132 replies to this topic

[Daniel Cooper]

Trehalose doesn't spike insuline and it doesn't promote glycation, so it should be diabetic safe.

 

All the liposomal delivery is doing is shielding the trehalose from trehalase enzyme in the gut so that it passes into the bloodstream without being broken down into two sucrose molecules.  I also believe it will to an extent shield it from trehalase digestion in the liver.  It really might be an ideal way to deliver trehalose to the vascular endothelium to help reverse atherosclerosis.  The only question I have about liposomal delivery is how well it works for other applications like degenerative brain diseases like Huntington's, Parkison's, and Alzheimer's.  Certainly those liposomes are not going to cross the BBB, but I do think there is a reasonable possibility that ultimately the liposome will disgorge it's trehalose payload and some of that will make it across the BBB, better than straight oral ingestion in any case.  It would be nice to get someone with some knowledge on the pharmacokinetics of liposomal delivery vis-à-vis the BBB to comment on those aspects.

 

 

 

[poonja]

If price is right, I would participate in a group buy.

[OP2040]

Sounds good.

 

Your logic seems right on the BBB.  I can't see any reason why it wouldn't reach since Trehalose is known to pass.  The only question would be if it makes it there in sufficient therapeutic amount.  I happen to be the proud owner of one copy of the famous APOE4 gene, so this is definitely a part of my motivation as well.

[Hebbeh]

I'm interested

[extendcel]

Is it a commercial company or a lab company? I won't be participating as I have the ability to make my own liposomes through a variety of conventional methods (not ultrasonic). However I'm a bit skeptical that the liposomes can bypass the liver though I haven't researched it much.

[Daniel Cooper]

Commercial company in the business of making liposomal supplements.  

 

My understanding ... which may be off base .... is that liposomes stay intact in the bloodstream until they delivery their payload directly to the target cell membrane.  That being the case, they should shield the encapsulated trehalose from breakdown via trehalase in the liver, or at least slow it down.  

 

Even if that is not the case, once you are successfully past the gut wall you're no worse off than IV delivery.  Any slowing of trehalase metabolism is a bonus.

 

So, once you've made your DIY lipsomal encapsulation - how do you know you were successful?  How do you know how much encapsulated product that you ended up with?

 

 

 

Edited by Daniel Cooper, 19 April 2018 - 08:56 PM.

[extendcel]

Yes that is the ideal theory if it works in practice.

You can usually tell just by looking. In addition, liposomes without preservatives are very unstable. They are prone to aggregation. If proper liposomes are made, the solution will be somewhat cloudy at the start but mostly homogeneous. Over time, clumps will form until all of the phopsholopids precipitate.

However you can't tell if you add excess lecithin which turns the whole solution into an emulsion, which is what most of these companies do. I'd actually like to start a liposome company because many of these products currently out are just emulsions.

[ceridwen]

I would be interested in a group buy.

[OP2040]

I've been reading up on liposomal drug delivery and I see nothing special about the liver interfering with it's delivery.  Several chemo drugs already use oral liposomes for drug delivery.   I assume the clinical trials would have studied whether the drug was actually delivered or not, especially since it's still considered a newly commercialized delivery mechanism.

 

The wiki article mentioned that the manufacturing process has a great effect on efficacy, see quote below.  I'm not sure if these are routine quality control procedures or not.  If not, it may be worth mentioning to the company.

 

 

It is important to note that certain influential factors have far-reaching effects on the percentage of liposome that are yielded in manufacturing.^[22] These influences also have an effect on the actual amount of realized liposome entrapment and the actual quality of the liposomes themselves. These are very crucial elements which lead to the long term stability of the liposomes. These complex yet significant factors are the following: (1) The actual manufacturing method and preparation of the liposomes themselves; (2) The constitution, quality, and type of raw phospholipid used in the formulation and manufacturing of the liposomes; (3) The ability to create homogeneous liposome particle sizes that are stable and hold their encapsulated payload. These primary and key elements comprise the foundation of an effective liposome carrier for use in increasing the bioavailability of oral dosages of dietary and nutritional supplements.

 

 

None of this limits my enthusiasm for a group buy.  There's simply way too much upside potential for this, so it has to happen.

Edited by OP2040, 19 April 2018 - 09:58 PM.

[StanG]

I just finished reading this blog and would like to get in on the group buy. Liposomal delivery is fine but I question how long it will hold up. However the benefit would still be worth it to me

[Rocket]

How do we know we liposomal will work with this chemical?

[OP2040]

I think Daniel has addressed some of that. 

 

It's is just a delivery mechanism so I don't know why it would have to work with the substance being delivered.  I assume the packaging is dissolved at a certain rate, and whatever it is holding will reach the bloodstream based on that rate.  Someone mentioned whether it will get past the liver, but again isn't that really about whether the liposomes will get past the liver?  If it does for other uses, then why wouldn't it do so for this?

 

I'm genuinely asking because I know very little about any of this, so I'm forced to use common sense instead of real evidence. 

[smithx]

I wonder about the effect of putting a lot of liposomes into the blood.

 

They are designed to get directly into the bloodstream, but what happens when they break open?

 

Are we certain they are completely harmless and won't create their own plaque or cause other damage over time, especially if take in large doses?

 

 

 

 

[OP2040]

That's a good question smithx.  I am seeing a lot of debate on this and other potential issues with liposomes.  It's strange because it's been around for a long time, and yet no one has bothered to study it intensively.  I will chalk it up to another calculated risk, and only test one time for a predetermined period with lots of attention to my body's reaction.  Here is some relevant text from WikiLectures, which is both reassuring and disturbing at the same time.  Gotta love biology...

 

 

Liposomes are composed of biocompatible and biodegradable material, which makes it a safe way of drug delivery.

 

On the other hand, there are certain disadvantages associated with this delivery system. For example, liposomes could be quite physicochemically unstable. The ester bond in the bilayer could be hydrolyzed and/or the drug can be leaked due to the fusion of liposomes to form larger particles. In addition, liposomes could be rapidly cleared out of the circulation system to the work of the reticuloendothelial system. Also, it is hard to sterilize liposomes since phospholipids’ bilayer is sensitive to heat. Other disadvantages may include a high production cost.

 

[OP2040]

Hi Daniel,

any updates from the vendor yet?

[OP2040]

ok, you guys can laugh at me but I'm surprised no one has mentioned this idea.  What about rectal administration?  It would seem to have two obvious advantages, one being that the area has a lot of permeable blood vessels, and the second being that it likely completely avoids any trehalase.  The main issue would be how to administer, especially without encapsulation. 

 

From wiki:

 

A drug that is administered rectally will in general (depending on the drug) have a faster onset, higher bioavailability, shorter peak, and shorter duration than the oral route.^[1][2] Another advantage of administering a drug rectally, is that it tends to produce less nausea compared to the oral route and prevents any amount of the drug from being lost due to emesis (vomiting). In addition, the rectal route bypasses around two thirds of the first-pass metabolism as the rectum's venous drainage is two thirds systemic (middle and inferior rectal vein) and one third hepatic portal system (superior rectal vein). This means the drug will reach the circulatory system with significantly less alteration and in greater concentrations.

 

Aside from having to shove something up your butt daily (for some may be a plus lol), the only downside here might be the faster processing.  I'm not sure if trehalose needs to hang out in the system for a period of time or not.  If the mechanism of action is increased autophagy and macrophage reprogramming, then the faster processing may or may not matter.

 

Thoughts?

[Daniel Cooper]

This is my last response from our proposed vendor:

 

Hello,

the amount we need from you depends on your required encapsulation amount. My guess is that 200 mg per 10 ml daily dosage is a reasonable value. This would require 20.000 mg/liter = 80.0000 mg/4 liters = 80 grams. One ml would then contain 20 mg of trehalose.

Our liposome size has an average of 120 nm with a strong peak there but with also smaller and larger particles present (see current particle analysis attached).

Have you thought about preservation? Alcohol or potassium sorbate?

Beste wishes,

Carsten Cabe

 

I've asked if we can get a higher concentration of trehalose per ml.  I personally wouldn't mind seeing about 5x that concentration as I'd like to hit about 100mg per ml.  I'd like to consume at lest 1g encapsulated trehalose per day and 10ml is about two teaspoons of liquid which isn't objectionable.  Also I need to know the pros/cons on alcohol vs potassium sorbate.  

 

Do any of you guys have any preferences on preservative?  I'm thinking alcohol unless there is a compelling reason for potassium sorbate.

 

 

[OP2040]

No preference here.

[Greene]

+1 for a group buy if still an option.

[Daniel Cooper]

I think I've got all the info need for a group buy.  I'll start a separate group buy thread this evening and see how much interest we have.  Will post a link here.

 

 

 

[OP2040]

I have a question for anyone who can answer.  The study I'm basing my intervention on is the mouse study from just last year, in which the mice had atherosclerotic plaque reduction. 

 

In the study, the mice were given "2 g/kg–1 by weight" intraperitoneally.  I know I am being lazy, but also the mouse to human translations are always confusing to me, so I'm looking for a second/third opinion on what this would be translated to in human terms. 

 

Using the following formula:

HED (mg/kg) = Animal Dose (mg/kg) x [Animal K_m / Human K_m]

HED (mg/kg) = Animal Dose (2) x [₃ /₃₇]

HED (mg/kg) = Animal Dose (mg/kg) x [Animal K_m / Human K_m]

HED (mg/kg) = .162 mg/kg

 

This would then come out to 13.6 grams for a 185 lb man.  So translated directly from the study, that would be 13.6 grams every other day for two weeks.  I'm sure the time period would need to be much longer for humans as well. 

 

I'm perfectly willing to try to get to these extreme amounts as long as it was only for say  6 months.  But are my calculations correct?  Am I missing something? 

[OP2040]

I think I've got all the info need for a group buy.  I'll start a separate group buy thread this evening and see how much interest we have.  Will post a link here.

 

Fantastic news! thanks for all your diligence.

[Daniel Cooper]

I have a question for anyone who can answer.  The study I'm basing my intervention on is the mouse study from just last year, in which the mice had atherosclerotic plaque reduction. 

 

In the study, the mice were given "2 g/kg–1 by weight" intraperitoneally.  I know I am being lazy, but also the mouse to human translations are always confusing to me, so I'm looking for a second/third opinion on what this would be translated to in human terms. 

 

Using the following formula:

HED (mg/kg) = Animal Dose (mg/kg) x [Animal K_m / Human K_m]

HED (mg/kg) = Animal Dose (2) x [₃ /₃₇]

HED (mg/kg) = Animal Dose (mg/kg) x [Animal K_m / Human K_m]

HED (mg/kg) = .162 mg/kg

 

This would then come out to 13.6 grams for a 185 lb man.  So translated directly from the study, that would be 13.6 grams every other day for two weeks.  I'm sure the time period would need to be much longer for humans as well. 

 

I'm perfectly willing to try to get to these extreme amounts as long as it was only for say  6 months.  But are my calculations correct?  Am I missing something? 

 

 

I think you've got that right. The conversion factor I use is Mouse Dose(mg/kg)/12.33 = Human Dose (mg/kg) which I believe yields the same results.

 

For my dosing guidelines I'm looking at the BioBlast human clinical trials.  These are for Parkinson's disease and not atherosclerosis, but I think they get us in the ballpark.  They were doing up to 27g IV once per week.

[OP2040]

Good, just wanted a second opinion.  It is what it is, and I'm going to try to get close to that level or dosage. 

 

My target is atherosclerosis, which I assume everyone at my age has.  But also, the brain stuff is something that would be great for future protection.  And honestly if the target is the lysosomal-macrophage system, then this should help with a very diverse array of aging targets. 

 

It would be great to have some way to measure the effectiveness when we do start taking it.  That way we would know how to adjust dosage, and when to quit.  I don't see this as a lifetime therapeutic intervention.  It shouldn't take a lifetime to clear out most of the junk.  And I'm not sure I want super-macrophages running around indefinitely.  It sounds pretty great, but you never know what the consequences may be.  What is your plan of action, if you don't mind me asking?

[Daniel Cooper]

As far a measuring progress, the only thing I can suggest is a CAC score and maybe a carotid ultrasound.  Ideally both because the first is looking at calcified plaques and the later is at least looking at a proxy for soft plaques. 

 

They are relatively cheap tests.  In my area, a CAC is a $99 walk in procedure and a carotid ultrasound is that or cheaper.  Of course, you'd want to do before and after scans.

 

 

 

[Greene]

I was looking at cyclodextrins in my researching on plaque removal before stumbling on the cyclo. thread which in turn lead me here. At the time HPBC seemed to be one of the main easily available candidate substances to achieve the end goal of clearing my arteries. My research on either is not complete, but I do not want to miss a good opportunity with this group buy if liposomal Trehalose looks to be worthwhile and with Trehalose having possibly more than one positive effect, but I’m still thinking about experimenting with cyclo. It seems to me that doing IV/subQ injections of HPBC might be a relatively safe and worthwhile option, and if I will iron out some kinks I might well give it a shot (no pun intended).

 

 

I haven't yet worked out the details or analysed all the risks but it seems to be quite doable overall. I’m thinking about preparing proper solution using buffered saline purchased from my local med supplies store, sterilize it, seal it and keep in the fridge for a few weeks, long enough to be able to give myself a few SubQ or IV injections. I also wonder if preparing Trehalose for IV injections (even if it means 10ml solution per injection) would be worth it, and if so I might consider that option as well. I'll start a separate thread if I get more serious about, but posting it here for now to see if I spark anyone’s interest in the topic.

 

In short - I'm looking at preparing HPBC and possibly Trehalose injection (as opposed to infusion) solutions and considering subjecting myself to such experimentation under conditions of calculated risks. I will appreciate any input on the subject and time permitting will try to post my thoughts on the topic either here or in the Cyclodectrins or in a new thread. 

 

Cheers!

 

 

Edited by Greene, 08 May 2018 - 12:53 PM.

[OP2040]

Greene,

It seems we have walked the same path my friend.  I started out really interested in the Cyclodextrins, but ended up here.  The main reason being that Trehalose has a better safety profile.  B-Cyclo did cause even more dramatic plaque reduction in one mouse study. 

 

But if I'm remembering correctly, there are two issues with Cyclodextrins.  First they don't easily cross the BBB, which is why the clinical trials for lysosomal storage diseases inject into the spinal fluid.  The second reason is that there were hints of negative effects on the kidneys or lungs at least for some Cyclos, and that's something I just don't want to take a chance on, even if the evidence is not very convincing.  The most worrying part of it was that the more effective the Cyclos seemed to be for targeting different kinds of junk, the more unsafe their profiles seemed to be.  So, it looked a lot like a catch-22, where getting the benefit implied increasing risk.   Having said that, they are very much still on my radar, but would like to try Trehalose first.  If you ever end up going the Cyclo route, please start a thread as I'd be very interested to hear your story.  It is definitely nice to have more than one option.

 

 

[ceridwen]

I'm interested in a group buy

[Daniel Cooper]

Group buy thread here:   https://www.longecit...lose-group-buy/

 

 

 

[William Sterog]

Maybe this question is stupid, I haven't saw it answered, although I recognize that I have not read the whole thread. Do you think that topical trehalose would do anything against scalp calcification in male pattern baldness?