153 replies to this topic

[Rocket]

Garlic???

 

http://www.life-enha...arterial-plaque

 

 

 

[YOLF]

Garlic is an oldie but a goodie, but it still doesn't reverse the plaques... taking garlic and raising klotho, sach as via tocotrienols, will likely lead to an improvement, maybe some level of regression... Garlic cuts the plaque accumulation rate by 80%, and tocotrienols have in specific genotypes reversed sclerotic plaques... so I imagine some pretty good results can be had from taking 1g of garlic a day. When I stick to my regimen, I take a few g ea of turmeric, garlic, onion, and ginger.

 

Just be aware that garlic can lead to anemia in those who are predisposed to it as it chelates iron. make sure to take an iron supplement away from the garlic supplement.

[Daniel Cooper]

I found a patent on using cyclodextins for reversing arterial plaques that was filed way back in 2001.  This appears to be a group from Australia, The Heart Research Institute Ltd., not the international team that published the mouse study this month.

 

 

Cyclodextrins and reversal of atherosclerosis

http://www.google.co...2043742A1?cl=en

 

Interestingly, it appears that this idea has been percolating since the mid to late 1990s.

 

The pace of medical research can be very frustrating at times.  Here we have a substance that is generally recognized as safe, at least one very good mouse study, and apparently almost 20 years of thought behind it, versus a widespread and deadly disease, but we haven't had a single human clinical trial.

 

 

Edited by Daniel Cooper, 15 April 2016 - 08:22 PM.

[YOLF]

So is it bunk? How long does an Australian patent last?

[Daniel Cooper]

So is it bunk? How long does an Australian patent last?

 

I certainly didn't mean to imply that it's bunk nor to I believe that.

 

I was merely pointing out that this is an idea that has been around for awhile and has been pursued by multiple researchers.

 

Unfortunately, no one has scrapped together the funding for a clinical trail.  Probably because it would be difficult to end up with a multibillion dollar drug that would survive patent challenges.

 

This approach looks promising.  It has the potential to be a very low risk/high reward treatment in terms of effectiveness.  Some university somewhere ought to be running a clinical trial on this, but they too are off chasing the next billion dollar block buster drug.

 

It seems there is very little support these days for fundamental research that doesn't have a large payoff dangling at the end.

[sthira]

What do y'all think of this? http://www.amazon.co...ds=cyclodextrin

[YOLF]

Hmmm... I'm thinking it would be a bad idea to use this stuff as more than a one off, so 10g 1x/week may even be too often. This stuff destroys cholesterol, so which cholesterol does it destroy and how long does it last? Sex hormones, neurosteroids, and all sorts of other hormones and steroids are made from cholesterol. Destroying it this efficiently on a daily basis would quickly result in brain damage, loss of function in sex organs, kidneys, the liver, adrenals, you name it! If results can be gained by using it in a once in a while fashion, that's really how it should be used. So my question is, what was the half life of this stuff? How long did it take for sex hormones and all the other important cholesterol byproducts to return to normal function? How extensive was the damage from depletion? Do we have access to supplemental sex hormones such as T (NO!) to correct from this if we have problems? 

 

I think that's why this didn't go anywhere. It would have to be done with quite a bit of monitoring across a ton of different fronts. Virtually everything could be effected. On a one off basis, I imagine the damage would be negligible, daily would be deadly... so at what frequency could this be done as a preventative measure with a reasonable expectation of good results, how long after receiving this kind of therapy would one need to abstain from too much physical activity, and what kinds of physical activity would be acceptable. To avert all these things, we'd basically have to be pin cushions and rely on instant in house tests

 

I still think this has alot of potential, but we must proceed cautiously and determine how extensively this stuff destroys cholesterol. In food, it DESTROYS EVERYTHING 100%! That could be QUITE DANGEROUS.Emphasis added for people who are already buying this and trying it who might be injuring themselves with daily dosing.

[Daniel Cooper]

I think that's just disinformation.

 

It doesn't DESTROY cholesterol.  Cyclodextrin appears to have two major effects:  1.) It solubilizes cholesterol such that it promotes efflux out of arterial walls.  2.) It reprograms macrophages from the pathological state that is characteristic of arterial plaques.  In fact, the Zimmer paper only shows slightly lower blood plasma levels of cholesterol in their mouse test.

 

And let's face it ..... if you have significant coronary plaques .... the fact that your sex hormones are pristine will be of small comfort as you lay on that operating table waiting to undergo coronary bypass, or you're in a box in the ground because you died of a heart attack.

 

At least as far as oral administration goes, you do realize that the FDA classifies cyclodextrin as "Generally recognized as safe".  It is used in food and pharmaceuticals today.

 

 

Edited by Daniel Cooper, 16 April 2016 - 07:18 PM.

[Daniel Cooper]

What do y'all think of this? http://www.amazon.co...ds=cyclodextrin

 

That may or may not help you lose weight, but it won't do anything to reverse arterial plaques.  The bio-availability of cyclodextrin is very low.  Little to none if it will make it from the gut to your bloodstream.

[YOLF]

I think that's just disinformation.

 

It doesn't DESTROY cholesterol.  Cyclodextrin appears to have two major effects:  1.) It solubilizes cholesterol such that it promotes efflux out of arterial walls.  2.) It reprograms macrophages from the pathological state that is characteristic of arterial plaques.  In fact, the Zimmer paper only shows slightly lower blood plasma levels of cholesterol in their mouse test.

 

And let's face it ..... if you have significant coronary plaques .... the fact that your sex hormones are pristine will be of small comfort as you lay on that operating table waiting to undergo coronary bypass, or you're in a box in the ground because you died of a heart attack.

 

I wouldn't say it reprograms the macrophage really, it's just removing the item from it which is causing the pathology. The arterial walls will still need to replace their structural components which come from cholesterol byproducts as a result of any deficiency. So we'd first need to characterize the length of effects/elimination rate/time, and which cholesterol molecules are being destroyed in order to determine what kind of dosing regimen will be safe. Do we have that information? Maybe I'm wrong, maybe it takes more than 10g slowly perfusing from the subQ inj site to remove all of our cholesterol the way all of it is removed in food. But we need to see that kind of discussion, otherwise we can't justify using this stuff on the basis of a few dying case study patients and some rodents. The studies so far, or at least afaiaa, haven't used daily administration. So maybe it runs it's course without adversely affecting the patient's cholesterol metabolism. Either way, proper cholesterol metabolism maintenance will be as much a factor in recovery from sclerotic plaques as removal. It's the weakness of surfaces that allow them to start accumulating plaques in the first place. So keep the structural material available in optimal ratios if you don't want to just see an accelerated relapse of the disease.

[YOLF]

I'd be up for supporting some blood testing grants (if it's in the LC budget, of finding sponsors to pay for it) if people are going to do this. Contact me if you're going to try it and see what I can setup to make sure the community benefits from your experience and you aren't killing yourself.

 

I'd also like to see if we can do some of this in rodents at one of our partner labs and get more info from them. I'll invite some people as I think of them.

[Lonjaimity]

@Yolf (hi, I'm new, but a lurker for awhile)

 

As far as I know, you'd have to inject IV or SubQ.  Oral bioavailability is low.  It's in mayonnaise, and GRAS, but nobody's been injecting mayonnaise, so it's a bit of a '?.'  Thing is, the studies I've seen used a spinal tap for availability in the BBB, and I believe it was 700mg a few times a week.  Not so much.  The side effects involved loss of high frequency hearing, which is interesting if uneventful for someone who will die or get early onset alzheimers (its current indication).

 

I think everyone is getting too excited, though.  Plaque is not only cholesterol.  It's also calcium, (extra?) muscle, and probably some other stuff.  This is just one part of what you'd have to do.  The study "Targeted chelation therapy with EDTA-loaded albumin nanoparticles regresses arterial calcification without causing systemic side effects" (sorry, can't post links) largely vindicates the idea of EDTA actually accomplishing something w/r/t removing calcium in places it shouldn't be.  K2 mk4/7 might also do something.

 

That EDTA paper is really interesting.  Probably more interesting than anything I've seen in awhile.  I'm not sure if it would penetrate the intimal area, though.

 

The closest I can get to a total-solution-idea is targeted EDTA+Beta-cyclodextrin+AGE-breakers+K2.

Edited by LONJAMITY, 16 April 2016 - 07:44 PM.

[YOLF]

Does the high frequency hearing return? I think I'm more interested in this from a prevention standpoint. Is the cause of the hearing loss described anywhere? Maybe this would be a target for us to study in mice... perhaps comparing some parts of their brain after administration to see if it's getting absorbed or ripping away important bits of brains or ears in those or other areas where we might not so readily notice it happening.

 

As this is something of a short term study, it might be worth it to use larger animal models for this.

[Lonjaimity]

I can't post much more today, but I found it in "Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin."

 

It was found in cats, which are said larger mammals.  So it might be true.  But it seems like lower dosages over longer periods might mitigate, and a few hair cells dying on an eardrum sounds better than dying on an operating table.

Edited by LONJAMITY, 16 April 2016 - 07:55 PM.

[YOLF]

I can't post much more today, but I found it in "Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin."

 

It was found in cats, which are said larger mammals.  So it might be true.  But it seems like lower dosages over longer periods might mitigate, and a few hair cells dying on an eardrum sounds better than dying on an operating table.

 

Well it certainly better than dying on an op table. The hair is there for a reason, though can get infected and what not... so it sounds like it's affecting some cholesterol bit or another which is active in ear hair, did it affect other parts of the hair? Do cats grow more ear hair as they age?

 

I have a crotchety old cat that survived kidney disease on some other research compounds... he's still kicking after around 3 years but definitely showing his age and he's a little off balance, I'm wondering if it would be worth it to give him some of this. Hearing can affect balance regardless of species iirc.

[Daniel Cooper]

I can't post much more today, but I found it in "Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin."

 

It was found in cats, which are said larger mammals.  So it might be true.  But it seems like lower dosages over longer periods might mitigate, and a few hair cells dying on an eardrum sounds better than dying on an operating table.

 

Keep in mind hearing loss is only an issue if cyclodextrin is given intrathecally (which it is when used to treat Niemann-Pick disease).  Or if you give it to immature mammals which haven't fully established their BBB.  Cyclodextrin doesn't cross the blood brain barrier, which is why you have to give it intrathecally if you're treating Niemann-Pick.

 

For IV or subcutaneous administration this isn't an issue.

Edited by Daniel Cooper, 16 April 2016 - 08:31 PM.

[Daniel Cooper]

 

I think that's just disinformation.

 

It doesn't DESTROY cholesterol.  Cyclodextrin appears to have two major effects:  1.) It solubilizes cholesterol such that it promotes efflux out of arterial walls.  2.) It reprograms macrophages from the pathological state that is characteristic of arterial plaques.  In fact, the Zimmer paper only shows slightly lower blood plasma levels of cholesterol in their mouse test.

 

And let's face it ..... if you have significant coronary plaques .... the fact that your sex hormones are pristine will be of small comfort as you lay on that operating table waiting to undergo coronary bypass, or you're in a box in the ground because you died of a heart attack.

 

I wouldn't say it reprograms the macrophage really, it's just removing the item from it which is causing the pathology. The arterial walls will still need to replace their structural components which come from cholesterol byproducts as a result of any deficiency. So we'd first need to characterize the length of effects/elimination rate/time, and which cholesterol molecules are being destroyed in order to determine what kind of dosing regimen will be safe. Do we have that information? Maybe I'm wrong, maybe it takes more than 10g slowly perfusing from the subQ inj site to remove all of our cholesterol the way all of it is removed in food. But we need to see that kind of discussion, otherwise we can't justify using this stuff on the basis of a few dying case study patients and some rodents. The studies so far, or at least afaiaa, haven't used daily administration. So maybe it runs it's course without adversely affecting the patient's cholesterol metabolism. Either way, proper cholesterol metabolism maintenance will be as much a factor in recovery from sclerotic plaques as removal. It's the weakness of surfaces that allow them to start accumulating plaques in the first place. So keep the structural material available in optimal ratios if you don't want to just see an accelerated relapse of the disease.

 

 

Macrophage reprogramming is one of the major methods of action put forth in the Zimmerman paper ( Cyclodextrin promotes atherosclerosis regression via
macrophage reprogramming ) and in that patent I posted earlier.

[Lonjaimity]

 

I can't post much more today, but I found it in "Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-β-cyclodextrin."

 

It was found in cats, which are said larger mammals.  So it might be true.  But it seems like lower dosages over longer periods might mitigate, and a few hair cells dying on an eardrum sounds better than dying on an operating table.

 

Keep in mind hearing loss is only an issue if cyclodextrin is given intrathecally (which it is when used to treat Niemann-Pick disease).  Cyclodextrin doesn't cross the blood brain barrier, which is why you have to give it intrathecally if you're treating Niemann-Pick.

 

For IV or subcutaneous administration this isn't an issue.

 

Are you sure?

 

The inner ear provides a unique opportunity for local drug delivery. Access to the inner ear is limited by the presence of a blood-cochlear barrier, which is anatomically and functionally similar to the blood-brain barrier [1, 2]. (1. Juhn S. Barrier systems in the inner ear. Acta Otolaryngol Suppl. 1988;458:79–83. [PubMed])

 

Seems dicier, but yeah.  You're probably right.

[YOLF]

Seems dicier, but yeah.  You're probably right.

What do you mean? 

[Lonjaimity]

 

Seems dicier, but yeah.  You're probably right.

What do you mean? 

 

 

I mean I'm less sure that IV or SubQ delivery won't make it to the inner ear than he is.  These poor kids that got it intrathecally got it that way so it would get past the BBB.  But the ear doesn't have a BBB (not exactly, anyway -- see papers in prior post), and I'm pretty sure gentamicin makes people go deaf when administered intramuscularly.  So it's not quite as bulletproof as the BBB, right?  I'd want to see how much gentamicin gets into the brain, but I didn't think so.  If so, it doesn't get to the brain, yet somehow it blows out your ear? Last post of the day.

Edited by LONJAMITY, 16 April 2016 - 08:48 PM.

[Daniel Cooper]

 

 

Seems dicier, but yeah.  You're probably right.

What do you mean? 

 

 

I mean I'm less sure that IV or SubQ delivery won't make it to the inner ear than he is.  These poor kids that got it intrathecally got it that way so it would get past the BBB.  But the ear doesn't have a BBB (not exactly, anyway -- see papers in prior post), and I'm pretty sure gentamicin makes people go deaf when administered intramuscularly.  So it's not quite as bulletproof as the BBB, right?  I'd want to see how much gentamicin gets into the brain, but I didn't think so.  If so, it doesn't get to the brain, yet somehow it blows out your ear? Last post of the day.

 

 

 

Sure, I'd be cautions and research it further, but the only cases of hearing loss I've been able to find so far is in Niemann-Pick patients that are getting it intrathecally or study rodents that were young enough to have an immature BBB.  And keep in mind that those Niemann-Pick patients are getting enormous doses of this stuff.

 

Gentamicin's molecular weight is about 468 Daltons. 2-hydroxypropyl-b-cyclodextrin's is about 1375 Daltons, so about 3x bigger.  That's a pretty large molecule.  So even if the blood-cochlear membrane is a bit more permeable we've got that in our favor.  Also, cyclodextrin is externally hydrophillic, which the BBB is pretty good at rejecting.  I assume the BCB would as well but would need to confirm that.

 

 

Edited by Daniel Cooper, 16 April 2016 - 09:08 PM.

[Lonjaimity]

Actually, as I recall, the original discovery that HBPCD was helpful was accidental.  I believe it was mixed in with a drug that was injected.  It took some time to realize the drug wasn't actually the substance that was helping, and it was the HBPCD the whole time.  Importantly, it was injected, but I can't find the study atm, and I believe it was in mice, not humans.

 

Of course everyone was then probably less interested because nobody can make money on HBPCD.  If someone can pull up the study, it would give me less to Google.

 

 

[YOLF]

 

 

Seems dicier, but yeah.  You're probably right.

What do you mean? 

 

 

I mean I'm less sure that IV or SubQ delivery won't make it to the inner ear than he is.  These poor kids that got it intrathecally got it that way so it would get past the BBB.  But the ear doesn't have a BBB (not exactly, anyway -- see papers in prior post), and I'm pretty sure gentamicin makes people go deaf when administered intramuscularly.  So it's not quite as bulletproof as the BBB, right?  I'd want to see how much gentamicin gets into the brain, but I didn't think so.  If so, it doesn't get to the brain, yet somehow it blows out your ear? Last post of the day.

 

 

Well, all the more reason to dissect some rodents and find out. Lifespan trials take a long time, but this stuff can basically be done overnight and without sclerotic plaques we'd definitely live longer. So there's got to be something we can take to reverse the pathology forming in the ears or prevent it once we understand it... I'm not thinking of anything, but we got lots of people with ideas around here.

[YOLF]

Actually, as I recall, the original discovery that HBPCD was helpful was accidental.  I believe it was mixed in with a drug that was injected.  It took some time to realize the drug wasn't actually the substance that was helping, and it was the HBPCD the whole time.  Importantly, it was injected, but I can't find the study atm, and I believe it was in mice, not humans.

 

Of course everyone was then probably less interested because nobody can make money on HBPCD.  If someone can pull up the study, it would give me less to Google.

 

I did see it, I know what you're talking about... but not sure what to look for to find it. 

[Logjam]

RE: "There is not a single compound called 2-HP-b-CD, but various products that differ by the number of 2-hydroxypropyl groups attached to the exterior of the cyclodextrin."

 

I think this is the part that's most concerning.  Depending on the number of said groups the compound is more or less soluble in water (and possibly blood), but is it also more or less toxic or does it have different characteristics or solubility in blood (vessels)?

 

It _does_ make it to the brain in cats with very high dosages:

In the current study, the Penn Vet team administered HPβCD subcutaneously to cats with NPC at various concentrations, as had been done in mice, but found that the dose needed to achieve neurological benefits caused the cats to develop serious lung disease.

 

That said, it's apparently in some injectable medications, so at least some people think it's innocuous.

 

Also found the quote:

"The discovery was totally serendipitous," said Walkley, a co-author and professor of neuroscience, pathology and neurology and director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center at Einstein. "We were at the time repeating published studies that had found that a certain drug dissolved in 2-hydroxypropyl-beta-cyclodextrin, or HPβCD, was beneficial in the mouse model of NPC disease. Turns out, carefully controlled studies revealed it wasn't the drug having the benefit at all but rather what it was dissolved in, namely the HPβCD. Our studies in NPC mice clearly showed that this compound had the ability to dramatically ameliorate the lysosomal pathology in the brain."

 

 

[Logjam]

And then there's Xanthohumol.  See "Xanthohumol ameliorates atherosclerotic plaque formation, hypercholesterolemia, and hepatic steatosis in ApoE-deficient mice," but I'm skeptical of these mouse studies with mice deliberately manipulated to croak.

 

"Yet another break-through in medical health for mice. I hope the rodents appreciate all that we do for them!"

 

But yeah, you can buy it from Swanson, and it's a natural substance (not an additive) in the food supply in small quantities already.  Thoughts?

[Daniel Cooper]

And then there's Xanthohumol.  See "Xanthohumol ameliorates atherosclerotic plaque formation, hypercholesterolemia, and hepatic steatosis in ApoE-deficient mice," but I'm skeptical of these mouse studies with mice deliberately manipulated to croak.

 

"Yet another break-through in medical health for mice. I hope the rodents appreciate all that we do for them!"

 

But yeah, you can buy it from Swanson, and it's a natural substance (not an additive) in the food supply in small quantities already.  Thoughts?

 

 

The thing about Xanthohumol is that it is a CETP inhibitor.  That gives me a little pause for concern given the number of failed CETP inhibitors littering Phase II trials  They didn't all fail for the same reason (several had issues with toxicity that presumably Xanthuhumol wouldn't have), but even in the ones that weren't toxic, they didn't show efficacy.

 

That said, I think the risk is low enough that I'm taking the Swanson product you reference daily.  I'm not very worried about toxicity, but it very well might not do anything for me.

 

 

 

Edited by Daniel Cooper, 18 April 2016 - 12:41 AM.

[YOLF]

There is of course also alagebrium, it failed in the second human study, though achieved results in the first. I'm wondering if there was something different in the preparation or if it just comes down to genetics. Perhaps we can find something that would enable the mechanism that occurred where alagebrium worked?

[Daniel Cooper]

There is of course also alagebrium, it failed in the second human study, though achieved results in the first. I'm wondering if there was something different in the preparation or if it just comes down to genetics. Perhaps we can find something that would enable the mechanism that occurred where alagebrium worked?

 

 

If you're looking to reverse arterial plaques, then the question is - Are AGEs a significant component of arterial plaques?

 

There is less information on this question than you might hope.  I found one journal article that said that AGEs are a component of plaques, but the impression I got is that they weren't a significant component.  But, that was some reading between the lines of a study who's primary focus wasn't this question.

 

Now, alagebrium will improve arterial elasticity which can improve blood pressure, which is a risk factor for the formation of new plaques, so there is that.

 

I have a bottle of alagebrium on deck ready to experiment with.  I've just got other things in line first.

[Logjam]

You can find methylglyoxal and its brethren in clogged carotids.  AGE is implicated in calcified arteries.

 

From what I gather, alagebrium is indirectly involved because:

1. Like @Daniel says it will make the arteries less stiff and that may discourage injuries that start a problem off to begin with!
2. But it's also known that AGE+RAGE receptors result in at least temporary transdifferentiation of VSMC tissue to bone-like tissue.  In other words, it's not just that calcium gets deposited -- your body deposits it there. Whether vitamin K2 mk4/7 mitigates this is unknown.  The way warfarin causes calcification may be different, and that's the model/trigger I usually see.  It is possible that the removal of the calcium will result in the tissue behaving normally again regardless.  And not all AGE is cross-linked.  CML can be removed.  Usually this kind of glycation-instigated calcification is referenced w/r/t medial ("Monkeberg") calcification.  I don't know if it also applies to intima, but probably somewhat if it's changing how cells behave.  I see that as a pattern.  Calcification makes VSMC behave like bone tissue and non-calcified plaque makes VSMC behave like macrophages.  When the irritant goes away, do could the behavior<?>  It would be good news if the tissue doesn't actually really transdifferentiate.  That means if you get some of the AGE to clear via breakers or turnover, it may not come back.
3. So if you consider medial calcification atherosclerosis, clearing out AGE is a good idea because RAGE is bad.  There are studies that note that sRAGE (I think soluble RAGE receptor) actually acts as a decoy for AGE.  I don't think I've seen anyone try to upregulate sRAGE, but it sounds like a good plan. 

If anyone can figure out more about sRAGE, I'm interested.

 

Very much like crystalized cholesterol activates inflammatory processes, AGE does too.  This looks like a trend to me, and it's a theory of mine.  "Irritants" cause a sort of quasi-transdifferentiation.  Remove them, and it undoes itself somewhat.

 

This appears to be so in the cyclodextrin studies.

 

Anyway, there are numerous studies that show alagebrium clears or mitigates CML, CEL, and methylglyoxal.  Lots of carotid arteries are found with methylglyoxal and methylglyoxal-related substances.  My guess is that alagebrium only really works if you take it chronically, and at the right age.  It may have a totally different effect on a younger person vs. and older person or someone who is more prone to accelerated glycation rather than slowly formed glycation.

 

Understandably, older people like Aubrey are more interested in those types of crosslinks.  YMMV if you're younger and worried about CML.

 

It worked on 30 year old chimps, so it's pretty plausible it actually works in humans of the same age.  Those weren't mouse studies.

 

 

 

There is of course also alagebrium, it failed in the second human study, though achieved results in the first. I'm wondering if there was something different in the preparation or if it just comes down to genetics. Perhaps we can find something that would enable the mechanism that occurred where alagebrium worked?

 

 

If you're looking to reverse arterial plaques, then the question is - Are AGEs a significant component of arterial plaques?

 

There is less information on this question than you might hope.  I found one journal article that said that AGEs are a component of plaques, but the impression I got is that they weren't a significant component.  But, that was some reading between the lines of a study who's primary focus wasn't this question.

 

Now, alagebrium will improve arterial elasticity which can improve blood pressure, which is a risk factor for the formation of new plaques, so there is that.

 

I have a bottle of alagebrium on deck ready to experiment with.  I've just got other things in line first.

 

 

Edited by Logjam, 18 April 2016 - 07:41 PM.