25 replies to this topic

[neonglow]

Hi everyone,

I don't know if you remember me but my name on here was Xenix (the guy with chronic carbon monoxide posioning). I cannot remember my password on here and there seems to be no way to reclaim a user account by way of 'forgotten password'.

Anyway, after trying many different research compounds and having mixed results, I have read much into ISRIB and it has my full attention. I truly believe that it is very much a state-of-the-art research chemical.

I am very much interested in starting a group buy, and I would like to see who else would like to get the ball rolling as soon as possible. Any and all input from people who have experience with custom syntheses would be greatly appreciated.

Please let me know!

[LocalConsignment]

Hello NeonGlow,

 

Yes, I would be interested in joining a group buy for ISRIB - don't know much about the group buys but I have a bank account!

 

Thanks!

 

LocalConsignment guy

[dodo40000]

I also definately would join such a group. I think to figure out how it works we should contact one of the guys who of the first group buy in 2014 in this forum.

 

Best regards.

[Mind_Paralysis]

Why don't you start by telling us what ISRIB does, and what you're hoping it will do for you?

Your issue and the damage is potentially also fairly specific - do you have MRI and fMRI-scans of your brain so that you know what parts of your brain was damaged by carbon Monoxide?

 

People that get in on the Group Buy needs to know what parts of the brain the drug will enhance or improve - who's supposed to be helped by this drug?

 

If you're going to market this group buy, you need to add this to your post, so as to get the right people excited for it. You would do well to post every available information on the drug there is, as well.

 

 

EDIT:

 

Well, here's the wikipedia. It's pretty thin though, and doesn't mention if it's being considered for human testing, nor if anyone's trying to turn it into a commercial product.

 

https://en.wikipedia.org/wiki/ISRIB

 

Hmm. Ok, I believe this is an EPIGENETIC drug? It reverses the phosphorylation (apparently inactivation?) of elF2a - which is a complex protein which then controls the expression of genes inside of our cells.

 

https://en.wikipedia...ki/EIF2#Disease

 

This... actually seems a bit dangerous... because ISRIB alters a very important and complex process in genetic function and division - phosphorylation isn't just bad, in fact, it's essential for some of the processes of encoding DNA, making copies, and dividing cells. Now, it's a specific form of phosphorylation which ISRIB inhibits, but still...

 

Now, yes, some of this looks pretty cool and promising, but not very well-understood what the long-term effects could be.

 

 

EDIT:

 

Anyone with actual, DEEP biomolecular and biochemic knowledge that's willing to chime in on my post here, perhaps explain the process, it's role in disease and neurodegeneration (perhaps degeneration in general?) and stressor-induced cellular damage?

 

Just what is this process the drug alters?

What's actually happening inside of the bodies of these rats, when this process is altered?

 

What happens to this process when the cells of a living animal are damaged?

 

Etc... so many questions here... this drug is far beyond the normal range of this board, as well as my own limited knowledge of the brain.

Edited by Mind_Paralysis, 23 June 2018 - 12:54 PM.

[George2]

Hello, I tried to contact you sometime back regarding your last group-buy, but you seemed to have disappeared. Glad that you are back. If you will be so kind to enlighten me on the following, that'd help me to decide if I should use ISRIB on my close relative who had a severe TBI and ensuing memory impairement. 

1. From your previous posts, you indicated that you were going to try ISRIB. WHAT WAS THE RESULT? 

2. How did you address the solubility problem? 

i have done a lot of research work on ISRIB and even contacted people working in the field. It seems a very logical approach, however, there is no human data -- not even anecdotal data other than some interesting result from Prof. Giovani Mallucci's lab wherein they discovered that Trazadone (a safe anti-depressant) inhibits integrated stress response pathway much like ISRIB and resumes protein synthesis. However, that study was also in mice. Interestingly, there are some reports of Trazadone improving memory in Alzheimer's patients. ISRIB seems to improve memory in normal animals too, but Trazodone doesn't do that. So it is not clear if Rosi's discovery of ISRIB boosting memory in animals with traumatic brain injury and and neurodegenerative disorders can be translated to humans. THIS IS THE REASON THAT YOUR EXPERIENCE WITH ISRIB WILL BE SO IMPORTANT NOT JUST FOR ME, BUT FOR THE SCIENTIFIC COMMUNITY. Also, are you aware if any of the other members of the last Group-buy benefited from using ISRIB?

 

Thanks a ton, George

[Painkillerrr]

i was interested as well, but it could have bad and long-lasting side effect. Id just wait for a clinical trial before trying it. lets make a group buy for "my" pde4d nam instead

[George2]

i was interested as well, but it could have bad and long-lasting side effect. Id just wait for a clinical trial before trying it. lets make a group buy for "my" pde4d nam instead

Thank you. ISRIB is the only compound so far shown to reverse memory loss in the chronic phase of traumatic brain injury, the condition I am interested in for my relative - but the results as you are well aware was in mice. So your point is well taken, the side-effects in humans are unknown even though preliminary animal data showed no apparent toxicity. However, i read some blogs where people have tried ISRIB dissolved in DMSO for improving memory (they get it from the Chinese manufacturers, I suspect)

[Painkillerrr]

Thank you. ISRIB is the only compound so far shown to reverse memory loss in the chronic phase of traumatic brain injury, the condition I am interested in for my relative - but the results as you are well aware was in mice. So your point is well taken, the side-effects in humans are unknown even though preliminary animal data showed no apparent toxicity. However, i read some blogs where people have tried ISRIB dissolved in DMSO for improving memory (they get it from the Chinese manufacturers, I suspect)

 

I usually dont trust reviews on the internet unless they are made by "reliable people", i have read the thread of 2014 group buy and if i remember well only the guy who purchased it had any positive effects (maybe he had suffered from traumatic brain injury and the drug "healed" his brain, while other that did not suffered from that has no positive outcome). I really dont know, and i think that when "you dont know" you should not risk to worsen your condition.

 

anyway ll probably buy it after other positive reviews (of "healthy" people (you are healthy as well, i would not like to sound a dick (for healthy i mean people without brain injury)))

 

sorry my english.

[George2]

I usually dont trust reviews on the internet unless they are made by "reliable people", i have read the thread of 2014 group buy and if i remember well only the guy who purchased it had any positive effects (maybe he had suffered from traumatic brain injury and the drug "healed" his brain, while other that did not suffered from that has no positive outcome). I really dont know, and i think that when "you dont know" you should not risk to worsen your condition.

 

anyway ll probably buy it after other positive reviews (of "healthy" people (you are healthy as well, i would not like to sound a dick (for healthy i mean people without brain injury)))

 

sorry my english.

You are absolutely right. One cannot rely on reports of individuals in blogs -- especially on a topic like memory which no one knows how it works. There could be placebo effects, or improvement due to other reasons. Only a properly formatted and controlled clinical study with precise inclusion/exclusion criteria would give the answer. However, such data is years away. Most likely they will have to do some serious formulation work to make ISRIB soluble or even change the chemistry for that matter. However, the results of Prof Rosi are spectacular and the mechanism of action has been confirmed in other systems and in other models.

I am interested in Traumatic Brain Injury. I have exhaustively searched for research publications on compounds that improve memory in traumatic brain injury. While there are studies which show one compound or another reducing the severity of injury in animal models (by preventing secondary injuries like glutamate excitotoxicity) but needs to be administered within few hours of injury (an impractical approach in most cases), I have not seen any result in animals or humans where memory is restored in the chronic phase of traumatic brain injury as is the case with ISRIB. In mice this was 28 days which probably translates to many months in humans -- a viable approach. This makes the discovery very important considering the massive number of traumatic brain injury patients with memory issues. The concept that memory can be restored months after the initial injury seems logical because in most cases, past memory is not erased, but inaccessible in a timely manner or new memory is formed by is not consolidated and stored properly (long-term potentiation) probably due to the lack of forming proper neuronal connections which requires protein synthesis and which ISRIB helps to connect. 

Prof. Giovanni Mallucci in UK had shown in another set of elegant studies that the same pathway that ISRIB acts upon -- namely the Integrated Stress Response pathway -- can be inhibited in animals infected with prions (a neurodegenerative condition with ensuing loss of memory function) can be be blocked by a common antidepressant drug called TRAZODONE and produce similar effect as ISRIB in these mice. Unfortunately, Prof. Mallucci didn't test Trazodone in mouse models of traumatic brain injury (TBI). If Prof Mallucci had shown that Trazodone can mimic ISRIB in TBI animals, that would have been another "remarkable discovery" for TBI patients because they will have a safe drug to experiment with to see if it will improve their memory. I have indeed tried Trazodone on a close relative who suffered severe TBI and has memory loss (both long-term and working memory, but otherwise perfectly fine) the observed improvement in memory was modest and could also be attributed to the natural recovery  -- in any case, nothing remarkable. Perhaps the dose of Trazodone was lower than what is needed to see a striking improvement in memory in humans, but these are hypothetical questions and there are limits to which how much a drug can be given. However, there are anecdotal evidence that Trazodone does improve memory -- albeit modestly -- in some patients with neurodegnerative diseases (but not TBI).

Under the circumstances, despite potential toxicity or lack of solubility of ISRIB, it seems to be something worth trying given the fact that there is nothing else out there and waiting for clinical trial results to emerge is not a practical solution for many young people who have memory loss from TBI, but are otherwise healthy. Agencies like NIH should have been proactive and already put such molecules in clinical trials on a war-footing (like they did for AIDS), but unfortunately, such agencies (and even academia) are very conservative and unwilling to take bold initiatives while great inventions sit on the lab shelves for years.  

[LocalConsignment]

OK - So what would be the next step to initiate this group buy?

 

Thanks!

 

LocalConsignment

[George2]

Why don't you start by telling us what ISRIB does, and what you're hoping it will do for you?

Your issue and the damage is potentially also fairly specific - do you have MRI and fMRI-scans of your brain so that you know what parts of your brain was damaged by carbon Monoxide?

 

People that get in on the Group Buy needs to know what parts of the brain the drug will enhance or improve - who's supposed to be helped by this drug?

 

If you're going to market this group buy, you need to add this to your post, so as to get the right people excited for it. You would do well to post every available information on the drug there is, as well.

 

 

EDIT:

 

Well, here's the wikipedia. It's pretty thin though, and doesn't mention if it's being considered for human testing, nor if anyone's trying to turn it into a commercial product.

 

https://en.wikipedia.org/wiki/ISRIB

 

Hmm. Ok, I believe this is an EPIGENETIC drug? It reverses the phosphorylation (apparently inactivation?) of elF2a - which is a complex protein which then controls the expression of genes inside of our cells.

 

https://en.wikipedia...ki/EIF2#Disease

 

This... actually seems a bit dangerous... because ISRIB alters a very important and complex process in genetic function and division - phosphorylation isn't just bad, in fact, it's essential for some of the processes of encoding DNA, making copies, and dividing cells. Now, it's a specific form of phosphorylation which ISRIB inhibits, but still...

 

Now, yes, some of this looks pretty cool and promising, but not very well-understood what the long-term effects could be.

 

 

EDIT:

 

Anyone with actual, DEEP biomolecular and biochemic knowledge that's willing to chime in on my post here, perhaps explain the process, it's role in disease and neurodegeneration (perhaps degeneration in general?) and stressor-induced cellular damage?

 

Just what is this process the drug alters?

What's actually happening inside of the bodies of these rats, when this process is altered?

 

What happens to this process when the cells of a living animal are damaged?

 

Etc... so many questions here... this drug is far beyond the normal range of this board, as well as my own limited knowledge of the brain.

Let me try to answer Mind_paralysis. 

The story of ISRIB begins with the discovery that in neurodegenrative diseases a biochemical pathway called Integrated Stress Response (ISR) is activated. Another stress response pathway is called Unfolded Protein Response (UPR) is also activated. Stress response pathways are activated when the cells are stressed during lack of nutrition or other stress factors like free radicals, endoplasmic reticulum stress, heavy metals etc. In these stressful situations, cells try to conserve nutrients by partially turning off protein synthesis. Also, when cells are stressed, - particularly when there is lack of nutrients, amino acids in particular or when the endoplasmic reticulum is stressed (ER stress) -- proteins don't get folded properly, which is detrimental to cells including neurons. Again partially shutting down protein synthesis helps to use nutrients for synthesis and folding of essential proteins properly thus saving the cell. The stressed cell may also increase production of proteins that help to fold other proteins correctly (chaperons). When attempt by the UPR/ISR to correct the defect fails, the cells are targeted for suicide death (apoptosis). This is likely one of the mechanisms by which there is neuronal loss in neurodegenerative conditions or traumatic brain injury conditions, but I haven’t seen a direct study confirming this (unless I missed it).

 

In the second part of the story, several reports show that inhibition of protein translation by ISR/UPR prevents memory formation possibly by preventing new neural connections and synaptic connections. There are other reports which show that ongoing protein synthesis is necessary for memory formation (Lopez et al 2015 and others). Hence inhibiting ISR/UPR response may help brain to improve memory formation, especially at the hippocampal level. However, ISR/UPR has very important functions in the body, hence complete inhibition is not desirable and such compounds have shown pancreatic toxicity. ISRIB is one molecule that only partially inhibit ISR pathway, hence has so far not shown toxicity.

 

ISR/UPR works though a translation factor called eIF2. When ISR/UPR is activated, eIF2 gets phosphorylated Just to simplify the science, phosphorylation of eIF2 inhibits formation of another translation complex called eIF2B which is essential for translation initiation. ISRIB doesn’t prevent phosphorylation of eIF2, but helps in the formation of eIF2B complex thus overcoming the inhibition to translation caused by ISR.

 

ISRIB seems to be very potent and works in the nanomolar range, but the problem is that it is very poorly soluble in water. Prof. Rosi and others injected ISRIB into the abdominal cavity (intraperitoneal injection) so solubility was not an issue, however, she also suggested that the molecule is so potent that even the small amount that can dissolve in water and get in through oral ingestion may be sufficient to exert biological activity (seems to be a suggestion only).

 

Last year, Prof Giovanna Mallucci at Cambridge, UK, screened many neuroactive drugs and found that an FDA-approved drug called Trazodone can also inhibit ISR/UPR by interfering with the pathway. Trazodone is an anti-depressant from the 60’s discovered by Italian scientist having excellent safety profile although currently it is used mostly as a sleeping pill (a side effect of the drug). It is a multifunctional drug meaning that it interacts with many targets, but it is designed as serotonin reuptake inhibitor, which means that it increases the concentration of serotonin in the synaptic cleft by preventing re-uptake, thus producing anti-depressant effects. The inhibition of ISR/UPR pathway is another property of the drug that was unknown until now. Prof Mallucci was able to show that in prion-infected mice injection of trazodone (or another drug candidate called Dibenzoyl methane, a minor component of licorice) was able to prevent memory loss in these animals by inhibiting ISR/UPR pathway (it also reduces tau tangles by an unknown mechanism). While Prof Mallucci translated the dose given to these mice to a human dose of about 190 mg/day (within the accepted dose of trazodone), it is far from certain that this dose will work in humans in the absence of proper dosing studies. There is anecdotal evidence the trazodone reduces memory decline in Alzheimer’s patients, but these studies had very few patients, so it is not confirmatory.

 

[Painkillerrr]

MAYBE IMPORTANT:

 

i was westing my pointless time (no exam in the next weeks ) googling about myelin and the possibility of enhancing processing speed, i have therefore even looking at Multiple sclerosis treatment (it couse loss of white matter (myelin)), and [here](https://www.ncbi.nlm...les/PMC4674562/) i found this:

 

"A third small molecule screen identified two additional FDA-approved drugs that promote oligodendrocyte differentiation and enhance remyelination in in vivo models (118): miconazole, an antifungal agent, and clobetasol, a corticosteroid used to treat eczema and psoriasis. Both act directly on oligodendrocytes as remyelinating drugs and impact eIF2 signaling, thyroid hormone receptor/retinoic acid receptor (TX/RXR) activation, and cholesterol signaling. Interestingly, miconazole acts through MAPK signaling and has no effect on the immune system, whereas clobetasol acts through glucocorticoid receptor signaling and is also a potent immunosuppressant in addition to being a remyelinating agent. With their high safety profile already established, approval for phase 2 trials to establish efficacy in MS could occur quickly."

 

[here](https://www.ncbi.nlm...les/PMC4674562/) search for eIF2 (with "find in page"):

"Miconazole and clobetasol Activates eIF2, TX/RXR, and cholesterol signaling

Promoted oligodendrocyte differentiation and enhanced remyelination in in vivo models"

 

 

[here](https://www.biorxiv....222257.full.pdf)  how ISRIB SHOULD WORK:

 

"ISRIB, a drug like eIF2B activator, reverses the effects of eIF2 phosphorylation and, remarkably, in rodents enhances cognition and corrects cognitive deficits after brain injury.

 

miconazole and clobetasol are both very safe and fda approved so they might be a good alternative to ISRIB (as i said at least until a clinical trial don't prove isrib safety); and since they work kind a same way isrib could be safe as well (keep in mind miconazole and clobetasol works even on by other pathway)

 

 

BUT do they cross bbb?? yes:

 

[clobetasol](https://www.ncbi.nlm...les/PMC4845317/) since it ma nage to increase myelin in rat.

 

[miconazole](ncbi.nlm.nih.gov/pmc/articles/PMC5795799)

 

 

well i have just seen this similarity without reasoning or search to much about it, but i think i may have managed to prove the safety of eIF2 activator and find some alternatives to ISRIB.

 

PS: isrib is a eIF2B while its in the stuff i have linked its written they are eIF2 activator so they might activate just A but if you look at "miconazole eIF2b" on google you can find the they active eIF2B

 

EDIT:  sorry i thought longecity could link to urls like reddit does.

 

EDIT 2: looking more about clobetasol seems not so safe, but miconazole should be very safe.  seems that clobetasol is sold only as cream

Edited by Painkillerrr, 12 July 2018 - 02:48 PM.

[dodo40000]

Still anybody seriously  interested in a group buy?

I mean, common  we all know there is a risk and there are only those two studies with mice. However, there are people with TBIs, consussions, ones who have relatives with severe injuries and many other reasons which definately exceed the risks.

If you are worried too much about it  you will  have to wait another 10 years but there are people who do not have this time.

What i can see is there are a couple of people here who definately are willing to try it out so the next step should be:

 

to determine...

..who actually definatelly would participate

..where to get a Quality source as this kind of  substance obviously cant be purchased by private persons very easily

.. a way of connecting with each other to plan distribution and paying  methods 

 

and to  exchange experiences afterwards

 

So those who would participate please give me a feedback.

 

 

 

Edited by dodo40000, 14 July 2018 - 04:34 AM.

[Painkillerrr]

have you read what i wrote?? Miconazole works like isrib as activator of eIF2.

 

why dont you just try it? since it safe and fda approved??

 

at best you have the same effect you would have with isrib.

 

at worst you weste some buck (<50$) and you get nothing.

Still anybody seriously  interested in a group buy?

I mean, common  we all know there is a risk and there are only those two studies with mice. However, there are people with TBIs, consussions, ones who have relatives with severe injuries and many other reasons which definately exceed the risks.

If you are worried too much about it  you will  have to wait another 10 years but there are people who do not have this time.

What i can see is there are a couple of people here who definately are willing to try it out so the next step should be:

 

to determine...

..who actually definatelly would participate

..where to get a Quality source as this kind of  substance obviously cant be purchased by private persons very easily

.. a way of connecting with each other to plan distribution and paying  methods 

 

and to  exchange experiences afterwards

 

So those who would participate please give me a feedback.

 

[LocalConsignment]

Regarding,

 

to be determine...   I can offer some feedback here, but as to my experience in direct participation of a GROUP BUY -it will start with this one

..who actually definatelly would participate  - please count me as   YES, I WILL PARTICIPATE

..where to get a Quality source as this kind of  substance obviously cant be purchased by private persons very easily -Of the overseas options, I understand that ALIBABA is as reputable an operation as most other online purchasing sites (true?)  -is there feedback available for its reliability for this type of GROUP BUY? -what might be a better option? -is a direct buy from an overseas supplier an option to consider? -which ones?

.. a way of connecting with each other to plan distribution and paying  methods  -one method would be REPLY(S)  -a chain of them- within this topic to the designated GROUP BUY Lead (we have one of those, correct? )

 

FWIW

LocalConsignment

[George2]

I am very interested in trying ISRIB on my relative who had severe traumatic brain injury and his main and probably only deficit is memory. I even contacted 4 Chinese companies which are offering ISRIB. The price is generally in the range of $100/gm although one company offered $36/gm provided I buy 100 gms. The specs seemed fine although I would run all the analytical tests again before if I were to use it. At $36/gm it may be affordable to most.

However, the biggest question is 

A. DOSE - what is the dose to use in humans? 

B. How much of it is absorbed (most of the animal studies used IP injections)

C. The most important of all is solubility. We all know that it is very poor in water. It is soluble in DMSO, but I doubt if it is a good idea. 

So you see, I am grappling with these three key issues before using it on my relative given that we know nothing about human toxicity although it did not seem toxic in mice, but long-term toxicity was not studied. 

I had written to Prof Susaanna Rosi to see if she would throw some light on the above questions, but didn't receive a reply. 

IF ANYONE HAS ANSWERS TO THE ABOVE QUESTIONS, I WOULD BE VERY INTERESTED IN PARTICIPATING IN THE GROUP BUY WITH MORE CONFIDENCE. 

[George2]

ISRIB is turning out to be an important molecule which a well-defined biochemical mode of action (formation of eIF2B complex). If you haven't seen this publication, this is yet another evidence of its role in neurodegnerative diseases. The publication is from Calico, the company which has licensed the molecule. Calido is owned by ABC, which is the parent company of Google

 

https://elifescience.../articles/32733

DOES ANYONE HERE HAVE ANY CLUE AS TO (A) HOW TO DISSOLVE ISRIB (other than DMSO) (B) WHAT IS THE DOSAGE YOU NEED FOR HUMANS. I did not get an answer from Prof Rosi. So anyone here has an insight, it would be most helpful in deciding to join the Group Buy

[dodo40000]

Regarding,

 

to be determine...   I can offer some feedback here, but as to my experience in direct participation of a GROUP BUY -it will start with this one

..who actually definatelly would participate  - please count me as   YES, I WILL PARTICIPATE

..where to get a Quality source as this kind of  substance obviously cant be purchased by private persons very easily -Of the overseas options, I understand that ALIBABA is as reputable an operation as most other online purchasing sites (true?)  -is there feedback available for its reliability for this type of GROUP BUY? -what might be a better option? -is a direct buy from an overseas supplier an option to consider? -which ones?

 

 

 

Ok so which source has it been in the previous group buy? As far as i know they had been scammed before? 

I have asked a lot of companies and they usually do not sell for private use. The only comp. which was willing to sell was the one below with a Price of 220 USD per gr. But of course it is not clear wether it is a reputable source.

 

 

 

Rubin bari
Wuhan Nutra Biotechnology Co.

 

 

Best regards.

[George2]

Ok so which source has it been in the previous group buy? As far as i know they had been scammed before? 

I have asked a lot of companies and they usually do not sell for private use. The only comp. which was willing to sell was the one below with a Price of 220 USD per gr. But of course it is not clear wether it is a reputable source.

 

 

 

Rubin bari
Wuhan Nutra Biotechnology Co.

 

 

Best regards.

There are at least 4 Chinese companies that sell ISRIB at reasonable prices. One has given the NMR data sheet which looks OK (I will do it again though before buying it)

1. Jinan ENoch Imports and Exports $100/gm

2. Wuhan Hengheda Pharm Co., Ltd $3600/100 g or 41300/10 g

3. Wuhan Nutra Biotechnology Co., Ltd 1 gm - $250 + $50 shipping. 

#2 and 3 are manufacturers 

I haven't decided if I should buy it (I have the ability to test purity and composition) but am worried about the solubility. Dr Rosi had to dissolve it in DMSO/Ethanol and then warm it to dissolve it before injecting it IP into mice. It may not dissolve in the gut fluids and will be excreted I am afraid. I have no answers to this question from anyone. If I have an answer to this, I may consider buying the compound either from Group buy or from Chinese 

[Painkillerrr]

Im in for  100$

 

Edited by Painkillerrr, 31 July 2018 - 03:44 PM.

[dodo40000]

There are at least 4 Chinese companies that sell ISRIB at reasonable prices. One has given the NMR data sheet which looks OK (I will do it again though before buying it)

1. Jinan ENoch Imports and Exports $100/gm

2. Wuhan Hengheda Pharm Co., Ltd $3600/100 g or 41300/10 g

3. Wuhan Nutra Biotechnology Co., Ltd 1 gm - $250 + $50 shipping. 

#2 and 3 are manufacturers 

I haven't decided if I should buy it (I have the ability to test purity and composition) but am worried about the solubility. Dr Rosi had to dissolve it in DMSO/Ethanol and then warm it to dissolve it before injecting it IP into mice. It may not dissolve in the gut fluids and will be excreted I am afraid. I have no answers to this question from anyone. If I have an answer to this, I may consider buying the compound either from Group buy or from Chinese 

 

Hi George,

 

Two questions:

1.what do you mean by either Group Buy or from Chinese? 

2. Is there any contact to the guys from the first group buy? That'll help a lot.

3. Do you know wether these companies sell to private persons?

 

 

 

Greetings

[George2]

Hi George,

 

Two questions:

1.what do you mean by either Group Buy or from Chinese? 

2. Is there any contact to the guys from the first group buy? That'll help a lot.

3. Do you know wether these companies sell to private persons?

 

 

 

Greetings

Hello Dodo40000

1. What I meant is one can buy directly from the Chinese manufacturer (but for safety you need to run independent analysis on quality even if they will provide test certificates). Alternatively, one can join the "group buy" that is being discussed here.

2. No contact with the first guys. I wrote to the person who promoted the group buy (through this site), but there was no reply). Yes, it would have been nice to know the response as well as the dose and how they dissolved it. There was a talk in the first group buy thread about dissolving in DMSO, but I don't think it is a good way 

3. Yes, these companies sell to private people as research chemicals. 

I know that people at Calico are trying to work on a variant (pro-drug) of ISRIB that is more soluble. But they are very tight-lipped about it. They know that ISRIB, while not toxic in animals, has a serious solubility problem. It soluble only in sub-therapeutic dose in water. So the pill will probably not be absorbed in the gut in sufficient quantities. 

For the animal studies, they used 2.5 mg/kg body weight in mice. This translates to approximately 12.5 mg in humans using the surface area conversion tables typically used for converting mouse dose to humans (humans need only much smaller dose than mice due to the lower surface area/body mass ratio - am not sure how they derived it, but is widely used for calculating Phase I clinical study dosage). 12.5 mg will not dissolve in the gut. I could not find data on the solubility of ISRIB in water. Every one lists it as insoluble or sparingly soluble, which means  that most of a12.5 mg will not dissolve in the gut and be passed out with the feces. 

I hope my assumptions are correct. 

I was thinking of mixing it with phospholipids to see if I can form some sort of emulsion (like a liposome) by sonicating the mixture. But I am not sure I want to do too much experimentation on a molecule which has been shown to work only in mice. 

[FunSponge]

Is this group buy still happening?, I need to get in on this, anyone feel free to PM me or reply to this message, thank you.

[motorcitykid]

ISRIB back in the news:

 

https://www.ucsf.edu...ine-within-days

[moomoo]

Is this group buy still happening?, I need to get in on this, anyone feel free to PM me or reply to this message, thank you.

Well hello there.

[REBUILDER]

Bumping this. Anyone down for a group buy? Administration instructions from Reddit:

 

https://old.reddit.c...tration_theory/

 

Trans-ISRIB
Water soluble 0.02mg/ml
DMSO soluble 1mg/ml

How it was used in animal models:

Mice were usually given 2.5mg/kg which would be equivalent to 0.28mg/kg in Humans.However solbulity is pretty poor. 5mg dissolves in 1ml DMSO. However I assume 100% DMSO is pretty toxic.. thats why the Studies ended up with a stock solution of 0.1mg/ml. Which is kind of impossible to inject in a human. I saw one study pointing out that solubility was one of the main problems why this cant be developed into a "human" medication.
I assume this substance can not be absorbed any other way.

ISRIB solution was made by dissolving 5 mg ISRIB in 1 mL dimethyl sulfoxide (DMSO) (PanReac AppliChem, 191954.1611). The solution was gently heated in a 40 °C waterbath and vortexed every 30 s until the solution became clear. Next 1 mL of Tween 80 (Sigma Aldrich, P8074) was added, solution was gently heated in a 40 °C waterbath and vortexed every 30 s until the solution became clear. Next, 10 ml of polyethylene glycol 400 (PEG400) (PanReac AppliChem, 142436.1611), solution was added gently heated in a 40 °C waterbath and vortexed every 30 s until the solution became clear. Finally, 36.5 ml of 5% dextrose (Hospira, RL‐3040) was added. The solution was kept at room temperature throughout the experiment. Each solution was used for injections up to 7 d maximum. The vehicle solution consisted of the same chemical composition and concentration (DMSO, Tween 80, PEG400 and 5% dextrose). Stock ISRIB solution was at 0.1 mg/ml

Anecdotes from Reddit Users:

Start with 5 mg diluted with 3-5ml of DMSO. You MUST use DMSO or else it will not absorb in your body.
Put your ISRIB and DMSO mixture (in something like a shot glass) surrounded by a larger container of boiling hot water to heat it (help it mix faster). Try to ensure that the solution is as transparent as possible.
Then use the needle to puncture two holes (to stop it from exploding) into a fish oil capsule. Squeeze the oil out. Now draw up your ISRIB+DMSO and inject it into the capsule. Swallow, repeat.