1230 replies to this topic

[resveratrol_guy]

Yeah, Logic posted on  lipopolysaccharide  on page 24. Dayglow bolded and underlined: He got four upratings for that!

Why do only the popular kids always get away with things! I want to be popular too.

 

MPL A appears to be a very powerful adjuvant and so the FDA is being very cautious.

There have been rare occurrences of auto-immune responses to it.

Strangely, one report noted that there was an over 12 times increase in narcolepsy in those receiving an MPL A. (?)

Those at risk have an identified risk genotype. 

 

Probably with the anti-AD effect, it is more that the MPL A creates a short term powerful anti-amyloid effect and

then the inflammation subsides.

 

 

I have been looking up where to get dosed up with MPL A.

All I am seeing is Ceravrix in the US.

Europe has the hepatitis B vaccine Fendrix and there is the allergy vaccine Pollinex Quattro.

 

 

 

http://www.enzolifes...c-ready-to-use/

 

It's surprising that Longecity seems to have missed this back in 2013. I think I know how it works.

 

It causes an enhanced immune reaction at the injection site, which causes responding macrophages to signal back to the bone marrow to release more of themselves, via GCSF. But once GCSF does that, the body soon figures out that the "infection" (MPLA) is fake because it does not spread virulently. So we're left with excess macrophages (chiefly, nuetrophils). These have nothing better to do than to home in on endothial inflammation sites. As a result, their populations increase in the cerebrovasculature, leading to BBB repair. But some of them cross the BBB, especially where it happens to be compromised. Some sort of signalling between the neutrophils and the microglia ensues, resulting in activated microglia. But then the same problem occurs, namely, that the infection was fake. So the microglia end up attacking brain plaque, having nothing better to do until they become deactivated over time. Meanwhile, cognitive enhancement sets in.

 

GCSF is expensive. So is MPLA. Unfortunately, I can only find it for sale from US vendors, apparently because it requires a bacterium to manufacture. Perhaps this situation may change in the near future, however, so I would keep MPLA on the short list.

 

I would not take Cervarix (or Gardasil, for that matter), even if I were a woman. Dr. Mercola has a strong case against it, and whatever you may think of him, I find his argument is compelling.

 

IL-33 looks like a better route, IMO.

[mag1]

Would be pretty humorous if the girls in America have been accidentally protected against Alzheimer's with the Cervarix vaccine even if it doesn't help so much with the HPV.

Not so humorous that these girls might in a few years have to be the caregivers for the boys who went on to develop dementia because they never received the vaccine.

 

The MPL A does not look that expensive.

Page 21 from the gsk pdf notes that their Cervarix vaccine has 20 micrograms of MPL A.

The enzo site lists 100 micrograms at $264.00 (not sure  if this formulation would be appropriate for humans).

 

From the science daily report noted above: "In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period."

 

Also: "Importantly, MPL is safe in humans and has been administered to millions of patients as a component of several vaccine formulations such as the Cervarix vaccine"

 

"Our data demonstrate that chronic, systemic administration of MPL ameliorates AD-like pathology by decreasing the cerebral Aβ load through the stimulation of the phagocytic capacity of innate immune cells."

 

Also: "MPL treatment reduces Aβ levels and cognitive deficits in APP_swe/PS1 mice. MPL (50 μg), LPS (3 μg), or PBS was administered once a week by i.p. injection in 3-mo-old APP_swe/PS1 mice for 12 consecutive weeks"

 

So what would be the scale up to humans of MPL (50 μg) per week in mice?

(Remember to divide final answer by 12.5.)

The human vaccine was only using 20 micrograms, so a total dose of 12x 10x 20 (or more) micrograms might be out of range for human dosing.

 

Our loved one has had a full round of Cervarix vaccinations.

Would it be a good idea to try another full round?

 

Perhaps someone on the site could do an n=1 experiment for the good of humanity: 10 weekly doses of 20 microgram of MPL A with before and after amyloid scans.

Would need someone with at least some amyloid to start, maybe someone in their mid-50s with an APOE epsilon 4 allele.

Such a person would have something to gain from this.

If amyloid were in fact present in their brain, then Alzheimer's related mild cognitive impairment would not be unexpected within 10 to 15 years.

 

Cost of $500 for the MPL A and a few thousand for the amyloid scans.

A whole bunch of people would be interested to know what the results might be.

Edited by mag1, 24 April 2016 - 10:24 PM.

[mag1]

Just been going through the dosing numbers.

That 50 μg in the mice seems like it would be quite a bit in terms of people.

Scaling up a 0.02 gram mouse to a 60 kg person gives you 3000 times-- reduce by the scaling factor of 12.3 gives you 244 times.

 

$23,000 for a curative dose AD of MPL A?

If you were to buy the 25 mg size, you would be down to $12,500. 

https://avantilipids...product/699800/

 

Wonder what side effects might occur in a human with that much MPL A.

 

This article notes that Tusko, the elephant, received a lethal dose of LSD when this dosing calculation was done wrong.

http://www.ncbi.nlm....les/PMC2737649/

Edited by mag1, 24 April 2016 - 10:19 PM.

[mag1]

Combination of another TLR4 ligand greatly boosted the effectiveness of MPL A in a cancer setting.

Notice the effect on tumour volume in Figure 4.

 

http://www.ncbi.nlm....pubmed/26811064

 

A large amount of research has been done on MPL A.

I suspect that dosing studies might have been done to find the maximum tolerated dose.

Wonder what the MTD was.

[mag1]

Hey, res: http://www.longecity...-of-alzheimers/

 

Apparently MPL A is being added to some of the newer AD drugs working their way through the clinic.

Not sure which ones.

Suppose it would not be the first time that the adjuvant was a more active ingredient than the active ingredient.  

[resveratrol_guy]

Suppose it would not be the first time that the adjuvant was a more active ingredient than the active ingredient.  

 

LMAO!

 

Seriously, though, we ought to be able to obtain pure MPLA somehow. Sounds like a poor man's GCSF. Presumably $23,000 is 10X or 100X what we could get it for in China, once they start manufacturing. I'd be looking to Sino Biological, which has experience making RNA-encoded compounds from bacteria.

 

Poor elephant!

 

Uh wait a sec, what the hell does this mean: "In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques." Do they really mean this, or are they merely discussing abeta, which is of minimal consequence in cases of established neurodegeneration? Can you post a link direct to the paper?

Edited by resveratrol_guy, 25 April 2016 - 07:11 AM.

[Der Springende Punkt]

@resveratrol_guy

 

Have you heard of Masitinib? It's in a phase 3 trial for Alzheimer's, passed a non-futility test last year and the company AB Science recently published positive interims analysis of a phase 3 clinical trial for ALS. One of the proposed mechanisms is inhibition of the Macrophage colony-stimulating factor. I'm not familiar with the colony-stimulating factors and you mostly are referring to the Granulocyte colony-stimulating factor but maybe it can be of interest for you, though? Masitinib seems to be rarely on the radar here maybe because there are no US sites in the phase 3 trials...

Edited by Der Springende Punkt, 25 April 2016 - 07:58 AM.

[Logic]

 

http://www.pbs.org/w...lzheimers-cure/

 

This looks really interesting. It looks like it might in a broad sense work in a similar method to Nilotinib. Also M13 shouldn't be too hard to get a hold of. I'm not sure why NeuroPhage doesn't just use M13 but decided to make NPT088.. Also they mentioned that intranasal delivery didn't make sense, but that's what was used in animal trials, it seems that is an easy delivery mechanism to me.

 

Thoughts?

 

 

You can't patent a naturally occurring bacteriophage, but you can patent a synthetic means to producing the same protein? t produces...

This is the same reason all bacteriophage therapy/research, which is VERY promising is on a shoestring budget. 

[Logic]

The modulation of the immune system seems to be the hot topic here atm as is the prevention of all types of neurological decline, so this may be of interest?
 

"...the drug T20K, derived from the traditional medicinal plant Oldenlandia affinis, helped mice with MS...Cyclotides are present in a range of common plants, and they show significant potential for the treatment of autoimmune diseases..."
http://www.upi.com/H.../3661460391555/

 

The study:

"...Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs..."

http://www.pnas.org/...5/3960.abstract

While I'm on the subject of MS and as fungal brain infection has been mentioned:

"...The team...wanted to find a drug that would encourage stem cells in the brain and spinal cord to become the type of cell that produces myelin, which are called oligodendrocytes... miconazole, which is found in over-the-counter antifungal treatments such as athlete’s foot, and clobetasol, which is used to treat skin conditions such as eczema...were best at stimulating the conversion of these blank stem cells into myelinating cells..."

http://awarenesssoci...s-nerve-damage/

 

 

mag1:

 

I hardly ever dayglow bold and underline words, but in this case I felt it necessary to do my utmost to highlight the importance of lipopolysaccharide in mental decline.  Perhaps people know me/this and that's why I got away with it!?  

IMHO the importance of gut health is vastly underappreciated in both mental a physical longevity.
Keep in mind that this barrier between you and near instant death by septicemia is replaced every 5 days making it age faster than the rest of us.

IMHO the aging gut then begins to let through a lot of toxins and pathogens it blocked when we were young, increasing inflammation, NF-kB etc, and causing chronic infections, and bringing the rest of the body 'down' with it.

The first thing to do is keep the gut's stem/progenitor cells' telomeres long with telomerase activators. as well as protect the gut with things as simple as vitamin C.
http://www.longecity...ndpost&p=761825

 

NB that the stem/progenitor cells in the gut are way more accessible to us.

ie:  If you take astragalus it seems it will come into direct contact with theses cells..!?

http://www.longecity...g-in-zebrafish/

http://www.longecity...lthy-longevity/

Then, as 'we all live on bacteria shit', it's a damn good idea to make sure we approve of the types of bacteria taking a dump in our intestines!  
The most effective and specific way to kill off specific, bad bacteria only, like the lipopolysaccharide producing gram negative bacteria, is the bacteriophages mentioned earlier... IMHO.

 

[mag1]

yeah, masitinib has been out there for such a long time.

Seems like it has went through every disease indication cancer, ALS, Alzheimer's.

 

Interesting that there is only 1 trial location listed on the below url.

Wonder when results might be ready?

 

 

https://clinicaltria...sitinib&rank=22

[Der Springende Punkt]

yeah, masitinib has been out there for such a long time.

Seems like it has went through every disease indication cancer, ALS, Alzheimer's.

 

Interesting that there is only 1 trial location listed on the below url.

Wonder when results might be ready?

 

 

https://clinicaltria...sitinib&rank=22

 

They didn't update the clinicaltrials entry: the enrollment was increased to 600 patients and an interims analysis is planned for 2017.

[mag1]

Would the FDA accept a single center phase 3 trial as definitive?

Or would they then need to do another phase 3?

 

Is masitinib already available for dog cancer?

 

Um, er, woo woov. woov,wooz... Woof, woof?

Needed a little practice.

If it barks like a dog and bites like a dog.. then it's a dog.

Edited by mag1, 25 April 2016 - 07:15 PM.

[Der Springende Punkt]

Woof. Yes, it's available for dog/pet cancer or it was, don't know the current status (for the US it is/was stated Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-308).

 

It's only one phase 3 study and I'm wondering the same ... but it's not single centered: recruitment countries are:

 

Czech Republic, France, Germany, Greece, Poland, Romania, Serbia, Singapore, Slovakia, South Africa, Spain, Taiwan, Tunisia, United Kingdom, United States (my previous info was wrong)

 

http://www.nhs.uk/co...10-021218-50-SK

 

[mag1]

Hmm, treatment is only for 24 weeks.

When treatment is over such a short period of time, you really start to wonder whether the effect is truly disease modifying.

 

Some of these shorter treatments might give you a boost in the near term, though disease progression ultimately catches up with you.

[resveratrol_guy]

Hey Der Springende Punkt, thanks for bringing up masitinib. I was not aware of it and this is something that I would want to research further.

 

But I would find it surprising if it were able to ameliorate dementia via inhibition of granulocytle macrophage colony stimulating factor (GMCSF), the injection of which has been tied to cognitive improvements in rheumatoid arthritis sufferers, ironically because their disease causes the release of GMCSF, which has a side effect of microglial activation, resulting in plaque clearance. In that sense, it operates in a manner similar to IL-33. So less GMCSF sounds like a bad idea.

 

However, I was asking lostfalco about a similar apparent paradox the other day, in particular IL-33's cognitive enhancement via immune upregulation vs. ibudilast's enhancement via the opposite. His take seems to be that we want a strong antiplaque response for acute periods of time, followed by very long periods of low immune activity in the CNS. I had not previously considered this nuanced theory, but it makes good sense to me.

Edited by resveratrol_guy, 26 April 2016 - 05:19 AM.

[mag1]

Alzheimer's cured? Or more tabloid headlines?

http://www.express.c...ug-stop-disease

[mag1]

https://clinicaltria...lzheimer&rank=2

 

Wow, a phase 2 randomized trial ends in January ...  2017?

An investigator for this trial is quoted in the previous post as saying the trial has already been shown to stop progression in the phase 2.

“From what we have seen it is at least going to stop the progression of the disease."

 

https://clinicaltria...lzheimer&rank=1

 

https://www.ncbi.nlm...5?dopt=Abstract

[mag1]

"GLP-1 derivatives such as exenatide and sitagliptin"

 

Exenatide-4 Alzheimer trial ends in July.

https://clinicaltria...heimer's&rank=1

 

..." assuming that the drug will reach less than 0.5 percent of the 107 million people in the United States classified as obese,

and a daily price of $30 over 6 to 12 months' use." wiki

 

"A study on mice in 2014 found that Liraglutide reduced the damage caused by dementia and resulted in memory improvements.

The mice had late-stage dementia and performed significantly better on an object recognition test and their brains showed a

30 per cent reduction in plaque build." wiki

 

https://en.wikipedia...ide#Controversy

Edited by mag1, 28 April 2016 - 09:15 PM.

[mag1]

What is the usual protocol in instances such as this where the Principal Investigator steps forward and claims that Alzheimer progression has

been halted, while the trial is still in progress. (I can't day glow it or capitalize it, I am just not as popular as others on this forum.)

 

I am guessing that everyone in the trial should be put on the active arm. 

Edited by mag1, 28 April 2016 - 10:15 PM.

[Logic]

What is the usual protocol in instances such as this where the Principal Investigator steps forward and claims that Alzheimer progression has

been halted, while the trial is still in progress. (I can't day glow it or capitalize it, I am just not as popular as others on this forum.)

 

I am guessing that everyone in the trial should be put on the active arm. 

 

while the trial is still in progress

 

[mag1]

Yeah, yeah,(What no Capitals?), Logic you are popular, and special... You are LOVED!

 

Wonder if the PI hit his numbers in the liraglutide trial.

I mean I am not sure whether being popular or having a PhD would cover you, if you stepped up and ran ahead of the hard numbers, and the

hard numbers came in at a p value of 5.0001 %. No happy campers there.

Edited by mag1, 29 April 2016 - 02:15 AM.

[Logic]

A lot of these substances look very interesting.
As I will be getting Nilotinib for the 2nd group buy within next month; I will ask the supplier if they have, or can produce IL-33, Masitinib etc?

 

Gut-Brain:

Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways.

http://www.ncbi.nlm....pubmed/20347053

 

• Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1.
• Effects of Epimedium flavonoids on proliferation and differentiation of neural stem cells in vitro.
• etc

http://www.longecity...ndpost&p=565043

 

 

 

 

[mag1]

Won't have to work too hard to get cheap liraglutide.

Website offers a savings card in which patients pay no more than $25 for a prescription.

Anyone know whether this applies to non-US customers?

 

https://www.victoza....vings-card.html

 

Considering the benefits this has for brain cell growth, it surpeises me that the noot community is not all over this one.

[mag1]

Hey Logic you seem to know the right people.

Do you know where one might be able to pick up some gram positive minicells?

[Logic]

A lead from mlsirkis.  Thx.

 

While I have only scanned the most recent posts here and the belo, what QR Pharma is saying seems to fit in well with RG's thinking?

 

Neurotoxic aggregating proteins, such as APP, aSYN, tau, SOD and prions display the same behavior, from gene activation, to protein synthesis to folding, misfolding, toxicity and aggregation:

1.Transcription is regulated by Cu/Zn/cytokines

2.Translation is regulated by Fe

3.At low concentrations they have a normal function

4.At high concentrations they form toxic oligomers

5.Oligomers can infect other cells in the brain and spread

6.They are degraded by the proeasome

7.The cell sequesters these toxic oligomers into aggregates to neutralize them

 

Posiphen Inhibits APP, tau and aSYN Synthesis

http://qrpharma.com/...on_short_21.pdf

 

Posiphen  Recovers Memory, Learning and Brain Function in Alzheimer Transgenic Mice

http://qrpharma.com/...-22-2012_22.pdf

http://qrpharma.com/

[Logic]

Hey Logic you seem to know the right people.

Do you know where one might be able to pick up some gram positive minicells?

 

Hey mag1

I assume you are looking for minicells that produce a specific protein?

ie:Specific minicells?

The Nilotinib supplier is into synthed chems rather than live cultures etc, but I can ask around if you can be more specific?

[mag1]

Minicells have been shown to cure mice of cancer when loaded with nanogram scale dosing of chemo with bispecific antibodies.

 

"This was despite an ∼8000-fold lower Pac dose being administered via ^EGFRminicells_Pac (∼0.05 μg/mouse) compared to free Pac (∼400 μg/mouse)"

 

http://www.ncbi.nlm....pubmed/17482133

 

Brain cancer in dogs

http://www.ncbi.nlm....les/PMC4822833/

 

 

They have been dosing just below the curative dose in people because there has been a little trouble with LPS.

http://www.ncbi.nlm....pubmed/26279503

 

These gram positives are considered GRAS.

http://www.ncbi.nlm....pubmed/25341464

 

We already have published phase 1 results so we are all clear under Right to Try.

 

Some gram positive minicells (say 10^12) with EGFR bispecifics could be quite handly.

Edited by mag1, 29 April 2016 - 03:52 AM.

[mag1]

Not another one! (cure that is)

Put it over there with all the rest.

 

http://www.bidnesset...xl-stock-today/

[deetown]

As a stock trader for 20 years I can say without a doubt AVXL is a scam.  

[albedo]

I am following the work of Dr Claudio Franceschi, much involved in the inflammation theory of aging and nutrition (see NU-GO project). The following study (not read in full though) points to very limited drugs response and likely the need of different and more holistic approaches. Looks to me in line with some of the recent comments on this thread:

 

Effects of donepezil, galantamine and rivastigmine in 938 Italian patients with Alzheimer's disease: a prospective, observational study.

http://www.ncbi.nlm....pubmed/20088621

 

"Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people." (emphasis mine)