All About Salbutamol

[Merckx index]

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?

Edit: Here are links to most of the issues discussed in this thread,as of 12/28/17:

Pharmacokinetics of salbutamol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1401185/pdf/brjclinpharm00122-0093.pdf
http://onlinelibrary.wiley.com/doi/10.1002/cpt1972136861/full
https://link.springer.com/article/10.1007/BF02456001

Studies measuring urine levels following inhaled and/or oral doses
http://sci-hub.la/10.1249/MSS.0b013e3181b2e87d
http://sci-hub.la/10.1097/JSM.0b013e31823513e1
http://sci-hub.la/10.1055/s-2005-865627
http://sci-hub.la/10.1002/dta.1568
http://sci-hub.la/10.1002/dta.367
http://sci-hub.la/10.1097/jsm.0000000000000072
http://sci-hub.tw/10.1097/JSM.0b013e3181705c8c
http://sci-hub.la/10.1002/dta.1828

Performance enhancing effects of salbutamol
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

Studies of tolerance to salbutamol
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1975.tb00557.x/pdf
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.1974.tb00255.x/full
http://www.atsjournals.org/doi/abs/10.1164/arrd.1980.121.6.973
http://www.sciencedirect.com/science/article/pii/S0091674999701788
http://www.sciencedirect.com/science/article/pii/014067369392695P
http://erj.ersjournals.com/content/21/5/810.long

Studies of metabolic effects of salbutamol, including weight loss and muscle growth
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439523/#bib104
http://dmd.aspetjournals.org/content/39/5/864.long
http://dmd.aspetjournals.org/content/35/10/1797.long
https://www.ncbi.nlm.nih.gov/pubmed/26239482
https://www.ncbi.nlm.nih.gov/pubmed/7916118

Studies of amount of salbutamol inhaled under various conditions
http://sci-hub.la/10.1016/j.pupt.2017.06.004
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806-37132011000600008&lng=en&nrm=iso&tlng=en

Urine specific gravity levels in cyclists
http://sci-hub.la/10.1123/ijsnem.2015-0188
http://sci-hub.la/10.1519/JSC.0b013e318240f677
http://sci-hub.la/10.1111/sms.12343
http://sci-hub.la/10.1097/JSM.0b013e3181b47c93
http://sci-hub.la/10.1136/bjsm.2008.049551
http://sci-hub.la/10.1186/1550-2783-11-12
http://sci-hub.la/10.1258/smj.2011.011287
http://sci-hub.la/10.1080/15438627.2011.582827
http://sci-hub.la/10.4085/1062-6050-49.3.85
http://sci-hub.la/10.1007/s00421-011-2024-y
http://sci-hub.la/http://journals.humankinetics.com/doi/abs/10.1123/ijspp.2012-0369

Legal issues, including WADA protocols and cases of other athletes
http://sci-hub.tw/10.1002/dta.2184
http://sci-hub.la/10.1385/CRIAI:31:2:259
http://www.cyclingnews.com/news/innocently-guilty-the-petacchi-case/
http://autobus.cyclingnews.com/news.php?id=news/2007/aug07/aug06news2
http://autobus.cyclingnews.com/news.php?id=news/2007/jun07/jun13news2
http://autobus.cyclingnews.com/news/?id=2003/mar03/mar24news2
https://jurisprudence.tas-cas.org/Shared%20Documents/1362,%201393.pdf
http://www.tas-cas.org/fileadmin/user_upload/Award__FINAL_.pdf
https://www.wada-ama.org/sites/default/files/resources/files/wada-td2017dl-v2-en_0.pdf

 

[Red Rick]

Is the study without dosage in the abstract available in full, perhaps through sci-hub.la ?

 

[Strange Loop]

Re:

Is the study without dosage in the abstract available in full, perhaps through sci-hub.la ?

Given the reference, I could also check if I have access. I work for a university, so it does depend on whether that journal is part of a subscription package.

 

[bigcog]

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

 

[ScienceIsCool]

I have some personal anecdotes and some observations which might add to your excellent post.

- I prefer the 50 ug inhaler over the 100 ug because 100 ug is usually overkill.

- 200 ug in a day usually means something is going wrong for me and will be accompanied by a lot of mucus, also nasal mucus.

- My doctor has told me that if I need 2 x 100 ug doses in a week for any period of time, then my asthma isn't "under control" and it's time to introduce a preventative strategy such as inhalable corticosteroids

- 16 x 100 ug doses is a LOT of inhaler. It's a bigly amount.

- I can see a doctor prescribing 3 x100 ug doses in a race because it's fast acting, whereas corticosteroids are a long acting solution, with the understanding that something is going wrong with the patient and it needs monitoring. I.e., symptoms generally have an underlying cause that needs to be treated

- In real use cases, an inhaler does not deliver a full dose. This is referred to as lung deposition rate. Studies have shown that inhalers have a deposition rate of between 7 and 40%. So that means when Froome uses his 100 ug inhaler, he's at best getting a 40 ug dose. http://erj.ersjournals.com/content/erj/7/10/1839.full.pdf

- I'm guessing that in all the studies that are published, some care is taken to make sure of the actual dose inhaled, so probably not just handing an inhaler to the test subjects. More likely it's something like adding a metered dose to an oxygen mask.

- to get to 1600 ug, he would have had to take 40 x 100 ug puffs at a minimum, or use a different delivery method

- A mask and holding chamber (ex: aerochamber) increases lung deposition to 30-70%, but they're normally given to children, who are generally awful at using their inhaler

- Using an inhaler on the bike is awful because your respiration rate is higher, meaning a very low deposition rate. In one spring race I had to take 5 hits from the inhaler to feel okay. Of course by that point my day was already over since you wait a minute or two between doses to see if it worked.

- I don't recall observers saying they saw Froome taking lots of puffs during stage 18, which means his main dosage was pre-race and it's the 3 x 100 ug that is responsible for his AAF. That seems very unlikely. An oral dose in the mg range fits the data a lot better. I guess we'll see.

John Swanson

 

[Merckx index]

Thanks for the information, all. I didn’t realize that Froome used an inhaler during an actual race. I thought that a dose lasted about 6 hours, which would just about cover most GT stages. If he did take the dose before the race, the detected urinary concentration would depend a lot of whether he pissed at some time during the stage. I know the peloton sometimes stops to do this, but how common is it? Because the peak urinary concentrations occur within four hours after an oral or inhaled dose, so if he took the dose before a stage, and stopped to relieve himself somewhere in the middle, let alone near the end, his urinary concentration as tested after the stage would be a lot lower than if he didn’t urinate at all during the stage. As he no doubt would know.

Here are some more links, dealing with pharmacokinetics. A couple are very old, but these methods have been around a long time, and the results shouldn’t be considered outdated. What has changed, I hope, are attitudes towards the subjects. One of the papers reads “Larger doses were not well tolerated…subjects experienced tachycardia, hypotension, nausea and severe malaise.” !! I had to check to make sure this was a study of human subjects!!

22- Analytical Profile of Salbutamol. (PDF Download Available). Available from: https://www.researchgate.net/publication/231349902_22-_Analytical_Profile_of_Salbutamol [accessed Dec 14 2017].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1401185/pdf/brjclinpharm00122-0093.pdf

https://link.springer.com/article/10.1007/BF02456001

https://www.wada-ama.org/sites/default/files/resources/files/backer_0.pdf

Collating information from these links, about half of an oral dose of salbutamol goes into the circulation, with a dose of 4 mg resulting in a peak plasma concentration of about 10 ng/ml. A rider might transfuse at most about 500 ml, so that is about 5 ug. If that were then transfused, as much as half of it, or 2.5 ug, might be excreted in the urine within four hours. Assuming a urine volume of 250 ml., that is 10 ng/ml, which is far below the allowed limit of 1000 (or is it 1200? I’m seeing that referred to as recently as at least 2015). Those are very rough calculations, with some simplifying assumptions, but for an order of magnitude estimate they should work.

Of course, an oral dose of four mg is not the maximum possible, and injection is also possible, though I don’t think athletes inject it IV? Anyone have an idea of how large a dose someone might reasonably take? It’s not particularly toxic, I have seen LD50 values for rodents in the g/kg range.

Luigi, the group that makes up most of the citations in your passage has four papers on salbutamol at Pub Med, but not much to support an effect on endurance. The most recent, in 2012, reported an effect in short-term sprint power. A second paper, in 2002, found no effect on power in a 10 minute cycling exercise. The third paper, in 2000, alludes to an effect on both anaerobic and aerobic power, but no details are given in the abstract. From what's said in your passage, it seems that any significant effects they found for aerobic power resulted from a few outliers. This is interesting, but sort of reminiscent of beet root juice. But I need to see the whole paper.

Edit: OK, here's the 2000 paper:

http://www.physiology.org/doi/pdf/10.1152/jappl.2000.89.2.430

The key data are in Fig. 1. Subjects took 4 mg of salbutamol three times a day for three weeks, then were tested the following day. They rode a cycling ergometer at 80-85% V02 max, and the mean time to exhaustion increased almost 30%, from about 23 to 30 minutes. Seven of the eight subjects showed an increase, with the one subject showing a relatively small decrease of about 10%.

 

[attila]

Found on reddit in the the r/peloton sub...excellent points/counterpoints on this analysis in the sub as well, not going to post all of it but worth a read. I'm guessing he was snorkeling his inhaler but what do I know.

http://www.feltet.dk/nyheder/laeserbrev_ingen_tvivl_om_at_froome_snyder/
Google Translated:
"Chris Froome is tested positive for salbutamol. Asthma treatment or cheating?
Froome has asthma and uses his asthma medicine - salbutamol - as an inhalation to deal with his asthma symptoms. According to WADA's doping list, salbutamol is allowed as inhalation and the maximum permitted intake is 0.8 mg salbutamol over 12 hours and 1.6 mg over 24 hours. In order to distinguish between authorized use as asthma medicine and non-authorized use (doping), WADA has established a limit in urine samples for salbutamol of 1000 ng / ml. If the urine sample exceeds this limit, it accepts it as unauthorized use (doping).
One must be diligent user of his inhaler to achieve a salbutamol concentration of 2000 ng / ml in a urine sample. Conscious cheating or wildly unprofessional? The latter is at least not typical Team Sky!
Controlled pharmacokinetic studies have shown that a maximum intake of allowed inhaled salbutamol dose over 12 hours (0.8 mg) inhaled at one time in elite asthma patients causes urine concentrations up to 1000 ng / ml. If you ingest (either as inhalation or in pill form) 8 mg becomes about 3000 ng / ml in urine.
If you inhale 0.4 mg every second time over fire times, when you recover the maximum daily intake, you will reach 1100 ng / ml in the urine. This intake is currently not allowed, as a maximum of 0.8 mg in 12 hours must be administered.
If you inhale 8 mg at one time, then cycle and perform maximum oxygen uptake test and multiple submaximal tests, manually up 3000 ng / ml in urine, even when corrected for the urinary density and thus potentially concentration of salbutamol due to dehydration in the practitioner.
Therefore, I believe that there is no doubt that his value at 2000 ng / ml must be due to supraterapeutic use and thus cheating!
Exciting if Sky will fix it anyway."
Jimmi Elers is head of department, PhD, gynecological obstetric department at Nordsjælland Hospital in Hillerød. He has written a PhD thesis on salbutamol and treatment against doping.

 

[miguelindurain111]

Re:

Jörg Jaksche is making a bold call that this is a case of transfusion. As mentioned by the OP above. For those who didn't see it already, it's a one-line tweet, one of only 5 tweets by Jaksche in the whole year 2017.

That would be an important angle to explore- if Jaschke is correct, possibly Froome could get busted on the blood-bag plasticizers, in the same way that Contador did. The motives for using salbutamol are often the same as for using clenbuterol - less effective, but with plausible deniability by claiming salbutamol medically necessary for asthma

"Doesn't compute. As the blood you infuse would be diluted by your existing blood pool 20 fold. So initial blood concentration would have to be so high you would have an arythmia."

 

[ScienceIsCool]

Of course, an oral dose of four mg is not the maximum possible, and injection is also possible, though I don’t think athletes inject it IV? Anyone have an idea of how large a dose someone might reasonably take? It’s not particularly toxic, I have seen LD50 values for rodents in the g/kg range.

This is exactly why doctors tend to over diagnose asthma. None of the ones I've met have even used a peak flow meter. If they can hear noise in your chest and you're struggling a bit, you'll get an inhaler. There's just really no danger in giving someone an inhaler and it can help clear the lungs even if you don't have an asthma attack. It's prescribed for COPD patients and I'll admit I've used it when I have a cold just to reduce coughing and congestion.

John Swanson

 

[hazaran]

The Clinic is keeping its reputation, not even a second page yet and you are quoting Jaksche for science :lol:

 

[hrotha]

Apparently, WADA tests for free salbutamol plus salbutamol glucuronide:

Despite the granting of any form of TUE, a urinary concentration of salbutamol (free plus glucuronide) greater than 1000 ng.mL-1 in a doping test is considered as adverse analytical finding.

https://www.wada-ama.org/sites/default/files/resources/files/backer_0.pdf

 

[ppanther92]

Re:

The Clinic is keeping its reputation, not even a second page yet and you are quoting Jaksche for science :lol:

Whats your point? The thread is highly interesting and points heavily to a direction from where its hard to believe it was unintentionally or not for performance enhancement.

If you have clinical trials, studies or other facts that counter the arguments in here, feel free to post them.

 

[bigcog]

If I am reading this article correctly in terms of dosage taken, section on salbutamol this suggests it's possible to get AAF's from allowed dosage/intake:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933613/#C8

not suggesting that is what happened here mind.

 

[hazaran]

Re: Re:

The Clinic is keeping its reputation, not even a second page yet and you are quoting Jaksche for science :lol:

Whats your point? The thread is highly interesting and points heavily to a direction from where its hard to believe it was unintentionally or not for performance enhancement.

If you have clinical trials, studies or other facts that counter the arguments in here, feel free to post them.

The point is that if you want to have a thread with only scientific publications, you should aggressively cleanse it of Jaksche twitter "cites" and press quotes from gynecologists whose own research states quote

"Urinary concentrations show high individual variability irrespective of the route of administration"

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

 

[Kretch]

Re: Re:

Jörg Jaksche is making a bold call that this is a case of transfusion. As mentioned by the OP above. For those who didn't see it already, it's a one-line tweet, one of only 5 tweets by Jaksche in the whole year 2017.

That would be an important angle to explore- if Jaschke is correct, possibly Froome could get busted on the blood-bag plasticizers, in the same way that Contador did. The motives for using salbutamol are often the same as for using clenbuterol - less effective, but with plausible deniability by claiming salbutamol medically necessary for asthma

"Doesn't compute. As the blood you infuse would be diluted by your existing blood pool 20 fold. So initial blood concentration would have to be so high you would have an arythmia."

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

 

[gillan1969]

Re: Re:

The Clinic is keeping its reputation, not even a second page yet and you are quoting Jaksche for science :lol:

Whats your point? The thread is highly interesting and points heavily to a direction from where its hard to believe it was unintentionally or not for performance enhancement.

If you have clinical trials, studies or other facts that counter the arguments in here, feel free to post them.

The point is that if you want to have a thread with only scientific publications, you should aggressively cleanse it of Jaksche twitter "cites" and press quotes from gynecologists whose own research states quote

"Urinary concentrations show high individual variability irrespective of the route of administration"

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

the interplay between physiology, pharmacology and sport ethics are not well represented in scientific publications and this is not an academic forum.

its for throwing around ideas which formal science may then suggest backs up a hypothesis or doesn't. Jaksches hypothisis is just that..thrown out there for discussion....

 

[brownbobby]

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.

 

[Merckx index]

Re: Re:

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.

So, for example, if an athlete takes a large dose, say, 10 mg of salbutamol, withdraws 500 ml of blood, and later transfuses it back, the transfusion is effectively like a dose of probably just several hundred micrograms at most, which would not be expected to result in a urine concentration near the WADA allowed level. The proportionality assumed here is not exactly right, but it's close enough.

In addition to this issue, there are others that suggest Froome's salbutamol level did not result from a blood transfusion. As an elite rider who can afford the best resources, if he does transfuse, he probably does it by withdrawing blood in the off-season and centrifuging it to remove red cells, which can be stored frozen. This is much easier and safer than making regular withdrawals and transfusions throughout the season. When he wants to transfuse, he just adds some saline to the platelets. So almost all of the relatively little salbutamol that was in the blood withdrawn would be discarded, anyway.

Even if he did use the withdrawal-transfusion paradigm, it's not obvious that he would withdraw blood right after taking salbutamol, which would be necessary if the blood were to have a peak concentration of the drug. Unless he were taking large doses of the drug daily, which would seem to be pretty risky, chances are that when he did withdraw blood, there would not be a maximal concentration of drug in his blood. 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.

On top of all this, one would think that after all the speculation about Contador (and before him, Floyd), riders would understand that if you're withdrawing blood to be transfused later, you want to avoid having a high concentration of any banned substance in the blood at that time. But maybe a lot of them haven't figured that out.

 

[nayr497]

I just hope he's on the sidelines long enough for us to enjoy a few competitive GTs.

 

[brownbobby]

Re:

I just hope he's on the sidelines long enough for us to enjoy a few competitive GTs.

Sorry, i'm not getting the science or research element of your post

 

[thehog]

Re:

I have some personal anecdotes and some observations which might add to your excellent post.

- I prefer the 50 ug inhaler over the 100 ug because 100 ug is usually overkill.

- 200 ug in a day usually means something is going wrong for me and will be accompanied by a lot of mucus, also nasal mucus.

- My doctor has told me that if I need 2 x 100 ug doses in a week for any period of time, then my asthma isn't "under control" and it's time to introduce a preventative strategy such as inhalable corticosteroids

- 16 x 100 ug doses is a LOT of inhaler. It's a bigly amount.

- I can see a doctor prescribing 3 x100 ug doses in a race because it's fast acting, whereas corticosteroids are a long acting solution, with the understanding that something is going wrong with the patient and it needs monitoring. I.e., symptoms generally have an underlying cause that needs to be treated

- In real use cases, an inhaler does not deliver a full dose. This is referred to as lung deposition rate. Studies have shown that inhalers have a deposition rate of between 7 and 40%. So that means when Froome uses his 100 ug inhaler, he's at best getting a 40 ug dose. http://erj.ersjournals.com/content/erj/7/10/1839.full.pdf

- I'm guessing that in all the studies that are published, some care is taken to make sure of the actual dose inhaled, so probably not just handing an inhaler to the test subjects. More likely it's something like adding a metered dose to an oxygen mask.

- to get to 1600 ug, he would have had to take 40 x 100 ug puffs at a minimum, or use a different delivery method

- A mask and holding chamber (ex: aerochamber) increases lung deposition to 30-70%, but they're normally given to children, who are generally awful at using their inhaler

- Using an inhaler on the bike is awful because your respiration rate is higher, meaning a very low deposition rate. In one spring race I had to take 5 hits from the inhaler to feel okay. Of course by that point my day was already over since you wait a minute or two between doses to see if it worked.

- I don't recall observers saying they saw Froome taking lots of puffs during stage 18, which means his main dosage was pre-race and it's the 3 x 100 ug that is responsible for his AAF. That seems very unlikely. An oral dose in the mg range fits the data a lot better. I guess we'll see.

John Swanson

Froome has already stated he uses a non-salbutamol based inhaler as his daily preventive medicine. If you use a spacer on your inhaler you generally can get the full dose, the regular way a lot can be left on the tounge and inside of the mouth. Right you are when using whilst riding. It becomes very hard to get the salbutamol deep into the lungs.

 

[red_flanders]

Re: Re:

In addition to this issue, there are others that suggest Froome's salbutamol level did not result from a blood transfusion. As an elite rider who can afford the best resources, if he does transfuse, he probably does it by withdrawing blood in the off-season and centrifuging it to remove red cells, which can be stored frozen. This is much easier and safer than making regular withdrawals and transfusions throughout the season. When he wants to transfuse, he just adds some saline to the platelets. So almost all of the relatively little salbutamol that was in the blood withdrawn would be discarded, anyway.

Even if he did use the withdrawal-transfusion paradigm, it's not obvious that he would withdraw blood right after taking salbutamol, which would be necessary if the blood were to have a peak concentration of the drug. Unless he were taking large doses of the drug daily, which would seem to be pretty risky, chances are that when he did withdraw blood, there would not be a maximal concentration of drug in his blood. 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.

On top of all this, one would think that after all the speculation about Contador (and before him, Floyd), riders would understand that if you're withdrawing blood to be transfused later, you want to avoid having a high concentration of any banned substance in the blood at that time. But maybe a lot of them haven't figured that out.

I get what you're saying, but at the end of the day it boils down to the fact that he did something stupid at some point. Taking a large OOC dose and then drawing blood seems far less stupid and more likely than taking a large dose during the Vuelta. That said, either, as we've seen repeatedly in the past, are quite possible. Riders have done stupid things forever and have gotten caught for it.

 

[Kretch]

Re: Re:

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.

So, for example, if an athlete takes a large dose, say, 10 mg of salbutamol, withdraws 500 ml of blood, and later transfuses it back, the transfusion is effectively like a dose of probably just several hundred micrograms at most, which would not be expected to result in a urine concentration near the WADA allowed level. The proportionality assumed here is not exactly right, but it's close enough.

In addition to this issue, there are others that suggest Froome's salbutamol level did not result from a blood transfusion. As an elite rider who can afford the best resources, if he does transfuse, he probably does it by withdrawing blood in the off-season and centrifuging it to remove red cells, which can be stored frozen. This is much easier and safer than making regular withdrawals and transfusions throughout the season. When he wants to transfuse, he just adds some saline to the platelets. So almost all of the relatively little salbutamol that was in the blood withdrawn would be discarded, anyway.

Even if he did use the withdrawal-transfusion paradigm, it's not obvious that he would withdraw blood right after taking salbutamol, which would be necessary if the blood were to have a peak concentration of the drug. Unless he were taking large doses of the drug daily, which would seem to be pretty risky, chances are that when he did withdraw blood, there would not be a maximal concentration of drug in his blood. 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.

On top of all this, one would think that after all the speculation about Contador (and before him, Floyd), riders would understand that if you're withdrawing blood to be transfused later, you want to avoid having a high concentration of any banned substance in the blood at that time. But maybe a lot of them haven't figured that out.

Thanks for the detailed explanation - makes sense.

On the Froome thread I asked if anyone knows if testing for salbutamol is standard and if he would have been tested for it from Stage 3 on. In other words, would WADA have his salbutamol profile over the course of the race? That data could be very instructive.

 

[brownbobby]

Re: Re:

In addition to this issue, there are others that suggest Froome's salbutamol level did not result from a blood transfusion. As an elite rider who can afford the best resources, if he does transfuse, he probably does it by withdrawing blood in the off-season and centrifuging it to remove red cells, which can be stored frozen. This is much easier and safer than making regular withdrawals and transfusions throughout the season. When he wants to transfuse, he just adds some saline to the platelets. So almost all of the relatively little salbutamol that was in the blood withdrawn would be discarded, anyway.

Even if he did use the withdrawal-transfusion paradigm, it's not obvious that he would withdraw blood right after taking salbutamol, which would be necessary if the blood were to have a peak concentration of the drug. Unless he were taking large doses of the drug daily, which would seem to be pretty risky, chances are that when he did withdraw blood, there would not be a maximal concentration of drug in his blood. 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.

On top of all this, one would think that after all the speculation about Contador (and before him, Floyd), riders would understand that if you're withdrawing blood to be transfused later, you want to avoid having a high concentration of any banned substance in the blood at that time. But maybe a lot of them haven't figured that out.

I get what you're saying, but at the end of the day it boils down to the fact that he did something stupid at some point. Taking a large OOC dose and then drawing blood seems far less stupid and more likely than taking a large dose during the Vuelta. That said, either, as we've seen repeatedly in the past, are quite possible. Riders have done stupid things forever and have gotten caught for it.

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.

 

[Eyeballs Out]

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