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All About Salbutamol

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What will the verdict in Froome's salbutamol case?

He will be cleared
43
34%
3 month ban
4
3%
6 month ban
15
12%
9 month ban
24
19%
1 year ban
16
13%
2 year ban
21
17%
4 year ban
3
2%
 
Total votes : 126

Re: All About Salbutamol

02 Mar 2018 05:39

Merckx index wrote:Froome must be wishing he played in the NCAA...

Allonzo Trier, the AZ basketball star who claimed that a second positive for ostarine resulted from substance retained in his body for more than a year following the first positive, has been cleared to play. The NCAA not only bought his outrageous explanation, but Trier missed only two games. So the entire process I guess took only about a week to ten days.

No long investigative process, no calling of expert witnesses, no citing of peer-reviewed studies, certainly no lab tests, just this confident statement from his lawyer:

“The experts tell us Ostarine can be stored in fatty tissues for a long time, and tests can be negative but then later be positive as the substance comes out. The medical evidence also shows that the reappearance of a trace amount in his system now creates absolutely zero competitive advantage.”


https://sports.yahoo.com/ill-timed-gaffe-costs-louisville-signature-win-needed-secure-ncaa-bid-033540007.html

See how smoothly things can run when you don't even pretend to care about doping? I'm not sure why the NCAA even bothers to test athletes. This opens the door for other athletes who test positive for the same substance twice, in fact, it encourages them to look at the first positive as a future get-of-jail-free card. It's sort of like developing immunity. Once you've tested positive to some drug, you never have to worry about future positives to the same drug.

Oh, and on the same day as this was announced, Arizona announced they were retaining the basketball team's coach, who was caught in an FBI wiretap offering $100,000 to one of Trier's now current teammates.

All's well in the world of college sports.


When a butterfly flaps its wings in ... c'mon, that's easy for a scientist like you, MI. ;)
Alpe73
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02 Mar 2018 12:20

When it comes to criminal behavior, NCAA is real close behind FIFA and IOC.
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02 Mar 2018 14:49

MI - You are 100% right - Why on earth are NADO's wasting time on Amateur sports, even though I'm certain 'under the table' payment's happen in the NCAA - My guess is NADO's rely on the payments from these agencies for conducting tests.
yaco
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27 Apr 2018 15:54

Dopeology's take on salbutamol:

https://www.dopeology.org/products/Salbutamol/

EDIT: A fair summary, MI?
Wiggo's Package
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Re:

29 Apr 2018 01:17

Wiggo's Package wrote:Dopeology's take on salbutamol:

https://www.dopeology.org/products/Salbutamol/

EDIT: A fair summary, MI?


It better be! I wrote it. Nice to know that people actual read those summaries. The site manager told me, though, that there are visitors from news and other organizations, some of whom use it to check on doping in sports other than cycling.

Since this thread has been revived, I might as well post this link to one of the body-building sites:

https://steroidly.com/clenbuterol-albuterol-salbutamol/

For weight loss, they suggest taking an oral dose of at least 2 mg four times daily for 15-30 days. Based on other studies I posted here earlier, that amount of salbutamol would probably trigger a positive test up to at least twelve hours after the final dose, and you'd certainly be unlikely to beat the threshold during the dosing period. So if you wanted to follow that regimen, you'd need to find a period of at least two weeks during the off-season when you felt you wouldn't be tested. Otherwise, use a lower dose. I think the maximum oral dose anyone could probably get away with is 2 mg/day, though there's so much variability that some individuals likely could take 4 mg or even more.
Merckx index
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Re: Re:

29 Apr 2018 09:25

Merckx index wrote:
Wiggo's Package wrote:Dopeology's take on salbutamol:

https://www.dopeology.org/products/Salbutamol/

EDIT: A fair summary, MI?


It better be! I wrote it. Nice to know that people actual read those summaries. The site manager told me, though, that there are visitors from news and other organizations, some of whom use it to check on doping in sports other than cycling.



:D
Wiggo's Package
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29 Apr 2018 11:10

A must read for the fanboys. But then they still wouldn't believe it.
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Re: All About Salbutamol

02 May 2018 18:52

I'm an actual exercise enduced asthma sufferer. 200ug Salbutamol tends to do the tricks.

It started in the summer of 2003. Winters I was fine for a while, and then winters were added.
This winter I needed Salbutamol to somewhat decently get through my bike commute. It's mostly urban, so I am not TT'ing this one.
When I hit a nasty "cold" in January, I went to stock up on vitamines, I'd been out for a while. A friend tipped to get some Vitamine E. No particular reason, just good to supplement.
Guess what? Asthma went, from one day to the next. I've not taken a hit since. Even when running at around my LT.

I then looked it up, and indeed Vit. A is associated with possible improvement of asthmatic symptoms. Just, in bottled capsules, usually it's supposedly the wrong of 2 variations. Still, despite being the wrong one, I seem to be getting the advantages. With a sub-maximum advised dosage no less, and I'm a big dude.
Come June my asthma will be tempted much more, in July I'll know whether this is the CURE.

Anyone else try Vit. E for their symptoms?
Cloxxki
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04 May 2018 09:25

Another one in Froome's favor?

Using available pharmacological knowledge, we demonstrate that the current approach to detect excessive salbutamol use is fundamentally flawed and cannot differentiate between illegal and allowed use," said co-author Jules Heuberger, of the Centre for Human Drug Research, in Leiden, The Netherlands. "If the doping community is determined to control for excessive salbutamol use, these procedures should be changed, ideally in collaboration with clinical pharmacologists."
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Re: All About Salbutamol

04 May 2018 21:15

edit
pastronef
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04 May 2018 23:10

https://sci-hub.tw/10.1111/bcp.13619

Froome's team must be aware of this paper. This may be what he has been referring to when he’s expressed confidence in getting off. It would also seem to be what his team would have been referring to when trying to argue that the salbutamol test was invalid, as was initially reported a few weeks ago, though then denied by Lappartient.

So, how much does this help Froome? The first thing to point out is that this is a theoretical study—no new data are being reported. The authors built a model of salbutamol elimination from various published pharmacokinetic data, and used it to estimate how much salbutamol would be present in the urine various times after a permitted dose (800 ug within twelve hours). They claim that about 15% of the time, the urine concentration one hour after this dose would exceed the 1000 ng/ml. threshold. A second conclusion—and this is important, as it could get lost in all the speculation about Froome—is that 8 mg salbuamol taken orally every day will usually be indetectable within two days after the last dose.

So they’re arguing not only that the WADA threshold may frequently be exceeded by athletes taking the permitted dose, but that the test won’t catch a lot of intentional dopers, either. IOW, the worst of both worlds—a high false positive rate coupled with a high false negative rate.

Before Froome supporters jump for joy, though, here are some points to keep in mind. First, the 15% figure is for urine level one hour after the dose. Froome reportedly took a few puffs at the end of that Vuelta stage, but there’s no indication he took anywhere near 800 ug at that time. Two or three puffs shortly before testing aren’t gong to make the case. He would need to show that he took a lot more during the last hour or two of the stage, and that he didn’t urinate during that period. He can’t presumably prove how much he took and when, and certainly taking that much salbutamol in such a short period of time would be very unusual.

Second, the model estimates urine concentrations assuming no urination between taking the dose and testing. For the one hour time point, that’s certainly reasonable. For longer times, it probably wouldn’t be. E.g., if a rider inhaled a large amount of salbutamol before a race, and urinated some time during the race, the estimated levels would be significantly lower. Indeed, the possibility of very high urine concentrations after one hour also means the possibility of getting rid of much of the drug just by urinating once. That would actually work in favor of riders. IOW, if you are one of that 15% minority with very high urine levels after one hour, your odds of beating the test are better if you urinate at some point between taking the dose and being tested.

Third, the authors focused on the 1000 ng/ml threshold, not the 1200 ng/ml decision level, let alone the 2000 ng/ml level Froome reported. They do note that if one uses the 1200 ng/ml level, 10% of the one hour samples are above the threshold. They don't provide an estimate for 2000 ng/ml, but I'd guess it's less than 5%, maybe as as low as 1-2%.

Fourth, if I understand this study correctly, the model is based on inter-subject variability, i.e., the amount of samples exhibiting a certain urine level are from different subjects. The assumption is that most of the variability is between subjects, rather than within a subject being tested at different times. If a subject is in that 15% pool one time, he therefore should be in it on subsequent tests, whereas if he isn't in that pool once, he won't be in it at other times. This is undoubtedly an oversimplification, and the authors themselves emphasize that their will be some intra-subject variability, but the implication is that if a subject exceeds the threshold once, he's likely to do it again.

This doesn't help Froome. By my count he has been tested 79 times in GTs, and presumably a few more times in other races or OOC, so there should be a large body of data bearing on his salbutamol excretion. Unless in this one stage he took a large dose near the end, and never or very rarely did this ever before, one would expect if he were one of the outlier subjects, he would have exceeded the threshold previously. For the same reason, one would think that he could demonstrate this in a lab test.

So while of course Froome will be using this study to support his defense, I’m not at all convinced it will (or perhaps I should say, ought to) help him that much. This same study predicts that if he took most of the 800 ug earlier in the race or before the race, and urinated at some time during the race, a 2000 ng/ml level would be very unlikely. Even if he took the entire 800 ug in the last hour or two of the stage, no urination before testing, the probability of 2000 ng/ml would still be quite low, probably close to the beyond reasonable doubt range. Moreover, keep in mind that doping cases are supposed to be decided by evidence between preponderance, > 50%, and reasonable doubt. Reasonable doubt comes into the design of the test—it could be used to argue that a test is invalid—but it wouldn’t apply to a specific case. So Froome would have to argue that this paper invalidates the test. Remember a few weeks ago it was reported that he was doing this, but then Lappartient denied this.

Finally, does this invalidate all the empirical data that WADA has based its test on? No. It mostly shows that if one maximizes the possibility of exceeding the threshold—by taking the full 800 ug, then being tested one hour later—in theory, the threshold may be exceeded a significant number of times. In practice, in the actual studies, the threshold was exceeded far less often. Part of that is because not all the studies tested urine one hour later. The model these authors used predicts about 3% of the values would be > 1000 ng/ml if tested four hours after the dose, and they note this is consistent with an actual study in which 1/28 subjects exceeded this threshold. I also previously estimated about 3% based on about half a dozen studies, with varying times between dose and testing. If Froome had exceeded the threshold by a relatively small amount, I believe his case would be much stronger, but 2000 ng/ml remains a very high level to explain.

In addition, though, the model is of course not necessarily perfectly accurate. The authors note that they had to estimate plasma and urine concentrations from separate studies, and they also had to obtain some parameters from animal studies, which then had to be corrected to fit with human values. These factors don't invalidate their model at all, but of course they introduce some uncertainty into it.

Edit: I’ve had a chance to look at this paper a little more closely, and I see some more potential issues. First, Fig. 2 shows the predicted and actual (according to one study) urine concentrations following an inhaled dose of 1600 ug. While there are several samples > 1000 ng/ml, the median predicted value is < 1000 ng/ml. Now look at Fig. 3, which shows predicted urine concentrations for 800 ug. inhaled dose. The median value is about 800 ng/ml, practically the same as predicted for twice the dose, as indicated in Fig. 2.

Why? Figure 3 is based on steady state kinetics, i.e., instead of considering a single 800 ug dose, it’s assumed the subject takes 800 ug every twelve hours over a period of time. While most of the salbutamol is excreted after 12 hours, not all of it is, and it builds up over time. Apparently—they don’t discuss this—this effect is enough to make 800 ug almost the same as 1600 ug. The question is whether this is realistic, i.e., would a rider actually take the maximum dose every twelve hours over a period of time? I assume if he did, he must have a very serious problem. Keep in mind he would have to dose heavily during the night to maintain a regimen like this.

Second, Fig. 3 shows the maximum (and minimum) predicted urine concentrations in 99.9% of the subjects (dotted blue line). Assuming a normal distribution, this corresponds to 3.3 SD above and below the mean. The mean or median is about 800 ng/ml (solid red line), and the peak blue line value is 4000 ng/ml, from which it follow that the SD should be about 1000 ng/ml. But if that’s the case, about 16% of the subjects should have urine levels > one SD above the mean, viz., 1800 ng/ml. Yet the authors say that about this proportion of subjects (15.4%) are predicted to exceed a much lower level, 1000 ng/ml. They also say that about 10% of subjects are predicted to have levels > 1200 ng/ml. These two data points, together, suggest a SD of a little more than 300 ng/ml.

So I don’t understand how they’re coming to their conclusions; they don’t provide enough data to clarify them. It’s a very critical point, because obviously one would like to use their model to predict how likely it is that a rider, such as Froome, would return a level of 2000 ng/ml. The probability seems very low, and they obviously could have easily determined it, but they don’t, and that together with the apparent inconsistency in their values leaves me, at least, at a loss to do it myself.

Maybe a statistician can help out here?
Last edited by Merckx index on 05 May 2018 08:40, edited 1 time in total.
Merckx index
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Re: All About Salbutamol

05 May 2018 01:49

Not sure if I linked this correctly but the paper referred to in the 'EPO is Apparently Useless' topic is by the same lead author innit?

viewtopic.php?f=20&t=33344
Tyre Byter
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Re: All About Salbutamol

05 May 2018 02:23

Tyre Byter wrote:Not sure if I linked this correctly but the paper referred to in the 'EPO is Apparently Useless' topic is by the same lead author innit?

viewtopic.php?f=20&t=33344


Good catch! Yes, two of the three authors of this new theoretical salbutamol study also were authors of that EPO study:

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.12034
Merckx index
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Re: All About Salbutamol

05 May 2018 03:00

Merckx index wrote:
Tyre Byter wrote:Not sure if I linked this correctly but the paper referred to in the 'EPO is Apparently Useless' topic is by the same lead author innit?

viewtopic.php?f=20&t=33344


Good catch! Yes, two of the three authors of this new theoretical salbutamol study also were authors of that EPO study:

https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.12034


As they say, you can't make this sh*t up. I hope this will be brought up in court. No doubt (for me), the study was paid by Froome's legal team. Explains both the delay and his confidence.
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Re: All About Salbutamol

05 May 2018 03:52

fasthill wrote:
As they say, you can't make this sh*t up. I hope this will be brought up in court. No doubt (for me), the study was paid by Froome's legal team. Explains both the delay and his confidence.


Well, in the pre-publication version I have, there's no mention of funding. They will have to acknowledge this when it appears in the journal. There's certainly nothing wrong with commissioning such a study, if one is transparent about it, and the judge understands that the authors are in effect acting as expert witnesses on behalf of the defense. However, the authors seem to deny this:

The authors declare no conflicts of interest. JH is a recreational cyclist and is a fan of professional road cycling, but other than as a spectator and from its clinical pharmacology aspects not involved in the sport. SvD and AC watch professional cycling but are mainly excited by its clinical pharmacology aspects.


Anyway, while they may have no conflict of interest, I find it very interesting that they mention Froome specifically; in fact, he's the subject of the opening paragraph of the introduction, beginning with the first sentence:

Recently one of the most successful male cyclists of the last decade, Chris Froome, came into
disrepute due to news of a potential doping violation.


Followed later by:

Currently, over six months since the concerned urine sample, there is still no news of such a controlled study, which is perhaps not surprising: the burden is with the accused and setting up a robust study requires expertise.


I don't agree with that, riders are routinely tested for salbutamol, setting up a study is basically repeating a ride, in the lab. The only potentially difficult aspect is if one wants to mimic as closely as possible the conditions on the road.

They also play the not-likely-doping card:

beta-2 agonists might give an advantage in sports, but only at very high concentrations and for very short (power) disciplines. It is therefore doubtful that multi-stage (endurance) cyclists like Chris Froome would benefit even from high doses of beta-2 agonists apart from when treating asthmatic symptoms.


Interestingly, the Netherlands seems to be a center for research aimed at showing that doping is greatly exaggerated. Another Dutch team, which cited the EPO paper, published a multi-part study of GT time trials, from which they concluded that the increase in speeds in 1990s and early part of this century was quite consistent with earlier increases, providing little evidence for doping:

https://www.scitechnol.com/lance-armstrongs-era-of-performance-part-i-are-his-time-trial-performances-much-different-from-other-winners-pWG0.php?article_id=592
.
.
Merckx index
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Re: All About Salbutamol

05 May 2018 17:23

You must take responsibility for what you “ingest,” meaning what you eat and drink and anything that
may enter your body. The essential rule is this: if it is in your body, you are responsible for it. In legal
terms, this is called “strict liability.”

It is not a defense that a prohibited substance or method would not have improved your performance


https://www.wada-ama.org/sites/default/files/resources/files/wada-reference-guide-to-2015-code.pdf
Last edited by 70kmph on 05 May 2018 18:27, edited 2 times in total.
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05 May 2018 17:51

It's even possible, that Froome/Sky financially supported the authors when they were drafting article ... .

Second point, we have to re-view the Vuelta stage in question since since effect of such level of salbutamol would be shaking hands. Did hands of Froome shaked during or after the stage? I would say it would be more visible after the race, is anyone aware of any recording of Froome's press conference or just any recordings of him after the stage?
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Re: All About Salbutamol

05 May 2018 18:24

70kmph wrote:You must take responsibility for what you “ingest,” meaning what you eat and drink and anything that
may enter your body. The essential rule is this: if it is in your body, you are responsible for it. In legal
terms, this is called “strict liability.”

https://www.wada-ama.org/sites/default/files/resources/files/wada-reference-guide-to-2015-code.pdf


Except there is no strict liability for salbutamol. EPO, sure.
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Re: All About Salbutamol

05 May 2018 18:40

hazaran

Except there is no strict liability for salbutamol. EPO, sure.


“Specified” substances are not necessarily less effective doping agents than “Non-Specified” substances, nor do they relieve athletes of the strict liability rule that makes them responsible for all substances that enter their body.

https://www.wada-ama.org/en/questions-answers/prohibited-list-qa#item-387
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Re:

05 May 2018 21:35

fasthill wrote:Another one in Froome's favor?]

The synthesised model was able to predict the literature data well. Simulations showed a very large range of salbutamol concentrations, with a significant portion of virtual subjects (15.4%) exceeding the WADA threshold limit of 1000ng/mL at 1 hour post‐dose

Pros
- Useful to Froome's defense since casts doubt on a certain salbutamol concentration which in simulation was exceeded 'accidentally' 15 percent of the time

Cons
- A meta-study combining lots of different tests done by other groups under different protocols and conditions
- A theoretical study using computer math equations alone, which has no physical basis
- Offers nothing new to explain how 2000ng/ml could have been 'accidentally' exceeded, since no iteration of their computer model is claimed to have reached 2000ng/ml. That actually is more damaging to Froome's case than helpful
- Comes out too late for Froome's defense at Anti-Doping Tribunal, anything that his legal team wanted to submit to Ulrich Haas had to be submitted on paper a long time ago, new 'evidence' is not accepted at this point
- Very suspicious in its timing and specific references to Froome, tailor-made to his doping case, low rank of the journal, British nationality of editors
- In press, not actually published, so the final version and date of publication is unknown

So it won't save Froome from being banned by ADT, but is likely to be used as a reference during his appeal to CAS
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