413 replies to this topic

[Rocket]

The title of the abstract is right there in quotes. Just google it. I'm having issues with my browser and cut and paste.

[The Capybara]

There are a few issues I have with the previously referenced berberine article. The first, and primary issue, is the method used to expose the mice to berberine. It was administered IP which bypasses GI absorption. Oral administration of berebrine to most (all?) animal models and humans results in barely detectable blood levels of the compound.

Maybe a better article, which is also more contemporary, is contrasting, and uses the same mouse model is: https://www.ncbi.nlm...les/PMC5089944/

"Berberine activates peroxisome proliferator‐activated receptor gamma to increase atherosclerotic plaque stability in Apoe ^−/− mice with hyperhomocysteinemia"

[mikey]

There are a few issues I have with the previously referenced berberine article. The first, and primary issue, is the method used to expose the mice to berberine. It was administered IP which bypasses GI absorption. Oral administration of berebrine to most (all?) animal models and humans results in barely detectable blood levels of the compound.
Maybe a better article, which is also more contemporary, is contrasting, and uses the same mouse model is: https://www.ncbi.nlm...les/PMC5089944/
"Berberine activates peroxisome proliferator‐activated receptor gamma to increase atherosclerotic plaque stability in Apoe ^−/− mice with hyperhomocysteinemia"

[mikey]

Having limited access currently so I don’t have the citation at hand the 2009 study that reported an adverse effect was contradicted by a 2014 study. However, aren’t we looking into claramine, not Berberine? And so going back to claramine seems to remain our question. I’ll provide the 2014 berberine citation for consideration when I have access.

[Daniel Cooper]

Another paper on Claramine.  This one on it's antimicrobial activity.

 

 

Claramines: A New Class Of Broad‐Spectrum Antimicrobial Agents With Bimodal Activity

 

 

[mikey]

Ah. good find. Connecting the dots. Anti-microbial to the reversal of plaque.

[Daniel Cooper]

Ah. good find. Connecting the dots. Anti-microbial to the reversal of plaque.

 

I would not assume that.  A bacterial cause of atherosclerosis has been proposed, but it is far from mainstream thinking and there isn't a lot of evidence for it at present.

 

My take is that we don't really know with any certainty how these compounds work.  Maybe PTP1B inhibition, maybe anti-microbial, maybe something that no one has thought of.

 

Trodusquemine seems to reverse atherosclerosis so rapidly, I'm a little skeptical that it's PTPIB inhibition.  But who knows.

 

I just posted the link to that paper because it might have some relevant dosing information.

 

Any updates on obtaining Trodusquemine or Claramine? 

 

It's very frustrating to have these potential cures dangling out there with no way to access them.  Our drug approval agencies are doing no one any favors at this point.

[mikey]

Ah. good find. Connecting the dots. Anti-microbial to the reversal of plaque.

 

Please allow me to apologize for the lack of a detailed response.

 

This is an interesting "find." That's all it is. As Daniel noted, an "anti-microbial" effect is based on one hypothesis of the mechanism from which plaque forms.

 

Whatever is or are the mechanisms that render trodusquemine an interesting candidate to help produce "clean" youthful arteries requires elaboration.

 

It does inspire coffee-fueled reading, but most specifically seeing increased industrial trodusquemine production that causes its cost to come within range of a number of us experiencing it and reporting our experiences.

[Ambrosia]

I've been reading about  Trodusquemine it is indeed "the good stuff" for clearing plaque, nothing comes close to it.

 

count me in

Edited by Ambrosia, 21 January 2019 - 12:40 PM.

[Daniel Cooper]

I got this email from TLR over the weekend:

 

Re: Claramine

 

I hope all is well.

 

As you are aware, Claramine is a near identically active alternative to Trodusquemine, but noted as not as difficult and costly to synthesize.  Though, notably, it is indeed challenging and not inexpensive itself. 

 

The current best we can do on Claramine is 10g at $17,850USD

There were a few who wanted it so if we can get that as a group buy or enough people are willing to buy enough grams at say $2,400 per gram; or $6500/3g we would have ability to proceed from point of worth being achieved. 

 

Lead time from the point we can commence given the funding being met as needed is about 4 weeks.

 

Kindly your thoughts. 

 

Brgds,

E

 

 

I would much prefer to work with Trodusquemine as that's what we have real data on, but it seems to be unobtainium in terms of price.  Given that, do we have any guess as to what a therapeutic dose of Claramine might be?  This stuff isn't exactly cheap either.

 

 

 

 

 

[Daniel Cooper]

I got this from TLR the other day regarding figuring out dosing.  This is some reasonable evidence that Claramine and Trodusquemine are equipotent, at least in terms of PTP1B inhibition.
 
Abstract referenced below here:  Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound

 

I'll post the full text this evening.
 
___________________________________________________________________________________________________________________________
 
 

 

If you need assistance with the dosage, as relates to the "standard", Trodusquemine, it is largely equipotent (as below).   The full text displays equivalent dosages had very similar potency and efficacy:

 

Biochem Biophys Res Commun. 2015 Feb 27;458(1):21-7. doi: 10.1016/j.bbrc.2015.01.040. Epub 2015 Jan 24.

Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound.

Qin Z1, Pandey NR1, Zhou X1, Stewart CA2, Hari A1, Huang H1, Stewart AF3, Brunel JM4, Chen HH5.

Author information   Abstract

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-β (IRβ), Akt and GSK3β. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes.

 

Edited by Daniel Cooper, 28 January 2019 - 04:08 PM.

[Daniel Cooper]

Here's the full text of that abstract above:

 

 

 

Attached Files

•  Functional properties of Claramine.pdf   1.53MB   14 downloads

[mikey]

Do you have a pointer to that abstract on berberine or a reference to the article?

Generally berberine is thought to lower cardiovascular issues

 

I just received blood tests back and it appears that berberine has optimized my cardiovascular markers. I have not been as careful with my carb consumption recently, so I expected less favorable results.

 

Total cholesterol - 184 - (I eat only fully organic grass-fed dairy fats, cheeses, butter, avocados, organic veg fats, but I don't hold back. I eat a lot of cholesterol-laden saturated fats. Yum. Much more satiating than carbs and I've never seen this cause "high cholesterol" in blood tests. Total cholesterol in my last blood test was 132, which data infers is TOO low.)  

Triglycerides - 75 -- (my alcohol intake predicts higher triglycerides)

HDL - 75 - (I have NOT been getting adequate exercise and expected HDL to be just a bit over 39, maybe 49, when I'm not exercising much.)

VLDL - 15

LDL - 94

T. Chol/HDL Ratio 2.5 - (0 -5.0 is the Reference Interval) 

 

I take one of Dr. Whitacker's Berberine a couple times a day.

You might check out https://www.ncbi.nlm...les/PMC5871262/

[smithx]

Thanks for posting. Could you post your numbers previous to the berberine? It would be very helpful.

 

Also, how long between the tests, and did anything else change?

 

I just received blood tests back and it appears that berberine has optimized my cardiovascular markers. I have not been as careful with my carb consumption recently, so I expected less favorable results.

 

Total cholesterol - 184 - (I eat only fully organic grass-fed dairy fats, cheeses, butter, avocados, organic veg fats, but I don't hold back. I eat a lot of cholesterol-laden saturated fats. Yum. Much more satiating than carbs and I've never seen this cause "high cholesterol" in blood tests. Total cholesterol in my last blood test was 132, which data infers is TOO low.)  

Triglycerides - 75 -- (my alcohol intake predicts higher triglycerides)

HDL - 75 - (I have NOT been getting adequate exercise and expected HDL to be just a bit over 39, maybe 49, when I'm not exercising much.)

VLDL - 15

LDL - 94

T. Chol/HDL Ratio 2.5 - (0 -5.0 is the Reference Interval) 

 

I take one of Dr. Whitacker's Berberine a couple times a day.

You might check out https://www.ncbi.nlm...les/PMC5871262/

 

[mikey]

Thanks for posting. Could you post your numbers previous to the berberine? It would be very helpful.

 

Also, how long between the tests, and did anything else change?

 

I am in the middle of a move to Oregon, after living for 25 years in LA. Boxes are being unpacked, but I do not yet have access to the many years of blood tests that I've done.

 

Everything is being digitized going forward.

 

So, my report is a quintessential anecdote, based on my memory of many in-depth blood tests that look at fractions of blood lipids and how they correlate to my food consumption and supplementation.

 

I wish that I could provide more hard data, but I do believe that it is likely that berberine may gain as much  - or more - scientific support as curcumin over time.

 

Please also see: https://www.ncbi.nlm...les/PMC5871262/

 

I am not saying that I think that berberine would equal the expected effect of trodusquemine, though.

 

I still wait for trodusquemine to be available at a reasonable cost.

[mikey]

When I calculate the HED for Claramine I come up with something like 70 mg for my bodyweight.

 

So, if one IV exposure completely reversed plaque in rats with Trodusquemine, and Claramine is about equal in dosing, it wouldn't require much to see if the desired effect occurs. Blood pressure would drop in days. Cardiovascular health would be as fresh as a child's soon. 

 

A problem is that TLR is talking about selling grams of Claramine. It would take quite a few of us to require gram quantities if my math is correct.

 

Please chime in with ideas about the math, etc...

[mikey]

Thanks for posting. Could you post your numbers previous to the berberine? It would be very helpful.

 

Also, how long between the tests, and did anything else change?

 

I must note that the Berberine appears to improve my blood lipids considerably.

 

But this doesn't mean that it is reversing plaque - or doing it quickly - as I can still have elevated blood pressure while taking Berberine.

 

My HDL is way up with Berberine, but having high HDL could still take years to transport accumulated plaque away from my artery walls so that BP would drop way down. (Which it did do after high dose Dasatinib/quercetin, and stayed that way for a couple of months before rising again.

 

Maybe if I was taking Berberine thirty+ years ago I wouldn't have elevated BP now, but I do. My arteries exhibit damage via elevated BP.

 

Again, it is Trodusquemine that has magnetized my attention to resolve plaque. 

[mikey]

 

I got this email from TLR over the weekend:

 

Re: Claramine

 

I hope all is well.

 

As you are aware, Claramine is a near identically active alternative to Trodusquemine, but noted as not as difficult and costly to synthesize.  Though, notably, it is indeed challenging and not inexpensive itself. 

 

The current best we can do on Claramine is 10g at $17,850USD

There were a few who wanted it so if we can get that as a group buy or enough people are willing to buy enough grams at say $2,400 per gram; or $6500/3g we would have ability to proceed from point of worth being achieved. 

 

Lead time from the point we can commence given the funding being met as needed is about 4 weeks.

 

 

 

So we see a problem. If my math on the HED for me is 70 mg and there are maybe a dozen of us that want to do a Group Buy, we barely need a gram. (800 mg?) TLR doesn't want to just make a gram of Claramine. Or if they would how much would they charge?

Or do some people want to do multiple doses. If ONE exposure completely reversed plaque in mice, that's all I would want, one exposure. I don't want to do IV, but I would if it was once. Some quandaries here, gang.
 

Edited by mikey, 03 February 2019 - 11:23 PM.

[Daniel Cooper]

So we see a problem. If my math on the HED for me is 70 mg and there are maybe a dozen of us that want to do a Group Buy, we barely need a gram. (800 mg?) TLR doesn't want to just make a gram of Claramine. Or if they would how much would they charge?

Or do some people want to do multiple doses. If ONE exposure completely reversed plaque in mice, that's all I would want, one exposure. I don't want to do IV, but I would if it was once. Some quandaries here, gang.
 

 

Another way to look at this is what are you willing to pay for access to this compound, versus to buy the minimum quantity we'd like to dose.

 

I've been talking to Team TLR and they are willing to do 2 grams of Claramine for $8,100.  If we get a dozen buyers, that's $675USD for 160mg each.  More would bring the price and quantity down accordingly.

 

The good news is that Team TLR has said that they will take the orders directly on their website with the proviso that we have to hit the 2 gram minimum.  That's good news since that means none of us will have to handle the funds or the product and our risk of having this group buy go sideways like some others should be very low.

 

Here is the link to the compound on their website:  https://teamtlr.com/...ine-analog.html

 

If anyone has any questions they may address them directly to Team TLR at tlr@teamtlr.com.

 

So, why don't we do a show of hands to gauge what our level of interest is.  Clearly there is no commitment at this point.

[Vermonter]

A couple of comments.

 

The animals received the cmpd by intraperitoneal injection. That is not something that can be safely done at home.

 

Let us compare the bioavilability profiel to squalamine, which is likely similar in some fundamental ways. Squalamine has shown itself to be very irritating - when given intravenously, and where there has been interstitial leakage, there has been significant  tissue inflammation lasting up to 5 days. This tissue inflammatory process would include white cells and their digestive enzymes, so there is a good chance that a subcutaneous dose, even if you were willing to tolerate the inflammation, may not be effective at all. 

 

Bioavilability for squalamine is very poor after oral administration. It remains in the gut, where it is metabolized. It does not enter the bloodstream. Do we know if  claramine  is any   any different in this regard?

 

That leaves IV dosing (careful), and perhaps sublingual. I will not do IV, personally.

 

Finally, TLR should ensure the product is a lactate salt and not a TFA salt. And for those willing to use it subcut or IV, that it is sterile and endotoxin free. 

 

These are the issues I remember from my reading. I may have made a mistake somewhere, so others should check to make sure I have not made and erroneous or unreasonable assumptions.

 

I Initially thought subcut was the way to go, but based on the squalamine reaction, I am now not so sure.

 

 

[smithx]

It would be great if a single dose, or even multiple doses of trodusquemine really cleared away plaque, but looking closely at the original paper (linked earlier in this thread, https://www.longecit...a/#entry857744)I'm not so sure.

 

The data, as shown in the graphs shows a few really odd things. In figures 5, 6, 7 and 8 there are more pronounced changes with a single dose than with chronic administration of trodusquemine.

• 5C - Photos of arterial plaque show that a single dose cleared it almost entirely, while chronic administration shows visually almost no difference in blockage compared to a control mouse who received no treatment
• 5D - Mice given one dose of trodusquemine had far greater plaque reduction than mice given trodusquemine chronically.
• Figs 6 - chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 7 A, B, C and E - again, chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 8 - same again

How can we explain that a single dosage apparently cleared up all the arterial plaque, but chronic dosage for a few weeks didn't. Is it that the mice who had chronic trodusquemine initially had all their plaque cleared up by the first dose, but subsequent doses brought it all back again in 8 weeks? That somehow seems rather unlikely.

 

More likely is that the sample size was too small and the results are spurious artifacts. The comparison between single dose and chronic administration is too odd to be explained easily in another way. I think the jury is still out on trodusquemine.

 

[Rocket]

Very odd. Been wondering about this and waiting for someone smarter than me to discuss.

[ryukenden]

It would be great if a single dose, or even multiple doses of trodusquemine really cleared away plaque, but looking closely at the original paper (linked earlier in this thread, https://www.longecit...a/#entry857744)I'm not so sure.

The data, as shown in the graphs shows a few really odd things. In figures 5, 6, 7 and 8 there are more pronounced changes with a single dose than with chronic administration of trodusquemine.

• 5C - Photos of arterial plaque show that a single dose cleared it almost entirely, while chronic administration shows visually almost no difference in blockage compared to a control mouse who received no treatment
• 5D - Mice given one dose of trodusquemine had far greater plaque reduction than mice given trodusquemine chronically.
• Figs 6 - chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 7 A, B, C and E - again, chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 8 - same again

How can we explain that a single dosage apparently cleared up all the arterial plaque, but chronic dosage for a few weeks didn't. Is it that the mice who had chronic trodusquemine initially had all their plaque cleared up by the first dose, but subsequent doses brought it all back again in 8 weeks? That somehow seems rather unlikely.

More likely is that the sample size was too small and the results are spurious artifacts. The comparison between single dose and chronic administration is too odd to be explained easily in another way. I think the jury is still out on trodusquemine.

Which original study are you referring to? The one which need purchasing? There are so many links and are you able to probably link?

[smithx]

Which original study are you referring to? The one which need purchasing? There are so many links and are you able to probably link?

 

If you follow the link, you find a post with an attachment. That is the study to which I am referring.

[aribadabar]

If you follow the link, you find a post with an attachment. That is the study to which I am referring.

 

The link contains an extra bracket at the end that messes up the pointing to the particular post.

 

Here is the corrected link: https://www.longecit...ta/#entry857744

 

That being said, that study has only 5 (not 8) figures published so pretty sure it is not the one you are referring to.

It sounds more like the one attached to this post: https://www.longecit...ndpost&p=857762

Edited by aribadabar, 12 February 2019 - 04:02 PM.

[smithx]

The link contains an extra bracket at the end that messes up the pointing to the particular post.

 

Here is the corrected link: https://www.longecit...ta/#entry857744

 

That being said, that study has only 5 (not 8) figures published so pretty sure it is not the one you are referring to.

It sounds more like the one attached to this post: https://www.longecit...ndpost&p=857762

 

Sorry, it was an error on my part. I'm referring to this article:

https://www.longecit...ta/#entry857762

 

Pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) protects against atherosclerotic plaque formation in the LDLR mouse model of atherosclerosis.pdf

[ZCKZ]

I'm interested in getting in on the group buy.

[mikey]

It would be great if a single dose, or even multiple doses of trodusquemine really cleared away plaque, but looking closely at the original paper (linked earlier in this thread, https://www.longecit...a/#entry857744)I'm not so sure.

 

The data, as shown in the graphs shows a few really odd things. In figures 5, 6, 7 and 8 there are more pronounced changes with a single dose than with chronic administration of trodusquemine.

• 5C - Photos of arterial plaque show that a single dose cleared it almost entirely, while chronic administration shows visually almost no difference in blockage compared to a control mouse who received no treatment
• 5D - Mice given one dose of trodusquemine had far greater plaque reduction than mice given trodusquemine chronically.
• Figs 6 - chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 7 A, B, C and E - again, chronic dosage mice look quite similar to control mice, while single dosage mice look very different
• Fig 8 - same again

How can we explain that a single dosage apparently cleared up all the arterial plaque, but chronic dosage for a few weeks didn't. Is it that the mice who had chronic trodusquemine initially had all their plaque cleared up by the first dose, but subsequent doses brought it all back again in 8 weeks? That somehow seems rather unlikely.

 

More likely is that the sample size was too small and the results are spurious artifacts. The comparison between single dose and chronic administration is too odd to be explained easily in another way. I think the jury is still out on trodusquemine.

 

smithx, you just did a good job of shooting a hole in the trodusquemine "is the answer" notion. Truly, it makes no sense that one dose would reverse plaque, but multiple doses would leave the arteries the same. Unfortunate, but is trodusquemine simply a waste of time?

[smithx]

Probably we need another study with a much larger sample size to figure out what, if anything, is going on.

 

It could be that a single dose does actually work and that chronic dosing doesn't, but without a sufficiently powered study it's very difficult to draw any conclusions.

 

On the other hand, if I had very significant blockage and nothing else was working, and I had a lot of money, I might consider giving this a try as a last-ditch effort.

 

smithx, you just did a good job of shooting a hole in the trodusquemine "is the answer" notion. Truly, it makes no sense that one dose would reverse plaque, but multiple doses would leave the arteries the same. Unfortunate, but is trodusquemine simply a waste of time?

 

[Quattro64]

While we're waiting for TD to be available and cheap there is always the Linus Pauling protocol. Mega-doses of Vit-C and Lysine smaller doses of D3, K2. Anecdotally, after a year of supplementing this, many experimenters saw their arteries get clear.