1230 replies to this topic

[resveratrol_guy]

Is this true 

 

There have been several reports that anti-tumor necrosis factor alpha (TNFa) agents may affect amyloidosis in inflammatory disease, such as rheumatoid arthritis and familial Mediterranean fever.2,3 Rapid cognitive improvement after perispinal etanercept administration had been reported.4,5 This may be the first report to suggest an effect on Ab/p-tau in a person with AD by anti-TNF. Similar results were obtained in animals.6,7 A previous study indicated that intracerebroventricular administration of infliximab reduced amyloid plaques and tau phosphorylation in APP/PS1 mice.8 The case report suggests the pivotal role of TNF-a and the interaction between TNF and amyloid in the pathogenesis of AD. The efficiency and safety of infliximab need to be researched further in large sample trials or randomized control trials. The current results suggest that intrathecal infliximab offers a superior alternative therapeutic approach for AD and potentially for other neurodegenerative disorders in which TNF-a is involved in the pathogenesis, such as Parkinson’s disease and amyotrophic lateral sclerosis.

 

 

There is also a DR, in US who claims tht perispinal entrancept also works through tumor necrosis factor  and has treated several patients.

 

I've studied Etanercept in some detail. First of all, I do think it's the most effective short term remedy for dementia systems; there's a considerable amount of video evidence for that. However, its effects generally appear to last hours to days. When they wear off, symptoms return. In theory, if the research you mentioned extends to humans, repeated administrations would actually reduce plaque load of both major forms, and therefore might induce longterm remission from disease.

 

There are a few problems, however. One is cost: you're looking at $900 or so per shot, at least in the US. (Perhaps it's cheaper elsewhere.) Secondly, you need the patient to remain near the clinic so as to be able to receive a shot every few days. Thirdly, it requires injection into the cervical spine in the neck, which is an exceedingly dangerous procedure except for doctors properly trained in such injections; this is not like injecting steroids in your leg. And finally, although TNFa is proinflammatory, it has a protective role to play in the CNS, which as the name suggests is tumor destruction. So in theory, you're trying to swap dementia for an increased risk of brain or spine tumors. My own take on the human data I've looked at, none of which being in the form of a controlled trial, is that it might actually cure dementia, but unless you have $100K in the bank or have a cheap gray market source, it's not viable.
 

[resveratrol_guy]

For what it's worth, here is at least one case in which Etanercept failed to stop Alzheimer's progression, despite over 100 doses. However, what's not clear is whether or not it slowed the disease, or whether it might have stopped it in patients with less severe pathology, or to what extent genetics influence outcome. Critics are quick to point to this case in order to "prove" that it's all a fraud, but that conclusion is not supported, one way or another, by the evidence.

What we do seem to know, according to Table 1 of this article posted above, is that infliximab (another TNF inhibitor like Etanercept) causes disaggregation of abeta-42 and phosphotau-181, but not abeta-40, for some reason. Furthermore, while its short term effects may be purely antiinflammatory (which would by definition be an expected result of TNF inhibition), there seems to be a pronounced effect on plaque efflux into the circulatory system which would be very hard to create via placebo and might not directly relate to TNF. In theory, early enough in the disease process, such efflux might be sufficient to arrest progression at least long enough for something better (gene therapy, tau vaccine, etc.) to come along.

Furthermore, there is at least one rodent study demonstrating that TNF inhibition ameliorates behavioral deficits. While having no direct implications for human dementia, the point is simply that this strategy isn't just a blind approach based on a hunch. I think this deserves more study, especially in mild cognitive impairment, but it either won't occur or won't occur soon enough.

Doctor: Patient, I have some good news and some bad news. The bad news is that you have a serious illness. You are not expected to survive for more than a year.

Patient: That's terrible! So what's the good news?

Doctor: Well, a new experimental drug came out recently which seems to cure half the people who have your disease.

Patient: Oh great! I'll try it!

Doctor: I'm afraid I can't give it to you just yet because we need to determine whether or not it would be safe and effective in your case.

Patient: OK, so how long will that take?

Doctor: About two years.
 

Edited by resveratrol_guy, 12 August 2016 - 09:21 PM.

[mag1]

It is so frustrating to watch chemicals such as Etanercept linger for years and years without any update on their clinical status in regards

to Alzheimer's. There needs to be a mechanism to move the research forward!

 

It is almost unbelievable, The anti-AD claims made for Etanercept have been out there for years. They talked of nearly instant changes

in cognitive status. We need to get to a point where we have reality shows or something that can take these claims and test them.

With Etanercept it could even be done in real time. Of course,  Etanercept is an FDA approved medicine so there is no clear reason

why this has not been done.

 

The same could be done for 3-Bromopyruvate. You could select those cancer patients who would have a massive anti-cancer effect

and show them in a reality show in real time as their cancer disappeared. In those who respond to 3-BP, ATP levels in cancer cells might

decrease over 90% within 30 minutes. Perhaps it might be somewhat exploitative, though viewers could experience all the joys of those who could escape terminal cancer. It is very unclear to me why this has not been done.

 

It would make for great dramatic TV and it would also end any discussion about whether 3-BP is an effective cancer medicine. As it is, this discussion has now been ongoing for the last 15 years and there could be another few decades of navel gazing yet to come.   

Edited by mag1, 12 August 2016 - 10:07 PM.

[resveratrol_guy]

I don't think the answer is a reality show. (Imagine the lawsuits!) The answer is research-friendly jurisdictions such as the Bahamas, Colombia, and a few others. The problem as I see it isn't that the researchers aren't motivated, and isn't that those jurisdictions wouldn't welcome them, it's frankly that we need to motivate the researchers to relocate themselves accordingly. Perhaps telemedicine could help here, in the sense of allowing researchers in overregulated economies to supervise trials in less regulated ones via the net, but thus far I've never heard of such a trial design. In any event, we need to do something to improve this situation.

 

Imagine what an uproar would result if your government prevented you from buying certain stocks in the stock market because they're "too risky for you". Why this nanny mentality nevertheless pervades medical research focussed on curing serious diseases is beyond me. I'm a strong advocate for thorough risk disclosure, but patient decisions should be up to the patient to the extent that their finances provide.

Edited by resveratrol_guy, 12 August 2016 - 10:54 PM.

[mag1]

Why I concentrated on a reality show was that the claims can be shown to be true!

So much alternative medicine is one form of deception or another.

 

Even in mainstream medicine it is quite possible to believe in placebo effects or other confounders.

​When they actually get around to doing the controlled study (such as with hormone replacement)

the results can be not what were expected.

 

The power with a reality TV or a court room type scenario with 3-BP is that it could all be done

under scrutiny in real time. The ability of regulators or others to withhold these treatment choices

could simply be overwhelmed by the power of observable evidence. What effect would curing

someone of terminal cancer (this could be determined beforehand by simply doing an oncoscreener,

as suggested by res) in real time reality TV with 3-BP have on the public perception of 3-BP or the

authority of government to control access?  

 

This is one of the few opportunities that I am aware of (besides perhaps Etanercept) where a falsifiable

statement concerning an alternative medicine exists. Typically claims about alternative medicines

are very difficult to rebut. I do not understand why especially with 3-BP such grandstanding has not occurred.

There is not particularly compelling reason that we need to adhere to the same methodologies of research

has created a nearly compete fossilization of the status quo.

 

[resveratrol_guy]

Why I concentrated on a reality show was that the claims can be shown to be true!

So much alternative medicine is one form of deception or another.

 

Even in mainstream medicine it is quite possible to believe in placebo effects or other confounders.

​When they actually get around to doing the controlled study (such as with hormone replacement)

the results can be not what were expected.

 

The power with a reality TV or a court room type scenario with 3-BP is that it could all be done

under scrutiny in real time. The ability of regulators or others to withhold these treatment choices

could simply be overwhelmed by the power of observable evidence. What effect would curing

someone of terminal cancer (this could be determined beforehand by simply doing an oncoscreener,

as suggested by res) in real time reality TV with 3-BP have on the public perception of 3-BP or the

authority of government to control access?  

 

This is one of the few opportunities that I am aware of (besides perhaps Etanercept) where a falsifiable

statement concerning an alternative medicine exists. Typically claims about alternative medicines

are very difficult to rebut. I do not understand why especially with 3-BP such grandstanding has not occurred.

There is not particularly compelling reason that we need to adhere to the same methodologies of research

has created a nearly compete fossilization of the status quo.

 

If you want to pursue this idea, I would recommend contacting Dayspring or some such other fringe clinic to see if they'd be interested. It could have tremendous social value for the reasons you stated, assuming that you could actually convince them to participate. They might actually be interested, because while they all probably realize that formal studies will probably never be done on substances like c60oo or 3BP, it could raise the profile of their business if people could see, firsthand, the rapid improvement in their patients. Just the same, it would also speak volumes if they refused to discuss the idea.

 

If you can find any takers, start a thread about it, or better yet, an Indiegogo campaign.

[resveratrol_guy]

On another note, did you all see this article by Reason? Here is the video interview and the paper. On the plus side, it would seem that this stuff should be obtainable now, if in fact the science is supportive. I can't comment on that at the moment, but it's too good not to share.

[mag1]

res, the impressive part is that Dayspring did step up to a similar idea. I was impressed!

The best way to detect fraud is to simply see how people respond to verifying their claims.

 

A ways back a bile duct patient with massively severe illness started a gofundme campaign to

get treatment at Dayspring at 3-BP. Even this patient had at least some response to treatment

(reported to decrease markers by 6% after a week or two of treatment) though had to stop

treatment due to symptoms from the underlying illness.

 

Dayspring has accepted cancer patients with very severe illness for 3-BP treatment that few other

clinics would touch.

 

With the recent incident at a German 3-BP we might be approaching a very good opportunity if a public

inquiry is held to show what 3-BP could do in real time. The court room theatrics could offer a truly

devastating rebuttal to those who deny that 3-BP can have treatment effects.

 

For example, the defence might call a witness by internet connection with terminally severe cancer who

has been selected on the basis of large potential for 3-BP treatment. The oratory repertoire available

to an attorney would be extensive. If the government regulators declined to grant permission to treat

such a patient with 3-BP, the attorney could grandstand by saying that he would grant such permission

and face what ever consequences might follow. Watching the level of the patient's ATP fall by over

90% within the next 30 minutes would simply eliminate any moral authority held by the government.

 

The response to 3-BP could be easily predetermined (as you have mentioned res).

 

It makes no sense at all to me why there is this dogmatic insistence on thinking of clinical trials as the only

possible way of determining the utility of medical treatment. Perhaps another way could be through some

sort of a gambling arrangement. Patients could be presented with some sort of known phenotype/genotype

of an illness.

 

For example, predetermined response to 3-BP. There would then be a betting round to determine

what the response should be. A priori inducing a metabolic cure of cancer in a terminally ill patient within 30 minutes

should be granted odds of a million to one. We would know within 30 minutes what the truth was.

 

Instead of the mantra being: Show us the evidence by conducting decades worth of clinical trials costing billions of dollars,

            the mantra could be: Show me the money!

                 If you think this is bogus fine put your money where your mouth is.

                 Here's a whole line of terminally ill patients that have been pretested and are known

                 to have shown a large 3-BP LDH response.

 

                 Let's see how much regulators or others are willing to lose on their million to one odds.

                 Talk is cheap. Over 90% drop in LDH within 30 minutes is priceless.  

 

                

                   

 

   

[ceridwen]

Will it be possible to buy Mefenamic acid without prescription?

[mag1]

res, do you have any ideas of how CRISPR might be used in AD?

There has been talk lately of the first CRISPR gene trial in cancer that should soon start using an ex vivo approach.

 

Given that AD also has some notable immune system connections, how might an ex vivo approach with CRISPR work?

Ex vivo CRISPR modified T-cells?

Some sort of an immune cell that could produce therapeutic anti-amyloid antibodies?   

[resveratrol_guy]

res, do you have any ideas of how CRISPR might be used in AD?

There has been talk lately of the first CRISPR gene trial in cancer that should soon start using an ex vivo approach.

 

Given that AD also has some notable immune system connections, how might an ex vivo approach with CRISPR work?

Ex vivo CRISPR modified T-cells?

Some sort of an immune cell that could produce therapeutic anti-amyloid antibodies?   

 

There are plenty of CRISPR targets, but none of it matters because no one is doing any trials. Even BioViva is only proposing turning on TERT in one small area of the hippocampus. (How would that stop the loss of white matter elsewhere? I don't know.) My hope is that banana republics will come to the rescue at some point, offering a menu of genes that you might want to flip on or off (other than those which would affect future children).

 

CRISPR is so far ahead of clinical reality, it's sad. It's not as though the technology could not be used tomorrow, but for reasons of bureaucratic idiocy, it's going nowhere. Yeah, it's untested. Yeah it might even kill you in some cases. But its use should be for patients and their guardians to decide, not Nanny.

 

The ex vivo immune approach has been used in cancer, especially leukemias, for some time and with considerable success. Logically, what we want is a bunch of modified microglia who have an insatiable appetite for brain plaque. On the other hand, this is unrealistic because it's a one-off approach that would be in trials forever, and some patients might well die from the resulting temporary but intense inflammation. CRISPR is much more promising because it's so much more generic and can be delivered via a simple craniotomy or maybe even just a lumbar puncture.

 

If you want an answer that's even close to practical, look to Axon Neurosciences' tau vaccine candidate. Their patients, on average, remained cognitively stable during the phase 1 (safety) trial. Dose escalation might result in disease reversal to some extent.

 

Good luck with your reality show. We need all the funding we can get for research driven by a desire to reverse disease, as opposed to generating recurring revenue based on marginal efficacy. I don't know if the betting house approach is the best one, but if it were me, I'd be more than happy to have people bet on my outcome if the result of that process were funding for my therapy.

Edited by resveratrol_guy, 13 August 2016 - 03:05 AM.

[resveratrol_guy]

Will it be possible to buy Mefenamic acid without prescription?

 

Well you can find it from a variety of Indian manufacturers here. I have no idea as to which of them are trustworthy.

 

Anyone considering taking mefenamic acid needs to be aware of the hazards, to begin with. I would also want to get input from other members here first.

[mag1]

Very cool about the tau vaccine! I had not been aware of the progress of this vaccine into phase 2.

They are also talking about 24 month treatment intervention which is somewhat unusual in AD trials.

Perhaps with some trials you really would prefer not to know what happens to the treatment effect once

you get past 18 months. The phase 1 extension trial will have 24 month treatment results at the end of

this year. Very encouraging!  

[resveratrol_guy]

Yeah, tau vaccine is probably the most promising dementia therapy currently in trials. We wouldn't need to worry much about growing new neurons, if only we could halt progression, because a few months of neuroplasticity can compensate for a lot of deficits, provided that the damage is diffuse as opposed to local, which is the case with most dementias.

It has come to light in recent years that certain brain plaque species are more virulent than others. After all, there's ample evidence of elderly people who have died with brains loaded with abeta, yet who didn't seem to suffer from dementia. Acetylated tau, on the other hand, is one of the particularly toxic species.

Teaching the microglia to consume toxic forms of tau is a great idea supported by rodent research, and it may well prove successful in trials. However, in that case, I think we all know that it will be too expensive for too long, and will be unavailable to all but those with established diagnoses. In other words, it will have no preventative value in the sense that a vaccine should have.

We're not getting any younger, so we have to be practical, which means doing what we can by way of prevention with the tools available to us in light of budgetary constraints. To that end, and given the universal failure of antiamyloid interventions despite successful plaque removal in humans, it seems to me that toxic forms of tau are the single most significant enemy. If that's the case, then salsalate could be our best practical option.

It was mentioned in this thread a year ago, but seems to have received little attention. According to this summary of the science, it reversed cognitive deficits in mice with frontotemporal dementia (FTD) and is now in a clinical trial for progressive supranuclear palsy. I see no reason to assume that, on a molecular level, FTD is any different than the tauopathy commonly known as Alzheimer's; it just happens to start in a different brain region. The paper is paywalled, unfortunately, but at least the author affiliations look like credible California institutions. For its part, salsalate seems to restore insulin sensitivity, which is about the last thing one would expect from an NSAID cousin of aspirin, unless in fact the effect is due to the disaggregation of brain plaque which interferes with central blood sugar regulation. The new research suggests that its mechanism of action involves the inhibition of p300, which normally causes the formation of toxic acetylated tau. The result is that the brain's native disaggregation and macroautophagic mechanisms can get ahead of the accumulation of garbage, allowing the net removal of acetylated tau.

Salsalate, unlike almost every other compound we've discussed, sells for all of $2/day in the 1350 mg/d dose mentioned in the original Longecity thread. It requires a prescription but there are plenty of offshore sources available, for example. Considering its low molecular weight (258 g/mol), it should be easy to authenticate via third-party labs.

Maybe I'm missing something here. Maybe there was a good reason that Longecity seems to have ignored it, but if so, the reason is not evident to me. Perhaps the thinking was that we'd soon know the supranuclear palsy trial results, which might in fact be the case, but academic institutions are never in a rush to publish anything, so I wouldn't count on that.

Edited by resveratrol_guy, 13 August 2016 - 06:55 PM.

[mag1]

res, you should have said something about this man.

The people depend upon you.

[resveratrol_guy]

Well, yeah, I should have commented on it, but I'm sure I never saw it because otherwise I would have.

It modulates AMPK and lowers blood sugar in diabetics.

What's ridiculous, frankly, is that the blood sugar results came out in 2010, yet until 2014 no one seems to have pursued the obvious question: why? I mean, aspirin has been around for a century. If it were effective at lowering HbA1c, we'd know that by now. (To be clear, as an antiinflammatory, it surely does help mitigate the damage due to diabetes, but does nothing to address the cause.) In light of the FTD study, it seems to me that the most likely explanation is that salsalate (not aspirin) is clearing acetylated tau (and probably other plaque species) out of the brain, thereby enhancing the insulin and leptin sensitivity of individual neurons. After all, a neuron surrounded by plaque is less fit to respond to environmental signals. But if this is true, then why would diabetic reversal be the only effect? It should improve neural signalling in general.

But first let's consider its negative side effects.

The worst such effect would be expected to be blood thinning, which is great if you're trying to avoid blood clots, but not so great if you're at risk of hemorragic stroke or physical injury. Generally, however, thinner blood is associated with longevity. And in this case, "No increase in gastrointestinal bleeding was reported in those on salsalate".

More concerning is the increase in urinary albumin, which is a sign of kidney impairment -- in particular, an inability to retain protein required by the body. However, levels returned to baseline upon cessation. And remember, these people were diabetics who in all likelihood were following some form of SAD diet. It seems probable that proper diet, and in particular a low methionine diet, could have prevented this.

Another "problem" is a small increase in LDL cholesterol. Even assuming that this is statistically significant, I don't see any commentary about kernel size. Large kernel LDL is essential to preventing Alzheimer's. But let's assume it was small kernel; just drink more olive oil.

There was also some mild hypoglycemia reported. Whatever, this can be cured with a teaspoon of sugar or better yet, rendered moot with coconut oil.

Finally, a slight weight gain was observed, consistent with the effects of other pharmaceutical interventions for diabetes. (Is this bad? Maybe they converted visceral fat to muscle because they had more energy to exercise.)

On the plus side, "people taking the medication saw their A1C levels drop by 0.37 percent compared to placebo" (e.g. HbA1c 7.4% -> 7.0%). Uric acid, triglycerides, adiponectin, and hematocrit levels also improved.

The author concluded: "At this point, it's premature to recommend the use of salsalate for people with type 2 diabetes". Then he goes on to make the usual comment about needing more studies, just so he covers his ass and develops a case for more funding. But I don't blame him. Researchers seldom get rewarded if their studies help people, but will get fired or sued if they're found to be flawed. I guess he wasn't compelled by his own P values, which by the way also indicated a probable dose-response relationship: "Mean HbA1c changes were −0.36% (P = 0.02) at 3.0 g/d, −0.34% (P = 0.02) at 3.5 g/d, and −0.49% (P = 0.001) at 4.0 g/d compared with placebo." 0.5% may not sound like a lot, but it's a major disease alteration in diabetes.

Previously, Logic mentioned that salsalate caused "reversible auditory side effects in a significant minority of subjects" in an osteoarthritis study of the drug. Based on my own similar experience with aspirin, I suppose this is referring to tinnitus, which is annoying but somewhat treatable with melatonin.

The main problem here is that this is, as usual, virtually guaranteed to go nowhere from a research standpoint. After all, what's the incentive to spend millions of dollars to monitor thousands of patients for years, for the sake of a drug which costs $2/day? At least, this time, it's actually available.
 

Edited by resveratrol_guy, 13 August 2016 - 09:52 PM.

[ceridwen]

I haven't known melatonin to cure tinnitus!

[resveratrol_guy]

I haven't known melatonin to cure tinnitus!

 

Me neither. As I said, it's "somewhat treatable" with melatonin. This is based on what I've read and my own experience. I think this just comes down to melatonin's proven effectiveness as a sleep aid for most people. In other words, it allows one to sleep despite tinnitus.

 

Personally, I take 3 mg of the non-time-release variety an hour before bed, then keep working at my desk until I feel like I'm gonna keel over. I hit the sack and seldom awaken less than 6 hours later. Those with trouble staying asleep may prefer the time-release variety or some mix of the two.

 

Here is a brilliant podcast interview of a melatonin researcher back in 2007, which presents essential knowledge regarding this compound and its many health benefits. Thanks to my buddy Ovidus for the link.

[docmaas]

Is this the full paper?  https://www.research...nitive_deficits.  Same author; same drug.  250mg/kg for mice works out to @20mg/kg for the two legged variety.  

 

Mike

 

Yeah, tau vaccine is probably the most promising dementia therapy currently in trials. We wouldn't need to worry much about growing new neurons, if only we could halt progression, because a few months of neuroplasticity can compensate for a lot of deficits, provided that the damage is diffuse as opposed to local, which is the case with most dementias.

It has come to light in recent years that certain brain plaque species are more virulent than others. After all, there's ample evidence of elderly people who have died with brains loaded with abeta, yet who didn't seem to suffer from dementia. Acetylated tau, on the other hand, is one of the particularly toxic species.

Teaching the microglia to consume toxic forms of tau is a great idea supported by rodent research, and it may well prove successful in trials. However, in that case, I think we all know that it will be too expensive for too long, and will be unavailable to all but those with established diagnoses. In other words, it will have no preventative value in the sense that a vaccine should have.

We're not getting any younger, so we have to be practical, which means doing what we can by way of prevention with the tools available to us in light of budgetary constraints. To that end, and given the universal failure of antiamyloid interventions despite successful plaque removal in humans, it seems to me that toxic forms of tau are the single most significant enemy. If that's the case, then salsalate could be our best practical option.

It was mentioned in this thread a year ago, but seems to have received little attention. According to this summary of the science, it reversed cognitive deficits in mice with frontotemporal dementia (FTD) and is now in a clinical trial for progressive supranuclear palsy. I see no reason to assume that, on a molecular level, FTD is any different than the tauopathy commonly known as Alzheimer's; it just happens to start in a different brain region. The paper is paywalled, unfortunately, but at least the author affiliations look like credible California institutions. For its part, salsalate seems to restore insulin sensitivity, which is about the last thing one would expect from an NSAID cousin of aspirin, unless in fact the effect is due to the disaggregation of brain plaque which interferes with central blood sugar regulation. The new research suggests that its mechanism of action involves the inhibition of p300, which normally causes the formation of toxic acetylated tau. The result is that the brain's native disaggregation and macroautophagic mechanisms can get ahead of the accumulation of garbage, allowing the net removal of acetylated tau.

Salsalate, unlike almost every other compound we've discussed, sells for all of $2/day in the 1350 mg/d dose mentioned in the original Longecity thread. It requires a prescription but there are plenty of offshore sources available, for example. Considering its low molecular weight (258 g/mol), it should be easy to authenticate via third-party labs.

Maybe I'm missing something here. Maybe there was a good reason that Longecity seems to have ignored it, but if so, the reason is not evident to me. Perhaps the thinking was that we'd soon know the supranuclear palsy trial results, which might in fact be the case, but academic institutions are never in a rush to publish anything, so I wouldn't count on that.

 

[ceridwen]

I sleep really well anyway but I might now have sleep apnea I'm told. I need to get that checked. I do 1 night shift a week but even there sleep between 6-7am.

[ceridwen]

Sleep definitely changes the sound of the tinnitus but not as much as the mega doses of Vitamin C that I take now. Also thinking of doing aerobics just as soon as I can understand how to load YouTube videos into it. feed back would be welcome

[resveratrol_guy]

 

Is this the full paper?  https://www.research...nitive_deficits.  Same author; same drug.  250mg/kg for mice works out to @20mg/kg for the two legged variety.  

 

Thanks, docmaas! Yes, that's the paper. It's an interesting read, which ultimately speculates, as mentioned above, that suppression of the p300 machinery for tau acetylation is the root cause of salsalate's effects, which has nothing to do with its antiinflammatory properties. (This is why strong COX2 inhibitors, for example, do not create this effect despite being strongly antiinflammatory.) The authors note that p300 is involved a variety of biological functions, so its inhibition might be expected to cause havoc elsewhere, although the diabetic study suggests that the side effects are manageable. In particular, it would be important to be on the lookout for symptoms of Reye's syndrome, which is probably preventable but can occur with aspirin and thus perhaps salsalate as well.

It's clear in Figure 5h that the treated mice were functionally indistinct from the nontransgenic (NTG) normal mice at 10 months, which is impressive in light of the obvious hippocampal volume loss in untreated transgenic (PS19 veh) mice as distinct from treated transgenic mice (PS19 SSA) in Figure 5a.

The authors note that salsalate seemed to target acetylated tau (acetylation at site K174, i.e. ac-K174, specifically), thereby reducing the downstream formation of neurofibrillary tangles (NFTs), while leaving other toxic tau species intact. Nevertheless, they observed this obvious cognitive benefit, suggesting that ac-K174 tau may be one of the most  important drug targets in AD therapy. Moreover, total tau decreased, along with the relative fraction of ac-K174 tau, suggesting not merely disaggregation but frank efflux from the brain.

The authors put considerable effort into demonstrating that the K174 acetylation site is responsible for salsalate's main effect. They did this by creating an analog to ac-K174 tau, which they called ac-K174Q, apparently with glutamine already bound to the same site, thus preemptively eliminating the possibility of acetylation by p300. The fact that salsalate failed to ameliorate the resulting cognitive deficits supports the hypothesis that, indeed, it works by preventing p300 from acetylating K174. (The study presents this argument rather circuitously, so read carefully.)

 

If salsalate were a novel chemical entity  just invented by Big Pharma, I would estimate the probabilty of it being useful in humans at nearly zero. However, given the robust human data supporting reduced AD risk in individuals on longterm lose-dose aspirin regimens, and the authors' confirmation that postmortem human AD brains contain the same K174 acetylation site as in the mice, this looks rather promising.



 

Edited by resveratrol_guy, 14 August 2016 - 06:05 PM.

[ceridwen]

"The salsalate failed to ameliorate the cognitive defects"? So what's the point of that then
?

[resveratrol_guy]

Yeah I know it's a bit confusing. The failure was used to confirm the mechanism of action. Salsalate was very effective at preventing hippocampal atrophy and its associated memory deficits due to tau acetylation at K174, which occurs in humans as well as mice. It's really surprising that intervening with this one particular site, which does not even involve phosphorylation, could have such a massive effect, but it did.

[mag1]

res, I really hope that the phase 2 tau vaccine trial does not aimlessly drift like the LMTX trial as well as so many other AD trials.

The effect size that taurx is claiming for those on LMTX without other AD medications is simply massive. Why didn't interim clinical

trial analyses pick up what was going on and adaptively respond to the evolving information flow? We certainly need to have such

adaptation during AD trials.

 

I am very worried that this lesson which has not been learned time after time in AD trials will not be learned again.

If the phase 2 trial for the tau vaccine shows in an interim analyses that it has worked or it appears likely to have worked, then the ball

should be in motion to run a concurrent phase 3 trial. This is too important for there not to be prompt actions taken.

 

alzforum is talking of developing a large standing AD patient registry to help with clinical trials. The tau vaccine trial might

be a very good opportunity to give it a try.  

[resveratrol_guy]

Tau vaccine will definitely go to phase 3 if phase 2 pans out as hoped. There's too much money riding on it for that not to be the case. But as I said before, it's pretty much moot, because almost no one will benefit from it for decades, until long after this vaccine goes generic, assuming that it even works. It was in the act of researching it that I stumbled upon the salsalate study. Salsalate isn't as good as tau vaccine or ex vivo modification of microglia would be, but it's cheap and it's here today.

 

What we really need is a country which fully deregulates medicine, apart from basic sanitation standards and truth-in-advertising. As I've mentioned before, there are a few bright spots, and I kind of suspect China, South Korea, or the Bahamas to take the lead. But it will be a long time coming. I still can't walk into a clinic, even in a banana republic, and CRISPR myself however I want.

 

So unfortunately, I think the only practical advice at this point is to focus on compounds we can obtain and reasonably afford. That, and learn to eat foods that taste terrible but make you feel stronger, just like the pain of going to the gym can accomplish the same.

Edited by resveratrol_guy, 15 August 2016 - 02:45 AM.

[mag1]

res, I am not sure I understand your comment about the tau vaccine taking decades to benefit anyone. The phase 1 trial was in mild to milderate Alzheimer patients and they appeared to benefit from the vaccine.

[resveratrol_guy]

res, I am not sure I understand your comment about the tau vaccine taking decades to benefit anyone. The phase 1 trial was in mild to milderate Alzheimer patients and they appeared to benefit from the vaccine.

 

To be sure, the research appears to be on a positive trajectory. But can you imagine how much this will cost? For example, even a decade after the Guardasil HPV vaccine came out (which some have said will not actually prevent cervical cancer), it still costs around $700. Tau vaccine could add months, if not years, to the life an AD patient in the advanced stages, and might prevent the disease entirely in preclinical patients. That puts it in the same league as cancer immunotherapy drugs like Yervoy, which implies that the cost should be in the range of $10K to $100K per shot. In other words, it seems destined to become Elysium medicine not meant for the masses.

 

It's worse than that, of course, because it's hard to imagine that the FDA will allow anyone to take it, other than in cases of severe AD, where there are so many problems that even clearing mutated tau would only result in a modest stabilization of disease. They'll say "it needs more study" for the next thousand years before it can be used in healthy individuals. And of course insurance wouldn't pay for it except under such dire circumstances. Think of it this way: if the flu vaccine were invented today, who would get insurance approval to take it? Just people dying of the disease. The vaccine company would then need to charge $100K per shot because only a small percentage of people die from the flu, as opposed to other illnesses. The same investment payoff argument applies to AD.

 

Unfortunately, I don't think it's possible to look at the history of cancer drugs -- some very few of which have actually worked well -- and conclude that the business and regulatory model for effective AD drugs would be any different.

 

If it works, and we're really lucky, the manufacturer will be stupid enough to market it for cheap in a banana republic somewhere, not realizing that healthy individuals could simply fly over there and obtain it, particularly since its effects probably last years if not for a lifetime. I'm unaware of this occurring with other vacccines, although it does clearly occur for drugs.

[ceridwen]

They should fast track it. If they can release the Ebola vaccine early why can't they do the same for the AD vaccine?

[Cobenzl]

http://www.kurzweila...ease-model-mice

Article copied from KurzweilAI....

Anti-inflammatory drug reverses memory loss in Alzheimer’s-disease-model mice
August 12, 2016

(credit: NIH National Institute on Aging)

Anti-inflammatory drug mefenamic acid completely reversed memory loss and brain inflammation in mice genetically engineered to develop symptoms of Alzheimer’s disease and amyloid beta-induced memory loss, a team led by David Brough, PhD, from the University of Manchester has discovered.

The non-steroidal anti-inflammatory drug (NSAID) drug targets an important inflammatory pathway called the NLRP3 inflammasome, which damages brain cells, according to Brough. This is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Brough said.

“Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs. We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans.”

“There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer’s disease worse. Until now, no drug has been available to target this pathway, so we are very excited by this result.”

The research, funded by the Medical Research Council and the Alzheimer’s Society, paves the way for human trials that the team hopes to conduct in the future, but Brough cautions that more research is needed to identify its impact on humans and the long-term implications of its use.

The findings were published Thursday Aug. 11 in an open-access paper authored by Brough and colleagues in the journal Nature Communications.



Stu