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Animal study: ITPP boosts effect of EPO

Myo-Inositol-Trispyrophosphate (ITTP)
Don't quote us, but it looks as though endurance athletes may be able to improve their times with a new substance that hasn't made it to the doping list yet but that boosts the effect of EPO - and might even be a partial substitute. Dozens of posts on ITPP have already appeared on bodybuilding forums, and bio-scientists have started to patent all sorts of applications for the stuff. Time to find out exactly what ITPP is.

Myo-Inositol-Trispyrophosphate [the full name of ITPP] first appeared in the literature in 2005, when Konstantina Fylaktakidou, a chemist at ISIS-Université Louis Pasteur, wrote in Bioorganic and Medicinal Chemistry that she had synthesised nine salts of inositol-tripyrophosphate. [Bioorg Med Chem Lett. 2005 Mar 15;15(6):1605-8.]

One of these is ITPP and, according to the in-vitro studies that Fylaktakidou did, this compound is extremely interesting: it forces its way into red blood cells and extracts oxygen from the haemoglobin molecules [structure of these is shown on the right]. That means that ITPP can increase the transport of oxygen to tissues.

And substances that boost oxygen transport are interesting for oncologists, because they can intensify the impact of cancer therapies. More oxygen means for cancer cells at least more radical damage, and therefore reduced survival chances. Oxygen boosters are also interesting for cardiologists, who use these to help heart patients, and also for neurologists seeking to soften the effects of brain disease such as dementia. And of course the same substances are of interest to endurance athletes.

Myo-Inositol Hexaphosphate (IHP)
Fylaktakidou's research manager, Claude Nicolau, has been investigating ways of inducing blood cells to release more oxygen for years. Together with others, Nicolau set up the biotech company NormOxys, which is perfecting these methods to make them commercially viable. Nicolau has put a lot of effort into studying myo-inositol hexaphosphate [IHP], a plant-based compound that is also found in many animal cells. You might recognise it under its other name, phytate [structural formula on the right].

As long ago as the 1970s Nicolau demonstrated that red blood cells release more oxygen if they contain more IHP. [Blut. 1979 Jul;39(1):1-7.] But it's difficult to make blood cells to absorb more phytate. This has to happen outside the body. In the 1990s Nicolau published the results of a study in which he had subjected blood outside the body to electrical pulses, causing the IHP molecules to enter the cells. [Transfusion. 1995 Jun;35(6):478-86.]

But if the ITPP molecule was used instead you might be able to avoid the cumbersome process described above, Fylaktakidou suspected. And indeed, when cardiologists at Boston University Medical Center published the results of an animal study in 2009 in which they had given ITPP to mice, her suspicions were confirmed. [Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1926-9.] For the record we note that the American study was partially funded by NormOxys, Nicolau's own company - and that Nicolau already had a long list of patents filed [] for the use of compounds including IHP and ITPP in his name.

In this particular animal study the researchers injected ITPP directly into the small intestine. With a little imagination it's possible to say that they imitated the effect of oral administration. The effect was optimal for the first two days after administration, had halved after five days and had completely disappeared after twelve days.

In mice that had been genetically modified to have a heart defect, and as a result had 40 percent less endurance capacity than the non-modified animals, ITPP normalised the number of metres the mice were capable of covering in a treadmill. The figure below shows this. The researchers tested the animals 24 hours after they had been given a dose of ITPP.

Animal study: ITPP boosts effect of EPO

ITPP also boosted the endurance capacity of the ordinary mice, as the figure below shows. The administration of 2 or 3 g ITPP per kg bodyweight boosted the mice's endurance capacity by about 50 percent. You can calculate the human equivalent of these doses here.

Animal study: ITPP boosts effect of EPO

"ITPP is an attractive therapeutic candidate to alleviate symptoms in patients with reduced exercise capacity caused by low cardiac output heart failure", the researchers conclude. "ITPP may also enhance physical performance of otherwise healthy individuals, in particular, under extreme conditions such as high attitude or intense physical exercise."

A patent application [WO 2008134082 A1] that two co-authors of the study submitted together with Nicolau gives you an idea of the ways in which doctors and athletes may be able to use ITPP in the future. "Erythropoietin complementation or replacement" is the name it goes by.

It might be that athletes are already using ITPP. The stuff is available in online stores, where it's billed as a "horse energizing pharmaceutic product". [ 18 November 2011]

Since 2010 there have been rumours that ITPP is being used on racehorses and greyhounds. [ 4 Nov 2010] Horse racing organisations are taking these rumours so seriously that they have already got scientists to develop a doping test for ITPP. [Drug Test Anal. 2012 May;4(5):355-61.]

Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1926-9.

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