Xenon and sports doping – does it work?

I have taken a while to write this promised blog about the performance effects of xenon and doping. The reason being that I really could not find anything relevant. As I said in my previous blog on the matter [1], animal studies suggest xenon can activate hypoxia inducible factor. This, in principle, can increase EPO levels, which in turn can increase red blood cell number, which in turn can increase aerobic sports performance. 

The animal papers suggest xenon might be more effective than low oxygen (or altitude training) in raising EPO. Presumably people doping with xenon have access to secret human performance data; this would help them to optimise the treatment. But there are no human studies I could find, or at least none that I could readily access in the scientific literature. Still, given its use as an anaesthetic, I suspect there must be some xenon EPO data hidden in the results section of a paper looking at something else (or even in some hospital records of blood samples following xenon administration) - I just haven’t found it yet!

Anyway I asked my old collaborator, the neonatologist Dr. Nikki Robertson, what she thought of this. Dr. Robertson is looking at the effect of xenon at protecting newborn babies at risk of brain damage. She didn’t know of any studies looking at the long lasting effects of xenon on hematocrit. However, she is currently managing a UK Medical Research Council neuroprotection trial using xenon [2] so she will take a look at her data and see if she can see an effect (although it has to be said that sick babies are about as far removed as you can get from elite athletes, the principle may be the same).

Interestingly another noble gas, argon, is potentially even better than xenon at neuroprotection. If this works via EPO activation it would be even more interesting to athletes as argon is a lot cheaper to buy than xenon!

[1] Xenon and sports doping – should it be banned?

[2]  The TOBY Xe Study: Neuroprotective effects of hypothermia combined with inhaled xenon following perinatal asphyxia

Asafa Powell: the defence of his doping ban

Just a follow up to my last blog, Asafa Powell claims [1] that he was a victim of a contaminated supplement i.e. the oxilofrene he tested positive for was not a listed ingredient in Ephinany D1.  I think this is true; he therefore has a case that, in this regard, the 18-month ban is longer than some that have been handed down for similar offences. He may well win an appeal at the Court of Arbitration for Sport.

However, I would contend that the unbanned “stimulants” that are listed on the Epiphany D1 label are not that different to oxilofrene if taken in high doses. Aniracetam in particular is a prescription drug used to treat central nervous system disorders, such as Alzheimer’s Disease. If Powell was taking it in a pure pill form as a patient, he would surely have declared it on a therapeutic exemption certificate. I am assuming that Epiphany D1 was not listed on any form as athletes, and their coaches, try to keep their supplement regimes as secret as their training regime. In any case I don’t see much difference between taking a cognitive enhancer such as aniracetam versus a banned stimulant like modafinil which has resulted in any number of doping bans (see my book for details).

As an aside it does seem to me that Powell has a case to sue the manufacturers of Epiphany D1, Dynamic Life Nutrition, LLC for loss of earnings and reputation. They even have a GMP (or “Good Manufacturing Practice”) label on their web page after all - though it is rather fuzzy and difficult to read. However, a quick read of their terms and conditions [2], suggests otherwise:

“OUR AGGREGATE LIABILITY (WHETHER FOR BREACH OF CONTRACT, TORT OR ANY OTHER LEGAL THEORY) SHALL IN NO CIRCUMSTANCES EXCEED THE COST OF THE PRODUCTS YOU ORDERED.”

And even better:

“Company neither endorses nor is responsible for the accuracy or reliability of any opinion, advice or statement on the Company Websites”

and again:

“It is your responsibility to evaluate the accuracy, completeness or usefulness of any information, opinion, advice or other content available through the Company Websites. Please seek the advice of professionals, as appropriate, regarding the evaluation of any specific information, opinion, advice or other content, including but not limited to financial, health, or lifestyle information, opinion, advice or other content.”

Caveat emptor

[1]         Asafa Powell vows to appeal against 'unjust' 18-month doping ban

[2]        http://www.epiphanyd1.com/terms_and_conditions.aspx

Xenon and sports doping – should it be banned?

 A number of people have asked me about xenon gas and doping. Russian athletes were alleged to use Xenon extensively when preparing for the Sochi Winter Olympics. It is somewhat unclear whether it is banned under current would anti doping (WADA) rules; there is a current investigation [1].

Xenon is proposed to work [2] by activating hypoxia inducible factor (HIF); this in turn increases EPO levels which then increase red blood numbers. More red blood cells means enhanced oxygen delivery and therefore enhanced performance in aerobic sports such as long distance running, cycling and cross country skiing. Using pharmaceuticals (drugs) to increase EPO levels via HIF activation is clearly banned. Altitude training or sleeping in low oxygen tents to achieve the same effect is not banned. In my opinion the reason for this difference is, at least in part,  a bias against using medicines to enhance sports performance, whereas physiology, however extreme, is viewed as OK. However, rooted in this “bias” is the legitimate issue that drugs can increase EPO levels - and therefore red blood cell levels -  above those that can be achieved “naturally”. And hence there is the real possibility of a danger to health if used recklessly. Despite my earlier comment, I am somewhat sympathetic to this point, though it has to be said that other systems do ultimately step in to rebalance the red cell count. Still whether or not they SHOULD be banned, there is no doubt this is the rule and pharmaceutical HIF activators ARE banned.

So should Xenon be banned? It is an anaesthetic drug when used at high doses (a use that is is on the increase). However, at lower doses it has a different effect, appearing to protect against tissue damage when an organ is deprived of oxygen. This effect is called “ischemic preconditioning”. This can be thought of as a small heart attack protecting against a big one. The small attack triggers the body’s defences; the body is then primed and ready to respond when the big attack comes (rather like an army mobilising its defence forces when it knows an invasion is imminent). Consequently xenon gas has recently been shown to enhance the efficacy of brain cooling when used to prevent brain damage to newborn infants, a research area I was involved in when I worked at University College London Medical School in the 1990s [3].

In these cases xenon is being used as a drug intervention – being a gas makes it no different than any other pharmaceutical in the requirements for clinical testing and regulation.

Conclusion - Xenon should be banned by WADA

But low oxygen has the same effect as Xenon. So if you wanted to precondition a patient to protect them in an operation where you thought they might suffer from oxygen deprivation, you could propose either xenon or sleeping in a low oxygen tent. In both cases you would need to carry out appropriate clinical testing. So here xenon is the same as low oxygen therapy. Low oxygen is not banned.

Conclusion - Xenon should NOT be banned by WADA

What is the answer to this? The relevant section of the WADA code is that what is prohibited is “Artificially enhancing the uptake, transport or delivery of oxygen, including, but not limited to, perfluorochemicals, efaproxiral (RSR13) and modified haemoglobin products (e.g. haemoglobin-based blood substitutes, microencapsulated haemoglobin products), excluding supplemental oxygen.”

It seems that xenon should fall foul of “Artificially enhancing the uptake, transport or delivery of oxygen” as it lacks the specific exclusion that oxygen supplementation gets. But you could just as well argue that sleeping in a low oxygen tent is “artificial”. Yet it is not banned. As I said in my book anti doping regulations are in essence no different than any other rule of sport – and so in some cases will be somewhat arbitrary. So we just need a definitive ruling from WADA - as I have showed above either decision can be defended.

Of course there is the added complexity of banning something that cannot be detected. Xenon, though readily measurable in exhaled air, won’t last long in the system after its use is stopped. So in practice it is undetectable. However, I don’t think we need not worry about the lack of detection as long as long as we have an athlete biological blood passport in place [4]. If Xenon is having a dramatic effect on the red blood cell count this should appear as an anomaly in the passport. If it only has minimal effects then it won’t be detectable in the passport. But then who cares? If it is no better than low oxygen tents, so can’t be detected by the passport system, then it is no better than oxygen tents and there is no real point in banning it.

In short as long as there is an effective blood passport system in place the question of whether to ban Xenon or not is a bit moot. It is unlikely to be a game changer in the world of doping.

Of course as a scientist I am interested in the question does Xenon work? Is there good evidence that it is as good or better than low oxygen tents? Is it on a par with pharmaceutical HIF activators or EPO injections?

That will be the topic for my next blog.

References

[1]  Sochi 2014: Russia Winter Olympics 'gas' claims investigate

[2]  Xenon Preconditioning Protects against Renal Ischemic-Reperfusion Injury via HIF-1α Activation JASN April 2009 vol. 20 no. 4 713-720

[3] Mild Hypothermia after Severe Transient Hypoxia-Ischemia Ameliorates Delayed Cerebral Energy Failure in the Newborn Piglet Pediatric Research (1995) 37, 667–670

 [4] Blood Doping and Blood Passports

CJC-1295 and sports doping – an update

This was one of the peptides used by some Australian sports players (see my previous blog Australians doping with designer peptides: do they work as sports drugs?) and also this article. As I explained in my blog it is designed to be a growth hormone releasing compound, enhancing the natural production of the hormone. Hence the interest as an agent that could theoretically increase muscle mass.

But why were these kind of compounds developed in the first place when human growth hormone (and human growth hormone releasing factor or GHRH) are themselves easy to obtain? As is usual the economic driver is medicine not sports performance.

CJC-1295 was made by a Canadian biotechnology company called ConjuChem (hence the acronym CJC). It was engineered to be longer lasting in the bloodstream, making it more effective than authentic GHRH. GHRH is a peptide (or small protein). We learn in school biology that proteins cannot be absorbed in the diet in their native state and so have to be broken down into smaller parts (peptides and then amino acids) by enzymes. That is why you need to inject a peptide drug, rather than swallow a pill, if you want it to have any effect in the body. However, enzymes that can digest peptides are not restricted to the gut. There are some in the blood and these naturally break down GHRH. So injected GHRH does not last long in the body. CJC-1295 is a form of GHRH, modified so it can bind to serum albumin – a very abundant protein in the plasma. Here it “hides” from the enzymes that are trying to degrade it. This makes CJC-1295 a potentially more effective drug than GHRH in treating growth hormone efficiency.

The modifcations that have been engineerd into CJC-1295 are a bit of a double edged sword for dopers. So, yes the drug could be more effective, but it is also easier to test for because it is: (a) completely artificial so cannot be confused with a “natural” version already in the body; (b) lasts longer in the blood stream so there is a longer “window of opportunity” for testers to act. In 2010 a US group gave 0 CJC-1295 to healthy individuals to try and develop an indirect test as part of a biological passport [1]; in 2010 the Norwegian anti doping lab was able to detect it in a formulation used by bodybuilders [2].  

So what became of ConjuChem and did they make their millions from CJC-1295? Sadly for their investors the answer is no. CJC-1295 never did make it as a clinical product. ConjuChem ran out of money in 2010. All is not lost for the CJC name however. Its assets were bought by US investors, and it moved from Montreal to warmer climes in Los Angeles. Its main product is now CJC-1134-PC, a molecule designed to enhance insulin action in Type II diabetes. Again it hides from destruction by binding to albumin. Although some athletes dope with insulin, a quick trawl of the Internet revealed no one seems to be selling this particular peptide on the black market. Give it time I guess ....

[1]        Henninge, J., Pepaj, M., Hullstein, I., and Hemmersbach, P. (2010) Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug testing and analysis 2, 647-650.

[2[        Sackmann-Sala, L., Ding, J., Frohman, L. A., and Kopchick, J. J. (2009) Activation of the GH/IGF-1 axis by CJC-1295, a long-acting GHRH analog, results in serum protein profile changes in normal adult subjects. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 19, 471-477.

Australians doping with designer peptides: do they work as sports drugs – an update?

I have to confess this is a bit of a fake blog. My blog last year on this topic Australians doping with designer peptides: do they work as sports drugs?) was far and away my most popular one. The hits keep on coming every week even now. But I also get a lot of spam from people trying to get me to sell peptides or advertise them on this site. So I thought I would use the same title and see if it was just the title, or the content itself, that was so popular.

Having said that I felt guilty (must be my Catholic upbringing) at fooling my genuine readers into looking at a blog with no science in it. So there will be a real update about one of the peptides in my next blog.