1229 replies to this topic

[resveratrol_guy]

Curiosity got the better of me and I purchased the article.

While I can't legally post it here, I can answer any questions you all might have.

Here are the highlights:

 

1. The patient was a 68-year-old man with mild AD (beyond mild cognitive impairment, but still quite functional).

2. The 40% memory improvement was on this test. Based on the description, it sounds similar to various brain games I've played. I don't think a 40% improvement in raw score is possible for most people, but this patient managed exactly that. Impressive.

3. Although the authors acknowledged that the use of bexarotene in AD started with rat studies showing a reduction in cerebral amyloid, those studies could not be reproduced. Indeed, the patient's PET scan showed worse metabolism (1.94) at the end of the 6-month 300 mg/d dosing regimen than at the beginning (2.08). They did measure amyloid, tau, and phosphotau in the CSF, but the relationship to their cerebral counterparts is unclear. In any event, plaque reduction does not seem to have caused the memory improvement.

4. The authors suspect enhanced neuronal cholesterol efflux as the reason for the memory improvement. This goes back to the ancient hypothesis that AD is a lysosome storage disorder. Evidently, in addition to accreting plaque, sufferers accumulate excessive amounts of cholesterol inside neurons, impeding their function. This is aggravated by positive APEO4 gene status, which is involved in cholesterol transport; the patient had a single copy (of a maximum 2). Indeed, during the study, the patient's LDL rose as high as 175. Otherwise, no side effects were recorded. Extra olive oil consumption would be well advised until cholesterol levels return to baseline; in my view, that would indicate the attainment of maximum effect.

5. Family and relatives observed improvements in daily living, but not a normalization of memory function. Unfortunately, there is no report as to the degree to which his family thought that memory had improved, despite not having normalized. Perhaps earlier intervention could have accomplished that.
 

[mag1]

Taking one for the team again res. Good on you!

 

Interesting. Bexarotene was originally sold as a massive amyloid drainer.

 

Was the patient APOE epsilon 4? This has been a large question mark in Bexarotene research.

[resveratrol_guy]

The recent genericization of Targretin might add obstacles to further reports of positive responses in AD patients.

Anyone have a quote on the current cost of Targretin? It seems as though it might be quite inexpensive now. 

 

It's roughly $1000 for 300 mg, as I mentioned above, or about $1 from China. But you would probably need to get it from China anyway, because no one would prescribe it to you as an AD prophylactic. You could then have it tested at a reliable lab for maybe $500. The real problem with stuff from China isn't that it's fake (usually); it's the contaminant level. In this case, while I doubt that heavy metals would be much of a problem on account of the small dose, volatile organic compounds might be, as they are usually used in the synthesis.

 

The patent expires in 2016, but given the FDA hurdles that even a generic must jump over, it still won't be anywhere near economical to acquire through conventional channels. No doubt insurance won't cover it, either, even if you have AD, because it's a cancer drug.

Edited by resveratrol_guy, 17 October 2015 - 12:09 AM.

[resveratrol_guy]

Taking one for the team again res. Good on you!

 

Interesting. Bexarotene was originally sold as a massive amyloid drainer.

 

Was the patient APOE epsilon 4? This has been a large question mark in Bexarotene research.

 

You're welcome. He was heterozygous (1 of 2 possible copies.)
 

I think it's actually good news that bexarotene is a failure at amyloid drainage, because this suggests that it would act synergistically with substances like lipidated curcumin.

[mag1]

I do not understand. the url I posted above said that Mylan started making Targretin in July of this year with 180 competition free period. 

There should be no reason to sneak around to China.

 

Generic prices for Targretin probably should be fairly reasonable.

 

Ah, and about the epsilon 4 status of the AD in the article? 

A 34? Hmm, that is interesting. there has been some question whether increasing the APOE dosage in carriers of a 4 would be a good idea or not.

 

I am not sure about all this talk about the initial results not replicating. If I were in the shoes of the original researchers and others claimed that

they could not replicate the results, then I would probably be lividly mad if they had not replicated it to the letter. Lots of times replications do not

seem to be true replications at all. Did they use the exactly identical formulations (e.g. micronized bexarotene), the same genotype of mouse,

using the same dosage etc. etc. . I really do not understand the rebuttal that such exact replications are not helpful because they have no general 

applicability over a robust range of conditions.

Edited by mag1, 17 October 2015 - 12:20 AM.

[ceridwen]

Sounds about my level of disintegration. Where can I get it? Does anyone know if his disease was halted or just reversed a little?

[resveratrol_guy]

I do not understand. the url I posted above said that Mylan started making Targretin in July of this year with 180 competition free period. 

There should be no reason to sneak around to China.

 

Generic prices for Targretin probably should be fairly reasonable.

 

Ah, and about the epsilon 4 status of the AD in the article? 

A 34? Hmm, that is interesting. there has been some question whether increasing the APOE dosage in carriers of a 4 would be a good idea or not.

 

I am not sure about all this talk about the initial results not replicating. If I were in the shoes of the original researchers and others claimed that

they could not replicate the results, then I would probably be lividly mad if they had not replicated it to the letter. Lots of times replications do not

seem to be true replications at all. Did they use the exactly identical formulations (e.g. micronized bexarotene), the same genotype of mouse,

using the same dosage etc. etc. . I really do not understand the rebuttal that such exact replications are not helpful because they have no general 

applicability over a robust range of conditions.

 

The best price I could find was $49,000 for 200 75 mg capsules, so yes, that's $980 for 300 mg -- a whopping 2% discount! And again, there's the presciption problem. It's beyond hopeless. Even having AD won't help you get it. I think China is a reasonable risk because we have mass spectrometers. If there's a synthesis route described in the patent, then we would also have some clue as to which toxins to look for.

 

To your point about amyloid drainage, yes, it's of course possible that it occurs under conditions which we simply don't understand. But it doesn't seem to have occurred to any significant extent in this man. CSF amyloid increased by 10%, so perhaps the cerebral counterpart decreased by as much. That probably wouldn't result in detectable cognitive improvement.

 

I don't get your reference to "34".

[ceridwen]

It might well be that it can help people with a certain genotype or a certain level of decline and others not at all. We might not even know what these factors are at this stage of research

[ceridwen]

Maybe he got lucky and lived a few weeks or days longer than he otherwise would. Every little counts.
But personally there's no way I could afford that.

[resveratrol_guy]

It might well be that it can help people with a certain genotype or a certain level of decline and others not at all. We might not even know what these factors are at this stage of research

 

This is certainly true. But based on the plasma cholesterol effect, I think their cholesterol efflux theory has merit. Perhaps if APOE4 individuals used bexarotene periodically after age 40, they would not develop the disease anymore than normal individuals.
 

[resveratrol_guy]

Maybe he got lucky and lived a few weeks or days longer than he otherwise would. Every little counts.
But personally there's no way I could afford that.

 

$1 a day for 6 months is all of $180. Add in shipping etc. and maybe it's $400. Want it mass spectrometrized? OK, maybe it's $1000 for the whole 6 months, vs. that much per day with the "safe" suppliers that won't sell to you anyway.

 

AFAIK he's still alive.
 

Edited by resveratrol_guy, 17 October 2015 - 12:44 AM.

[ceridwen]

It's all a bit pointless unless there are some billionaires in need here. It's certainly too expensive for the NHS too and probably doesn't work. Very disappointing
Where from ?
Ah I didn't read won't sell to you anyway

[resveratrol_guy]

It's all a bit pointless unless there are some billionaires in need here. It's certainly too expensive for the NHS too and probably doesn't work. Very disappointing
Where from ?
Ah I didn't read won't sell to you anyway

 

From China. For example, see here. I make no claim that any of those vendors is reliable, but I do trust various labs to tell me if the product is real.

 

Oh, and Wiki says you want CAS number 153559-49-0. So those "bexarotene intermediates" are not what you want.

Edited by resveratrol_guy, 17 October 2015 - 12:49 AM.

[mag1]

epsilon 34

[ceridwen]

Thanks. I'll look more closely tomorrow.

[resveratrol_guy]

epsilon 34

 

There is no mention of APOE34, only APOE4.

 

Attached is a graph showing the effects. The measured performance in the following areas: executive function, memory, visualspatial, and language. They should have used a bar graph for each of the tests, but they used a line graph, which is misleading. There are only 2 time periods: start and 6 months, which are blue and yellow, respectively. As you can see, the most significant effect was on the M2 memory test. Sorry I don't know what the specific rules were for that test.

 

By the way, his M2 test score 7 months prior to start was identical (negative 6), so it's not likely that he just happened to have a bad day when the test was administered at the start. 19 months prior to start, his score was negative 1, so it seems that bexarotene saved him more than a year of memory decline.

Attached Files

•  score.jpg   33.37KB   5 downloads

Edited by resveratrol_guy, 17 October 2015 - 01:17 AM.

[mag1]

I do not understand the $49,000 quote. A generic drug should move toward marginal cost which often with pharmaceutical drugs is almost zero.

[ceridwen]

Amazing graph.

[mag1]

So the patient was epsilon 3, epsilon 4. Interesting.

The above graph shows improvement in memory performance.

This is the type of improvement that one would expect.

 

Memory would be the first cognitive skill that you would expect to be stressed.

The other measures might simply not have moved because they were not pressured at this early stage of the illness.

 

Other clinical trials have run into this problem. No improvement sometimes results because there is no measurable deficit

to start with.

 

 

 

 

 

 

[resveratrol_guy]

I do not understand the $49,000 quote. A generic drug should move toward marginal cost which often with pharmaceutical drugs is almost zero.

 

Yeah, it's freaking ridiculous! But we live in a pharmocracy. Don't get me started...
 

[resveratrol_guy]

So the patient was epsilon 3, epsilon 4. Interesting.

The above graph shows improvement in memory performance.

This is the type of improvement that one would expect.

 

Memory would be the first cognitive skill that you would expect to be stressed.

The other measures might simply not have moved because they were not pressured at this early stage of the illness.

 

Other clinical trials have run into this problem. No improvement sometimes results because there is no measurable deficit

to start with.

 

I think you're right. Olfactory competence is the first to decline, followed by short term memory, then everything else. At least, that's the usual progression. So these neuropsychological scores support the assertion that he was early stage. What I would like to see is the same regimen applied to someone with mild cognitive impairment (i.e. pre-early-stage), where presumably maximum therapeutic effect would be possible.

[mag1]

Yes, but there are laws. If this is going generic the price is about to plummet.

Generic prices move to marginal cost.

 

I do not believe that Targretin costs $49,000 for a few grams of it.

The Chinese appear to be able to produce it for a few dollars a gram.

This is the true marginal cost.

 

The price should migrate to such a price point as the generics come online.

 

I am worried, though, that when true generic pricing takes effect that the AD research into will lose momentum.

 

 

 

 

 

 

[ceridwen]

APOE3 is supposed to protect against neurodegenerative decline isn't it. Maybe that's why he could be helped? Whereas it might be useless for a homozygous APOE4?

[mag1]

The thinking was that Targretin increased the gene dosage. Increasing gene dosage for epsilon 3 would seem to be a good idea.

However, the original concern was that increasing gene dosage for an epsilon 4 would be a bad idea: You would be giving the patient more

epsilon 4 which is the leading genetic risk factor for AD!

 

Yet, here we are with an early AD patient with epsilon 3, epsilon 4 improving with Targretin treatment!?

 

 

Downright giving it away.

http://www.pharmacyg...les_p_2078.html

Edited by mag1, 17 October 2015 - 01:35 AM.

[ceridwen]

Does this mean that I should contact 23andme to find what my genetic status is?
Too much for me

[resveratrol_guy]

I see no reason why bexarotene would exacerbate disease, regardless of APOE status. It's just that APOE4 copies predispose people to earlier onset. In any event, just as old arteries contain oxidized atherotic plaque, old neurons contain an similarly degenerate form of cholesterol. IMO removing it should be helpful regardless of genetics. In any event, seeing such an improvement in a heterozygus individual is encouraging. I wonder what would have occurred, had he applied all the other proven techniques to support brain health.

 

@ ceridwen 23andMe is currently under an injuction imposed by the FDA. They are not permitted to supply any genetic testing services, other than to show existing users their old data. Thank goodness that we have Nanny to protect us from seeing things unfit for our eyes!

Edited by resveratrol_guy, 17 October 2015 - 01:44 AM.

[mag1]

You should definitely know your APOE status.

There is no need to contact them, though this is such a sensitive topic that 23andme requires that you opt into this genotype.

 

APOE status is often stratified in AD clinical trials. For some of the trials it seemed that different genotypes experienced different

outcomes.

 

It is not yet clear which way Targretin will break with respect to genotype. Results of a clinical trial in AD are expected with Targretin soon that could

help clarify things.

Edited by mag1, 17 October 2015 - 01:44 AM.

[ceridwen]

How do I get genetically tested then?
Looking for a cheap but effective test.

[resveratrol_guy]

How do I get genetically tested then?
Looking for a cheap but effective test.

 

I actually looked into this several months ago. Basically, you would need a prescription, at least in the US. Having said that, I'm not aware of any lab which does it.

 

Personally, I'm of the view that APOE4 status doesn't actually matter because it doesn't change the nature of the disease, just the time of onset. There isn't much difference in the treatment, except that APOE4 homozygous individuals may find it harder to stick to a ketogenic diet. There are surely other differences, but I think the basic therapy, and the means of prevention, should be the same.

[mag1]

Water anyone?

 

Here's some early studies showing efficacy.

http://www.ncbi.nlm....pubmed/23400965

http://www.ncbi.nlm....pubmed/23031079

http://www.ncbi.nlm....pubmed/25378931

http://www.ncbi.nlm....pubmed/25936373

http://www.ncbi.nlm....pubmed/22146068

http://www.ncbi.nlm....pubmed/22607973

 

(Weren't we just talking about MMP3?)

http://www.ncbi.nlm....pubmed/24929023

 

http://www.ncbi.nlm....pubmed/24274030

 

Of course I suppose that water could be dangerous.

A 20 year double blind study might be needed to provide initial evidence for safety.

However, earlier in the thread there was mention of H2S. I'd rather stick with hydrogen water.

 

Here's how to make it.

http://www.ncbi.nlm....pubmed/26504515