Sunday, 23 February 2014

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/


[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.


  

5 comments:

  1. Just for you to know, it does actually increase aerobic endurance in humans as well as it's fat reducing properties. There is a lot of anecdotal evidence from people who have been using it for these very reasons out there. The people who have been using it (for, shall we say, self research purposes) seem to be finding a dosage of 10mg per day effective for fat loss purposes while 20 mg per day also appears to be the dosage that produces the performance enhancing benefit. Unlike many substances (mainly anabolic steroids) these people have taken, there does not appear to be any side effects of note other than increased libido and prolonged sexual stamina. It's a shame Glaxo dropped the research on this as it appears to be a very interesting compound.

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  2. Glaxo dropped the research as it caused cancer in animals in the routine toxicology studies required to get drug approval for human use. End of story for any pharmaceutical development by them or any other company. And as they do not know why it caused the cancer, I suspect they chose to get put of this area completely as otherwise they would be throwing good money after bad (it costs a LOT to get a drug approved for human use).

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  3. Chris: In all the GW501516 studies showing an increased risk of developing cancer, is it true that the dosages used were far greater than those used by athletes for performance enhancement purposes? In the studies that I've been able to find, the lowest dosage used was 5 mg/kg per day. This would translate to 350 mg per day for a 70-kg person, which is much greater than the 10 to 20 mg per day used by athletes. Have you come across any studies that show an increased cancer risk but that use dosages on par with those used by athletes?

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  4. Thanks for making this point "anonymous.". I agree, but my point is that there is no data that the micro dosing that athletes seem to use has any effect whatsoever (positive or negative). As far as I can see 10 - 20 mg in an adult will not activate the transcription factor at all. So presumably this is all placebo. See my later blog on this issue.

    all the best

    Chris

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  5. to Anonymous: http://www.ergo-log.com/calculatethehumandosage.html
    after reading this link,i understand that dosages differ in humans and rats/mice.and after conversion,GW dosages would be practicaly the same

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