All About Salbutamol

[red_flanders]

Re: Re:

If we're using stupidity, or lack thereof as one measure of the likelihood of what happened here, then Froome innocently taking a dose within the advised limits but still coming up with these high levels in his urine is the least stupid of all possibilities.
Not a popular theory i know, but certainly not impossible, as a few of the studies quoted in the last couple of days have shown. And indeed the very reason, i would presume when formulating the rules on Salbutamol, that the authorities, no doubt from consultation with medical expert advice, have classified this drug the way they have.

Not popular? I'd say not likely. Hence not popular.

 

[ScienceIsCool]

Re:

Do we know the average half life for Salbutamol whether via inhaler or tablet or IV ? I've seen 4 hrs quoted but not sure which route / regimen. Wouldn't a short half life be another reason to think blood bag very unlikely since the blood bag would almost certainly be the evening before ?

Also the tmax (time to peak concentration) for inhaler / tablet.

It would be interesting to know for example whether pre-race and / or post-race admin would show up to any great extent in a post-race urine test

Searching for salbutamol metabolism gives quite a few results. Most give short estimated half-lives of 2-4 hours by inhalation and 3-5 hours if taken orally, with >70% being excreted via urine in the first 24 hours. Peak plasma levels occur around the 2 hour mark.

ex: http://www.ch.ic.ac.uk/local/projects/j_hettich/salbutamol/project/biobody.html

Three puffs in the morning is 300 ug, which would peak just as the stage starts. From the numbers, it looks like excretion "half-life" is 12 hours in the urine, so he probably would've peaked in urine concentration some time around the drug testing more or less. But from all the literature, this would be a pretty low concentration and not double the limit.

Using the half life, there should only be <5% of any particular dose left in the plasma after 24 hours. This suggests that Froome has been taking a lot of Salbutamol daily and the 300 ug pushed way, way over the edge or that he took a large, non-therapeutic dose (likely orally) in the 24 hours between tests. One of these is more plausible than the other.

John Swanson

edit: much editing needed

 

[TheMight]

What's the benefit or how is it used as a masking agent?

 

[46&twoWheels]

Re: Re:

Ok, I generally understand the concept, but could you please outline the calculations?

When a rider is transfusing as part of a withdrawal-transfusion program, as opposed to transfusing for a targeted race, the procedure would not be done immediately before a race, but more likely during a period when he isn't competing. At such a time, he's less likely to be taking salbutamol, unless, as I said before, he's taking it regularly throughout the season, which seems to me unlikely. So when he withdraws blood, it's unlikely to have a very concentration of salbutamol in it.

The way most people are thinking about it is that salbutamol dopers seek advantage in a particular short-term event (a race or race-stage) by taking a large, acute dose for aerobic benefit. Whereas the main way the salbutamol would actually be used is out-of-competition in training. For many of the same reasons as clenbuterol - anabolic effect and leanness, among others.

Jaschke could be talking utter nonsense... or, for some reason he is not revealing, he could be right.
So, one purpose of this thread could be to decide whether transfusion is a plausible (additive?) source of the salbutamol. Why or why not? That's a legitimate question from MerckxIndex's original post.

Many questions
It remains to be seen what kind of advantages the athlete gains from using Salbutamol in training.
can he train at higher levels,hence adapting his body?
Wouldn't he need Salbutamol during races too? because Salbutamol is not supposed to have long term effects like corticosteroids.
How does he administer himself Salbutamol in the race-period aside from the useless "puff puff"?
Are we talking about pure aerobic effects? We can concur that Salbutamol is not a simple spasmolytic for people having broncospasms

physiological evidence (the textbook page posted initially): "improves aerobic endurance performance"
indirect evidence of the effect on metabolism (from the same page posted by ClassicomanoLuigi) : c-peptide,


(i've watched a bbc video on twitter where a journalist was explaining how Salbutamol does not bring any advantage "they only messed up. they were not trying to cheat" mmmm so they were only concerned about a nuclear-bomb-scale asthma attack ?)

 

[Kretch]

Re: Re:

Ok, I generally understand the concept, but could you please outline the calculations?

When a rider is transfusing as part of a withdrawal-transfusion program, as opposed to transfusing for a targeted race, the procedure would not be done immediately before a race, but more likely during a period when he isn't competing. At such a time, he's less likely to be taking salbutamol, unless, as I said before, he's taking it regularly throughout the season, which seems to me unlikely. So when he withdraws blood, it's unlikely to have a very concentration of salbutamol in it.

The way most people are thinking about it is that salbutamol dopers seek advantage in a particular short-term event (a race or race-stage) by taking a large, acute dose for aerobic benefit. Whereas the main way the salbutamol would actually be used is out-of-competition in training. For many of the same reasons as clenbuterol - anabolic effect and leanness, among others.

Jaschke could be talking utter nonsense... or, for some reason he is not revealing, he could be right.
So, one purpose of this thread could be to decide whether transfusion is a plausible (additive?) source of the salbutamol. Why or why not? That's a legitimate question from MerckxIndex's original post.

Many questions
It remains to be seen what kind of advantages the athlete gains from using Salbutamol in training.
can he train at higher levels,hence adapting his body?
Wouldn't he need Salbutamol during races too? because Salbutamol is not supposed to have long term effects like corticosteroids.
How does he administer himself Salbutamol in the race-period aside from the useless "puff puff"?
Are we talking about pure aerobic effects? We can concur that Salbutamol is not a simple spasmolytic for people having broncospasms

physiological evidence (the textbook page posted initially): "improves aerobic endurance performance"
indirect evidence of the effect on metabolism (from the same page posted by ClassicomanoLuigi) : c-peptide,


(i've watched a bbc video on twitter where a journalist was explaining how Salbutamol does not bring any advantage "they only messed up. they were not trying to cheat" mmmm so they were only concerned about a nuclear-bomb-scale asthma attack ?)

To the bold - fat reduction: https://thinksteroids.com/steroid-profiles/albuterol/

 

[Red Rick]

https://www.ncbi.nlm.nih.gov/pubmed/24518370

I posted this in the Froome forum earlier. One of the few studies i could find which specifically looks at the effects of exercise and dehydration on salbutamol levels in the body.

Can't access the full text, would be interesting if someone could.

http://sci-hub.la/10.1097/jsm.0000000000000072

You can always try sci-hub if you can't access a text. I swear it should be part of the first course of any university study.

 

[thehog]

https://www.ncbi.nlm.nih.gov/pubmed/24518370

I posted this in the Froome forum earlier. One of the few studies i could find which specifically looks at the effects of exercise and dehydration on salbutamol levels in the body.

Can't access the full text, would be interesting if someone could.

http://sci-hub.la/10.1097/jsm.0000000000000072

You can always try sci-hub if you can't access a text. I swear it should be part of the first course of any university study.

That test was done in 35 degree Celsius heat at 40% relative humidity. Stage 18 was 20c degrees.

 

[Teddy Boom]

Re: Re:

Thanks for the thread Merckx index, great idea!

Ok, I generally understand the concept, but could you please outline the calculations?

I provided some above. But to make it even simpler: There are roughly 7 liters of blood in the body, and a blood transfusion normally involves a maximum of 500 ml, or half a liter. So there is a dilution factor of about 15; i.e., whatever the concentration of a drug is in the blood when a withdrawal is taken place, it's decreased by about that amount when the withdrawn blood is transfused. But the factor is even larger, because when a drug is infused into the blood, it quickly enters extravascular spaces, resulting in a much larger volume of distribution. It's hard to estimate what this is, because transfusing blood containing a drug is not like infusing a drug over a period of time into the blood, which is how distribution volumes are generally calculated. Much more of the drug in a transfusion goes right to the kidneys and urine. But at any rate, a factor of 15 is a minimum; it would be more than that.

Just to make sure I've got it clear, the bolded are acting in opposite directions? And, accounting for both as well as the raw volumes, you suggest a dilution factor of at least 15:1 and maybe more than 20:1?

 

[Merckx index]

Re: Re:

Red Rick, thanks for the link to the full paper on the dehydration study. Brownbobby is right, this is an important study. It will certainly provide hope to Froome supporters, in that it shows that it’s possible to take 1600 ug of salbutamol—the maximum allowed in 24 hours—and attain urine concentrations above the 1000 ng/ml threshold (I also learned from this that the 1200 ng/ml level I’ve seen referred to is the so-called decision threshold, above which an AAF is triggered; but if that’s not the case, I’m still not clear on what the 1000 ng/level signifies).

However, note:

1) the 1600 ug dose was taken all at once, which would maximize the amount of drug in the circulation; this is not the way the drug is normally taken, of course, and I believe Froome’s own description of what he did indicates he didn’t take it in this matter. However, there may be more information on this I’m not aware of
2) Only 4/18 males in the study exceeded the 2000 ng/ml level reported for Froome (the other 14 subjects all had levels of < 1500 ng/ml); if female subjects are included, the number is 5/32. So even under the unusual conditions of this study, a level that high is not common
3) The subjects were instructed to keep water intake to a minimum during the exercise portion of the study, which of course is not what a rider in a GT stage would do; after the exercise portion, they were encouraged to drink as much as they wanted, but it’s not clear to me how long a period elapsed between the end of the exercise and collection of urine.
4) The study asked participants to perform in two kinds of exercise paradigms, one designed to lose 2% of body mass, and one 5%. The subjects did not always reach this criterion, in which case exercise was stopped after a fixed amount of time. The 5% loss is supposed to represent more severe dehydration, of course, but the authors reported there was no significant difference in urine salbutamol concentrations between the two conditions. There apparently was no measure of urine specific gravity.

I just want to add that if specific gravity is critical, this could presumably be measured in Froome’s original urine samples, and corrected if necessary. Normal SG is around 1.020, with a range of about 1.00 – 1.030. Higher SG values mean the urine is more concentrated. In one link I posted upthread, a urine concentration of salbutamol of > 1000 ng/ml was reduced by about 40% when the SG value was corrected. OTOH, in another study, the value was increased by about that much.

Some other points:

All studies of salbutamol I've seen, including this one, report very large variations in urine concentrations among different subjects. Some of this variation may reflect differences in metabolism, but my guess is that if you tested a single subject over a period of time, there would be a lot of variation in results, too. IOW, it's possible that if Froome took the same amount of salbutamol multiple times before testing, as I assume he has, that just by chance he could have an outlier value. This doesn't necessarily help his case, though, because if it is a statistical fluke, it could be very hard to replicate in the lab.

Wrt half life, the studies I’ve seen reported about 3-4 hours, for both inhaled and oral drug. This is in agreement with what SiS posted, as is the peak plasma concentration occurring 1-2 hours after administration. As I noted earlier, maximum urine concentrations are found in the period 0-4 hours after dosing.

However, calculations of the time necessary for complete excretion can’t use just the half-life unless only first order kinetics are involved, i.e., excretion follows one type of process throughout. I don’t believe this is the case; one study reported complete excretion required about three days. Nevertheless, the key point here is that the glow time is relatively short. A rider could take a large dose, say 10 mg daily, and within 24 hours after stopping dosing, his urine levels would probably have fallen within the limit. Thus such dosing could be used during training, if you had a reasonable expectation that you weren’t going to be tested over some period of time, but you would not want to take such a large dose before a stage after which you expected to be tested. So on this basis, people who are insisting that if this reflects intentional doping, it more likely resulted from a transfusion, have a point. It's hard to believe that Froome would take a huge oral dose right before a stage, though I could believe he intentionally took a dose somewhat larger than allowed, figuring from past experience that he wouldn't exceed the threshold. The link discussed above certainly supports that.

Another important point is that desensitization and/or down-regulation occur with large doses. This is explained in a very useful link someone posted upthread (body builders are frequently the best pharmacologists; they really know their stuff):

https://thinksteroids.com/steroid-profiles/albuterol/

When a drug is taken chronically, the affinity of the receptors on target cells for the drug is reduced (desensitization), and/or the number of receptors is reduced (down-regulation). Both are adaptive mechanisms to prevent the cell from overdose. So the same dose had increasingly less effect. This is one of the mechanisms underlying tolerance to drugs like opioids. Something I didn’t know that was mentioned in that link is that there is another drug, ketotifin, which can be used to reduce the amount of down-regulation. I don’t know if WADA has banned this substance, but it’s something to keep in mind.

Just to make sure I've got it clear, the bolded are acting in opposite directions? And, accounting for both as well as the raw volumes, you suggest a dilution factor of at least 15:1 and maybe more than 20:1?

Yes, I glossed over a lot of things. The 15:1 is a floor, a minimum dilution factor. (Note: As Luigi points out, I stand corrected. I was going from memory, but typical blood volume is apparently more like 5 l than 7. So make the dilution factor 10:1. But since we're getting into details here, I'll also note that 500 ml is a pretty large amount to transfuse, too. I think 250 ml is more typical). In any case, in practice, it will be a lot higher, because it takes time to infuse a drug, either as an injection, or if it's a contaminant in blood that's being transfused. The longer the period of infusion/transfusion, the more time the drug has to seek out these extra volumes, as well as, for that matter, to pass through the kidneys and be removed. All of this is just a way of saying that you can't determine plasma concentration just by dividing the total amount of drug by the volume of plasma. By the time all of the drug enters the blood, some of that drug is already out of the blood.

In my somewhat more detailed calculations upthread, I estimated a very low urine concentration following transfusion, on the order of 10 ng/ml. That might be too low, but the idea is that the actual level is probably going to be far below the 1000 ng/level WADA threshold.

 

[movingtarget]

Since salbutamol has become the drug du jour, probably the drug of the year (and 2018) as far as the Clinic is concerned, I think it warrants a separate thread. This one is for discussion of (among other topics):

1) research suggesting possible performance-enhancing effects of the drug;
2) the pharmacokinetics of salbutamol, an understanding of which is necessary, among other things, to evaluate the possibility that Froome’s level is consistent with the drug’s being administered through blood transfusion.
3) details of the WADA test, including what forms of salbutamol are quantitated, any corrections for urine specific gravity, and studies that provide the rationale for the currently allowed limits
4) Any future test results that Froome presents as evidence for his innocence
5) The results of other salbutamol cases, as they are relevant to Froome’s case

So basically just the science. General discussion of Froome, including implications of this AAF for his future as a rider as well as his legacy, reactions of other riders, his protestations of innocence, Sky's reaction, and so on, can continue in the thread for that purpose.

I will begin my reposting some links I posted in the Froome thread.

https://www.ncbi.nlm.nih.gov/pubmed/22388343
https://www.ncbi.nlm.nih.gov/pubmed/19927035

These two studies by the same group measured urinary levels of salbutamol four hours after inhaling 800 ug (which is the 12 hour limit set by WADA). In the first study, only 1/18 subjects exceeded the 1000 ng/ml. urinary limit, and not by much (1057). Eight of the subjects were described as elite athletes with ashthma, and had a mean urinary level of about 335 ng/ml. Moreover, if the urine concentration in that one high sample was corrected for specific gravity—i.e., dehydration makes the urine solutes more concentrated than normal—the salbutamol concentration dropped to 661. I don’t know whether in the WADA testing procedure, this correction is carried out or not, but regardless, I assume the 1000 ng/ml was found to be appropriate to however the urine is treated. I also need to point out I saw another study reporting that making the SG correction actually increased the effective concentration, so sometimes subjects being tested apparently have very dilute urine.

In the second study, the mean value of ten subjects was just 261 ng/ml. So clearly, at the maximum permitted doses, going over the urinary limit is not common. In contrast, in both these studies, subjects also took 8 mg (ten times the inhalation dose) orally. The mean urinary values were 2000-3000, though there was enormous individual variation, as indeed, is the case regardless of route of administration.

https://www.ncbi.nlm.nih.gov/pubmed/16541373

In this study, the authors administered 100 ug doses of salbutamol twice daily to ten subjects, and on the basis of the urinary levels, concluded that the WADA limit could be lowered to just 250 ng/ml. Someone here who takes salbumatol can comment on whether 200 ug/day is a reasonable dose, or whether the 800 – 1600 ug dose is really necessary.

Another study reported a false positive rate of 4% using 500 ng/ml as the limit, but the amount inhaled was not given in the abstract. Also, the amounts will vary depending on whether the free or conjugated forms of the drug are measured. I'm not clear yet on whether the WADA urinary limit refers to free salbutamol or total, which makes a substantial difference, and also whether, as I mentioned above, the urine is corrected to a typical value of specific gravity. But overall, I think we can conclude that a value of 2000 ng/ml, as reported for Froome, is far more likely to result from an oral dose than an inhaled one. From what I've seen so far, I'd be a little surprised if he could get a urinary level that high by inhaling within the WADA limit.

Another interesting aspect of this is that in theory, one can distinguish inhaled from oral salbutamol from the ratio of free to sulfated, but this is difficult, apparently because when one inhales, one may actually swallow some of the substance? Maybe an asthmatic can comment on this?

A lot of people use Ventolin incorrectly. They don't tilt their head back, they don't take a deep breath beforehand and blow it out fully and then breath in and hold the breath while the Ventolin has been inhaled and they don't rinse their mouth after using the Ventolin. If your asthma is bad, taking a deep breath of course is not easy but if you don't rinse your mouth often you start coughing either straight after the puff or soon after because some of the spray settles in the mouth and throat. Sometimes if you are too hasty with depressing the cannister you can see the spray or mist coming out your mouth before you breath out again. Many children use spacers as it traps the Ventolin in the chamber and stops leakage. It's actually possible to lose the entire dose if you cough immediately after removing the tube from your mouth then you have to repeat it. Especially if you have a cold or an already irritated throat. There is an aftertaste with Ventolin hence the recommended mouth rinse as some settles in the mouth.

The other most noticeable thing about taking Ventolin especially in large doses, for me is the increased heart rate. It sounds like Froome also uses a preventer which is a standard asthma plan. The preventer is used every morning one or two puffs and then the Ventolin should only be used if you start wheezing. It sounds like Froome has had asthma since childhood which is typical for most asthmatics, not many people develop it in adulthood. His asthma obviously improved over the years to become more or less only exercise induced, this is also typical for many asthmatics in adulthood. Chronic asthma as a child or adult is an entirely different beast and it is much more dangerous especially as the drugs sometimes don't work as they do for most asthmatics. Such people are semi invalids and have limited capacity for exercise and activities.

 

[Alex Simmons/RST]

I haven't really read the thread, just posting some links that may be relevant and many probably have already been posted. These are investigating potential ergogenic impacts (i.e. impact on athletic performance), and not the pharmacological impacts (e.g. metabolism rates, urine concentration etc).

There are probably a stack more.

Potential positive impact on athletic performance:
https://www.ncbi.nlm.nih.gov/pubmed/26197029
https://www.ncbi.nlm.nih.gov/pubmed/25077918
https://www.ncbi.nlm.nih.gov/pubmed/23559124
https://www.ncbi.nlm.nih.gov/pubmed/22230921
https://www.ncbi.nlm.nih.gov/pubmed/17264145
https://www.ncbi.nlm.nih.gov/pubmed/16687481
https://www.ncbi.nlm.nih.gov/pubmed/16195983
https://www.ncbi.nlm.nih.gov/pubmed/16195982
https://www.ncbi.nlm.nih.gov/pubmed/15459835
https://www.ncbi.nlm.nih.gov/pubmed/11071049
https://www.ncbi.nlm.nih.gov/pubmed/10926623
https://www.ncbi.nlm.nih.gov/pubmed/10912897
https://www.ncbi.nlm.nih.gov/pubmed/9200320
https://www.ncbi.nlm.nih.gov/pubmed/8587482
https://www.ncbi.nlm.nih.gov/pubmed/3293733


Not positive or possibly negative impact on athletic performance:
https://www.ncbi.nlm.nih.gov/pubmed/25894531
https://www.ncbi.nlm.nih.gov/pubmed/25856682
https://www.ncbi.nlm.nih.gov/pubmed/24790479
https://www.ncbi.nlm.nih.gov/pubmed/24451697
https://www.ncbi.nlm.nih.gov/pubmed/24100289
https://www.ncbi.nlm.nih.gov/pubmed/21327796
https://www.ncbi.nlm.nih.gov/pubmed/21083771
https://www.ncbi.nlm.nih.gov/pubmed/18091010
https://www.ncbi.nlm.nih.gov/pubmed/11514686
https://www.ncbi.nlm.nih.gov/pubmed/8894333
https://www.ncbi.nlm.nih.gov/pubmed/8781870
https://www.ncbi.nlm.nih.gov/pubmed/8365829
https://www.ncbi.nlm.nih.gov/pubmed/7552768
https://www.ncbi.nlm.nih.gov/pubmed/6656562
https://www.ncbi.nlm.nih.gov/pubmed/1435165


Each way bet:
https://www.ncbi.nlm.nih.gov/pubmed/23834392

 

[Netserk]

Re: Re:

Red Rick, thanks for the link to the full paper on the dehydration study. Brownbobby is right, this is an important study. It will certainly provide hope to Froome supporters, in that it shows that it’s possible to take 1600 ug of salbutamol—the maximum allowed in 24 hours—and attain urine concentrations above the 1000 ng/ml threshold (I also learned from this that the 1200 ng/ml level I’ve seen referred to is the so-called decision threshold, above which an AAF is triggered; but if that’s not the case, I’m still not clear on what the 1000 ng/level signifies).

However, note:

1) the 1600 ug dose was taken all at once, which would maximize the amount of drug in the circulation; this is not the way the drug is normally taken, of course, and I believe Froome’s own description of what he did indicates he didn’t take it in this matter. However, there may be more information on this I’m not aware of

And given that one is only allowed an intake of 800 ug in 12 hours, we have grounds enough to discard the study.

 

[Merckx index]

Some factors to consider in all this:

- Extremely high concentrations of salbutamol are possible in athletes using inhalers alone:

"Recently, in an urine of an athlete in competition, high concentration of Salbutamol (about 8000 ng/ml) was detected...."

http://www.doping.chuv.ch/files/salbutamol_03.pdf

Yeah, I saw that study, but I’m suspicious. How do we know he actually inhaled, rather than taking an oral dose? The literature is quite clear that urine levels > 1000 ng/ml are fairly rare following inhaling. Even the one study in which subjects took the full 24 hour allowable dose of 1600 ug all at once reported that only 15-20% of the subjects had levels > 2000 ng/ml, and none was even close to 8000 ng/ml. When the dose is taken over a period of time, such levels are far less common. See also what I say below.

This link to an interview with an anti-doping scientist was posted in the Froome thread:

http://www.velonews.com/2017/12/news/anti-doping-expert-on-froome-it-doesnt-quite-add-up_453381

He notes that since Froome was presumably tested several times before and after the positive, that seems to rule out the possibility that he was taking larger than permitted doses regularly. Checking, I see Froome wore the red jersey continuously beginning with the stage 3. So he would have been tested after all these stages--but was he tested for salbutamol every time? If he was, why did he go over the limit, and by a lot, only the one time?

One explanation, of course, is that Froome, as he claims, took more than he usually did. But what is his usual dose and when exactly during the day of the stage does he take it? Just considering dose, even if he doubled his usual dose, one would not expect that to result in a urine level of 2000 ng/ml unless his usual, smaller dose was pushing the envelope, yielding levels close to 1000 ng/ml. But as I discuss below, there is very little evidence suggesting that an 800 ug dose, the maximum he could allowably double, results in levels this high. So just on this basis, one would think Froome must have more than doubled his usual dose. We still haven’t heard any specific details, though, other than some claimed extra puffs.

But there are other factors, such as when he took the dose. If he usually took most of the dose before the stage, and relieved himself during the stage, his urine level at the end of the stage should be relatively low. If on Stage 18 he took much more of the dose during the stage, and didn’t relieve himself, at least not after taking the during-the-stage portion, that would increase the expected level. But given that he was tested after all those stages, it seems unlikely that his procedure would be so different on just one stage. I doubt that stage 18 was the only one in which he took some of drug during the stage, or that it was the only one in which he didn’t urinate.

So there is a problem here. I think it might be cleared up if we had more details, but of course we’re not likely to get a lot of the critical ones.

Another interesting thing he said during this interview, if I understand him correctly, Froome's lab test will not take place on a stationary bike. The researcher seemed to believe that Froome would just go into a lab, take a dose of salbutamol--presumably the highest allowed--then have his urine tested. He wasn't even certain if Froome would be allowed to be tested under dehydrating conditions. If it really is this simple, I find it very hard to believe Froome hasn't already submitted to the test, since he's had nearly three months to do so. And if he has, of course, he didn't pass, i.e., demonstrate a urine level consistent with the AAF finding.

Alex, thanks for all those links. I was hoping you would join the discussion, because the evidence for PE effects involves to a large extent ergometer studies that are right up your alley. I haven’t even clicked on all those links, but I have the impression most of the positive results are of muscle strength and anaerobic power. Studies demonstrating an anaerobic effect seem rarer.

And given that one is only allowed an intake of 800 ug in 12 hours, we have grounds enough to discard the study.

Good point. This means there is very little evidence supporting the notion that taking salbutamol within the allowed limits can result in a urine level of 2000 ng/ml. Here’s a study in which subjects inhaled 1600 ug, the maximum WADA allows per 24 hr, though it sounds as though they took it all within eight hours. In any case, only one of 20 subjects exceeded 1000 ng/ml, not by much, and when the value was corrected for specific gravity, it fell below the threshold.

https://www.ncbi.nlm.nih.gov/pubmed/21563035

In fact, the 12 hour rule pretty much means that only 800 ug doses are going to be relevant, since most the drug taken in a previous 12 hour period will have been excreted. Even in the dehydration study, the mean values following 800 ug taken all at once were around 200 – 400 ng/ml., with only one or two of the male subjects presenting with > 500 ng/ml. These results agree fairly closely with the studies of 800 ug in the two links in the OP. In one of those studies, just 1/18 subjects had a urine concentration > 1000 ng/ml, barely.

This has important implications for Froome, as noted above. His defense so far is that he took more than the usual dose. But it seems that to get to 2000 ng/ml from less than 1000 ng/ml, he would have had to increase his dose beyond the allowable limit.

 

[Kretch]

Re:

Although this paper is old it is quite interesting particularly for non-analytical chemists like me in terms of differentiating between inhaled and oral salbutamol and factors affecting it's measurement, of course things may have moved on since when it was written:

http://clinchem.aaccjnls.org/content/46/9/1365

Does anyone know if the current testing distinguishes between inhaled and oral ingestion? The linked paper suggests it is possible and on the CN podcast, Benson reckons they do. That would surely makes things a little clearer.

 

[Merckx index]

Re: Re:

Does anyone know if the current testing distinguishes between inhaled and oral ingestion? The linked paper suggests it is possible and on the CN podcast, Benson reckons they do. That would surely makes things a little clearer.

AFAIK, the answer is no. There have been attempts to distinguish the two by tests, but one problem is that in the process of inhaling, people apparently do swallow some of the drug. So while there are ratios of metabolites or stereomeric forms of the drug that do to some extent differentiate inhaling from oral, a highly variable amount of in effect oral ingestion while inhaling muddles the picture. So while I'm not positive, I'm fairly sure WADA does not have an approved test based on this. That's why the 1000 ng/ml threshold or 1200 ng/ml decision level are used. The assumption, based on numerous tests, is that if urine levels exceed these limits, then either oral doses, or really large inhaled doses, are being used.

 

[70kmph]

That's very serious then if he's using anabolic means, not just for asthma- 4 years

 

[Kretch]

Re: Re:

Does anyone know if the current testing distinguishes between inhaled and oral ingestion? The linked paper suggests it is possible and on the CN podcast, Benson reckons they do. That would surely makes things a little clearer.

AFAIK, the answer is no. There have been attempts to distinguish the two by tests, but one problem is that in the process of inhaling, people apparently do swallow some of the drug. So while there are ratios of metabolites or stereomeric forms of the drug that do to some extent differentiate inhaling from oral, a highly variable amount of in effect oral ingestion while inhaling muddles the picture. So while I'm not positive, I'm fairly sure WADA does not have an approved test based on this. That's why the 1000 ng/ml threshold or 1200 ng/ml decision level are used. The assumption, based on numerous tests, is that if urine levels exceed these limits, then either oral doses, or really large inhaled doses, are being used.

Thanks. That seems reasonable. But given at least 15 data points and the ability to distinguish between the two ingestion methods well enough to know what's going on, I reckon the lab knows what's going on. They've got him bang to rights, but how did it happen...

I initially liked the BB theory - until that was diluted. I don't see a worthwhile risk/reward with a large oral dose during the race. So, what about a nebulizer? - all the rage in xc skiing and even state-sponsorable.

 

[Merckx index]

Here are some details on salbutamol testing by WADA:

https://www.wada-ama.org/sites/default/files/resources/files/wada-td2017dl-v2-en_0.pdf

It begins with the distinction between threshold level (T) and decision limit (DL). T for salbutamol is 1000 ng/ml. DL is 1200 ng/ml. DL is determined by multiplying the maximum combined uncertainty in the measurement, which is 100 ng/ml for salbutamol, by 1.645, then rounding up to the nearest 100 ng/ml. So we get 164.5 ug/ml, rounded up to 200 ng/ml. Added to T, DL becomes 1200 ng/ml. Apparently this limit is created to ensure that there is a 95% probability that the threshold level is exceeded.

Then the urine specific gravity correction is made as follows. Normal specific gravity (SG) is assumed to be 1.020. Call the SG of the sample SGs. Then (SGs -1)/(SG-1) is the factor that T is multiplied by. For example, if the SG of the sample is 1.030, the ratio would be 3/2, and the corrected T would be 1500 ng/ml., while the corrected DL would be 1700 ng/ml.

A little math shows that for an uncorrected value of 2000 ng/ml to pass as a T value, the urine SG would have to 1.040 or greater, while to pass as a DL value, the SG would have to be 1.036 or greater. I’m not sure whether the DL or T value is the one that matters here, and I’m also not sure how commonly such values are obtained as a result of dehydration. And I’m not clear whether WADA already determined the corrected DL or T value. It would be simple enough to do when the test was conducted, and one would think that one would want to determine it then, so one could conclude whether or not the value obtained exceeded the corrected T or DL value. If it turned out that Froome’s value was within the corrected limit, they could have avoided all the publicity of a failed AAF. But if it wasn’t, I don’t see the point of trying to demonstrate he can get high values through dehydration. The correction step would seem to account for dehydration already.

A couple of other points. I assume all riders are tested for salbutamol, even if they aren’t asthmatics? If so, what happens if some of the drug is detected in the rider’s system, even if it’s below the threshold? As I understand it, he can’t be sanctioned. But wouldn’t WADA want to know why a rider who doesn’t have asthma is taking this drug? If, as far as I know, there’s no test distinguishing inhaled from oral, any rider could dope with at least small amounts of oral salbutamol. The alternative would be not to test riders not declaring as asthmatics, which of course would invite them to dope with massive amounts.

Finally, has Froome’s history as an asthmatic been well-documented? Like most here, I think, I wasn’t aware of this until recently, even more recently than when we learned about schisto. Does he actually have proof that he has been taking salbutamol for his entire pro career? Are there reports that document this, or pictures of him with an inhaler at races?

 

[jflemaire]

Are there reports that document this, or pictures of him with an inhaler at races?

Wasn't it at Romandie 2014 where he was seen taking a puff during the race?

 

[Bronstein]

Are there reports that document this, or pictures of him with an inhaler at races?

Wasn't it at Romandie 2014 where he was seen taking a puff during the race?

Dauphine 2014.

 

[olhell]

XC skier Martin Johnsrud Sundby was like Froome caught with too high levels of salbutamol in two test during Tour De Ski 2014/15 (1.340 μg/mL & 1.360 μg/mL).
This eventually went to CAS, and there is a lot of information in the final award.

Might be of interrest.

 

[Wiggo's Package]

Re:

I find it very hard to believe Froome hasn't already submitted to the test, since he's had nearly three months to do so. And if he has, of course, he didn't pass, i.e., demonstrate a urine level consistent with the AAF finding

This

And you can bet Team Sky and their hired scientists in conjunction with the clever lawyer who got Armistead off on a technicality are trying to find a way round this glaring problem

Because Froome going into a UCI lab hoping to trip the wire as par his AAF would be the last resort a final act of desparation the game would be up

 

[Eyeballs Out]

Re: Re:

I find it very hard to believe Froome hasn't already submitted to the test, since he's had nearly three months to do so. And if he has, of course, he didn't pass, i.e., demonstrate a urine level consistent with the AAF finding

This

And you can bet Team Sky and their hired scientists in conjunction with the clever lawyer who got Armistead off on a technicality are trying to find a way round this glaring problem

Because Froome going into a UCI lab hoping to trip the wire as par his AAF would be the last resort a final act of desparation the game would be up

Ignoring the possibility/probability that they never anticipated this matter becoming public.......

Why not take as much time as you are allowed to have your chosen panel of experts research / prepare for a PK test ?

Say they need to show that Froome has an issue in passing Salbutamol through his system such that he could take an allowed amount but have it build up to give a +ve urine test. Research might indicate that there are certain things that you can do to promote / cause that issue. Might be something they can do on the morning of the test, might be something that needs to be done over a longer period. Something dietary for example.

In the end if they have to accept a ban then it will no doubt be backdated anyway so what is the downside ?

 

[46&twoWheels]

2014 article looks into "Why didn’t we know about Froome’s asthma until now?" following his conspicuous use of an inhaler at the Dauphiné

“I do have exercise-induced asthma [Froome later clarified]. I don’t use [the inhaler] every time I race. Normally, only when I have a big effort coming up. It’s completely allowed by the UCI. I have done all my tests for my asthmatic problems and you don’t need a TUE for it. A lot of people see the interviews, I’m coughing afterwards. That’s one of the reasons, the narrowing of my airways. It’s a bit of a surprise everyone is talking about it now.”


<span class="skimlinks-unlinked">http://www.theroar.com.au/2014/06/12/didnt-know-froomes-asthma-now</span>/

"In fact, you may say that Froome’s puff on his inhaler was so ostentatious and undisguised that it was clearly done with a view to being seen"

So the author is not buying the official Sky narrative as to why Froome starting using salbutamol and when.

"Sky have since confirmed that the 2013 Tour de France champion has been using an inhaler since he was a teenager"

Alright, but the doesn't elaborate as to the source of this information, Sky confirmed this how, when and to whom?

Asthma is easily triggered by exercise in those predisposed people, no?
I find strange that he makes a selective use of the inhaler and salbutamol only for big stages (probably mountain stages?)
that's a "selective kind of Asthma". I mean,you're either asthmatic or you're not

I don't know at what point his asthma is triggered,if there's a treshold (all or nothing) or whether it reveals itself after a while. In the latter case any competitive race would trigger asthma

 

[Wiggo's Package]

Re: Re:

I find it very hard to believe Froome hasn't already submitted to the test, since he's had nearly three months to do so. And if he has, of course, he didn't pass, i.e., demonstrate a urine level consistent with the AAF finding

This

And you can bet Team Sky and their hired scientists in conjunction with the clever lawyer who got Armistead off on a technicality are trying to find a way round this glaring problem

Because Froome going into a UCI lab hoping to trip the wire as par his AAF would be the last resort a final act of desparation the game would be up

Ignoring the possibility/probability that they never anticipated this matter becoming public.......

Why not take as much time as you are allowed to have your chosen panel of experts research / prepare for a PK test ?

Say they need to show that Froome has an issue in passing Salbutamol through his system such that he could take an allowed amount but have it build up to give a +ve urine test. Research might indicate that there are certain things that you can do to promote / cause that issue. Might be something they can do on the morning of the test, might be something that needs to be done over a longer period. Something dietary for example.

In the end if they have to accept a ban then it will no doubt be backdated anyway so what is the downside ?

Fair point. But it depends which end of the telescope you're looking down

From Froome's perspective there's no downside to dragging the whole thing out while spending £££s on lawyers, scientific experts, PR advisors, etc. If the lawyer can't get Froome off on a technicality then as you say the experts can in the meantime do everything in their power to ensure Froome trips the wire when he goes into the UCI lab. And by spending £££s Froome ensures that the UCI will also have to spend big which the UCI can't really afford (for example the UCI won the Pelizotti biopassport case but took a huge hit on the legal fees which IMO is part of the reason they subsequently dropped the Krueziger biopassport case)

However from the UCI's perspective and indeed in terms of the impact on pro cycling's already battered reputation Froome dragging this saga out is going to be an unmitigated disaster. Clearly Team Sky are too shameless to stand Froome down while this plays out. And imagine if Froome wins the Giro and then the TdF and then maybe even the Vuelta (hell why not!) prior to getting a retrospective ban and being stripped of his titles. Will be interesting to see if RCS and/or ASO try to stop Froome starting the Giro and/or the TdF if this issue is still hanging over his head. Suspect there's not much they can do to stop Froome if he decides to brazen it out. For sure the doping thing is going to be the only story in town for pro cycling as 2018 plays out...