169 replies to this topic

[rwac]

Chemical drink breathes life into damaged hearts

• 22:00 09 February 2009 by Andy Coghlan

After drinking a chemical dissolved in water, mice with damaged hearts turn from couch potatoes into treadmill tearaways, researchers say. The finding raises hopes that the same substance can invigorate patients weakened from heart attacks by increasing the supply of oxygen to damaged cardiac muscle.

Designed to make haemoglobin release more of its oxygen than normal, the drug, myo-inositol trispyrophosphate (ITPP) boosted exercise levels in the ailing mice by 35% when given dissolved in water. When given by injection into the abdomen, exercise levels rose a massive 60%.

http://www.newscient...ged-hearts.html

Enhanced exercise capacity in mice with severe heart failure treated with an allosteric effector of hemoglobin, myo-inositol trispyrophosphate
<h1 id="article-title-1"></h1>
Abstract
A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5–3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 ± 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of Gαq, i.p. ITPP increased exercise capacity, with a maximal increase of 63 ± 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 ± 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1α mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.

http://www.pnas.org/...6/1926.abstract

Also, M&M has a thread on it as well.

http://www.mindandmu...showtopic=37088

[Infinite1]

Hoping to revive this old thread as I would think there could be a multitude of implications.

Here are a few excellent articles covering ITPP analogs, some of which increase allosteric binding of Oxygen by over 400%. From the looks of it (IHP) myo-inositol hexakisphosphate is the winner, since I personally despise Organic chemistry if anyone that enjoys that type of thing wants to have a look at these and give an opinion, that would be great!

Attached Files

•  Allosteric effectors.pdf   542.33KB   49 downloads
•  Effectors of hg.pdf   536.17KB   30 downloads

[kevinseven11]

Is this possible to obtain? Even for research purposes?

[Junk Master]

Myo-inositol-tripyrophosphate is already being used to "dope" horses and greyhounds. I would imagine it won't be long before it makes it's way to human athletes.

[Infinite1]

Yes some are available, though just for research. Besides the horse doping I have run across ITPP having been used as an alternative medicine for cancer treatment, it makes sense to me. I'm almost half tempted to give ITPP a try...I'd prolly wait for more research before venturing to the others.

For the other research compounds used in the research study:

All chemicals were purchased from Sigma, Aldrich, or Fluka and
were used without further purification. The resins Dowex 50WX8–
200 and Marathon C Na+ were purchased from Sigma–Aldrich and
washed with distilled H2O before the first use. 1H, 13C and 31P NMR
spectra were recorded on a Bruker AC-400 spectrometer. Mass
spectra were determined by the Service Commun de Spectrom-
trie de Masse at the Institut d’Ingnierie Supramolculaire. ITPP
(myo-inositol trispyrophosphate hexasodium salt) was manufactured
by Carbogen AMCIS (Switzerland) by following improved
synthetic procedures, derived from those previously described.[5, 7]
BPG (2,3-bisphospho-d-glyceric acid pentasodium salt) was purchased
from Sigma (USA), and IHP (myo-inositol hexakisphosphate)
was purchased from Sigma–Aldrich (Italy).

Here is an article covering the potential application of IHP being used for cancer treament: http://jn.nutrition....l/725S.full.pdf

Edited by Infinite1, 13 June 2012 - 08:43 PM.

[Junk Master]

Same stuff as this?

http://www.physician...ct=268&name=IP6

http://www.nutrabio....Mg#.T9kHZCtYvDM

If it were noticeably effective, I can't believe it wouldn't be more popular among the weekend warrior endurance athlete crowd.

[kevinseven11]

I am very interested now ha! What sort of dose should we expect to take? 500mg is used in body building supplements. Perhaps more is better!

[rwac]

This stuff is definitely not the same as IP6.

ITPP:
 I666020.png   15.55KB   25 downloads

IP6(aka inositol hexakisphosphate, phytic acid):
 200px-Phytic_acid.svg.png   4.51KB   18 downloads

Edited by rwac, 13 June 2012 - 11:32 PM.

[Infinite1]

This stuff is definitely not the same as IP6.

ITPP:
 I666020.png   15.55KB   25 downloads

IP6(aka inositol hexakisphosphate, phytic acid):
 200px-Phytic_acid.svg.png   4.51KB   18 downloads

Did you read either of the two articles? I would be interested to hear what your opinoin is of them. If IHP (IP6) is not a good compound then I would still be interested in hearing about the potential of ITPP. Also just noticed that in some literature it appears that Hexaphosphate is used interchangeably with HexaKIphosphate...umm

Edited by Infinite1, 14 June 2012 - 02:14 AM.

[Infinite1]

So I've run across a few potential sources for ITPP but I have yet to hear of it being used by anyone, just greyhounds and horses. Surely there are a few people out there that have tried this...

[violetechos]

What do you think the dosages are on this compound? I recently acquired some, and looking at the rat studies, it was 0.5-3.0g/kg orally... which seems like BIG plain ol' inositol dosages. I only have a gram of the compound, so I am thinking I may have to take it sublingually ... I am not sure how to extrapolate dosage info from rats to humans, but 'tis way different.

[violetechos]

I tried 200mgs and I really liked it. I bike every day and I biked way father than I usually do and it was easier. I think sublingual would be a nice way to dose this,inositols are sweet(literally). It felt like my brain was working better and I could breath in a different way. It would be awesome to combine this with some strong bronchiodilators .(and maybe some antioxidants at the point LOL).

Granted, I think 200mgs is probally way to small a dose. The doses used in the rat studies roughly translate to something like 200gs of ITPP!? i dont think thats right.

I think theres some anti-depressant potential in this one as well. I like inositol and this feels way more potent.

[RJ23_1989]

Granted, I think 200mgs is probally way to small a dose. The doses used in the rat studies roughly translate to something like 200gs of ITPP!? i dont think thats right.

Actually I think that this may be correct... i can't find it now, but someone asked Patrick Arnold his opinion of IPAA and that was one of the first things he brought up, was the human equivalent dosage was in the 100's of grams.

Edited by PatrickM500, 12 July 2013 - 09:34 PM.

[violetechos]

It was strange though, I felt what I would expect out of increased oxygen levels... to the point when I was woking out my skin was prickly, and It felt like I could breath way better...

You're talking about this : http://www.prohormon...ophosphate.html

Hmm. Don't take it sublingually BTW , it tastes terrible and burns.

[RJ23_1989]

Yep that's the thread! Looking closer at it I see he mentions its in the 10's of grams NOT 100's so that is good.

There's a conversion factor for lab animals that needs to be factored in that compensates for their much higher metabolism.


For reference, here is a good explanation:

If only animal experimental data is available for a given compound, it is reasonable to ask what the comparable human dose might be for the same compound. This problem is often faced by researchers when considering a new chemical substance for human trials for the first time. The following is a discussion of how this issue is typically addressed. (1)
The process starts with estimating Maximum Recommended Starting Dose (MRSD) for first-in-human clinical trials. It is based on the No Observable Adverse Effect Level (NOAEL) derived from animal toxicological studies. Once the NOAEL is known, the Human Equivalent Dose (HED) is calculated using the following formula: (2)
Human Equivalent Dose (HED in mg/kg) = Animal Dose (mg/kg) × Animal Km ÷ Human Km, where Km is a correction factor reflecting the relationship between body weight and body surface area. For a typical adult (body weight 60 lb, body surface area 1.6 m2), Km is 37. For the most often used laboratory animal species the average Km are as follows: Mouse 3 Rat 6 Guinea Pig 8 Rabbit 12 Dog 20 Human Adult 37
To calculate the MRSD, the HED derived from NOAEL is further divided by a safety factor (typically 10) to help determine a reasonable safety ceiling and help minimize the risk of toxicity in human clinical trials.
Determination of Human Equivalent of Pharmacologically Active Dose (PAD) is more complicated and depends upon many factors such as pharmacokinetics (i.e. absorption, concentration in the target tissue, metabolism, elimination, etc.) and differs markedly among pharmacological classes of drugs and clinical indications. Although far from ideal, the calculation method described above can be sometimes utilized. However, in the case of Pharmacologically Active Dose (PAD), dividing by safety factor is unnecessary. (2) Below is an example of conversion of a hypothetical PAD from mice to human:
Pharmacologically Active Dose (PAD) in mice 5 mg/kg
Human Equivalent Dose (HED) 5 × 3 ÷ 37 = 0.4 mg/kg
These calculations should only be considered preliminary and cannot serve as definitive dose determination. For more detailed information, please refer to the appropriate guidelines. (2)
References:

• Reigner B, Blesch K. Estimating the starting dose for entry into humans: principles and practice. European Journal of Clinical Pharmacology. 2002;57(12):835-845.
  
• Services USDoHaH, Administration FaD, (CDER) CfDEaR. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Rockville, MD 2005.

So....


That being said, the study used a dose range of 500 mg/kg - 300 g/kg and noted the increase in effect was dose dependent.
Using the above formula, the minimum effective dosage estimate would be (500 * 3 / 37) = 40 mg/kg. I'm going to assume a 70kg male so that works out to about 3 grams. I'd be curious as to what the bio-availability of the compound is oral vs. SubL vs. SubQ. Who knows??


Sounds like though, you got some positive effects from a relatively low dosage. Have you considered trying a few progressively higher doses and noting the effects?


I'd be interested enough to try it, I'll look into it. Since recovering from my herniated disk I've been putting in a lot of miles in lately getting ready for fall race season so adding something in I can usually tell pretty quick if its giving a net positive effect since I tend to train pretty close to the edge of my performance capabilities. I admit though I need to fully research it before making that decision. I still have a bottle of GW501516 sitting on the shelf that I was hesitant to try due to safety concerns and I'm really glad I didn't, b/c its got some major safety issues / no wonder it was dropped at phase II clinical trials.

Edited by PatrickM500, 13 July 2013 - 04:30 PM.

[RJ23_1989]

oops.. 300 g/kg should read 3 g/kg! Now that would be a lot

[violetechos]

Using the above formula, the minimum effective dosage estimate would be 500 * 3 / 37 = 40 mg/kg. I'm going to assume a 70kg male so that works out to about 3 grams. I'd be curious as to what the bio-availability of the compound is oral vs. SubL vs. SubQ. Who knows??


Sounds like though, you got some positive effects from a relatively low dosage. Have you considered trying a few progressively higher doses and noting the effects?

Thank you for calculating that Patrick, that's something I've wanted to understand animal to human dose calculations and you explained it nicely. So dosing being 3 grams #I feel like that's a pretty high dose honestly the price is very cost prohibitive at what i'm getting it at now...

I read amongst the research it doesn't have full bioavailbility, and off the top of my head I believe oral is really quite low at something around 20%, and injection is only around 60?! I need to track down where I read that...

So I tried to improve the bio-availability of it by complexing with 2-HPBCD , a cyclodextrin that in a nutshell surrounds molecules , especially hydrophilic ones, and improves transfer across mucous membranes.-"ITPP is very hydrophilic and ionizes extensively in aqueous medium"

I know that testosterone complexed with said dextrin , its sublingual bioavailabilty goes up to something ridiculous like 400%... It really seemed to help, and makes the molecule complexed somewhat time-released. This is dosed too high to take sublingually... perhaps complexing and intra-rectal administration will be ideal. Oral seems to work well, and I feel its a little wiser as the compound is close to an endogenous compound so perhaps there is more than membrane-diffusion only transport,protein bound facilitated-transport. I need to read more about inositol and ITPP metabolism, and its complex from what I recall.

I will try a larger dose soon.

Edited by lenses, 15 July 2013 - 04:25 PM.

[Infinite1]

I can also vouch for small doses having a noticeable/significant effect, I tested out a 200mg dose orally and was quite surprised. I think this could be a great staple in a stack comprised of T3 50-60mg, lipoic acid, Co-Q10, grapeseed extract, and perhaps something more exotic like methylene blue. I'm going to adopt this as a supplement to aid my Lyme disease treatment, in theory it should work exceedingly well. The only concern that I have is whether over time there is some form of consempatory mechanism that may develop, it would be good to see whether there is any type of tolerance that develops as that would be a good indicator that these mechanisms exist as it is a manifestation of this itself...as we all know the body is comprised of nearly an infinite number of feedback loops, rarely do we ever get something for free without some form of repercussion.

[Infinite1]

That should read 50-60 mcg instead of mg, just in case...

[violetechos]

Infinite1: Ill let you know if it effects me positively regarding chronic illness...I have HCV (somewhat similar to lyme) and it would seem that at the very least it can help with some of the weird mental effects said illnesses bring about, their link is the cytokines...

If we wanted to crank this one up, nitric oxide inducers (oooh l-arginine), a bronchiodilator (pure thc FTW!) and a cerebral vasodilator (a few noots I can't recall, some vinpocetine perhaps (PERHAPS.)

I get a slight next day headache. It would probally be wise to stay away from noxious fumes and smoke when under the influence of ITPP, more would get in your system me thinks.

Does anyone else find this helps their heat resistance and ability to do more with less food? The heat all of a sudden does not bug me.

Edited by lenses, 16 July 2013 - 05:52 PM.

[Infinite1]

Great! I'll of course be doing my own trial. You might want to be a bit on the conservative side when dosing with L-arginine. I'm not sure about HCV but in multiple other pathologies NO is upregulated along with cytokines, and since you are already experiencing mental effects you may just be feeding the fire. Please read this post for more info: http://www.mindandmu...s-no-inhibition. I do however agree that a vasodilator would be a good adjunct.

[Infinite1]

I should probably mention that my research has involved using fNIRS for the last year and I have a solid understanding of hemodynamics and neurovascular coupling. That being said in non-pathological states the concentration changes of oxy-Hb elicited by a discrete event or action potential is higher than that used for the metabolic processes, granted this is primarily in cerebral tissues- I don't have much of an idea about those taking place elsewhere. As a result the bottleneck is often in the cellular respiration or mitochondrial efficiency. This is why I have chosen those supplements that would benefit mito health.

[Dominicus]

So what's the concensus on best method of derlivery. Also where are you guys sourcing from?

[Infinite1]

I taking it orally, mostly because its suspension in ethenol making it pretty difficult to do sublingually.

Well I obtained mine from skyward research which is no longer in business. If anyone else has a solid source please pm me.

I taking it orally, mostly because its suspension in ethenol making it pretty difficult to do sublingually.

Well I obtained mine from skyward research which is no longer in business. If anyone else has a solid source please pm me.

[Dominicus]

I taking it orally, mostly because its suspension in ethenol making it pretty difficult to do sublingually.

Well I obtained mine from skyward research which is no longer in business. If anyone else has a solid source please pm me.

I taking it orally, mostly because its suspension in ethenol making it pretty difficult to do sublingually.

Well I obtained mine from skyward research which is no longer in business. If anyone else has a solid source please pm me.

There are suppliers, chem supply companies, that sell this on ebay of you just search the word: myo-inositol trispyrophosphate.

But it is in powder form. So I'm wondering now about dosage and putting powder in capsules? Or mix with water and drink? Or suppository?(hopefully not the last one lol)

[Infinite1]

Lol. On eBay? I'm not sure I would trust a random vendor. But if I get desperate...

[PalmAnita]

As a positive exception, this particular vendor on eBay seems to know what he's doing. Both chems I've bought from him were of good quality, albeit not lab testet yet. Still, the ITPP is pure enough that it is of crystalline structure and does really not taste too bad.

Have tested a threshold dosage of maybe 50 mg ... may or may not be placebo effect, as I am a healthy youth, but completely untrained, it's difficult to measure - subjectively there -is- a noticeable effect. Have to breathe much less hard when walking/running, feel like I need less time to "recover" before energy is ready again ... and maybe a nice side effect is that even when one isn't doing sports, the body feels somewhat "lighter" or more fit ... maybe also a tiny influence onto the brain.

Combines nicely with amphetamine (moderately dosed), with more ITPP the synergy will be even better I'd suggest. Where over-dosing with psychostimulants lefts one's body nervous but exhausted, this combo gives an unique opposite - that amphetaminergic energy, physically available ... if this does increase with dosage, it'll be incredible...

Just shivering what the side effects of ITPP may be ... acute use looks somewhat safe (to me at least, when staying hydrated and watch the body's needs), but what would intermediate to long-term / chronic usage do? Will exercise on ITPP be pro or contra? Will some kind of tolerance build up (allosteric modulation rings some alarm bell - thinking of benzodiazepines, but this might be completely wrong), possibly leaving one feeling exhausted, breathing hard when stopping taking that powder?

Thanks for your answers!

[Infinite1]

Apparently I waited to long to order some more of this and no longer see this listed on ebay. If anyone has any sources please PM me, thanks. and sorry mods if this post isn't appropriate, you can delete it if so.

[xks201]

Pm me too

[cargocultist]

It's on ebay again guys, two sellers. Including, I think, dopamimetiq's preferred seller.

Can someone in the US please test this substance? Preferably someone with access to an VO2 max test obviously.