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. 

GW501516, Endurobol and doping: what’s all the fuss about?

Given the lack of doping interest at the winter Olympics, I thought I should turn to a story I have meant to cover for a while.

GW501516 is the name of a Glaxo Wellcome drug (the GW stands for the company and the number is that of the product). It is also known as GW-501,516, GW1516, GSK-516). It is a PPARδ receptor agonist that was not taken further than clinical trials. As such it is banned in sport. It fits in a number of places on the list, including specifically as “a peroxisome Proliferator Activated Receptor δ (PPARδ) agonists (e.g. GW501516)”. But it would also come under WADA’s new catch all “non approved substances” section that aims to stop any unlicensed drug being used by athletes:

“Any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use (e.g drugs under pre-clinical or clinical development or discontinued, designer drugs, substances approved only for veterinary use) is prohibited at all times.”

GW501516 gained notoriety when WADA took the unusual, but not unprecedented, step of warning users of its potential health risk in a press release in March, 2013 [1]. This was not triggered by new safety data (this information had been known for a while) but by the fact that it was being marketed as a supplement touted to endurance training (called Endurobol) and that, probably because of this there had been several positive doping tests for it. Endurobol is clearly a name targeted at athletes. So it is seems inappropriate for companies to market a drug with this name, even if they say it is not intended for human consumption [2]. It should be sold as GW501516. By the way there is no chance of banning this compound in wider society. Like other drugs that modify cell function, it is a legitimate tool in biomedical research (I could see why I might use it in my laboratory studies for example).  There are over 200 research papers on this drug, and the majority are not about its alleged performance enhancing effects [3].

So what is GW501516 and what is its possible relationship to sporting performance? The key paper [4] was published in 2004 by US and Korean scientists entitled “Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PPARδ is a transcription factor i.e. a gene that can make a protein that controls many other genes. So making more PPARδ can elicit wide ranging developmental, physiological and biochemical outcomes. In this particular paper the amount of the PPARδ gene was dramatically increased in the skeletal muscle of mice. The resultant mice had more type 1 (endurance-type) muscle fibres and were resistant to obesity. The gene doped mice could run longer than normal mice on a treadmill (almost three times as long – you can see the videos here). The gene doping was done in the mouse embryo so is not directly applicable to what could be done in an athlete. However, the authors did show that activating the PPARδ gene in normal adult mice (using GW501516) showed the same gene expression effects as in the genetically altered mice. To the scientists this is good confirmation that the PPARδ gene controls the genes that determine muscle fibre type. However, this does not show that GW501516 can improve performance; in the adult mice it may be too late to make this change – their fibre type ratio having already been fixed during development. Indeed no performance effect was measured in this paper, nor has there been any significant paper published since claiming that GW501516 can change fibre type and improve performance in normal adult mice (or indeed humans).

What the 2004 paper did show was an effect of GW501516 on reducing obesity induced by a high fat diet. And of course this is why the drug companies were interested in this product. As I note repeatedly in my book, medical markets are much larger than any sports performance market for pharmaceutical companies.

So what became of GW501516? Glaxo has stopped the development of the product. You have to search around a bit to find out why. In two rather obscure short abstracts published in The Toxicologist, it was shown that, when rats and mice were given the drug for two years, they was a significantly increased risk of developing a range of cancer [5]. Normally bloggers concerned with evidence-based science would be wary of taking too much credence from reports that are not published in full peer-reviewed science journals. These two papers, however, are abstracts of reports presented at a scientific meeting; they describe negative results about a drug and are being published by the drug company and the toxicology service that did the work. So we can be pretty much sure they report a clear risk to health.

An effect of long-term use on cancer risk might not immediately rule out a drug if it was intended as a one off life-saving acute intervention. But as a long-term treatment for obesity or obesity-related syndromes it is clearly a disaster. Glaxo Wellcome stopped developing the drug and halted a clinical trial, although interestingly one Australian trial (not Glaxo Wellcome funded) did seem to show some positive effects [6].

This is becoming a long blog (for which my apologies). So perhaps a summary is in order at this point:

•       There is scientific evidence from animal studies that GW501516 (Endurobol) has the theoretical potential to improve performance in aerobic sports
•       However, when taken by adult humans GW501516 is unlikely to be directly effective in endurance sport, though it might affect body fat content
•      There are no reliable studies that demonstrate a performance enhancement with GW501516
•      Long term use of GW501516 is very dangerous and can cause cancer

WADA have become very aggressive in targeting the dangers of using drugs that are in preclinical animal trials, but have never been tested in humans. Even an absence of evidence of harm in the scientific literature does not mean that a drug is safe (drug companies do not necessarily publish all their toxicology data). For example, a drug I use in my laboratory biochemistry research was never taken forward by the pharmaceutical company. I know that the reason was they once tested a slightly higher dose and the animal dropped dead instantly. There was clearly an additional mechanism operating at doses just above normal that proved fatal. They could not take the risk that some people would be more sensitive to this effect and die at the normal therapeutic dose. So drug development was stopped. But I don’t think this was ever reported; they just moved on to test safer alternatives.

The moral is very clear. If you take a drug that has not been approved for human use, you are taking a risk.

Notes:

 [1]  “WADA issues alert on GW501516” http://playtrue.wada-ama.org/news/wada-issues-alert-on-gw501516/

[2] http://www.ecplaza.net/trade-leads-seller/endurobol--8411028.html

[3]  I should note in passing that Glaxo themselves were only interested in this drug for human use  - they do not sell it for biomedical research and, of course especially not for, athletic use. But once a drug formula is known the manufacturing process can usually be copied or adapted by other companies. So long as they are not claiming a benefit that infringes Glaxo’s patents, selling this compound is perfectly legal (ad in fact this benefits biomedical research science). Selling it for human consumption of course is not legal.

[4] Wang Y-X, Zhang C-L, Yu RT, Cho HK, Nelson MC, et al. (2004) Regulation of Muscle Fiber Type and Running Endurance by PPARδ. PLoS Biol 2(10): e294. doi:10.1371/journal.pbio.0020294

[5] Toxicological Sciences Volume 108, Number 1, March 2009 Abstracts # 895 and 896

  

[6] Ooi EM Watts GF, Sprecher DL, Chan DC, Barrett PH. Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. J Clin Endocrinol Metab. 2011