132 replies to this topic

[CycloQuest]

I would very much like to have others opinions on this topic and to try and centralise all the info on this here.Same compound should be mentioned is in clinical trials for the treatment of some types of ataxia

As a starting point I would point to this study:

 

 https://www.ncbi.nlm...les/PMC5467270/

 

I would like to know what others think and of course I will also explain what I intend to do based on this study.

 

Jump in and lets have an interesting debate, no nasty people please

[Daniel Cooper]

Thanks for bringing this research to our attention.  I was unaware of it till your posts.  Very interesting results and it looks like something that has a low risk/high potential rewards.

 

 

 

 

[CycloQuest]

Indeed you are right in regards to the risks vs rewards. If tou look into the research done by the israeli company Bioblast Pharma you can see clearly that the risks are almost none. The research is done for some types of ataxia but still there are some result even tho ataxia is a neurodegenerative disease and no notable side effects. It is very interesting and something that led me to start my own research a few months back and to decide to start a one year, once a week high dose iv trehalose infusion treatment.I am not a Member and I'm beeing prompted this is my last post for today .More to come tomorrow

[Daniel Cooper]

How are you going to obtain your Trehalose IV solution?

 

 

 

[CycloQuest]

How are you going to obtain your Trehalose IV solution?

I am going to compound endotoxin free trehalose and sterile IV water using a aseptic containment box and then using a Alaris GP infusion pump I am going to infuse at a rate of 300ml/hour ( 450ml). I will increase the dosage of trehalose up to 50g starting from 30g in 5g increments every 4 weeks until the 52nd.Last 8 weeks at 50g. So from 66mg/ml to 111mg/ml.

Edited by CycloQuest, 01 September 2017 - 10:31 AM.

[CycloQuest]

Pharmacokinetic Study in Healthy Volunteers Demonstrated Trehalose to be Safe and Well Tolerated at Twice the Dose Levels Used in Prior Clinical Studies

Results Support Weight-Based Dosing Paradigm in Future Studies

TEL AVIV, Israel, Oct. 24, 2016 (GLOBE NEWSWIRE) -- Bioblast Pharma Ltd. (NasdaqGM:ORPN), a clinical-stage, orphan disease-focused biotechnology company, today announced results of a double-blind, placebo-controlled pharmacokinetic (PK) study of intravenous (IV) trehalose 90mg/mL in healthy volunteers.

The primary objective of the study was to establish safety and tolerability of escalating doses of trehalose. The secondary objectives were to determine the Maximum Tolerated Dose (MTD) and pharmacokinetics of escalating doses of trehalose.

The key findings of the study that was conducted in 24 healthy volunteers include:

The MTD was determined to be 54 grams (g) administered IV over 60 minutes, which is twice the level of drug that has been given to patients in Bioblast’s oculopharyngeal muscular dystrophy (OPMD) and spinocerebellar ataxia (SCA3) Phase 2a studies.
54g of trehalose administered over one hour was generally safe and well tolerated with no changes in any safety parameters.
The PK of trehalose was linear; i.e. doubling the dose, doubled the exposure.
The half-life of trehalose was approximately 1.5 hours and did not change when the dose was increased.
There was no effect on serum glucose levels during or following the infusion.
The rate of trehalose clearance from the blood was directly related to the patient’s weight; i.e., the greater the weight the faster the clearance of drug.
“Based on the findings from this study, trehalose appears to be generally safe and well tolerated at twice the dose levels used in the previous clinical studies,” said Warren Wasiewski, MD, Bioblast’s Chief Medical Officer. “Since total clearance of the drug increased with weight, we plan to utilize a weight-based dosing paradigm moving forward. This will enable us to achieve a consistent serum concentration of trehalose in all patients regardless of weight in the upcoming double-blind, placebo-controlled Phase 2b study in patients with OPMD.”

More on the PK trial

This was a randomized double-blind, placebo-controlled single ascending dose study that included 3 groups of subjects, 8 in each group. In each group, 6 subjects received trehalose and 2 received placebo. The first group received 27g of IV trehalose as a one hour infusion. The safety and pharmacokinetic assessment of the data showed that trehalose was well tolerated and no safety signals were identified. The next group was then dosed with 54g. Safety and PK were acceptable permitting dosing of the next level of 81g.

Peak serum concentration increased with increasing doses from 27g to 81g. The mean elimination half-life (t½) ranged from 1.41 hours to 1.59 hours and was consistent as the dose increased. In the 81g dose cohort, one subject out of six had an increase in liver enzymes that resolved without treatment; no higher doses of trehalose were administered, thereby establishing the MTD for trehalose as 54g.

There was a positive relationship between clearance of trehalose from the blood and body weight over a range of 50 kilograms (kg) to 100kg. This finding suggested that clearance is related to body size and thus, weight-based dosing, i.e. g/kg, would be more appropriate to achieve consistent exposure across a range of body weights in future studies.

Trehalose is a protein stabilizer that also activates autophagy and crosses the blood-brain barrier

Trehalose is a low molecular weight disaccharide (.342 kilodaltons) that protects against pathological processes in cells. It has been shown to penetrate muscle cells and cross the blood-brain barrier. In animal models of several diseases associated with abnormal cellular-protein aggregation, it has been shown to reduce pathological aggregation of misfolded proteins as well as to activate autophagy pathways through the activation of Transcription Factor EB (TFEB), a key factor in lysosomal and autophagy gene expression. Activation of TFEB is an emerging therapeutic target for a number of diseases with pathologic accumulation of storage material.

Trehalose 90mg/mL IV solution is being developed as a treatment for OPMD based on several studies in cell and animal models of OPMD where it demonstrated the ability to reduce aggregation of the pathological protein (PABPN1) in muscle cells, the hallmark of the disease, by stabilizing the protein, reducing the formation of protein aggregations, and promoting clearance of abnormal proteins through activation of autophagy, thereby preventing muscle cell death.

Other information on trehalose in clinical studies

In a Phase 2a open label study of patients with OPMD, trehalose administered as a weekly infusion of 27g for 6 months showed an improvement in dysphagia as measured by the time to consume 80mL of cold water. In the 12 month follow up of that study designed as a withdrawal study, those patients who were randomized to stay on drug continued to have reduced drinking time and those who were withdrawn from drug had an increase in the drinking time. These data suggest that the treatment effect is sustained in the those who continue to receive trehalose and was lost in those who were withdrawn from treatment.

Beyond OPMD, Bioblast is currently conducting analyses to determine the next orphan disease that will investigate the use of trehalose as a therapeutic agent. Bioblast intends to make such a decision in the first half of 2017.

About OPMD

OPMD is an inherited myopathy characterized by dysphagia (difficulty in swallowing), eyelid drooping (ptosis), and the loss of muscle strength, with progressive limb weakness. Symptoms generally appear in mid-life and get worse over time. As the dysphagia becomes more severe, patients may become malnourished, may lose significant weight, and may suffer from repeated incidents of aspiration pneumonia. The disease is caused by a genetic mutation responsible for the creation of a mutant protein (PABPN1) with an expanded polyalanine domain that aggregates within patient muscle cells. There is currently no approved pharmacologic treatment for OPMD.

About Bioblast Pharma Ltd.

Bioblast Pharma is a clinical-stage biotechnology company committed to developing clinically meaningful therapies for patients with rare and ultra-rare genetic diseases, with a lead drug candidate -- trehalose 90mg/mL IV solution -- in Phase 2 development. Bioblast was founded in 2012 and is traded on the NASDAQ under the symbol “ORPN”. For more information, please visit our website, www.bioblastpharma.com, the content of which is not incorporated herein by reference.

[Daniel Cooper]

I think you said in the Cyclodextrin thread that you were going to have before/after CTA?  Do you mean a full CT angiography?  If so I was wonder why you wouldn't just do before/after CAC (Coronary Artery Calcium) score?  You're looking at 1.5 - 3mSV radiation exposure versus about 12mSv for the average CTA.  

 

Here in the States a CAC isn't covered by insurance, and they are consequentially therefore cheap, about $99USD (about €83).

 

 

[CycloQuest]

I think you said in the Cyclodextrin thread that you were going to have before/after CTA? Do you mean a full CT angiography? If so I was wonder why you wouldn't just do before/after CAC (Coronary Artery Calcium) score? You're looking at 1.5 - 3mSV radiation exposure versus about 12mSv for the average CTA.

Here in the States a CAC isn't covered by insurance, and they are consequentially therefore cheap, about $99USD (about €83).

Yes that makes alot of sense and this is one of the reasons I am here, suggestion about anything that will make
the protocol better are welcomed. Over here in UK the cost privately is around £500 from what I could find. But there are ways of having any investigations cheaper in other states in the EU.

[aribadabar]

Is taking Trehalose orally ( at higher doses) beneficial for plaque removal purposes or it is a waste if not administered via IV route?

[CycloQuest]

Is taking Trehalose orally ( at higher doses) beneficial for plaque removal purposes or it is a waste if not administered via IV route?

https://www.ncbi.nlm...ing-08-1167.pdf

This is the latest study on high dose oral trehalose supplementation. It is not to prove plaque removal but it does prove trehalose crossing into blood. I would not think it is enough to determine the autophagy process if not administered IV.

Edited by CycloQuest, 05 September 2017 - 09:06 AM.

[Daniel Cooper]

Good study.  Too bad they didn't run it longer and measure intimal thickness and/or do CAC scores.

 

If you could offset some of the sucrose/fructose in your diet (which you hopefully have very little) with some trehalose it seems like you might do yourself some good.  Trehalose is only about half as sweet as sucrose in moderate doses, and the sweetness factor falls off more quickly in low doses.

 

You'd want to be careful and not all a lot of carbs to your diet if you're going to take trehalose orally.  If you could swap out trehalose for sucrose I suspect you'd be ahead, but there is that issue of it being less sweet.

 

 

 

[Daniel Cooper]

 

How are you going to obtain your Trehalose IV solution?

I am going to compound endotoxin free trehalose and sterile IV water using a aseptic containment box and then using a Alaris GP infusion pump I am going to infuse at a rate of 300ml/hour ( 450ml). I will increase the dosage of trehalose up to 50g starting from 30g in 5g increments every 4 weeks until the 52nd.Last 8 weeks at 50g. So from 66mg/ml to 111mg/ml.

 

 

 

I'm sure you're probably aware that sterility issues with your trehalose solution is probably your biggest risk.  Assuming you aren't diabetic (and even then I think you could do this without issue) I don't think taking IV trehalose is very dangerous.   

 

I really envy your easy access to Eastern Europe where you can get some of these experimental things done cheaply and in relative safety.   

 

I personally am getting a bit more interested in IV trehalose over IV cyclodextrin.  I think maybe you're getting the same benefit at a somewhat lower risk.  Hopefully we'll see some more studies come out on this topic soon.

[CycloQuest]

How are you going to obtain your Trehalose IV solution?

I am going to compound endotoxin free trehalose and sterile IV water using a aseptic containment box and then using a Alaris GP infusion pump I am going to infuse at a rate of 300ml/hour ( 450ml). I will increase the dosage of trehalose up to 50g starting from 30g in 5g increments every 4 weeks until the 52nd.Last 8 weeks at 50g. So from 66mg/ml to 111mg/ml.

I'm sure you're probably aware that sterility issues with your trehalose solution is probably your biggest risk. Assuming you aren't diabetic (and even then I think you could do this without issue) I don't think taking IV trehalose is very dangerous.

I really envy your easy access to Eastern Europe where you can get some of these experimental things done cheaply and in relative safety.

I personally am getting a bit more interested in IV trehalose over IV cyclodextrin. I think maybe you're getting the same benefit at a somewhat lower risk. Hopefully we'll see some more studies come out on this topic soon.

To be honest sterility is my only concern, that is why I'll be using a compounding laminar flow glove box and after dilution the trehalose solution will be vaccum filtered thru a 0.20µm sterile filer. Only then the solution goes back into the sterile iv infusion bag. All done in a uv sterilized enviroment taking as much care as possible. Are there risks..well...yes but will keep them at the minimum. Everything used is going to be sterile or sterilized so it is just a matter of keeping it like this while compounding and should be fine.I am not diabetic so that is not a concern.

Edited by CycloQuest, 05 September 2017 - 04:54 PM.

[Daniel Cooper]

I suspect that here in the States that I might be able to get a compounding pharmacy that specializes in making up IV solutions to make that for me.  I expect it would costs a few hundred dollars per infusion bag, but I don't know that with any certainty.

 

Sounds like you know the risks and procedures.  Do you have a background in this field?

 

 

 

[CycloQuest]

I suspect that here in the States that I might be able to get a compounding pharmacy that specializes in making up IV solutions to make that for me. I expect it would costs a few hundred dollars per infusion bag, but I don't know that with any certainty.

Sounds like you know the risks and procedures. Do you have a background in this field?

Would a compounding pharmacy in the states just do it for you without having a prescription from a GP? If yes then that is amazing! I have about 4 years of bio-chemistry "training" under my belt but never worked in the field so everything is just theory and a bit rusty, but enough to serve me for this ( I think?). Lets put it this way :
1) iv trehalose does scare me as much as iv glucose does, not at all;
2) there are studies on the safe dosages of iv trehalose out there so that is a plus
3) only problem as you pointed could be the sterility : my iv water is sterile, all utensils and recipients/bottles/beakers are single use individualy packed sterile, the threhalose is endotoxin free ( does not mean it is sterile) from a reputable source will be sterilized thru vaccum filtration in a sterile uv and hepa H13 enviroment ( can not use heat to sterilize a sugar solution). It is not 100% maybe but it is the best of the best I can do and I am still working on improving it before starting.

[Daniel Cooper]

I think I know people that got phosphatidylcholine solutions made up a by a compounding pharmacy after lipostabil became unobtainable which they then took to a doctor for infusion.  But, I'm not 100% sure about that.  I think as long as the components you are using aren't controlled or require a prescription I can't think of a reason a compounding pharmacy here would refuse to do it except that everyone is so afraid of lawsuits they might be concerned that you might sue them if things went wrong.

 

 

[CycloQuest]

A bit more on trehalose :

https://www.nature.c...icles/srep28423

[thedarkbobo]

Hmm this sounds interesting really and more affordable than CD.

*edit: well not really...100g/day is around 30$...

 

https://www.ncbi.nlm...les/PMC4931825/

 

 

 

This is the first study to examine the potential therapeutic effects of trehalose on any type of physio-logical function with age in humans. The present findings provide novel evidence that 12 weeks of oral trehalose supplementation improves resistance artery EDD, a measure of microvascular function, through increasing NO bioavailability in MA/O adults. Improvements in resistance artery endothelium-independent dilation were also observed with trehalose treatment, indicating increased vascular smooth muscle sensitivity to NO. In contrast, trehalose supplemen-tation had no effect on conduit artery EDD or large elastic artery stiffness. Together, these findings demonstrate that oral trehalose supplementation has heterogeneous effects on different functional aspects of arterial aging, and may be a novel strategy to improve resistance artery EDD in healthy MA/O adults. Because microvascular function (resistance artery EDD) is an independent predictor of incident CVD, these findings have important clinical implications for the primary prevention of CVD with advancing age.

 

However, resistance artery EDD improved ∼30% following 12 weeks of oral trehalose supplementation in subjects who maintained their body mass within 2.3 kg, suggesting that this intervention is effective for subjects who are able to maintain their baseline body mass despite the caloric content associated with the intervention.

 

http://scholar.color...hy_gradetds/44/

 

 

Thirty-two men and postmenopausal women aged 50-77 years consumed 100g/day of trehalose or maltose (energy equivalent control disaccharide without the reported health benefits of trehalose) for 12 weeks (randomized, double-blind). Resistance artery NO-mediated EDD increased with trehalose in subjects remaining weight-stable, and this was associated with evidence of decreased endothelial cell inflammation. Contrastingly, trehalose did not modify conduit artery EDD or oxidative stress. These findings indicate that trehalose may be a novel therapy for reducing vascular inflammation and improving resistance but not conduit artery EDD in MA/O adults able to maintain stable body mass.

In a secondary protocol of the parent investigation, large elastic artery stiffness was assessed in 31 healthy adults 50-77 years before and after 12 weeks of oral trehalose or maltose supplementation (100g/day). Trehalose was not effective for reversing arterial stiffness in this population.

These studies indicate that although trehalose has heterogeneous effects on different aspects of arterial aging and its caloric content poses challenges, this may be an effective intervention for the primary prevention of CVD by reversing resistance artery EDD in healthy MA/O adults.

 

 

 

However, there is a relatively high caloric content associated with 100 g/day of trehalose (∼400 Kcals/day) and despite nutrition counseling every two weeks, not all subjects were able to maintain their body weight over the 12 week intervention period or keep the macronutrient composition of their diet constant.

 

Edited by thedarkbobo, 06 September 2017 - 11:35 AM.

[CycloQuest]

Hmm this sounds interesting really and more affordable than CD.
*edit: well not really...100g/day is around 30$...

https://www.ncbi.nlm...les/PMC4931825/

This is the first study to examine the potential therapeutic effects of trehalose on any type of physio-logical function with age in humans. The present findings provide novel evidence that 12 weeks of oral trehalose supplementation improves resistance artery EDD, a measure of microvascular function, through increasing NO bioavailability in MA/O adults. Improvements in resistance artery endothelium-independent dilation were also observed with trehalose treatment, indicating increased vascular smooth muscle sensitivity to NO. In contrast, trehalose supplemen-tation had no effect on conduit artery EDD or large elastic artery stiffness. Together, these findings demonstrate that oral trehalose supplementation has heterogeneous effects on different functional aspects of arterial aging, and may be a novel strategy to improve resistance artery EDD in healthy MA/O adults. Because microvascular function (resistance artery EDD) is an independent predictor of incident CVD, these findings have important clinical implications for the primary prevention of CVD with advancing age.

However, resistance artery EDD improved ∼30% following 12 weeks of oral trehalose supplementation in subjects who maintained their body mass within 2.3 kg, suggesting that this intervention is effective for subjects who are able to maintain their baseline body mass despite the caloric content associated with the intervention.

http://scholar.color...hy_gradetds/44/

Thirty-two men and postmenopausal women aged 50-77 years consumed 100g/day of trehalose or maltose (energy equivalent control disaccharide without the reported health benefits of trehalose) for 12 weeks (randomized, double-blind). Resistance artery NO-mediated EDD increased with trehalose in subjects remaining weight-stable, and this was associated with evidence of decreased endothelial cell inflammation. Contrastingly, trehalose did not modify conduit artery EDD or oxidative stress. These findings indicate that trehalose may be a novel therapy for reducing vascular inflammation and improving resistance but not conduit artery EDD in MA/O adults able to maintain stable body mass.
In a secondary protocol of the parent investigation, large elastic artery stiffness was assessed in 31 healthy adults 50-77 years before and after 12 weeks of oral trehalose or maltose supplementation (100g/day). Trehalose was not effective for reversing arterial stiffness in this population.
These studies indicate that although trehalose has heterogeneous effects on different aspects of arterial aging and its caloric content poses challenges, this may be an effective intervention for the primary prevention of CVD by reversing resistance artery EDD in healthy MA/O adults.

However, there is a relatively high caloric content associated with 100 g/day of trehalose (∼400 Kcals/day) and despite nutrition counseling every two weeks, not all subjects were able to maintain their body weight over the 12 week intervention period or keep the macronutrient composition of their diet constant.

$30 for 100g? Can't be as I pay around £30 for 2.5kg of Hayashibara food grade trehalose and I take 80g a day so that lasts me for a month. ~£360 for a year.

Edited by CycloQuest, 06 September 2017 - 01:38 PM.

[Daniel Cooper]

My problem with taking trehalose like that is that I don't add any sugar to anything that I can swap it out for.  So, I need to find 400kcal somewhere in my diet to reduce and that will of course not all be carbs.  So, more of a logistical problem than anything.

 

Also, we have evidence here that oral trehalose improves artery stiffness (a good thing), but we don't know that it actually reverses arterial plaques.  Too bad they didn't measure intimal thickness or coronary calcium, which are much close to the disease process we're trying to prevent and reverse.  EDD is a couple of steps removed from what we're actually trying to change.

 

CycloQuest - Have you noticed any BP improvement since you've started taking oral trehalose?

 

 

 

Edited by Daniel Cooper, 06 September 2017 - 02:03 PM.

[CycloQuest]

My problem with taking trehalose like that is that I don't add any sugar to anything that I can swap it out for. So, I need to find 400kcal somewhere in my diet to reduce and that will of course not all be carbs. So, more of a logistical problem than anything.

Also, we have evidence here that oral trehalose improves artery stiffness (a good thing), but we don't know that it actually reverses arterial plaques. Too bad they didn't measure intimal thickness or coronary calcium, which are much close to the disease process we're trying to prevent and reverse. EDD is a couple of steps removed from what we're actually trying to change.

CycloQuest - Have you noticed any BP improvement since you've started taking oral trehalose?

Indeed the study was not to show plaque reduction but it does prove crossing into the blood so maybe other benefits as well. I cant comment on blood pressure as mine has always been and still is good. Since starting taking trehalose I have started running 5k a day so that I can compensate for those calories and also watching for sugar intake.

[CycloQuest]

Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects
An interesting read

https://www.ncbi.nlm...les/PMC5292800/

[CycloQuest]

Just as a starting point in regards to prices/suppliers. Feel free to post any suppliers and prices you can find.

http://www.carbosynt...025727800523FFA

Edited by CycloQuest, 07 September 2017 - 11:26 AM.

[Daniel Cooper]

Bulksupplements.com is selling trehalose.  

 

You can buy it through Amazon https://www.amazon.c...=trehalose&th=1    $19.96USD shipped.

 

This would be food grade I would assume, not for IV injection.

 

Edited by Daniel Cooper, 07 September 2017 - 02:15 PM.

[CycloQuest]

Bulksupplements.com is selling trehalose.

You can buy it through Amazon https://www.amazon.c...=trehalose&th=1 $19.96USD shipped.

This would be food grade I would assume, not for IV injection.

It is food grade yes. Just have a look at the difference in price between fiod grade and endotoxin free, $600/kg for endotoxin free, but still reaonable for about 6 moths of IV infusions.

[CycloQuest]

And again a bit more on trehalose and autophagy:

http://hddrugworks.o...e-to-the-rescue

[Daniel Cooper]

Good stuff Cyclo.

 

What we really need is a human trial where they measure carotid IM thickness or CAC.  What would be nice would be if they measure these things during the clinical trials currently underway for other applications.  This would not be a controlled double blind experiment, but if you saw IM thickness or CAC decrease appreciably it would be a clue, as these things practically never improve on their own.

 

 

 

 

 

[CycloQuest]

That would be amazing but highly unlikely to happen in a human clinical trial for a different disease. I am aware we are interested in trehalose for the treatment of atherosclerosis but I will post research from any disease just because it is important to keep an eye on any aplication, just as you mentioned, we might spot that little thing that might not mean alot for that aplication but could be ground breaking for our aplication. You never know!

[Daniel Cooper]

Here's a PowerPoint from BioBlast Pharma concerning trehalose as a treatment for SCA3.

 

It has some general information of interest.  Particularly pages 7 and 8 concerning oral ingestion and IV administration.  They claim that in humans trehalose is metabolized at the gut wall into two D-glucose molecules and that only 0.5% of oral trehalose makes it into the bloodstream intact. 

 

IV administration seems the way to go for atherosclerosis, but other studies do show some positive effect from oral dosing which is surprising if this information is correct.

 

 

Attached Files

•  SCA3-POC-2015-International-Ataxia-Research-Conference.pdf   782.17KB   9 downloads

[aribadabar]

Guys,

 

would liposomal encapsulation of trehalose improve its potency/effectiveness via orally administration?

Edited by aribadabar, 15 October 2017 - 02:23 AM.