JPC16 you do have access to the right equipment now don't you? I just hope you didn't overdose and have become braindead.
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Does PKR inhibitor C16 could give photographic memory safely? Let's find out!
Started by
Googoltarian
, May 30 2013 01:41 PM
c16 photographic memory pkr safe inhibitor ultimate nootropic
238 replies to this topic
#216
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Posted 29 January 2014 - 03:43 PM
I can reassure you, I am fine. But I still haven't trialled it yet. My finals are finally done and right now have I have a bit more time. So I have been researching the PKR pathway and how C16 interacts with it, which allowed me to identify what I think are three nootropic mechanisms through which C16 works (more about this later). I am also starting to prepare the setup of the trial itself. But the good news is that I can give you guys a pretty definitive date about when the trial is about to happen. In about two weeks my second semester will start, which means I will have a little less time, but I also can finally access the equipment I need to prepare a couple of dosages. As I already have said before, I will also store a couple of dosages at room temperature for a reasonable amount of time (probably for two weeks). But actually after the research I have done about C16 I am starting to be fairly confident that C16 can be stored at room temperature for long periods of time (for example I thought that there was a patent that described C16 being synthesised in a boiling solvent at around 80°C). I am finding it more and more plausible that C16 stored dry has a pretty long shelf life (but I predict that diluted, in DMSO for instance, will reduce the shelf life quite substantially).So this makes sending out (dry) samples in the future plausible.
But anyway at this point I can say that the trial will happen before the end of February. So approximately one month from now.
I said I have been researching a bit and I think I found a natural (weak) PKR inhibitor that adds a little weight to the theory about LTM enhancement through PKR inhibition but also to one of the nootropic mechanisms through which C16 actually works. In this case I am talking about NR2B upregulation by CDK5 inhibition which has been proven in vitro: http://www.ncbi.nlm....les/PMC3320856/
The weak (weak because there is only autophosphorylation inhibition) inhibitor I am talking about is palmitic acid (palmitate). I know this has already been discussed on Longecity here before but I think it has never been linked to PKR inhibition before.
Here are some sources:
http://www.ncbi.nlm....pubmed/21192654
http://docsdrive.com...7/2653-2658.pdf
http://198.170.104.1...7/3650-3655.pdf
http://scialert.net/....2007.2653.2658
http://www.jhunewsle...t-memory-45255/
I know the nootropic mechanism that is originally theorized about palmitic acid is NOT inhibition of PKR autophosphorylation by palmitoylation near the ATP binding site of PKR (http://www.ncbi.nlm....pubmed/21192654). But it actually is (the bottom 4 links) that they regulate the expression of the NR2B subunit of the NMDA receptor by palmitoylation. I am not denying this mechanism, but when you know that C16 can upregulate NR2B expression (http://www.ncbi.nlm....les/PMC3320856/) by inhibition of CDK5 (a kinase related in structure to PKR, and is probably inhibited in the same way by C16 through occupation of the ATP binding sites) and when you know that palmitic acid can also inhibit other kinases besides PKR (http://www.ncbi.nlm....pubmed/21192654). Then you can conclude that C16 and palmitic acid may work a bit in the same way.
My explanation is a bit difficult but my point is that palmitic acid 'indirectly proves' an extra nootropic mechanism of C16 which is blocking another kinase (CDK5) which leads to NR2B upregulation. So C16 and palmitic acid work a bit in the same way by blocking ATP binding sites of kinases (PKR and cdk5).
I know this hypothesis is a long shot and depends on the assumption that palmitate and palmitic acid operate in the same way & that C16 can also inhibit CDK5 in vivo and not just in vitro.
Besides this there are according to me two other nootropic mechanisms through which C16 works:
- the 'normal' L-LTP threshold reduction through dephosphorylation of eif2a. This is actually what ISRIB does, although it doesn't seem to affect eif2a phosphorylation but rather seems to block eif2a phosphorylation further downstream through PERK signaling inhibition. (http://elife.elifesc...ontent/2/e00498).
gamma interferon release (phosphorylation of eIF2alpha creates a negative feedback loop and the production of IFN-gamma is progressively attenuated: http://www.ncbi.nlm....pubmed/16474427 & http://www.ncbi.nlm....pubmed/11832212). Knowing that gamma interferon increases excitability of neurons in the CA1 region in the hippocampus by GABAergic inhibition.
I suspect that the latter mechanism is also present in the ISRIB study. Although ISRIB does not affect eif2a phosphorylation, it does affect it further downstream somehow (maybe by increased activity of eif2b which is a good strategy knowing that reduced eif2b activity could result in VWMD: http://www.ncbi.nlm....pubmed/16807905)
This also would make sense since there doesn't seem to be a difference in effectivity between ISRIB and C16. According to me they both are equally as effective which can be seen when one compares the results of the studies.
Therefore I think that the nootropic mechanism of increased gamma interferon seems to be tied together with translation mediation through eif2 signaling. If they weren't, than the enhanced LTM wouldn't have been abolished completely by the gamma interferon antibody (NAb-IFN-g) in mice in the C16 study.
I know I have been rambling on for a while now but I will try (if I am not too busy) to put together a bigger, more constructive, cohesive and clear analysis in the future so I can receive some valuable input/critique from you guys. It also has been a long time since I researched this stuff and I made this analysis in one quick go, so I could be making some huge mistakes. After all, this stuff isn't easy. I will also try to further investigate the possible harmfull negative effects as a result of PKR suppression or more importantly the molecule C16 itself. I am for instance thinking about combining C16 (or ISRIB in the future) with resveratrol (and other antioxidants such as vitamine c and e) to reduce the negative impact of endoplasmic reticulum (ER) stress. Resveratrol in particular seems interesting since SIRT1 and eif2a seem to be associated with each other: http://www.nature.co.../srep00150.html &
http://d-scholarship.pitt.edu/6582/
Loss of SIRT1 results in increased phosphorylation of eIF2alpha, so maybe more activated SIRT1 could attenuate ER stress as a result of the reduced eIF2alpha phosphorylation
(http://www.ncbi.nlm....pubmed/21321189).
#221
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Posted 27 February 2014 - 09:49 PM
Eidetic memory/Photographic memory
Eidetic memory in a form that is absolute is a total falsehood. Eidetic memory is never absolute, but there is a scale of ability to recall, that varies as well as to the nature of what is being recalled and the 'perceived recall basis', which usually within this context is perceived to a high degree as via a 'photographic-imagery related basis'. As such, there is no 'true Eidetic memory/Photographic memory', but the appearance or perception of such. In essence, it should be viewed as a scale of recall ability within this memory-recall paradigm. 'Eidetic memory scale' is just a level of the degree of an enhanced form of recall, comprising a heightened ability toward recall that generally has some component of 'photographic-imagery related basis' or perhaps better 'perceived photographic-imagery related basis' within the mode of recall. It should be viewed and measured by degree.
Before I suffered some neurological trauma I had an extremely high degree of Eidetic memory/Photographic memory that included the associated high degree of 'photographic-imagery related basis'. I as well perceive that my neurological cognitive patterning may have expanded/shifted in some manner that increased other cognitive capacities at the expense of this aspect of memory, as well as that of my mmory/recall ability as a whole (most significantly, as within a further heightened degree of high Creative Intelligence degree [CID/CIQ, perhaps the most difficult 'Intelligence Factor' to distinctly measure] with a diminished Memory Intelligence degree [MID/MIQ]).
...Hopefully all for the best
There are as well of course many forms of enhanced memory/recall other than that of the Eidetic memory/Photographic memory paradigm.
Such is fairly well elaborated upon here:
http://en.wikipedia....eptional_memory
Eidetic memory in a form that is absolute is a total falsehood. Eidetic memory is never absolute, but there is a scale of ability to recall, that varies as well as to the nature of what is being recalled and the 'perceived recall basis', which usually within this context is perceived to a high degree as via a 'photographic-imagery related basis'. As such, there is no 'true Eidetic memory/Photographic memory', but the appearance or perception of such. In essence, it should be viewed as a scale of recall ability within this memory-recall paradigm. 'Eidetic memory scale' is just a level of the degree of an enhanced form of recall, comprising a heightened ability toward recall that generally has some component of 'photographic-imagery related basis' or perhaps better 'perceived photographic-imagery related basis' within the mode of recall. It should be viewed and measured by degree.
Before I suffered some neurological trauma I had an extremely high degree of Eidetic memory/Photographic memory that included the associated high degree of 'photographic-imagery related basis'. I as well perceive that my neurological cognitive patterning may have expanded/shifted in some manner that increased other cognitive capacities at the expense of this aspect of memory, as well as that of my mmory/recall ability as a whole (most significantly, as within a further heightened degree of high Creative Intelligence degree [CID/CIQ, perhaps the most difficult 'Intelligence Factor' to distinctly measure] with a diminished Memory Intelligence degree [MID/MIQ]).
...Hopefully all for the best
There are as well of course many forms of enhanced memory/recall other than that of the Eidetic memory/Photographic memory paradigm.
Such is fairly well elaborated upon here:
http://en.wikipedia....eptional_memory
Edited by VERITAS INCORRUPTUS, 27 February 2014 - 09:55 PM.
#224
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Posted 06 March 2014 - 11:27 PM
So this makes sending out (dry) samples in the future plausible.
But anyway at this point I can say that the trial will happen before the end of February. So approximately one month from now.
I said I have been researching a bit and I think I found a natural (weak) PKR inhibitor that adds a little weight to the theory about LTM enhancement through PKR inhibition but also to one of the nootropic mechanisms through which C16 actually works. In this case I am talking about NR2B upregulation by CDK5 inhibition which has been proven in vitro: http://www.ncbi.nlm....les/PMC3320856/
The weak (weak because there is only autophosphorylation inhibition) inhibitor I am talking about is palmitic acid (palmitate). I know this has already been discussed on Longecity here before but I think it has never been linked to PKR inhibition before.
Here are some sources:
http://www.ncbi.nlm....pubmed/21192654
http://docsdrive.com...7/2653-2658.pdf
http://198.170.104.1...7/3650-3655.pdf
http://scialert.net/....2007.2653.2658
http://www.jhunewsle...t-memory-45255/
I know the nootropic mechanism that is originally theorized about palmitic acid is NOT inhibition of PKR autophosphorylation by palmitoylation near the ATP binding site of PKR (http://www.ncbi.nlm....pubmed/21192654). But it actually is (the bottom 4 links) that they regulate the expression of the NR2B subunit of the NMDA receptor by palmitoylation. I am not denying this mechanism, but when you know that C16 can upregulate NR2B expression (http://www.ncbi.nlm....les/PMC3320856/) by inhibition of CDK5 (a kinase related in structure to PKR, and is probably inhibited in the same way by C16 through occupation of the ATP binding sites) and when you know that palmitic acid can also inhibit other kinases besides PKR (http://www.ncbi.nlm....pubmed/21192654). Then you can conclude that C16 and palmitic acid may work a bit in the same way.
My explanation is a bit difficult but my point is that palmitic acid 'indirectly proves' an extra nootropic mechanism of C16 which is blocking another kinase (CDK5) which leads to NR2B upregulation. So C16 and palmitic acid work a bit in the same way by blocking ATP binding sites of kinases (PKR and cdk5).
I know this hypothesis is a long shot and depends on the assumption that palmitate and palmitic acid operate in the same way & that C16 can also inhibit CDK5 in vivo and not just in vitro.
Besides this there are according to me two other nootropic mechanisms through which C16 works:Some info: http://jeb.biologist...209/3/vii.short
- the 'normal' L-LTP threshold reduction through dephosphorylation of eif2a. This is actually what ISRIB does, although it doesn't seem to affect eif2a phosphorylation but rather seems to block eif2a phosphorylation further downstream through PERK signaling inhibition. (http://elife.elifesc...ontent/2/e00498).
Some info: http://www.readcube....10.1038/nrn3177
- gamma interferon release (phosphorylation of eIF2alpha creates a negative feedback loop and the production of IFN-gamma is progressively attenuated: http://www.ncbi.nlm....pubmed/16474427 & http://www.ncbi.nlm....pubmed/11832212). Knowing that gamma interferon increases excitability of neurons in the CA1 region in the hippocampus by GABAergic inhibition.
I suspect that the latter mechanism is also present in the ISRIB study. Although ISRIB does not affect eif2a phosphorylation, it does affect it further downstream somehow (maybe by increased activity of eif2b which is a good strategy knowing that reduced eif2b activity could result in VWMD: http://www.ncbi.nlm....pubmed/16807905)
This also would make sense since there doesn't seem to be a difference in effectivity between ISRIB and C16. According to me they both are equally as effective which can be seen when one compares the results of the studies.
Therefore I think that the nootropic mechanism of increased gamma interferon seems to be tied together with translation mediation through eif2 signaling. If they weren't, than the enhanced LTM wouldn't have been abolished completely by the gamma interferon antibody (NAb-IFN-g) in mice in the C16 study.
I know I have been rambling on for a while now but I will try (if I am not too busy) to put together a bigger, more constructive, cohesive and clear analysis in the future so I can receive some valuable input/critique from you guys. It also has been a long time since I researched this stuff and I made this analysis in one quick go, so I could be making some huge mistakes. After all, this stuff isn't easy. I will also try to further investigate the possible harmfull negative effects as a result of PKR suppression or more importantly the molecule C16 itself. I am for instance thinking about combining C16 (or ISRIB in the future) with resveratrol (and other antioxidants such as vitamine c and e) to reduce the negative impact of endoplasmic reticulum (ER) stress. Resveratrol in particular seems interesting since SIRT1 and eif2a seem to be associated with each other: http://www.nature.co.../srep00150.html &
http://d-scholarship.pitt.edu/6582/
Loss of SIRT1 results in increased phosphorylation of eIF2alpha, so maybe more activated SIRT1 could attenuate ER stress as a result of the reduced eIF2alpha phosphorylation
(http://www.ncbi.nlm....pubmed/21321189).
Any updates man?
#227
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Posted 19 March 2014 - 12:30 PM
Maybe I missed something as I did not read the entire thread, but the speculation on the LD50 of this compound early in the thread should point to some conclusions that I believe can be derived to be considered factually evident if the given figures are correct.
The LD50 i.p. RAT was determined at 335ug/kg (LD50 determination in study cited)
The LD50 p.o. RAT was determined at 908mg/kg (cited Clewarsynth MSDS Tox data)
This would lend one to extrapolate an estimated oral bioavailability, of a highly negligible nature, of <0.01%
I am not sure where JPC26 derived his original assertions that 'injection' used for dosing within the animal study he is 'referencing' was an 'oral injection' (or equialent to such) as so noted within his original dose basis evaluation and methodology of oral dosing of an encapsulated 240ug DMSO solution. It is also not clearly stated (at least on that first page) as to just what he referenced to calculate his hypothesis for a viable starting dose to assay. -- ??????????????????????
Again, maybe I am missing something; though one thing that is clearly missing is responsible feedback in any remotely timely manner from JPC26.
It is quite true when someone dies of unknown causes there is the potential for a formal or informal forensic investigation into the cause. Thus was elucidated upon within this page by a Moderator wherein it was noted relatives of the deceased (or forensics) may 'investigate' websites/forums frequented by the deceased, sometimes using the account of the deceased. However, since he was taking the agent orally it would seem impossible to consume a lethal dose if the Clearsynth LD50 is accurate.
Sorry again if i simply missed something, but the speculation on the lethality of the substrate and the disappearance and/or lack of any viable feedback from JPC26 warranted my wanting to share some thoughts. I am not sure what may be the cause, but if he has visited the board (which I hope it was him and he is fine) it is a gross lack of responsibility to provide feedback in any remotely timely manner in that he volunteered to be afforded a free sample with the intention to commit to providing feedback in a responsible manner.
The LD50 i.p. RAT was determined at 335ug/kg (LD50 determination in study cited)
The LD50 p.o. RAT was determined at 908mg/kg (cited Clewarsynth MSDS Tox data)
This would lend one to extrapolate an estimated oral bioavailability, of a highly negligible nature, of <0.01%
I am not sure where JPC26 derived his original assertions that 'injection' used for dosing within the animal study he is 'referencing' was an 'oral injection' (or equialent to such) as so noted within his original dose basis evaluation and methodology of oral dosing of an encapsulated 240ug DMSO solution. It is also not clearly stated (at least on that first page) as to just what he referenced to calculate his hypothesis for a viable starting dose to assay. -- ??????????????????????
Again, maybe I am missing something; though one thing that is clearly missing is responsible feedback in any remotely timely manner from JPC26.
It is quite true when someone dies of unknown causes there is the potential for a formal or informal forensic investigation into the cause. Thus was elucidated upon within this page by a Moderator wherein it was noted relatives of the deceased (or forensics) may 'investigate' websites/forums frequented by the deceased, sometimes using the account of the deceased. However, since he was taking the agent orally it would seem impossible to consume a lethal dose if the Clearsynth LD50 is accurate.
Sorry again if i simply missed something, but the speculation on the lethality of the substrate and the disappearance and/or lack of any viable feedback from JPC26 warranted my wanting to share some thoughts. I am not sure what may be the cause, but if he has visited the board (which I hope it was him and he is fine) it is a gross lack of responsibility to provide feedback in any remotely timely manner in that he volunteered to be afforded a free sample with the intention to commit to providing feedback in a responsible manner.
Edited by VERITAS INCORRUPTUS, 19 March 2014 - 12:52 PM.
#228
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Posted 19 March 2014 - 10:40 PM
Ok guys, I know it has been a while and I am very sorry for that but I have been really, really, really busy.
Anyhow I finally have some good news. I arranged that I can measure a couple of dosages of C16 next week! I also have at least one day (that is what I think at this point in time) in that week during which I have enough time to test the drug. So the trial will happen about one month later than I originally promised, which is not that bad even if I said it myself. The trial itself is still not “official”, but it will happen. I have been working on this for too long for me to bail out now.
Secondly thanks to Veritas Incorruptus I have come to the conclusion that I have been stupid.
The problem is that dosages for intraperitoneal injections are not transferable to oral dosages, what I originally thought.
I think that the difference (between intraperitoneal and oral dosages) "usually" isn't that much. I know that this is the case for caffeine and methylphenidate for example (i.p. is twice as effective I think). But the difference for C16 seems to be a lot larger (if we can trust the data from clearsynth which I think we can). So this means that C16 only survives the stomach by a small percentage when taken orally in contrary to i.p. where most of the substance is absorbed through the veins.
So the conclusion of this all is, that the method of administration has to be changed (and not the dosage to be clear). For me, this leaves me with only a couple of options: insufflation or sublingual administration. I am not skilled in intravenous (or intramuscular) injections and this will probably make the lethal dose even lower than it already is which isn't really a good thing.
C16 by the way also has to be dissolved so it will be better to rule out insufflation. Meaning that sublingual administration is the preferred method of administration. I will also dissolve the C16 in water instead of DMSO, because I am pretty sure that I won't be able to hold a small amount of DMSO in my mouth for half an hour.
The solubility of C16 in water is actually pretty OK based on these predicted data: http://www.chemspide...re.4990932.html
I know the data is a prediction but since the dosage will stay the same, extremely low, I am pretty sure that the small amount of water I use will be enough to completely dissolve the compound.
All in all, I think that sublingual administration should work. C16 also should have a good bioavailability since it doesn't violate any of Lipinski's 5 rules. Irritation should be minimal as well since Draized rabbit eye test was moderate (with much higher dosages).
This is also VERY IMPORTANT INFORMATION FOR PEOPLE WHO ALREADY OBTAINED ISRIB AND FOR FUTURE ISRIB TRIALS. People who already tried ISRIB without any effect should probably up their dosage since ISRIB also was dosed intraperitoneal in animal studies. If the molecule itself also has difficulty “surviving” the acidic content of the stomach then you might have been underdosing.
Or you could try to insufflate it, if the ISRIB can dissolve itself in the mucus (which is mostly water) excreted from the mucous membrane. But I don't think that is possible since ISRIB is virtually impossible to dissolve in anything else except DMSO. This also makes sublingual administration of ISRIB unpractical. But if you do want to try this method of administration I advise that you heat up the DMSO a bit so you will have to use less of it.
Using “ISRIB-DMSO-nose drips/spray” probably won't work either because the amount of DMSO needed still will be too large.
I also don't know if smoking will work either. The flash and boiling point of ISRIB and C16 can be found on chemspider. Maybe vaporizing would work? Or maybe buccal administration? The thing is, I don't know right now. I hardly have the time to respond right know. I will try to figure out more about this stuff, this coming weekend ok.
So I think that the only thing you can do for now if you already tried ISRIB without any effect is increasing the dose. And since there is no lethal dose known for ISRIB, you should be very cautious in doing so (meaning small increments).
Anyhow I finally have some good news. I arranged that I can measure a couple of dosages of C16 next week! I also have at least one day (that is what I think at this point in time) in that week during which I have enough time to test the drug. So the trial will happen about one month later than I originally promised, which is not that bad even if I said it myself. The trial itself is still not “official”, but it will happen. I have been working on this for too long for me to bail out now.
Secondly thanks to Veritas Incorruptus I have come to the conclusion that I have been stupid.
The problem is that dosages for intraperitoneal injections are not transferable to oral dosages, what I originally thought.
I think that the difference (between intraperitoneal and oral dosages) "usually" isn't that much. I know that this is the case for caffeine and methylphenidate for example (i.p. is twice as effective I think). But the difference for C16 seems to be a lot larger (if we can trust the data from clearsynth which I think we can). So this means that C16 only survives the stomach by a small percentage when taken orally in contrary to i.p. where most of the substance is absorbed through the veins.
So the conclusion of this all is, that the method of administration has to be changed (and not the dosage to be clear). For me, this leaves me with only a couple of options: insufflation or sublingual administration. I am not skilled in intravenous (or intramuscular) injections and this will probably make the lethal dose even lower than it already is which isn't really a good thing.
C16 by the way also has to be dissolved so it will be better to rule out insufflation. Meaning that sublingual administration is the preferred method of administration. I will also dissolve the C16 in water instead of DMSO, because I am pretty sure that I won't be able to hold a small amount of DMSO in my mouth for half an hour.
The solubility of C16 in water is actually pretty OK based on these predicted data: http://www.chemspide...re.4990932.html
I know the data is a prediction but since the dosage will stay the same, extremely low, I am pretty sure that the small amount of water I use will be enough to completely dissolve the compound.
All in all, I think that sublingual administration should work. C16 also should have a good bioavailability since it doesn't violate any of Lipinski's 5 rules. Irritation should be minimal as well since Draized rabbit eye test was moderate (with much higher dosages).
This is also VERY IMPORTANT INFORMATION FOR PEOPLE WHO ALREADY OBTAINED ISRIB AND FOR FUTURE ISRIB TRIALS. People who already tried ISRIB without any effect should probably up their dosage since ISRIB also was dosed intraperitoneal in animal studies. If the molecule itself also has difficulty “surviving” the acidic content of the stomach then you might have been underdosing.
Or you could try to insufflate it, if the ISRIB can dissolve itself in the mucus (which is mostly water) excreted from the mucous membrane. But I don't think that is possible since ISRIB is virtually impossible to dissolve in anything else except DMSO. This also makes sublingual administration of ISRIB unpractical. But if you do want to try this method of administration I advise that you heat up the DMSO a bit so you will have to use less of it.
Using “ISRIB-DMSO-nose drips/spray” probably won't work either because the amount of DMSO needed still will be too large.
I also don't know if smoking will work either. The flash and boiling point of ISRIB and C16 can be found on chemspider. Maybe vaporizing would work? Or maybe buccal administration? The thing is, I don't know right now. I hardly have the time to respond right know. I will try to figure out more about this stuff, this coming weekend ok.
So I think that the only thing you can do for now if you already tried ISRIB without any effect is increasing the dose. And since there is no lethal dose known for ISRIB, you should be very cautious in doing so (meaning small increments).
#230
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Posted 20 March 2014 - 02:44 PM
This refers to JPC26 post above - I will not directly quote herein such to not cloud the thread with such content:
SubL/Buccal and i.n. (insufllation/intranasal) administration have variance based on the substrate, the individual, and the use of solvent(s) or lack thereof.
Within this variance it is not generally a good measure to assay substrates, especially for research purposes.
Note, Salvinorin A, a substrate with no oral bioavailability of significance (which is the case here), has been within anecdotal reports to display varying degrees of activity with subL/buccal administration. However, a true research study to assess this derived there was no effect derived from subL usage.
Moreover, subL and i.n. are NOT...again NOT!!!! equivalent to i.p., even generally in the best cases (in some instances such may be near equal).
Cocaine, the most commonly insufflated substrate, indeed has rapid onset and solid potency, but it is not equivalent to actual i.p. potency (or as inhaled freebase
).
While there is no dispute that in most all cases i.n and subL are superior in potency and onset to oral, such is not always the case. Notably, they are rarely equivalent to i.p., which is generally very similar to i.v, just to note. Vaporizing indeed can be most potent with immediate onset and high potency, but not a good means I would believe to initially assay any substance for report of course.
ISRIB, as I have read in a limited amount of bioassay reports, has seemed to have some negative effects and not much of a positive nature. I may just have not read a broad enough cross-section of reports. If someone if kind enough to relay what they have arrived at a per assessing a broad spectrum of reports and has a better evaluation of the general consensus that they could relay, I am much appreciated (PM please). If there have been negative effects as a common theme, raising the dose or using a superior mode of administration may not be a good way to go. Again, I do not know directly from any broad consensus, but wanted to note such; within that, if such is the case, ISRIB might be a 'loser'.
Also of note, many of these substrates can likely be metered into a solution superior to DMSO by a good compounder, as DMSO is generally a fallback solvent when there is a lack of water solubility. Unfortunately, many substrates have very sparse solubility data to assess from.
SubL/Buccal and i.n. (insufllation/intranasal) administration have variance based on the substrate, the individual, and the use of solvent(s) or lack thereof.
Within this variance it is not generally a good measure to assay substrates, especially for research purposes.
Note, Salvinorin A, a substrate with no oral bioavailability of significance (which is the case here), has been within anecdotal reports to display varying degrees of activity with subL/buccal administration. However, a true research study to assess this derived there was no effect derived from subL usage.
Moreover, subL and i.n. are NOT...again NOT!!!! equivalent to i.p., even generally in the best cases (in some instances such may be near equal).
Cocaine, the most commonly insufflated substrate, indeed has rapid onset and solid potency, but it is not equivalent to actual i.p. potency (or as inhaled freebase
). While there is no dispute that in most all cases i.n and subL are superior in potency and onset to oral, such is not always the case. Notably, they are rarely equivalent to i.p., which is generally very similar to i.v, just to note. Vaporizing indeed can be most potent with immediate onset and high potency, but not a good means I would believe to initially assay any substance for report of course.
ISRIB, as I have read in a limited amount of bioassay reports, has seemed to have some negative effects and not much of a positive nature. I may just have not read a broad enough cross-section of reports. If someone if kind enough to relay what they have arrived at a per assessing a broad spectrum of reports and has a better evaluation of the general consensus that they could relay, I am much appreciated (PM please). If there have been negative effects as a common theme, raising the dose or using a superior mode of administration may not be a good way to go. Again, I do not know directly from any broad consensus, but wanted to note such; within that, if such is the case, ISRIB might be a 'loser'.
Also of note, many of these substrates can likely be metered into a solution superior to DMSO by a good compounder, as DMSO is generally a fallback solvent when there is a lack of water solubility. Unfortunately, many substrates have very sparse solubility data to assess from.
Edited by VERITAS INCORRUPTUS, 20 March 2014 - 02:48 PM.
#231
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Posted 20 March 2014 - 03:19 PM
Doing some quick research, delaying what I really need to get to (lol), I found this on ISRIB:
"Taken together with other studies, it is clear that signalling through eIF2α is finely balanced, and that the chronic loss or stimulation of a single pathway can have highly deleterious effects."
http://www.ncbi.nlm....les/PMC3667575/
I really do not feel this is a good pathway to manipulate, may have a very narrow dose response window (as relates to the dose response curve), and a poor therapeutic index.
$0.02 of caution as to my very quick evaluation. If anyone wants to investigate this further, and the neurotoxic potential I believe that is also a notable concern, please do. As well, perhaps someone may wish to engender posting such within ISRIB threads if they are so inclined to merit worth within this.
This substrates looks less and less attractive from some initial investigation, but again, this was a very cursory glance; a wish to give some insight that may be of relevance and to stimulate further insight for those who have time and interest.
"Taken together with other studies, it is clear that signalling through eIF2α is finely balanced, and that the chronic loss or stimulation of a single pathway can have highly deleterious effects."
http://www.ncbi.nlm....les/PMC3667575/
I really do not feel this is a good pathway to manipulate, may have a very narrow dose response window (as relates to the dose response curve), and a poor therapeutic index.
$0.02 of caution as to my very quick evaluation. If anyone wants to investigate this further, and the neurotoxic potential I believe that is also a notable concern, please do. As well, perhaps someone may wish to engender posting such within ISRIB threads if they are so inclined to merit worth within this.
This substrates looks less and less attractive from some initial investigation, but again, this was a very cursory glance; a wish to give some insight that may be of relevance and to stimulate further insight for those who have time and interest.
#232
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Posted 29 March 2014 - 10:58 PM
Ok guys, I know it has been a while and I am very sorry for that but I have been really, really, really busy.
Anyhow I finally have some good news. I arranged that I can measure a couple of dosages of C16 next week! I also have at least one day (that is what I think at this point in time) in that week during which I have enough time to test the drug. So the trial will happen about one month later than I originally promised, which is not that bad even if I said it myself. The trial itself is still not “official”, but it will happen. I have been working on this for too long for me to bail out now.
Secondly thanks to Veritas Incorruptus I have come to the conclusion that I have been stupid.
The problem is that dosages for intraperitoneal injections are not transferable to oral dosages, what I originally thought.
I think that the difference (between intraperitoneal and oral dosages) "usually" isn't that much. I know that this is the case for caffeine and methylphenidate for example (i.p. is twice as effective I think). But the difference for C16 seems to be a lot larger (if we can trust the data from clearsynth which I think we can). So this means that C16 only survives the stomach by a small percentage when taken orally in contrary to i.p. where most of the substance is absorbed through the veins.
So the conclusion of this all is, that the method of administration has to be changed (and not the dosage to be clear). For me, this leaves me with only a couple of options: insufflation or sublingual administration. I am not skilled in intravenous (or intramuscular) injections and this will probably make the lethal dose even lower than it already is which isn't really a good thing.
C16 by the way also has to be dissolved so it will be better to rule out insufflation. Meaning that sublingual administration is the preferred method of administration. I will also dissolve the C16 in water instead of DMSO, because I am pretty sure that I won't be able to hold a small amount of DMSO in my mouth for half an hour.
The solubility of C16 in water is actually pretty OK based on these predicted data: http://www.chemspide...re.4990932.html
I know the data is a prediction but since the dosage will stay the same, extremely low, I am pretty sure that the small amount of water I use will be enough to completely dissolve the compound.
All in all, I think that sublingual administration should work. C16 also should have a good bioavailability since it doesn't violate any of Lipinski's 5 rules. Irritation should be minimal as well since Draized rabbit eye test was moderate (with much higher dosages).
This is also VERY IMPORTANT INFORMATION FOR PEOPLE WHO ALREADY OBTAINED ISRIB AND FOR FUTURE ISRIB TRIALS. People who already tried ISRIB without any effect should probably up their dosage since ISRIB also was dosed intraperitoneal in animal studies. If the molecule itself also has difficulty “surviving” the acidic content of the stomach then you might have been underdosing.
Or you could try to insufflate it, if the ISRIB can dissolve itself in the mucus (which is mostly water) excreted from the mucous membrane. But I don't think that is possible since ISRIB is virtually impossible to dissolve in anything else except DMSO. This also makes sublingual administration of ISRIB unpractical. But if you do want to try this method of administration I advise that you heat up the DMSO a bit so you will have to use less of it.
Using “ISRIB-DMSO-nose drips/spray” probably won't work either because the amount of DMSO needed still will be too large.
I also don't know if smoking will work either. The flash and boiling point of ISRIB and C16 can be found on chemspider. Maybe vaporizing would work? Or maybe buccal administration? The thing is, I don't know right now. I hardly have the time to respond right know. I will try to figure out more about this stuff, this coming weekend ok.
So I think that the only thing you can do for now if you already tried ISRIB without any effect is increasing the dose. And since there is no lethal dose known for ISRIB, you should be very cautious in doing so (meaning small increments).
Updates?
#234
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Posted 05 April 2014 - 12:49 PM
And with subL perhaps he best should use DMSO or DMSO within glycerin/alcoholic base solution as water is a poor conductor for subL; as well as I am not sure if there is any documentation if it is water soluble to any degree (haven't looked, but I assume not if DMSO was first go to for making a solution). One advantage is the dose is very small, so that will promote a means of administration that should not be invasive. Only will require <0.1cc DMSO to dissolve the dose.
#235
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Posted 05 April 2014 - 03:47 PM
Sorry for the long wait (again). Being swamped with work (as always).
But I do have good news. Two dosages already have been measured (actually happend about one week ago already). One dose is being stored at minus 18° C. The other one is being kept at room temperature.
I will take the first dose sublingually with water. The solubility of the compound in water is actually pretty good. According to chemspider the solubility of the compound is around 1000 mg/L. And since I will take a small amount, I will need less than one ml of water.
I probably won't use DMSO straight away since I know it has a horrible taste (even in small amounts). And I will have to keep it under the tongue for about (at least) half an hour. So I want to use it as a very last option.
The reason why I still didn't trial it yet, is because I wan't a FULL day to report al it's effects. Also of course in case something goes wrong. I want a full free day because I am pretty sure that the half life of the compound is around 10 to 12 hours based on this study: http://www.ncbi.nlm....les/PMC1470336/
The half life of the compound is around 3 to 4 hours in rats. If you "extrapolate" that to humans, you get around 10 to 12 hours (I think). Sublingual administration is also pretty slow, so I probably should be “on standby” for about 14 hours. I hope it doesn't interfere with my sleep
Thank god the log P of C16 is relatively small, otherwise the half life could have been days.
The other good news is that I have “vacation” right know so the trial is right around the corner (not going to make predictions anymore).
But I do have good news. Two dosages already have been measured (actually happend about one week ago already). One dose is being stored at minus 18° C. The other one is being kept at room temperature.
I will take the first dose sublingually with water. The solubility of the compound in water is actually pretty good. According to chemspider the solubility of the compound is around 1000 mg/L. And since I will take a small amount, I will need less than one ml of water.
I probably won't use DMSO straight away since I know it has a horrible taste (even in small amounts). And I will have to keep it under the tongue for about (at least) half an hour. So I want to use it as a very last option.
The reason why I still didn't trial it yet, is because I wan't a FULL day to report al it's effects. Also of course in case something goes wrong. I want a full free day because I am pretty sure that the half life of the compound is around 10 to 12 hours based on this study: http://www.ncbi.nlm....les/PMC1470336/
The half life of the compound is around 3 to 4 hours in rats. If you "extrapolate" that to humans, you get around 10 to 12 hours (I think). Sublingual administration is also pretty slow, so I probably should be “on standby” for about 14 hours. I hope it doesn't interfere with my sleep
Thank god the log P of C16 is relatively small, otherwise the half life could have been days.
The other good news is that I have “vacation” right know so the trial is right around the corner (not going to make predictions anymore).
#236
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Posted 05 April 2014 - 04:46 PM
^^^
Sublingual penetration is about near as quick as i.v., for that which actually penetrates and is not lost to ingestion within saliva. Try to keep your mouth/sublingual cavity as dry as possible before allowing the solution to drip into your sublingual cavity. Adding a couple of ml EtoH or alcohol will allow for superior penetration, though with such a small dose required sublingual penetration should be very high if you follow the above.
You'd almost think you were experimenting with some undefined, uncharacterized potential true 'psychoactive', lol Enjoy your vacay and let us know ASAP
Sublingual penetration is about near as quick as i.v., for that which actually penetrates and is not lost to ingestion within saliva. Try to keep your mouth/sublingual cavity as dry as possible before allowing the solution to drip into your sublingual cavity. Adding a couple of ml EtoH or alcohol will allow for superior penetration, though with such a small dose required sublingual penetration should be very high if you follow the above.
You'd almost think you were experimenting with some undefined, uncharacterized potential true 'psychoactive', lol
Enjoy your vacay and let us know ASAP
#237
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Posted 13 April 2014 - 07:26 PM
I said I have been researching a bit and I think I found a natural (weak) PKR inhibitor that adds a little weight to the theory about LTM enhancement through PKR inhibition but also to one of the nootropic mechanisms through which C16 actually works. In this case I am talking about NR2B upregulation by CDK5 inhibition which has been proven in vitro: http://www.ncbi.nlm....les/PMC3320856/
The weak (weak because there is only autophosphorylation inhibition) inhibitor I am talking about is palmitic acid (palmitate). I know this has already been discussed on Longecity here before but I think it has never been linked to PKR inhibition before.
Thank you for the hint!
Doing a little bit of research i found out something regards the CA2+ , ROS, calpain effect on p35-->p25 and how p25 bound CDK5 downregulates NM2A and activates NFkB (while p35 bound cdk5 brings up neurogenesis)
And this brought me to find an easy, clever way to avoid overstudying headaches:
VIAGRA!
Conversion of p35 to p25 deregulates Cdk5 activity an... [Nature. 1999] - PubMed - NCBI
Inhibition of calpain-regulated p35/cdk... [Biochim Biophys Acta. 2013] - PubMed - NCBI
Sildenafil restores cognitive function withou... [Br J Pharmacol. 2011] - PubMed - NCBI
Modulation of p25 and inflammatory pathways by fi... [Aging Cell. 2014] - PubMed - NCBI
(waiting for my order of fisetin to come in).
My memory still sucks ( :D ) but i've been able to study for the past 3 days and maybe sleep...10 hours overall (is clear that i'm using other stuff in conjunction, methylene blue, aspirin, the CILTEP stack, some racetams, Vit Bs and an insane dose of antioxidants).
WORKS GREAT WITH RACETAMS headaches too 
Also tagged with one or more of these keywords: c16, photographic memory, pkr, safe, inhibitor, ultimate, nootropic
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