Nation-hopping dopers

 I believe that there is a correlation between athletes who switch nationality and athletes who dope. Clearly not all athletes who change nationalities also take performance enhancing drugs, but consider this long list of world class athletes who have both switched nationality and served a ban for anti-doping rule violations:

Name Nationalities Accolades
Elvan Abeylegesse Ethiopia to Turkey 2 x Olympic silver medalist, former 5000m WR holder
Alemayehu Bezabeh Ethiopia to Spain 2 x Euro XC champ, sub 12:57 5000m PB
Abeba Aregawi Ethiopia to Sweden World indoor + outdoor champ, European champ, 3:56 1500m PB, 3 x Swedish records
Rashid Ramzi Morocco to Bahrain Olympic champ, 2 x world champ, Asian games champ, sub 3:29 1500m PB
Femi Ogonude Nigeria to Qatar World indoors bronze, Asian champ, 4 x Asian games champ, Asian record holder 100m (9.91) and 200m (9.97)
Hind Dehiba Morocco to France Continental Cup champ, World indoor bronze, European outdoor silver, European indoor bronze, French 1500m record (3:59.76)
Hamza Driouch Morocco to Qatar World junior champ, Asian junior champ
Mohammed Mourhit Morocco to Belgium 2 x World XC champ, World indoor + outdoor medalist, European record holder 3000m (7:26) + 5000m (12:49)
Eddy Hellebuyck Belgium to USA Winner of 21 international marathons, USA masters Marathon record.
James Theuri Kenya to France 60:54 HM, 2:10:39 Marathon
Mark Jelks USA to Nigeria 6.51 60m, 9.99 100m, 20.28 200m
Mark McKoy Canada to Austria Olympic 110h champ, World indoor champ, 3 x Commonwealth champ
Mo Trafeh Morocco to USA 8 x USA road champion, USA 25km record holder

There are not a huge number of world class athletes who have switched nationality; neither are there a huge number of world class athletes who have served doping bans. So the length of the above list is quite shocking to me, and I don’t believe it to be coincidental.

The athlete who inspired last week’s blog, Abeba Aregawi, is the prefect case in point here. Aregawi was initially accused of entering a sham marriage with husband Henok Weldegebriel, whom she divorced shortly afterwards, in order to gain Swedish citizenship. Then just two days prior to the news of her positive test, Sports Expressen cited documents from the tax authorities revealing that Aregawi admitted to submitting false information to Immigration Services when applying for citizenship. She also admitted to never having been a resident in Sweden.

The athletic benefits to Aregawi of representing Sweden include effectively allowing her automatic qualification into every major championship, provided that she achieves the relatively modest qualification standard. In Ethiopia, the qualification procedure is much more rigorous as she would have to compete with World record holder Genzebe Dibaba, world champs 4th placer Dawit Seyaum and world junior record holder Gudaf Tsegay, amongst many others, for a spot on the Ethiopian national team.  It appears as though Aregawi sought out a short cut to success, both by switching nationality and by using meldonium.

Many athletes switch nationality for monetary reasons.  The most famous example of this may be Stephen Cherono of Kenya, who by some reports received $1 million for switching his nationality to represent Qatar and changing his name to Saif Saeed Shaheen. Other reports claim that he was promised $1000/month for the rest of his life. Rumours of Kenyan athletics officials also accepting bribes from the Gulf States in exchange for enabling the transfers to go smoothly have long been rife.

These rumours gained traction recently after 3 Kenyan officials were suspended. The deal for which they are being investigated reportedly involved Isaiah Kiplagat, president of Athletics Kenya, accepting an “apparent gift” of two motor vehicles from the Qatar Association of Athletics Federations in the period from 2014 to 2015. Even in this instance, switching of nations and doping appear to be inexorably linked, as the allegations against the three officials also extend to ‘potential subversion of anti-doping process’.

There are several possible reasons for the observed correlation. Athletes who switch nations for financial gain appear to be more likely to take performance enhancing drugs, which can also lead to financial rewards e.g. increased prize money. The motives behind the two decisions are not dissimilar and both may have a basis in a desire to earn more money.

The more traditional motivations for competing in high level sport include pride at representing your home nation and striving towards your own absolute athletic potential; neither of these goals come with any inherent financial reward. When the primary motivation is money instead, the likelihood of doping appears to increase.

Doping is the scourge of modern sport and the subject of most of my writing. But the situation with athletes representing countries with which they have no genuine association is also becoming somewhat farcical. At the 2014 Asian Games in Incheon, 14 of the 22 individual running events were won by athletes of African origin who had switched nationality, either to Qatar, Bahrain or United Arab Emirates.

There is no easy solution to either the doping problem or the issue of athletes switching nationality on nefarious grounds. Immigration is a natural modern phenomenon that has arisen out of the huge inequality between nations and the relative ease of international transport. There is no issue with genuine immigrants representing their adopted homeland. As a side note, I am actually a big believer in allowing more immigration – I don’t think it’s right that quality of life can be so dramatically affected by where you happen to be born, and I’m in favour of any measures that serve to lessen this inequality. But athletes that have no desire to live or train in the country, but still compete under the flag, simply in return for payment, is a very different issue, and one which is having a negative effect on the sport that I am most passionate about.

Quite aside from the doping issue, it is now the status quo that in every major championship, there will be multiple athletes from Kenya, Ethiopia and Morocco competing for other nations, most often Qatar or Bahrain, despite the fact that they usually continue to live and train in the countries of their births. There should be a good reason for every transfer of allegiance, and these reasons should be well documented. Albert Rop is a Kenyan-born athlete representing Bahrain. He has a 5000m personal best of 12:51 – faster than Mo Farah – but I cannot find any information as to why he represents Bahrain instead of Kenya. Does he have a Bahraini wife or grandmother, or did he move there years ago to make it his home, for the greater sporting facilities and opportunities? I doubt that any of these scenarios are true, as it is reported that he continues to train at the Kipchoge Keino stadium in Kapsabet, Kenya.

It is the stories behind the athletes that make track and field exciting, but all that we are told by the IAAF about Albert Rop, is that he applied for a transfer of allegiance some time in 2013 and became eligible to compete for Bahrain in international competitions on April 1st, 2014. What was it that made him eligible for this switch? Is he adored by fans in Bahrain? I doubt it. But neither does he bring national pride to Kenya, as he no longer wears their colours. And thus, yet more of the drama and passion drains away from the ailing sport of distance running.

 

N.B. After writing last week’s blog about Meldonium/Mildronate, Maria Sharapova admitted that she had tested positive for that substance. There was not a great deal of information out there about it, so my blog received quite a lot of traffic and I was invited to speak on the radio and television about it. Below is a link to the TV interview for anyone who is interested. https://www.facebook.com/jake.shelley.37/videos/974975055922316/

 

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What is Meldonium/Mildronate?

Abebe Aregawi, the 2013 women’s 1500m world champion, has been provisionally suspended after Meldonium was found in her A sample. Days later, Endeshaw Negesse, the 2015 Tokyo marathon with a personal best of 2:04.52, was also banned after reportedly testing positive for the same substance. This news came in the same week that Solomon Meaza, the general secretary of Ethiopia’s anti-doping agency, told the Associated Press that nine of the country’s runners, five of them “top athletes”, are under investigation for doping. Aregawi represents Sweden, but was born and resides in Ethiopia, and Negesse is also Ethiopian.

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2013 world 1500m champion, Abebe Aregawi, tested positive (A sample) for meldonium

Meldonium is an anti-ischemic drug used clinically to treat angina, myocardial infarction and chronic heart failure. It is manufactured in Latvia under the commercial name of Mildronate and is one of the countries largest exports, with turnover reaching EUR 65 million in 2013. It is not yet approved by the FDA for use in the USA.

Meldonium was added to the WADA list of banned substances on January 1st, 2016 because of “evidence of its use by athletes with the intention of enhancing performance.” Therefore, none of the athletes banned for this substance will have performances prior to that date removed from the records and Aregawi will keep her 2013 world title.

The process by which WADA adds a substance to the banned list involves the substance first being placed on the WADA monitoring program. The addition of a substance to the monitoring program usually comes about as a result of athlete statements and any other evidence that WADA collects. The “other evidence” in this case was that WADA repeatedly detected Meldonium in urine samples during the validation of their new high resolution/high accuracy mass spectrometry multi-target screening assay. A peak at 147.1128 appeared in the MS spectra of many but not all urine samples during the validation process, indicating that the peak represented an exogenous substance. WADA determined that this peak indicated the presence of Meldonium. This evidence, coupled with athlete statements on sample use control forms reporting the use of Meldonium, led to the addition of Meldonium to the WADA monitoring program a year prior to its ban, on January 1st, 2015.

All substances on the monitoring program are evaluated to determine whether they have performance enhancing effects and, if deemed necessary, anti-doping tests for these substances are developed.

The WADA monitoring of Meldonium involved:

  • A literature review of the research conducted on the mechanism of action of Melodonium and its effects on sports physiology.
  • Development of an easily repeatable, accurate and reliable test for Meldonium
  • Analysis of 8320 random doping control urine samples for the presence of Meldonium.

The literature review showed that Meldonium is an effective anti-ischemic drug with further applications in immunomodulation and in the treatment of neurodegenerative disorders and bronchopulmonary diseases.

Meldonium is a structural analogue of the carnitine precursor, gamma-butyrobetaine. Carnitine is a key regulator of fat metabolism, since it is required to transport fatty acids into the mitochondria for fatty acid breakdown via beta-oxidation. Meldonium affects carnitine metabolism by inhibiting its biosynthesis and transport and this protects mitochondria from an overload of Fatty Acid metabolites.  Meldonium also increases gene expression related to glucose metabolism and thereby stimulates the aerobic oxidation of glucose (2).

Meldonium decreases the beta-oxidation of fatty acids and shifts cellular metabolism towards the oxidation of carbohydrates, which requires far less oxygen per ATP molecule than beta-oxidation of fatty acids. This sparing of oxygen could be of huge benefit under hypoxic conditions. The most obvious benefits have been seen in the treatment of ischemic heart disease, but there is evidence to suggest that Meldonium could be equally beneficial under the low oxygen conditions induced by intense endurance exercise (3).

One review (4) of the effects of Meldonium on exercise performance listed the following benefits:

  • Decreased levels of lactate and urea in blood
  • Improved economy of glycogen: level of glycogen increased in the cells during the long-lasting exercise
  • Increased endurance properties and aerobic capabilities of athletes
  • Improved functional parameters of heart activity
  • Increased physical work capabilities
  • Increased rate of recovery after maximal and sub-maximal loads
  • Activates CNS functions and protects against stress

A published human research study (5) on the effects of Meldonium on sports performance used Russian judokas and gave them a dose of 0.5-1.0 g twice a day before training, as a 14-21 day course during the training period 10-14 days before competition. Some of the above effects published in the review article were reported from this study. Unfortunately, quite a lot of the research into this topic is only published in Russian (6). Another Russian study, translated into English, showed a significant improvement in the swimming of rats after Meldonium supplementation (1).

WADA decided that there was enough evidence to investigate further as they developed two separate tests for Meldonium, which has the chemical name 3-(2,2,2-trimethylhydrazine)propionate dihydrate. Both tests use a urine sample – the first is easily compatible with current tests carried out for other substances in anti-doping laboratories and could be used to screen large numbers of samples, whilst the second is more specific to Meldonium and could unequivocally determine its presence in a sample (4).

Using these two tests in combination, a total of 8320 random doping control urine samples covering different classes of sport either from in- or out-of-competition were analyzed for the presence of Meldonium. 182 positive Meldonium findings (2.2%) in a concentration range between 0.1 and 1428 μg/mL were detected and confirmed using the more sensitive assay (4). This is shown in the graph below.

Picture1

Figure 1. Mildronate findings in official doping control samples (n = 8320) and distribution between in‐ and out‐of‐competition samples (IC/OOC), gender (f = female; m = male) and type of sports (team sports, endurance sports, strength sports, others) (4)

This data, along with the several bans that have arisen since Meldonium was placed on the banned list on January 1st, indicates that the use of Meldonium is fairly widespread and I expect to see several more cases in the coming weeks and months. Besides track and field, there has also been a confirmed positive case in cycling for Eduard Vorganov, the Katusha former Russian national road champion and 19th place Tour de France finisher, who was an important dometique rider for Joaquim Rodriguez in his 2nd place finish in last years Vuelta a Espana. There have also been 2 positives for fairly high-profile Ukranian biathletes. Given that the drug is manufactured and distributed mostly in Eastern Europe, I expect most positive cases to come from athletes in that region. It is being reported that a Ukrainian doctor may have been involved in the transportation of the substance into Ethiopia (7) so we may see more positives from Ethiopian athletes too.

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Katusha Rider, Eduard Vorganov, banned for Melodonium

I hope this article goes someway into showing how a substance can be added to WADA list of prohibited substances. It is clear to me that WADA is underfunded and is currently fighting a losing battle. They need a better network of intelligence so that they can more quickly identify the new substances that athletes are using/misusing. There should be better channels for anonymous athlete informants. Then they need more manpower in the laboratories so that tests can be developed more quickly. Adding substances to the banned list just once a year, on January 1st, is not enough. They should be added as soon as there is even an indication of a performance enhancing effect, or else the drug cheats will always be one step ahead, in their ever-changing, ever-expanding “grey area”.

References

  1. Baulin SI, Rogacheva SM, Afanaseva SV, Zabanova EV, Karagaycheva YV. Pharmaceutical Composition for Improving Physical Working Capacity. Bull Exp Biol Med. 2015 Nov;160(1):45-8.
  1. Dambrova M, Makrecka-Kuka M, Vilskersts R, Makarova E, Kuka J, Liepinsh E. Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. Pharmacol Res. 2016 Feb 2. pii: S1043-6618(15)30171-7.
  1. Dzintare M, Kalvins I. Mildronate increases aerobic capabilities of athletes through carnitine-lowering effect. Curr. Issues New Ideas Sport Sci. 2012, 5, 59.
  1. Görgens C, Guddat S, Dib J, Geyer H, Schänzer W, Thevis M. Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry. Drug Test Anal. 2015 Dec;7(11-12):973-9.
  1. Kakhabrishvili Z, Chabashvili N, Akhalkatsi V, Skhirtladze T, Chutkerashvili T. Mildronate effect on physical working capacity among highly qualified judokas. Ann. Biomed. Res. Edu. 2002, 2, 551.
  1. Petrova VV, Petrov AA, Rukavishnikov IV. Cytoprotectors and their application in sports medicine. Med Tr Prom Ekol. 2013;(9):22-6
  1. http://www.insidethegames.biz/articles/1034922/ethiopian-tokyo-marathon-winner-negesse-reportedly-fails-drugs-test-for-meldonium.),

 

 

 

 

 

 

 

The fight against doping – is the testing working?

When you study chemistry at school, you learn that litmus will go blue in alkaline solutions and red in acidic solutions and many people wrongly assume that drug testing is equally black or white.

Recently published was a very disturbing article (http://labtimes.org/labtimes/issues/lt2013/lt01/lt_2013_01_18_23.pdf) in which four Norwegian biochemists outlined a number of deficiencies in the methods used by the World Anti-Doping Agency (WADA) to detect the performance-enhancing drug CERA (Continuous Erythropoietin Receptor Activator), specifically relating to the failed test for this banned substance by the Norwegian race-walker Erik Tysse.

Tysse was banned for two years from all competition and organised training, however the compelling evidence presented by the authors makes me believe that this was an unjust and unwarranted punishment. I worry that he is not the only one to have suffered such a fate of wrongful conviction and what is perhaps equally worrying is that if WADA’s tests can produce false-positives, then they must surely also be letting some cheats slip through by producing false-negative results.

How can WADA get it wrong?

The Science

CERA is fundamentally hard to detect. EPO is a naturally produced hormone that triggers the production of red blood cells– CERA is a synthetic variant of EPO, designed to mimic the action of EPO. They are very similar in size and shape; in fact they have identical amino acid sequences. The one difference between them is that they have different post-translational modifications; meaning different chemical groups are added to the protein. In this case, CERA is pegylated, whilst EPO is glycosylated, leading to a difference in charge between the two.  This difference should, in theory, allow the tests to distinguish between EPO and CERA, as CERA should appear more basic and EPO more acidic. However, during the preparation and purification of the samples it is possible for one or more of the acidic groups attached to EPO to be removed, thus causing natural EPO to appear more basic. This makes it essentially indistinguishable from CERA.

The Bureaucracy

After testing positive, Tysse’s case was brought before The Tribunal of the Norwegian Confederation of Sports. The judge in this case openly admitted that much of what was discussed “went over his head”. When the case hinges on jargon like “negatively charged sialic acid unit” and “N-glycosylation states” it is clear that an unscientifically trained judge is unable to make a fully informed decision. Yet Tysse was still found guilty.

After appealing this decision, Tysse then went to the Court of Arbitration for Sport (CAS). In this second case, the data provided to the CAS by WADA was deliberately presented in a misleading way- that favoured the conclusion that CERA was present. The figures presented to the court were a cut-and-paste job. Reference bands taken from one gel were aligned next to Tysse’s samples from a separate gel. The relative sizes of the bands were also changed- with the image of Tysse’s sample being enlarged 40%. This data would be laughed out of my Monday morning lab meeting, with some serious questions asked, but it is easy to understand how those not familiar with the relevant techniques might readily accept the “expert opinion”.

What Next?

These decisions cannot continue to be made by people that lack the qualifications to interrogate the data presented to them; the presence of an independent panel with a basic understanding of the science behind the testing would have prevented this from slipping through. These decisions have destroyed an athlete’s career and thrown their life into turmoil, so we must do more to get them right.

Doping is the single biggest problem facing sport today, but as with all criminal cases, you are innocent until proven guilty. Cases such as this make a mockery of the whole system.

The testing laboratories must maintain the highest professional standards with strict protocols for the collection, transport, and analysis of samples, a scrupulous chain of custody and accurate application of fixed standards for the evaluation of doping evidence—with the anonymity of the athlete guaranteed at all steps of the process. Only then can we have full confidence in WADA.