wada backpedals on meldonium. hurts its science cred.

[python]

recently, there was an avalanche of the meldonium positives..

to remind, the drug was added to the banned list as of 1 jan 2016. to date, the sources that keep track, reported almost 150 cases. of those, 29 certifiably are russians (including sharapova) with well-informed rumours that 40 something belong to them as well.

many have advanced the conspiracy theory. i posted my opinion here that i don't think it is/was. rather, it was an example (i gave my arguments elsewhere) of wada taking the 'easy route'. sort of maxing on grabbing the low hanging fruit, in stead of sticking to its 'high road' mission via backing its all-important decisions by solid science.

turns out, in the case of meldonium if there was any science, it was incomplete, premature or simply none.

yesterday, wada basically confirmed my worst earlier suspicions in their official public NOTICE
- MELDONIUM. here it is:
https://wada-mailing-list.s3.amazonaws.com/2016-04-12-Meldonium_Notice_Final.pdf

read for yourself. in summary, per wada, if you were a sticky doper as of 1 jan 2016, perhaps as of 1 march 2016, you are not. of course, wada is trying to put the best face on its backpedaling, but it reveals pretty much its own incompetence (prior to jan 1 and still) in the following quote

In the case of meldonium, there is currently a lack of clear scientific information on
excretion times.

for those to busy to delve into the details and the science, it could be summarized as follows: you are a doper, but b/c we didn't and still don't know much as of 1 march 2016 here are grounds to save your ardz till we finish our studies.

that's our wada

 

[WillemS]

Well, I guess a way for the WADA-critics to really drive their point home is to debunk WADA's claim that there's no solid scientific evidence that the substance leaves the body rather quickly by providing scientific sources that specifically do state such a thing. Otherwise, the whole proceedings might still be shady as hell, but WADA's claim might actually be solid.

So, is there anyone with a background in biomedical science with access to journals who would like to do a dig of the literature? I might give it a go, but my background is in statistics and cognitive neuroscience, so my search would be inefficient and probably lacking.

However, my guess is that WADA did check and there is no solid scientific evidence, leaving a reasonable doubt for the defense to claim the use is prior the ban (but probably nothing more than "reasonable doubt" as I don't think there will be much evidence that the stuff will detectable for so long either).

 

[Mr.38%]

Wait what? All they do is to clarify there may be false positives for a very limited timespan which may actually bring justice to a few people. There is no incompetence whatsoever. You are spinning the story in a typical clinic fashion.

 

[python]

you clearly did not read or can't understand the original document brought over for everyone's convenience to make an independent judgement. the spin is mis or lack of understanding of the gravity of the issue...

the wada notice explains that they banned the substance without understanding the rates of its clearance in the body. iow, they made a very important decision based on incomplete scientific basis. this is not a responsible science by any measure.

wada admits that unlike the previous assumptions of fast clearance, they did NOT appreciate the substance can stay in an athlete's body for months in some cases. they now (only now !) are conducting studies to fully size up the issue.

to be fair to wada, they are now giving credence to some critical voices (both among the scientists and athletes) that it is basically unfair to tarnish as dopers those who stopped using meldonium way before 1 january b/c wada did not conduct proper studies.

the inclusion of meldonium in the banned list was perhaps justified, but the solid science was not there. thus the current backpedalling.

in and by itself, in the past wada was NOT wrong by rushing to ban certain substances BEFORE they had the science sorted out. such was the epo, for instance. the idea was to dissuade the abuse until the epo test was ready and give the police grounds for searching.

but in the mildronate case, imo, it was not justified. simply b/c it is a basic substance for which the gc-ms test was long available and the understanding of clearance was just a matter of proper studies.

shoot 1st and only then sort out the bodies isn't very scientific.

 

[veganrob]

I find it really hard to believe that WADA did not do all the proper testing before banning Meldonium, and then giving all athletes plenty of notice about it. But...

 

[arcus]

^^ WADA simply don't have the budget to do exhaustive pharmacokinetic clinical studies for every substance included in the prohibited list. They rely on information in the scientific literature.
With meldonium, prior studies suggested a relatively short half-life (of <10 hours). In this context, very protracted periods of retention/excretion would be fairly unusual, so I have some sympathy for them.

 

[python]

Re:

^^ WADA simply don't have the budget to do exhaustive pharmacokinetic clinical studies for every substance included in the prohibited list. They rely on information in the scientific literature.
With meldonium, prior studies suggested a relatively short half-life (of <10 hours). In this context, very protracted periods of retention/excretion would be fairly unusual, so I have some sympathy for them.

while it is true about the budgetary limitations, they rely on the science community outside wada in almost all cases to varying degrees.

there are 2 very specific additional scientific issues here where wada (imo of course) could have been more attentive;
a) the manifold increase in the modern instrumentation sensitivity allows nowadays detection of such trace amounts that in the older studies were plain undetectable. i am positive wada was aware but somewhat too sloppy/rushful..thus, more care was needed before referring to meldonium as a non-specified substance, though eventually, this is probably a correct stance for a substance that has no natural biology.
b) those studies on the meldonium half-life that were public and available are probably greatly outnumbered by those conducted by the russian military (for whom the drug was created) and therefore NOT available.

but as i said, wada still has to be given some credit for being flexible and open-minded. there are already numerous unofficial reports in the social media and forums that quite a few have tested below 1 micro gram/dL.

that is, per the current wada thinking, they may have a valid claim to administering the drug last year only.

 

[yespatterns]

172 athletes, no TUEs even after the ban? That's a lot of heart conditions going untreated...

 

[Maxiton]

If the reason for the ban was political, then perhaps it was put on the fast track, before all the data was in. Conversely, whether the ban was political or not, this slight backtrack might be, in that WADA in its haste stepped on some toes they didn't mean to step on; so now they are providing a window of escape.

I wonder if Sharapova will be able to avail herself of this?

 

[arcus]

Re:

If the reason for the ban was political, then perhaps it was put on the fast track, before all the data was in. Conversely, whether the ban was political or not, this slight backtrack might be, in that WADA in its haste stepped on some toes they didn't mean to step on; so now they are providing a window of escape.

I wonder if Sharapova will be able to avail herself of this?

If her AAF was based on a urine meldonium concentration of <1 μg/mL, then I believe the ITF would have already exonerated her, as it wouldn't have been possible to sanction her for an ADRV based on WADAs most recent press release...

Sharapova's press conference statements at no time suggested that she had stopped taking the drug before the ban (an obvious public defense). In fact, they strongly implied the opposite. So, it seems like the tribunal will go ahead, and the period of sanction will depend on the tribunals considered opinion of her intent when taking the drug in January.

Her legal team's approach will be to deny (intent to take the drug to enhance performance) and obfuscate.. WADAs prevarication might help them in this respect. Her lawyer is already playing that card.

 

[Alex Simmons/RST]

So the ban, announced in September 2015 with their annual notice on changes to the prohibited list (possibly their most important communiqué for the year), was insufficient notice? Considering it was announced in September 2014 that it was on the monitoring list? Why is that not enough time?

It's not WADA's responsibility to be concerned with metabolism rates of drugs. It's the athlete's responsibility to ensure drugs are not present when they should not be. It's like those drugs that are only banned in-competition. It's the athlete's responsibility to ensure enough time for clearance before they enter competition time frame. This drug was flagged well in advance.

 

[python]

Re:

I wonder if Sharapova will be able to avail herself of this?

just personally heard from a reliable source that sharapova's urine concentration of the stuff was under the wada just announced limit of 1 micro gram...she's getting ready for her next tour.

many of her fans will probably be relieved.

..and here's the 3-h old link to confirm it.
http://www.stuff.co.nz/sport/other-sports/78902245/maria-sharapova-could-be-cleared-as-wada-announces-meldonium-amnesty

 

[Benotti69]

Re: Re:

I wonder if Sharapova will be able to avail herself of this?

just personally heard from a reliable source that sharapova's urine concentration of the stuff was under the wada just announced limit of 1 micro gram...she's getting ready for her next tour.

many of her fans will probably be relieved.

..and here's the 3-h old link to confirm it.
http://www.stuff.co.nz/sport/other-sports/78902245/maria-sharapova-could-be-cleared-as-wada-announces-meldonium-amnesty

Isn't it great that Ms Sharapova can continue to play sport at the highest level with a debilitating heart condition. So happy for her!

WADA all part of the circus.

 

[arcus]

Re: Re:

I wonder if Sharapova will be able to avail herself of this?

just personally heard from a reliable source that sharapova's urine concentration of the stuff was under the wada just announced limit of 1 micro gram...she's getting ready for her next tour.

many of her fans will probably be relieved.

..and here's the 3-h old link to confirm it.
http://www.stuff.co.nz/sport/other-sports/78902245/maria-sharapova-could-be-cleared-as-wada-announces-meldonium-amnesty

Sharapova, who said she had been taking meldonium for more than a decade because of health problems but had not used it since Jan. 1, was provisionally suspended by the International Tennis Federation (ITF) in March after announcing she had failed a test at the Australian Open.

The article clearly implies that she said this. The problem is that she didn't.

 

[Maxiton]

Re: Re:

I wonder if Sharapova will be able to avail herself of this?

just personally heard from a reliable source that sharapova's urine concentration of the stuff was under the wada just announced limit of 1 micro gram...she's getting ready for her next tour.

many of her fans will probably be relieved.

..and here's the 3-h old link to confirm it.
http://www.stuff.co.nz/sport/other-sports/78902245/maria-sharapova-could-be-cleared-as-wada-announces-meldonium-amnesty

Thanks, python, very interesting.

Maybe when they cast the net for Russians, they forgot that some certain Russians are effectively Americans who make a lot of money for a lot of people. (". . . there has been a call by stakeholders for further clarification and guidance.") Cast the net a bit too wide. Maybe. Anyway, good for Sharapova.

 

[BullsFan22]

Good or bad, I hope they look at all the cases for meldonium that popped up since Jan 1 and also clear those people, as they did Sharapova. It would only be fair. I've read and heard from the Russians, that many non-athletes take this for health reasons. Legitimate health reasons. Pro athletes have taken it as well, for years now, and most of them got the memo on time, that the drug is going to be banned by WADA on January 1. The problem is, whether or not it is actually a PED and if so, how long does it actually stay in the system. I've heard a few hours, sometimes up to a couple months. I still think there is an 'agenda' for the Russians, but this might be a start that shows that perhaps there isn't. I am not holding my breath though. If the IOC, WADA, IAAF, and other governing bodies of world sport involved in the Olympics decide to ban Russia from the Rio Games, while letting countries like the US (check out all the doping cases from that country), Kenya, Jamaica, France (was non-compliant), Turkey (non-compliant), etc get away with it without some sort of a sanction, then it most definitely is political. And no, I am not a Putin supporter. Just so we get that out of the way.

 

[Merckx index]

This is classic:

The Russian Sports Ministry supports and welcomes the decision made by Wada because it has shown a willingness to understand the situation, rather than stick to the rulebook," Mutko said in a statement.

So the ban, announced in September 2015 with their annual notice on changes to the prohibited list (possibly their most important communiqué for the year), was insufficient notice? Considering it was announced in September 2014 that it was on the monitoring list? Why is that not enough time?

It's not WADA's responsibility to be concerned with metabolism rates of drugs. It's the athlete's responsibility to ensure drugs are not present when they should not be. It's like those drugs that are only banned in-competition. It's the athlete's responsibility to ensure enough time for clearance before they enter competition time frame. This drug was flagged well in advance.

Good points.

Here's an article that indicates meldonium, or mildronate, clears quite quickly:

J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 15;878(5-6):551-6. doi: 10.1016/j.jchromb.2009.12.030. Epub 2010 Jan 6.
Determination of mildronate by LC-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.
Peng Y1, Yang J, Wang Z, Wang J, Liu Y, Luo Z, Wen A.

After single intravenously administration of 250, 500 and 1000 mg mildronate, the elimination half-life (t(1/2)) were (5.56+/-1.55), (6.46+/-1.07) and (6.55+/-1.17) h, respectively.

A couple more relevant articles:

http://dmd.aspetjournals.org/content/28/6/687.long
This is an animal study, showing that > 90% of radiocactivity excreted within 72 hours. Much of the radioactivity is from metabolic products, so the actual % of meldonium remaining in the body at this point would be less.

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2005.tb00267.x/epdf
This paper describes the general properties of meldonium, and reports at one point that it has a half-life in humans of 18 hours.

But these are somewhat older studies. According to the WADA report Python posted, there are newer data suggesting a prolonged second phase, so that a small amount of the drug remains in the body for a long period of time. AFAIK, these have not actually been published yet.

As was discussed here extensively during the Contador CB case, newer technologies that allow very small concentrations of substances to be detected can greatly extend potential elimination times, because many drugs will persist in the body for long periods of time at very small doses. When WADA says, though, that: "Long term urinary excretion below 1 μg/mL down to several hundred ng/mL can persist for a number of weeks and in the low tens of ng/mL for a few months", I wonder if they actually have those preliminary data, or are just projecting them based on amounts found in urine during shorter intervals.

 

[BullsFan22]

Re:

This is classic:

The Russian Sports Ministry supports and welcomes the decision made by Wada because it has shown a willingness to understand the situation, rather than stick to the rulebook," Mutko said in a statement.

So the ban, announced in September 2015 with their annual notice on changes to the prohibited list (possibly their most important communiqué for the year), was insufficient notice? Considering it was announced in September 2014 that it was on the monitoring list? Why is that not enough time?

It's not WADA's responsibility to be concerned with metabolism rates of drugs. It's the athlete's responsibility to ensure drugs are not present when they should not be. It's like those drugs that are only banned in-competition. It's the athlete's responsibility to ensure enough time for clearance before they enter competition time frame. This drug was flagged well in advance.

Good points.

Here's an article that indicates meldonium, or mildronate, clears quite quickly:

J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 15;878(5-6):551-6. doi: 10.1016/j.jchromb.2009.12.030. Epub 2010 Jan 6.
Determination of mildronate by LC-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.
Peng Y1, Yang J, Wang Z, Wang J, Liu Y, Luo Z, Wen A.

After single intravenously administration of 250, 500 and 1000 mg mildronate, the elimination half-life (t(1/2)) were (5.56+/-1.55), (6.46+/-1.07) and (6.55+/-1.17) h, respectively.

But I need to look around some more.

Really? What is WADA's purpose then? Why are they around if that's not one of their duties? If science is not one of their duties, they should move to the side and let someone with more credibility take over. If there is such a thing anymore.

 

[arcus]

WADA cannot be expected to independently prove the elimination kinetics of every drug on (or potentially on) the prohibited list. To do so in a manner that would stand-up to legal scrutiny, they would need to sponsor rigorous independent clinical trials for each and every compound with; 1] sufficient numbers of athletes (of both genders) to account for genetic variation in drug metabolism); 2] individuals of variable body type (since body fat% might affect the results), and 3] potentially different sports (since differential training methods might affect elimination parameters)... This would be practically and financially beyond the wildest dreams of "sport", let alone WADA as a body with limited funding.

The same applies to the recently touted idea that WADA needs to "prove" the performance enhancement capability of drugs before banning them. This would be practically impossible, given the number of potentially prohibited compounds and methods, and the variability across sports ages and genders.

WADA is a necessary compromise. It exists to provide a universally agreed-upon anti-doping code/platform, based on best available scientific information, so that doping can be regulated in manner that is not contaminated by the variability and vicissitudes of hundreds of legal jurisdictions.

 

[python]

below pls find a surprisingly informative article on the wada backpedaling from a main western msm, the ny times ...

'surprisingly', b/c not only the tone seems balanced but also b/c the scientific essence of the wada memo i posted earlier was restated on the whole w/o the typical mistakes a non-specialist would make.

WADA Opens a Door for Athletes Who Tested Positive for Meldonium
http://www.nytimes.com/2016/04/14/sports/wada-meldonium-drug-testing.html?_r=0

here's some other latest news not in the article...reportedly, at least 1/2 (50%) of the positive tests taken in february and january produced a concentration below the wada new 1 micro gram limit...some international federations already responded positively to the new wada guidance, specifically, i heard of wrestling, winter biathlon, tennis and speed skating...

 

[Alex Simmons/RST]

Re: Re:

This is classic:

The Russian Sports Ministry supports and welcomes the decision made by Wada because it has shown a willingness to understand the situation, rather than stick to the rulebook," Mutko said in a statement.

So the ban, announced in September 2015 with their annual notice on changes to the prohibited list (possibly their most important communiqué for the year), was insufficient notice? Considering it was announced in September 2014 that it was on the monitoring list? Why is that not enough time?

It's not WADA's responsibility to be concerned with metabolism rates of drugs. It's the athlete's responsibility to ensure drugs are not present when they should not be. It's like those drugs that are only banned in-competition. It's the athlete's responsibility to ensure enough time for clearance before they enter competition time frame. This drug was flagged well in advance.

Good points.

Here's an article that indicates meldonium, or mildronate, clears quite quickly:

J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 15;878(5-6):551-6. doi: 10.1016/j.jchromb.2009.12.030. Epub 2010 Jan 6.
Determination of mildronate by LC-MS/MS and its application to a pharmacokinetic study in healthy Chinese volunteers.
Peng Y1, Yang J, Wang Z, Wang J, Liu Y, Luo Z, Wen A.

After single intravenously administration of 250, 500 and 1000 mg mildronate, the elimination half-life (t(1/2)) were (5.56+/-1.55), (6.46+/-1.07) and (6.55+/-1.17) h, respectively.

But I need to look around some more.

Really? What is WADA's purpose then? Why are they around if that's not one of their duties? If science is not one of their duties, they should move to the side and let someone with more credibility take over. If there is such a thing anymore.

Putting aside issues of credibility, for sure science (or the funding of science) is an element of what WADA do, but drug metabolism / clearance rates are low priority science for WADA since strict liability for athletes applies.

WADA doing science to help doping athletes avoid detection is hardly a good use of their limited science funding.

WADA's science would be more directed at determining whether a substance or method should or should not be prohibited or perhaps what might constitute an appropriate maximum concentration level if it is not to be zero. Hence for example the science that was funded to research potential ergogenic properties of meldonium during the review period so that a decision on its inclusion or otherwise on the prohibited list could be an informed one.

 

[Nick C.]

Do you think there was pushback by whatever tennis powers that be there are b/c Sharapova managed to get herself caught in the net or would this have been happening regardless?

 

[python]

Re:

Do you think there was pushback by whatever tennis powers that be there are b/c Sharapova managed to get herself caught in the net or would this have been happening regardless?

my opinion - the whole backpedaling has nothing to do with any individual sports federation...

it was likely the result of several factors combined. one - the necessary one - was wada's timely realization that in its haste to expose 'evil dopers' they stepped on one of their own fundamental principle: in stead of protecting clean athletes, they likely implicated dozens that have done nothing wrong. it is obvious to me.

another, i guess, was that wada likely put itself in a weak legal position that, if adjudicated at cas, (as i hear the russian olympic committee quietly threatened to do)...wada based on its poor science basis would probably lose. the russians were intending to challenge not only the lack of science on the clearance rate but also the very inclusion of meldonium on the banned list, not to mention the wrong section s4.

what followed was the legal political compromise, imo

 

[BullsFan22]

Re: Re:

Do you think there was pushback by whatever tennis powers that be there are b/c Sharapova managed to get herself caught in the net or would this have been happening regardless?

my opinion - the whole backpedaling has nothing to do with any individual sports federation...

it was likely the result of several factors combined. one - the necessary one - was wada's timely realization that in its haste to expose 'evil dopers' they stepped on one of their own fundamental principle: in stead of protecting clean athletes, they likely implicated dozens that have done nothing wrong. it is obvious to me.

another, i guess, was that wada likely put itself in a weak legal position that, if adjudicated at cas, (as i hear the russian olympic committee quietly threatened to do)...wada based on its poor science basis would probably lose. the russians were intending to challenge not only the lack of science on the clearance rate but also the very inclusion of meldonium on the banned list, not to mention the wrong section s4.

what followed was the legal political compromise, imo

Good post. There are so many fails in this (WADA) that it beggars belief.

 

[Nick C.]

Re: Re:

Do you think there was pushback by whatever tennis powers that be there are b/c Sharapova managed to get herself caught in the net or would this have been happening regardless?

my opinion - the whole backpedaling has nothing to do with any individual sports federation...

it was likely the result of several factors combined. one - the necessary one - was wada's timely realization that in its haste to expose 'evil dopers' they stepped on one of their own fundamental principle: in stead of protecting clean athletes, they likely implicated dozens that have done nothing wrong. it is obvious to me.

another, i guess, was that wada likely put itself in a weak legal position that, if adjudicated at cas, (as i hear the russian olympic committee quietly threatened to do)...wada based on its poor science basis would probably lose. the russians were intending to challenge not only the lack of science on the clearance rate but also the very inclusion of meldonium on the banned list, not to mention the wrong section s4.

what followed was the legal political compromise, imo

thanks.