All About Salbutamol

[brownbobby]

At his Science of Sport website, Ross Tucker has a 7 minute video discussing the kidney malfunction theory. He provides one piece of new information: he says that back in December, right after the leak of the AAF, he heard several sources close to the investigation report that this was going to be part of Froome’s defense. IOW, this isn’t necessarily a last resort, something Froome turned to because there was no other way of explaining the positive.

Watched the whole video, that is some important background information. Can't say for certain because it's all rumors reported by unspecified "knowledgeable sources" to the media. But explains what Sky may have been doing from September - early December. They didn't expect the doping positive to go public, but they did expect Froome would have to explain the AAF at some point. And were fiddling with every possible approach long beforehand

Finally, something that just occurred to me. If salbutamol excretion was inhibited, it would remain in the blood for a relatively long time. This means it would pass through the liver and be metabolized, mainly sulfated. This would affect the enantiomer test, which depends on differential rates of sulfation for the two stereoisomers.

Excellent point. That's another potential pitfall for the defense if they don't take it into account.

So this is a double-edged sword. On the one hand, assuming Froome's sample doesn't pass the enantiomer test, as I suspect has already been established, the renal impairment theory could explain this. OTOH, unless they have other solid evidence for this theory, like a string of very low levels preceding stage 18, some of the most important evidence won't help them. It can be interpreted as indicating intentional doping.

Froome's defense team are at a big disadvantage in not knowing what is in his urine samples from each day, so they are taking a shot in the dark. A theory of general renal failure can be easily disproved by UCI who have the bio-chemical evidence in hand of normal kidney function. Tucker says in the video "You can imagine that there's going to be some very hefty and detailed renal physiology... that could get quite murky and complicated to follow". Probably true, but I still don't see how any amount of conjecture and rambling by lawyers will prove an unprecedented claim of selective retention of salbutamol over the course of days. It's not a large molecule, does not have any really unusual functional groups, and is structurally similar to some very fundamental naturally occurring molecules...

For example, wouldn't a routine catecholamine test be enough to dispel this selectivity claim?

Won't the defense team have full access to allow them to know exactly what was in his samples from each relevant day?

 

[ScienceIsCool]

Won't the defense team have full access to allow them to know exactly what was in his samples from each relevant day?

I can't see why they would. I'm sure they could request the samples to be tested for a particular substance, but I doubt they'd be allowed to go fishing.

John Swanson

 

[veganrob]

How can Sky even present a ridiculous defense as this? Shouldn't they have to present proof the salbutamol retention story is fact not just some outlandish possibility. There is already prooof of the too high level in his system.

 

[Wiggo's Package]

Will the UCI/CAS be allowed to take into account more plausible but illegal reasons for Froome's salbutamol spike than his renal malfunction defence?

Of possible relevance are Ashenden's comments about Contador's CAS hearing where Contador's lawyers used legal sleight of hand to prevent Ashenden testifying on key issues - tactics no doubt if great interest to Froome's lawyer

Btw the whole of Ashenden's NYVelocity interview is well worth revisiting

http://nyvelocity.com/articles/interviews/behind-the-scenes-of-the-contador-cas-hearing-with-michael-ashenden/

'Ashenden Barred from Testifying

AS: Was that some of what you were prevented from testifying to, and was that information critical in allowing the arbitration panel to formulate its final ruling?

MA: I would refer you to paragraphs 147 and 148 of the CAS ruling, which describes both UCI and WADA’s views on how the hearing was conducted.

Among other things, I was prevented from testifying about non-DEHP bags. It was a surreal situation to be confronted with, because it was such a simple issue to resolve completely and without room for doubt in about 30 seconds, yet the arguments to prevent me from confirming that non-DEHP bags existed took hours. I recognise that arbitration hearings must be conducted in accordance with legal rules, but that does not remedy the frustration I felt when I was categorically ordered by the chairman not to answer the question, but instead the question was directed to the person sitting right next to me who did not know the answer.

The upshot was what you read in paragraph 409 – the Panel took into account the evidence and arguments presented by the parties, but because I could not present definitive evidence about the existence of non-DEHP bags the panel instead had to rely on the answers provided by Contador’s experts.

Likewise, I was prevented from talking about the volume of plasma that would be required to successfully mask haemoglobin levels. Calculations had been made about the volume of plasma that would have had to be infused to yield the amount of clenbuterol found in Contador’s urine. Contador’s expert had raised doubt whether those volumes could be safely infused in humans. By extension, this cast doubt on my transfusion theory. Their expert was just plain wrong, but I was not allowed to point this out to the panel because I had not mentioned it during my written submission. In simple terms, because I had not known six months earlier when I submitted my written opinion that their expert would raise such a spurious point during the hearing, I was not allowed to explain to the panel that his evidence was wrong.'

 

[Rollthedice]

Of possible relevance are Ashenden's comments about Contador's CAS hearing where Contador's lawyers used legal sleight of hand to prevent Ashenden testifying on key issues - tactics no doubt if great interest to Froome's lawyer

Since it's the same lawyers involved with Froome, it is quite possible. Nevertheless, Morgan was so "good" that Contador got 2 years and 2GTs stripped.

 

[Merckx index]

Froome's defense team are at a big disadvantage in not knowing what is in his urine samples from each day, so they are taking a shot in the dark. A theory of general renal failure can be easily disproved by UCI who have the bio-chemical evidence in hand of normal kidney function. Tucker says in the video "You can imagine that there's going to be some very hefty and detailed renal physiology... that could get quite murky and complicated to follow". Probably true, but I still don't see how any amount of conjecture and rambling by lawyers will prove an unprecedented claim of selective retention of salbutamol over the course of days.

This is a very good point. Though it hasn’t been reported one way or another AFAIK, I’ve been assuming they’re going to claim that there was just general renal impairment. You’re right, if there wasn’t, LADS can probably establish that by reporting levels of some markers, but my guess is this hasn’t been done yet.

Establishing selective impairment would seem to be very difficult. It begins with showing that salbutamol levels were unusually low in one or more stages prior to stage 18, but as others have pointed out, without proof of how much salbutamol Froome took during those stages, which I doubt he has, low levels don’t constitute strong evidence of altered renal function. Same with changes in the S/R enantiomer ratio. To interpret a high ratio as evidence of prolonged presence of salbutamol in the blood, they have to assume Froome didn’t take the drug orally, which of course is Q.E.D.

So then you consider levels of structurally similar endogenous adrenergic agonists, namely epinephrine (E) and norepinephrine (NE). They would need to establish some kind of a baseline for Froome, and demonstrate that his E or NE levels on one or more days before stage 18 were significantly below this baseline. But the problem is that these levels in the urine can vary over a very wide range, maybe as much as 50-fold, not because of any variation in renal function, but because of physiological and hormonal changes. Indeed, E and NE levels in the urine are used as an insight into one’s physiological or even psychological state. When one observes these levels fluctuate, one doesn’t take that as evidence of changes in renal function. To complicate matters further, both hormones are synthesized in the adrenal (of course) glands and can themselves alter urine output.

That said, here is a study of catecholamine excretion in patients with chronic renal failure. They concluded that dopamine and NE excretion correlated with creatinine clearance—i.e., that their excretion was reduced as general renal function declined—while E excretion did not correlate, though it was also reduced as renal failure progressed. So this study does provide some evidence for a selective effect on epinephrine—or more precisely, that epinephrine excretion may not follow general excretion patterns--which of the three catecholamines studied is most similar to salbutamol in that it has significant interaction with b2-receptors. I’m going to look into this further when I have more time.

http://sci-hub.la/10.1177/000456329903600504

 

[Netserk]

Re:

Of possible relevance are Ashenden's comments about Contador's CAS hearing where Contador's lawyers used legal sleight of hand to prevent Ashenden testifying on key issues - tactics no doubt if great interest to Froome's lawyer

Since it's the same lawyers involved with Froome, it is quite possible. Nevertheless, Morgan was so "good" that Contador got 2 years and 2GTs stripped.

He was only benched 6 months, and I doubt there was a scenario where he was more likely to sit out a shorter period of time. Likewise, I think Froome would love if when he is sanctioned that it is entirely backdated.

 

[TourOfSardinia]

But the problem is that these levels in the urine can vary over a very wide range, maybe as much as 50-fold, not because of any variation in renal function, but because of physiological and hormonal changes.

This one is awesome !

Hormone levels of world class cyclists during the Tour of Spain stage race
http://bjsm.bmj.com/content/35/6/424

British Journal of Sports Medicine, the experimental subjects were all racers in the 1999 Vuelta...
"Nine male cyclists from one of the world's leading professional teams were recruited to participate in the investigation"
Anyone wanna guess which team it was

This study was financed by Agrupación Deportiva Banesto.

 

[thehog]

Re:

How can Sky even present a ridiculous defense as this? Shouldn't they have to present proof the salbutamol retention story is fact not just some outlandish possibility. There is already prooof of the too high level in his system.

And remember Altitude Natives is a real thing proven by Sky and it’s specially commissioned study

 

[macbindle]

Re:

How can Sky even present a ridiculous defense as this? Shouldn't they have to present proof the salbutamol retention story is fact not just some outlandish possibility. There is already prooof of the too high level in his system.

It's all just part of the fun, Rob.

 

[Merckx index]

The Independent understands the case is still in the preliminary stage of assessing potential factors to have caused the test result and kidney malfunction – reported as Froome’s primary line of defence – is only one of a number of factors being examined.

http://www.independent.co.uk/sport/cycling/chris-froome-team-sky-cycling-news-uci-david-lappartient-tour-down-under-a8170606.html

So maybe the kidney defense isn’t the sole focus, after all? It seems we're back to square one, where everything is still on the table. If that's the situation after all this time, if they're still in "the preliminary stage", then obviously there's nothing in all the information they have, including Froome's levels in the preceding stages, that's particularly helpful. If the Independent is right--and maybe they're not, their view seems to contradict what others were reporting a few days ago--they don't have any theory that they even think might explain the facts.

I almost wonder if Froome's team threw out the kidney theory, watched it get ridiculed in social media, and quickly back-tracked to "it's just one of many possibilities". But why would someone who tried to hide the positive until it was leaked provide any clues to the public about his defense? My guess is that this is another way in which the pressure to either suspend Froome or resolve the case quickly is getting to him. By announcing that they think they have some specific way of explaining the positive, they're hoping that the cycling community will understand the reason for the delay, and why Froome feels entitled to ride the Giro. "Just be patient, everything will make sense soon". At the very least, I think if Froome's team was confident they had a valid explanation, they would emphasize this, as a way of taking off the pressure, whether or not they told anyone what the explanation was.

 

[Robert5091]

Since Froome has no logical explanation, then maybe his last hope is: that lawyers try to subvert the courtroom process itself, with baffling maneuvers and technicalities

I expect nothing less then a full blown circus with lawyers aplenty and the Chewbacca defense https://en.wikipedia.org/wiki/Chewbacca_defense. SDB doing lots of hand waving as well.

 

[Netserk]

Hehe, that bat-signal should see TFF appear pronto.

 

[lartiste]

Since Froome has no logical explanation, then maybe his last hope is: that lawyers try to subvert the courtroom process itself, with baffling maneuvers and technicalities

I expect nothing less then a full blown circus with lawyers aplenty and the Chewbacca defense https://en.wikipedia.org/wiki/Chewbacca_defense. SDB doing lots of hand waving as well.

The outcome of such defense in continental law system is very limited, lawyers are dealing with professionals not with dilettante (jury). Such defense may limit a bit losses, but most probably will not succeed. And even kind of such defense in Contador case did not succeed and he got the ban ... . For Froome, if I understand it properly, to found him guilty will be very damaging, he will loose his Vuelta title, WC time trial medal and possibly also option to ride Giro.

 

[Merckx index]

Here are some of the legal defenses currently being considered by Team Froome:

The lab test defense: If he can repeat it in Lausanne, you can’t give him a ban
The dehydration defense: If it’s over 1030, he can’t be so dirty.
The kidney defense: If it went to high from low, he gets to start the Giro.
The altered metabolism defense: If on diet it depends, you can’t his season suspend
The made a mistake defense: If he doesn’t try to hide it, you must let him ride it.
The innocent till guilty defense: If he’s banned but wins at CAS, we’ll bloody sue your ass.

 

[thehog]

Since Froome has no logical explanation, then maybe his last hope is: that lawyers try to subvert the courtroom process itself, with baffling maneuvers and technicalities

I expect nothing less then a full blown circus with lawyers aplenty and the Chewbacca defense https://en.wikipedia.org/wiki/Chewbacca_defense. SDB doing lots of hand waving as well.

The outcome of such defense in continental law system is very limited, lawyers are dealing with professionals not with dilettante (jury). Such defense may limit a bit losses, but most probably will not succeed. And even kind of such defense in Contador case did not succeed and he got the ban ... . For Froome, if I understand it properly, to found him guilty will be very damaging, he will loose his Vuelta title, WC time trial medal and possibly also option to ride Giro.

Depends on the court system and state in the US. Generally in criminal trials you are not allowed to provide an “alternate” version, you can only defend yourself against the charges. Alternate versions is what gets into Chewbacca territory and courts frown upon it. In Froome’s case he has to provide an alternate theory for his reading of Salbutamol but he also has to prove biologicallly that it’s true. That will be very difficult to do.

 

[Merckx index]

Now here's an interesting idea. Could having asthma actually benefit endurance athletes, because as with high altitude training, the body adapts to lower oxygen levels? One asthmatic claims something like this:

training with asthma is a lot like resistance training; you get used to a reduced ability to draw oxygen into your lungs, thereby restricting the supply that gets to your muscles. Its like reverse blood-doping. You get used to it and your body adjusts to the reduced supply of gun fuel. Then, on days when the air is clear and warm, you ride like you’re on EPO. I call this the “EPO-Effect”.

http://www.velominati.com/folklore/asthmatics/

There have been some studies that suggest asthmatics may actually have more efficient physiology because of this:

http://www.scielo.br/scielo.php?pid=S1806-37132011000600003&script=sci_arttext&tlng=en
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492492/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492492/#pone.0132007.ref006
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150973/

It's well known that large percentages of elite athletes have asthma, and one study reported that Olympic athletes with asthma actually won more medals per group size than athletes without asthma. The usual explanation for this is that having to take in large amounts of air during training may stress the lining of the lungs, so elite athletes are more at risk for developing EIA. But is it possible that another reason is that asthmatics undergo adaptive changes that increase metabolic efficiency?

Another interesting phenomenon is the refractory period that asthmatics experience. After you have an asthma attack, you are apparently protected against a further attack for a couple of hours. Posters who suffer from disorder can comment on this:

Sarah Koch and Michael Koehle at the University of British Columbia's Environmental Physiology Laboratory, funded by the World Anti-Doping Agency

…tested 42 elite cyclists, 10 of whom had "exercise-induced bronchoconstriction" (the correct term for asthma-like symptoms triggered by exercise). Each cyclist performed two 10-kilometre time trials, with or without drugs, in a double-blinded design. The result: no differences in finishing time, even for the asthmatics…

So why did the UBC study find no discernible effect? Dr. Koehle offers a surprisingly simple explanation: The subjects in his and other studies all had thorough warm-ups before their exercise tests, making them less likely to suffer an asthma attack whether they received the drugs or the inactive placebo.

It turns out that asthma attacks produce a "refractory period," during which the airways become temporarily immune from a further attack. As a result, a warm-up that is sufficiently long and intense to sensitize the airways may allow athletes to get through their competition or time trial without suffering an attack.

Most elite athletes already do this kind of warm-up as a matter of course, but others can benefit too. "With a better warm-up, you can get away with less drugs," Dr. Koehle says.

https://www.theglobeandmail.com/life/health-and-fitness/fitness/why-asthma-doesnt-stop-elite-athletes/article4445211/

 

[movingtarget]

Now here's an interesting idea. Could having asthma actually benefit endurance athletes, because as with high altitude training, the body adapts to lower oxygen levels? One asthmatic claims something like this:

training with asthma is a lot like resistance training; you get used to a reduced ability to draw oxygen into your lungs, thereby restricting the supply that gets to your muscles. Its like reverse blood-doping. You get used to it and your body adjusts to the reduced supply of gun fuel. Then, on days when the air is clear and warm, you ride like you’re on EPO. I call this the “EPO-Effect”.

http://www.velominati.com/folklore/asthmatics/

There have been some studies that suggest asthmatics may actually have more efficient physiology because of this:

http://www.scielo.br/scielo.php?pid=S1806-37132011000600003&script=sci_arttext&tlng=en
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492492/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492492/#pone.0132007.ref006
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150973/

It's well known that large percentages of elite athletes have asthma, and one study reported that Olympic athletes with asthma actually won more medals per group size than athletes without asthma. The usual explanation for this is that having to take in large amounts of air during training may stress the lining of the lungs, so elite athletes are more at risk for developing EIA. But is it possible that another reason is that asthmatics undergo adaptive changes that increase metabolic efficiency?

Another interesting phenomenon is the refractory period that asthmatics experience. After you have an asthma attack, you are apparently protected against a further attack for a couple of hours. Posters who suffer from disorder can comment on this:

Sarah Koch and Michael Koehle at the University of British Columbia's Environmental Physiology Laboratory, funded by the World Anti-Doping Agency

…tested 42 elite cyclists, 10 of whom had "exercise-induced bronchoconstriction" (the correct term for asthma-like symptoms triggered by exercise). Each cyclist performed two 10-kilometre time trials, with or without drugs, in a double-blinded design. The result: no differences in finishing time, even for the asthmatics…

So why did the UBC study find no discernible effect? Dr. Koehle offers a surprisingly simple explanation: The subjects in his and other studies all had thorough warm-ups before their exercise tests, making them less likely to suffer an asthma attack whether they received the drugs or the inactive placebo.

It turns out that asthma attacks produce a "refractory period," during which the airways become temporarily immune from a further attack. As a result, a warm-up that is sufficiently long and intense to sensitize the airways may allow athletes to get through their competition or time trial without suffering an attack.

Most elite athletes already do this kind of warm-up as a matter of course, but others can benefit too. "With a better warm-up, you can get away with less drugs," Dr. Koehle says.

https://www.theglobeandmail.com/life/health-and-fitness/fitness/why-asthma-doesnt-stop-elite-athletes/article4445211/

Certainly not my experience but that is with an intense warm up, only racing over 10 kms and using elite athletes. The Joe Average like myself didn't warm up like that or race like that in road races. Curious results I have to admit. The superior heart and lung function of elite athletes obviously plays a part. But not all EIA wheeze or have an attack every time they exercise either. If anything it makes me think that too many people are using asthma drugs without really needing them. Similar to other over prescribed drugs.

 

[samhocking]

Not scientific, I know, but the fastest natural runner on least amount of training I've ever known is my asthma-suffering wife. When we lived in London and her asthma was its worse, on the few days she could train at maximum without suffering symptoms that day she would post some really incredible times. Even if she took Ventolin and felt fine, if she was asthmatic that day before the run she would always be around 5% off. I never really thought of it as the good days were way above her optimum, but looking back they might have been. She was competitive even while suffering, but when she had a good day it was always a shock, just how good her times were considering she was just running for fun and fitness after work and stuff.

 

[thehog]

Not scientific, I know, but the fastest natural runner on least amount of training I've ever known is my asthma-suffering wife. When we lived in London and her asthma was its worse, on the few days she could train at maximum without suffering symptoms that day she would post some really incredible times. Even if she took Ventolin and felt fine, if she was asthmatic that day before the run she would always be around 5% off. I never really thought of it as the good days were way above her optimum, but looking back they might have been. She was competitive even while suffering, but when she had a good day it was always a shock, just how good her times were considering she was just running for fun and fitness after work and stuff.

You’re right, not scientific. Lovely story though

 

[thehog]

Bardet is 2,000km down on Froome on Strava this year. Someone is really trying hard to recreate something...

Looks like Froome is trying to recreate the entire Vuelta for his submission to the UCI?

 

[Rollthedice]

Bardet is 2,000km down on Froome on Strava this year. Someone is really trying hard to recreate something...

Looks like Froome is trying to recreate the entire Vuelta for his submission to the UCI?

He also recreated the crash which occured on stage 12 ?!

 

[Merckx index]

He also recreated the crash which occured on stage 12 ?!

A necessary part of his defense:

[Ulissi] tested positive in the Giro’s 11th stage to Savona. His urine test showed 1900 nanograms per millilitre of Salbutamol, nearly double the limit of 1000ng/ml. His team explained at the time that he was using an inhaler with Salbutamol spray, took two puffs ahead stage and a paracetamol from the race doctor after crashing.

Ulissi and his lawyer argued that the crash at the start of the stage caused a jump in values and the resulting positive test.

http://www.cyclingweekly.com/news/latest-news/diego-ulissi-banned-nine-months-doping-152990

As I noted upthread, paracetamol, aspirin and other non-steroidal anti-inflammatory drugs can cause renal impairment. I'd love to know if Ulissi's team actually argued that--maybe they even gave Froome's team the idea--but since the case documents have never been made public, no way to tell.

 

[bigcog]

Bardet is 2,000km down on Froome on Strava this year. Someone is really trying hard to recreate something...

Looks like Froome is trying to recreate the entire Vuelta for his submission to the UCI?

Why wouldn't he, if he thinks it will help 'prove' his argument. I have no idea whether it will or not but in his position he has to try. Obviously, the assumption most popular on here is he took an oral dose or something similar to get that test result. Perhaps, he/they think they can replicate the test result or near as possible whilst taking an allowed inhaled dose to convince the relevant bodies of his innocence.

 

[thehog]

Bardet is 2,000km down on Froome on Strava this year. Someone is really trying hard to recreate something...

Looks like Froome is trying to recreate the entire Vuelta for his submission to the UCI?

Why wouldn't he, if he thinks it will help 'prove' his argument. I have no idea whether it will or not but in his position he has to try. Obviously, the assumption most popular on here is he took an oral dose or something similar to get that test result. Perhaps, he/they think they can replicate the test result or near as possible whilst taking an allowed inhaled dose to convince the relevant bodies of his innocence.

Cool your jets BigCog. I’m not being critical of his attempt, merely observing. He needs to do something as at this point he is ***.