these studies.
=======================================================================================
Effect of Grapefruit Juice on the Pharmacokinetics of Nilotinib in Healthy Participants.
Authors: Yin, Ophelia Q. P.1 Ophelia.yin@novartis.com=======================================================================================
Effects of Yogurt and Applesauce on the Oral Bioavailability of Nilotinib in Healthy Volunteers. Authors: Yin, Ophelia Q. P.
Posted 05 January 2016 - 01:19 PM
One thing that everyone should keep in mind is that Nilotinib is sold for Leukemia, and that it is also been consider to treat Alzheimer's disease and dementia. So if you know anyone with these disease let them know about Nilotinib.
http://www.techtimes...-all-in-tau.htm
Cancer drug nilotinib may help cure Alzhei mer’s disease: It's all in tau
Scientists researching the causes of Alzheimer's disease say it may not be plaque, long considered the prime suspect, but rather protein than steals a person's memory and interferes with behavior and thinking by killing brain cells.
Both plaque consisting of amyloid-beta protein fragments and tangles of a protein known as tau are seen in the disease, but Georgetown University Medical Center researchers say they've found evidence it's the tau rather than the plaque that accelerates neuron death.
This could be the reason why some people with significant plaque build-up within their brains don't show any signs of dementia, and the findings could also lead to new drugs that could treat Alzheimer's, the researchers report in the journalMolecular Neurodegeneration.
"For a very long time, we believed, for almost 100 years, that [amyloid-beta] plaques are the main culprit in Alzheimer's disease," study senior investigator Charbel E-H Moussa says. "This study shows it's another protein -- a very, very important one, called tau, that is basically the main guilty one."
Inside a brain cell, tau provides a structure, something akin to a train track, which allows the cell to dispose of accumulations of unwanted toxic proteins.
If tau stops functioning -- possibly from aging or from errant genes -- the cell is unable to rid itself of the toxins.
Contrary to previously belief, it is the protein the cells can't dispose of and that remains inside neurons that causes them to die, not the plaques that build outside of the cells, the researchers say.
As part of their investigation, the researchers looked at the anti-cancer drug nilotinib, approved for used in adult leukemia patients, as a possible treatment to clear out such intercellular debris and control levels on nonfunctioning "bad" tau.
Nilotinib works by entering a cell to help clear it of debris, but can also reduce plaques building up outside the cell, says Moussa, who hopes to start clinical trials within weeks.
The discovery of the role of tau in Alzheimer's could lead to screening that could uncover signs of the disease at an earlier state and and help predict if a patient is likely to develop dementia, he says.
"Recent evidence suggests it appears that tau modification happens much earlier than amyloid plaques ... and because almost every patient who has tau modification has dementia, it's going to be a much more reliable and precise predictor of Alzheimer's and other dementias than [amyloid-beta]," Moussa says.
Such screening in combination with drugs that can reduce non-functioning tau in brain cells could slow down further tau breakdown and plaque buildup, helping patients avoid Alzheimer's or dementia, he adds.
Posted 05 January 2016 - 04:34 PM
For Full Text download: 
Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models.pdf 1.07MB
4 downloads
Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models
AbstractAlzheimer’s disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4 months in TgAPP and pre-plaque intracellular Aβ accumulation (2.5 months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2 months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6 months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.
I'm not sure is good for healthy young people use it for antiaging purpose, may be someone young can do 1 or 2 months on it to clear the garbage.
Nilotinib-mediated increase in fasting glucose level is reversible, does not convert to type 2 diabetes and is likely correlated with increased body mass index
In 2007, we reported for the first time that nilotinib, when used as second-line treatment in resistant/intolerant chronic myeloid leukaemia (CML) patients, induced hyperglycaemia as a side effect in 13 non-diabetic CML patients [1]. Indeed, we also measured Hb1Ac levels during therapy, but the median level was within the normal range, and none of the patients developed diabetic alterations. In one patient, the discontinuation of treatment due to other side effects resulted in a return to normal fasting glucose levels, thus indicating the reversibility of the adverse event. Following our report, le Coutre et al. [2] performed a large-scale analysis of the glycemic profiles of patients receiving nilotinib as a second-line therapy. The authors observed that 12.5% of chronic-phase and 6.7% of accelerated-phase patients developed grade 3/4 hyperglycaemia; none of the patients suffered from diabetic complications, such as ketoacidosis, hyperosmolar coma, hospitalisation due to these adverse events or increased weight. We reviewed our series of patients treated with nilotinib to identify features predisposing patients to this side effect or modifications of clinical outcomes pursuant to the emergence of hyperglycaemia. Overall, 62 patients at our institution received nilotinib as a second-line treatment (30 patients, 12 of whom were enrolled in phases II and IIIB sponsored Novartis trials, were all treated with 400 mg BID) or as a first-line treatment (32 patients, 27 of whom were enrolled in a GIMEMA phase II trial and 5 of whom were enrolled in a phase III ENESTnd trial, were all treated with 400 mg BID, except 2, who received 300 mg BID). The median age was 52 years (range 22–77.7 years); 38 patients were males, and 24 patients were females. None of these patients was diagnosed as having diabetes at baseline. Clinical features at the initiation of nilotinib treatment differed between the groups with regard to median age (58 years in patients who received the second-line treatment vs. 46 years in patients who received the first-line treatment), sex (a male/female ratio of 1.1 for patients treated after imatinib resistance and 0.6 for patients without imatinib resistance). Regarding comorbidities at baseline, no difference was observed between the groups of patients with respect to hypertension, heart conditions or hypercholesterolemia. The calculation of body mass index revealed that 15% of patients treated with nilotinib as second-line treatment and 18% of patients treated with nilotinib as first-line treatment were overweight/obese (BMI > 25). The median fasting glucose level at baseline in the whole cohort was 98 mg/dl. After a median follow-up of 1.5 years (range 1–4 years), this value was 109 mg/dl (p = 0.34). No difference was apparent between the groups regarding changes in the median value of fasting glucose from baseline to 12 months after the treatment began. In patients treated with nilotinib as second-line therapy, the median changed from 102 mg/dl at baseline to 110 mg/dl at 12 months; in patients treated with nilotinib as first-line therapy, values rose from a median of 95 mg/dl to 108 mg/dl. We detected grade 3/4 hyperglycaemia in only 7 patients (11%) among the entire cohort: 4 patients treated with nilotinib as second-line treatment and 3 patients treated with nilotinib as first-line treatment. None of these patients developed severe diabetic consequences: all patients discontinued the drug for a median of 8 days (range 4–12), and none had recurrent episodes of hyperglycaemia. No clinical difference was detected between patients who experienced grade 3/4 hyperglycaemia and patients who did not, except for BMI, which had a median value of 28 in the former group compared with a median value of 20 in the latter category (p = 0.02).
A causal relationship between nilotinib and hyperglycaemia is difficult to establish: changes in the stoichiometric conformation and lipophilic binding of imatinib might be involved in the origin of the metabolic effect. Because of the superior selectivity of nilotinib for BCR-ABL1, the drug has a different effect on glucose metabolism than imatinib. Imatinib has been reported to have a potential effect on glucose control in types I and II diabetic models in vitro as well as a metabolic effect in vivo [3]. For the first time, we reported FG reduction in type II diabetic CML patients treated with imatinib: the biological mechanisms involved in this effect are still unknown [4]. Hagerkvist et al. [5] suggested a possible inhibition of NF-κB activation, which in turn can reduce beta-cell apoptosis and act, through c-abl inhibition, on critical pathways leading to the same effect on beta cells. Through other pathways, such as PDGF-R inhibition, imatinib leads to reduced lipolysis and increased peripheral insulin sensitivity [6]. Our finding of increased BMI and hyperglycaemia in patients treated with nilotinib raises the question of possible inverse mechanisms inducing hyperglycaemia during nilotinib treatment, in contrast to the results obtained with imatinib. Our suggestion is that increased levels of fat tissue may reduce peripheral insulin sensitivity and increase the level of FG; however, the exact biological mechanisms inducing the side effects remain unclear. Recently, an increased risk of developing progressive peripheral arterial occlusive disease (PAOD) has been reported in CML patients treated with nilotinib: one of the possible mechanisms evoked in the pathogenesis of this phenomenon was the increased FG level induced as an adverse biochemical effect [7]. DDR1 inhibition was implicated in plaque formation in atherosclerosis [8]; conversely, data relating to the inhibition or deletion of this receptor showed attenuated atherogenesis, reduced inflammation and macrophage accumulation and calcification. The effect of nilotinib in newly diagnosed CML patients with pre-existing type 2-diabetes has recently been reported [9]. In the ENESTnd trial, hyperglycaemia occurred in 38% of patients treated with nilotinib 300 mg BID, 42% of patients treated with nilotinib 400 mg BID and 22% of patients treated with imatinib. No patient enrolled in the trial discontinued treatment because of hyperglycaemia or any other diabetes-related, serious adverse event. Fifty-seven diabetic patients were enrolled in the ENESTnd study (23, 18 and 16 patients in the nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib 400 mg arms, respectively). The median age of the diabetic patients was higher than that of the entire patient population (60 vs. 47 years). Sixty-eight per cent of patients were on diabetic medications (18% were on insulin); changes in metabolic parameters were minimal in all arms, and the response rates were similar to those of the overall population (major molecular response rate 69.6%, 55.6%, and 25%; complete cytogenetic response rate 69.6%, 77.8%, and 68.8%, respectively). No diabetic patient progressed to an advanced phase of disease after 18 months of follow-up. Eight patients in the nilotinib 300 mg BID arm, 5 patients in the nilotinib 400 mg BID arm and 6 patients in the imatinib arm discontinued therapy. Among these patients, 3, 5 and 4 patients, respectively, discontinued the use of the drug because of adverse events or laboratory abnormalities unrelated to diabetes. In conclusion, hyperglycaemia during nilotinib treatment appears to be manageable even in diabetic patients, is mostly associated with increased BMI and does not represent an obstacle to treatment.
Nilotinib cardiac toxicity: Should we still be concerned?
Nilotinib cardiac toxicity has been a concern since the early phase II studies in patients with imatinib resistant/intolerant disease. In those studies, 5 sudden deaths in 876 patients occurred which may have been related to ventricular repolarization. This was followed by a preclinical study done by Freebern et al. (Bristol Myers Squibb lab), where nilotinib did decrease the viability of primary rat cardiomyocytes at pharmacologically relevant concentrations. In addition, nilotinib more than imatinib or dasatinib lead to blockade of hERG K+ channels which may explain the prolonged QT interval seen more frequently with nilotinib [1]. This potential cardiac toxicity is especially relevant now that nilotinib is approved as frontline therapy for patients with CML and more patients will be receiving lifetime nilotinib therapy.Based on those concerns, in this issue of Leukemia Research, Dr. Wolf and colleagues (Novartis lab) conducted a preclinical study in a mouse model to evaluate the cardiotoxicity of nilotinib both in vivo and in vitro. In vitro, nilotinib did not induce changes in cellular viability [2] (as evidenced by LDH and cellular ATP content), increased apoptosis (as assessed using Mitotracker and caspase 3/7 activity) and increased endoplasmic reticulum (ER) stress reaction (as evaluated using CHOP mRNA levels) at concentrations similar to the human maximal concentration. Only the ratio of XBP1 spliced/unspliced (a measure of ER stress) was affected at clinically relevant concentration of nilotinib. Given that apoptosis did not increase, the significance of increased XBP1 splicing/unsplicing is not clear.In vivo mouse studies, using oral nilotinib at 2 different doses, did show some evidence of increased left ventricular (LV) weight to total body weight (TBW) ratio, however there was no difference in LV end diastolic volume by MRI between placebo treated mice and nilotinib treated mice. Histological examination of the cardiac muscle did show single or multifocal inflammatory foci of minimal to slight severity compared to minimal severity only in the placebo group. The authors explain that this is a common finding in male mice and do not think it is clinically significant. These effects were evaluated at 3, 14 and 28 days after administration of nilotinib.Clinically, in the early phase II studies with nilotinib, 8 patients (2.5%) had >60 ms change from baseline in QTcF interval and 4 patients (1.2%) had a post-baseline QTcF interval of >500 ms [3]. While in the randomized phase III trial of nilotinib vs. imatinib in patients with newly diagnosed CML, QTcF increases >30 ms occurred in 26% and 18% of patients on nilotinib and imatinib respectively. QTcF increases >60 ms occurred in <1% of patients on nilotinib and no patient had an increase of QTcF > 500 ms [4]. Of note, patients with a significant cardiac history were excluded from the study, and all patients had an EKG prior to therapy, one week after starting therapy and every 3 months thereafter.The cardiac toxicity of tyrosine kinase inhibitors (TKIs) is not a new concern. In 2006, Kerkela et al. reported that imatinib may have a cardiotoxic effect both in vitro and in vivo [5]. Those findings were not reproduced in a more recent preclinical study by Wolf et al. [6]. More importantly, several large clinical retrospective studies did not find evidence of clinical cardiotoxicity in patients receiving imatinib [7]. So despite the contradicting preclinical results, long term follow up of patients receiving imatinib was the most reassuring that imatinib does not have significant cardiac toxicity.What does all this mean? The preclinical and clinical data appears reassuring that nilotinib does not have any acute cardiotoxic effects. In the mouse model, the mice were evaluated after only 4 weeks of therapy. The clinical data is also reassuring in the short term only. With a median follow up of 18 months in the 1st and 2nd line setting studies, there were no significant cardiac toxicities. However, given the nature of TKIs, therapy is expected to last for years. These preclinical and clinical data do not clarify the long term cardiac effects of nilotinib. Only long term clinical follow up of patients receiving nilotinib will clarify the cardiac effects of nilotinib.In the meantime proper patient selection, close follow up of electrolytes and EKG, and patient education regarding the use of new medications while on nilotinib and drug administration are mandatory to prevent any complications.Conflict of interestE.A. is on the advisory board and has research support from Novartis.AcknowledgementsI would like to thank Dr. Jeanne Palmer for her help with writing this article.
Posted 06 January 2016 - 09:43 AM
I'm can get a box -of 28 pills- of Nilotinib for around USD 1,300 from Mexico, but that's still a bit high. Since Nilotinib is only sold by request, I most first pay half of money before the pharmacy place an order.
Is that the Novartis Nilitonib or a knockoff Noot?
Its still expensive, but if its the Norvartis product; maybe you can find out who normally buys it and perhaps get one pill from that person?
Some pics of original packaging etc would also help alleviate concerns here...
The dose in the study was 150mg/d to 300mg/d. I wonder if healthy people could take some to get an antiaging effect, since it suppose to remove some of the garbage that cause cells to die in parkinson patients.
The lack of mitophagy of mitochondria that should have been eliminated is a major reason for aging.
As I take C60oo once every week or two and there is a concern that C60oo may interfere with mitophagy; I would take a dose (150 mg) the day befor taking C60oo.
The clearance of misfolded proteins and Amyloid would be a bonus IMHO.
The main reason I am interested in this is for a friend with Parkinson's however.
I made a mistake when I first contacted the Chines manufacture & ask for Nilotinib in base form not the HCL form which is what the pill is. However, Logic mention of know a manufacture and I already contacted an other manufacture -which I'm waiting for a quote on. I'll be looking for a 3rd one just to allow us to have multiple source from where to choose one, as a group.
Good stuff Noot! 
(Noot and I are collaborating in this group buy effort)
Now to end in an up note, it seems is to be possible to cut Nilotinib dose in half by using grapefruit juice.
Thx Noot.
Grapefruit juice:
http://www.longecity...ndpost&p=210487
Posted 06 January 2016 - 06:12 PM
It's the real Novartis med, and I agree it's still expensive.
Cool.
Can you get the/a chemist to give you the contact details of a regualar customer and buy 1 pill from then?
Or perhaps get the chemist to contact the customer and negotiate buying one pill from the pack?
Posted 06 January 2016 - 06:29 PM
I have friends here who need help with their Parkinson. Let me know how this works out. I am wondering if a lab like the Health Ranger, Mike Adams, who has an ICP-MS, in house and is up on this type of data and testing. I would like to start out with 100 grams (+-$500). Do you you know how many daily doses are required to see results? Thanks.
Mike Adams and Natural News are considered swear words by most around here.
I don't think involving him would inspire confidence in this group buy overall?
Posted 07 January 2016 - 02:55 AM
One thing that everyone should keep in mind is that Nilotinib is sold for Leukemia, and that it is also been consider to treat Alzheimer's disease and dementia. So if you know anyone with these disease let them know about Nilotinib.
http://www.techtimes...-all-in-tau.htm
Cancer drug nilotinib may help cure Alzhei mer’s disease: It's all in tau
Scientists researching the causes of Alzheimer's disease say it may not be plaque, long considered the prime suspect, but rather protein than steals a person's memory and interferes with behavior and thinking by killing brain cells.
Both plaque consisting of amyloid-beta protein fragments and tangles of a protein known as tau are seen in the disease, but Georgetown University Medical Center researchers say they've found evidence it's the tau rather than the plaque that accelerates neuron death.
This could be the reason why some people with significant plaque build-up within their brains don't show any signs of dementia, and the findings could also lead to new drugs that could treat Alzheimer's, the researchers report in the journalMolecular Neurodegeneration.
"For a very long time, we believed, for almost 100 years, that [amyloid-beta] plaques are the main culprit in Alzheimer's disease," study senior investigator Charbel E-H Moussa says. "This study shows it's another protein -- a very, very important one, called tau, that is basically the main guilty one."
Inside a brain cell, tau provides a structure, something akin to a train track, which allows the cell to dispose of accumulations of unwanted toxic proteins.
If tau stops functioning -- possibly from aging or from errant genes -- the cell is unable to rid itself of the toxins.
Contrary to previously belief, it is the protein the cells can't dispose of and that remains inside neurons that causes them to die, not the plaques that build outside of the cells, the researchers say.
As part of their investigation, the researchers looked at the anti-cancer drug nilotinib, approved for used in adult leukemia patients, as a possible treatment to clear out such intercellular debris and control levels on nonfunctioning "bad" tau.
Nilotinib works by entering a cell to help clear it of debris, but can also reduce plaques building up outside the cell, says Moussa, who hopes to start clinical trials within weeks.
The discovery of the role of tau in Alzheimer's could lead to screening that could uncover signs of the disease at an earlier state and and help predict if a patient is likely to develop dementia, he says.
"Recent evidence suggests it appears that tau modification happens much earlier than amyloid plaques ... and because almost every patient who has tau modification has dementia, it's going to be a much more reliable and precise predictor of Alzheimer's and other dementias than [amyloid-beta]," Moussa says.
Such screening in combination with drugs that can reduce non-functioning tau in brain cells could slow down further tau breakdown and plaque buildup, helping patients avoid Alzheimer's or dementia, he adds.
noot_in_the_sky:
Just a note worthy of your observation that nilotinib is used in adult Leukemia patients. Amyloid is a peculiar protein, unlike most proteins, as it does not bind with a carbohydrate molecule when formed. Amyloid (is believed) to be formed [only] inside of bone marrow (think Leukemia) and appears to be a starchlike material. In fact when discovered it was named "starch like" in Latin/Greek = Amyloid. After years of debate, in 1859, it was determined to be a protein (a chain of > 50 amino acids; peptides are less than 50). The error was due to the method of slide staining, using common iodine red at that time and the starchlike structure observed.
So the Amyloid proteins created via defective bone marrow cells cause this type of protein (there are a little over 20 different Amyloid proteins) to NOT "unfold" like a normal protein would/should (another matter). This unfolding activity normally is preformed in milliseconds and when this occurs (or do not occur) these proteins go looking...they can attach to any organ and cell system (brain, heart, lungs, stomach, intestines, kidneys, etc). This is becoming more and more problematic now, today, with the abnormal, NOT unfolded, amyloid proteins, although still considered "rare". This is somewhat like the Alzheimer's / Parkinson nightmare; these diseases did not used to exist (maybe). Now Alzheimer's is considered the third main killer just behind cancers and heart diseases; in the USA that is. Why problematic? Amyloid's, unlike normal healthy proteins, are NOT soluble, NOT degradable, NOT recyclable amino acid structures. They accumulate, they have an infinity for one another, they produce a cascade effect of problems; domino's?.
These Amyloids' get snuggled into organs and they get "clipped", a normal occurrence with proteins, forming peptides. The "bits" (peptides) of the Amyloid protein start to unite due to their infinity and form geometric structures; plaques. One form type of structure is "beta" = Amyloid beta. This "A beta" plaque, group of peptides, accumulate/deposit between normal cells, taking up extracellular space causing the cells to "separate" from one another [? maybe defective or weak collagen ?] and the result is inflammation and a cascade of various occurrences leading to disease, abnormalities, depending on the organ infiltrated.
The beta "structure" formed is abnormal and foreign to the body so there are reactions to this. Immune reactions and others where materials start to accumulate (grow) on this "new" hard, durable, fibrous structure. If the peptide(s) become part of a neuron structure, a mass is created extracellular. NOW the article quoted above speaks of TAU protein doing a similar trick in growing within the neuron or become an integral part (intercellular) of a neuron and accumulating "garbage" that is not transported away due to it's structure and becomes toxic, causes inflammation, takes up valuable required spaces, uses energy and resources; a cascade effect, until the neuron expires or is activated to destruct; apoptosis.
if in fact nilotinib has an infinity to Leukemia cells and by it's mechanisms "clean up" that mess, as is theorized in the article quoted above, in the case of TAU proteins, to wit:
[Nilotinib works by entering a cell to help clear it of debris, but can also reduce plaques building up outside the cell, says Moussa, who hopes to start clinical trials within weeks.
The discovery of the role of tau in Alzheimer's could lead to screening that could uncover signs of the disease at an earlier state and and help predict if a patient is likely to develop dementia, he says.
"Recent evidence suggests it appears that tau modification happens much earlier than amyloid plaques ... and because almost every patient who has tau modification has dementia, it's going to be a much more reliable and precise predictor of Alzheimer's and other dementias than [amyloid-beta]," Moussa says.]
OKAY, Moussa says:
All of that has been said and "been there, done that" for years. That all sounds speculative to me, but what do I know. If he can do it then WOW.
Meanwhile, keep looking, this is going to take a while and a big stack of money to accomplish. Or am I missing something here?
Edited by LongLife, 07 January 2016 - 03:06 AM.
Posted 09 January 2016 - 06:35 AM
Interested in 50-100g depending on final price.
Would this be possible to simply put into capsules?
Thanks.
Roy
Yes, it possible to put it in a capsule.
Remember that I mention that the original supplier, didn't have Nilotinib HCL they only had the base form which means that the price will change.
I'll update everyone of the prices, onces the supplier give them to me.
Posted 10 January 2016 - 01:24 PM
I don't want to put anyone off, but as this is a powerful cancer drug I thought it pertinent to post Novartis' safety info here.
Note that the dosages used for Parkinson's are much lower than the dosages used chronically for cancer.
(800 mg as opposed to 150-300mg)
Hopefully people more qualified than I will comment?
Safety Information
IMPORTANT SAFETY INFORMATION for TASIGNA® (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose.
Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. Women taking Tasigna should not breastfeed.
Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.
The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.
https://www.novartis...rtfolio/tasigna
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