All About Salbutamol

[Merckx index]

Here's a potentially very relevant paper reporting that NSAIDs (pain-killers such as aspirin and paracetamol) inhibit transport of salbutamol across bronchial epithelium by effects on organic cation transporters (OCTs):

http://sci-hub.la/10.3109/02770903.2013.773518

There are several very important implications here. First, use of these drugs, by blocking uptake of salbutamol into the lungs, would reduce the effects of inhaling, perhaps resulting in a need to take more than the usual dose. Second, if the salbutamol is retained in the lungs for a period of time, it could build up, so that when it finally passes into the blood and then the kidneys, would be at increased concentration. The third implication is that NSAID inhibition of OCTs would also be a mechanism by which these drugs could reduce salbutamol excretion by the kidneys, since OCTs are present in renal proximal tubules, and thought to play a major role in excretion of many drugs. This paper reports effects of NSAIDs on OCTs in proximal tubule cells:

http://sci-hub.la/10.3109/02770903.2013.773518

This may be what Froome's team is looking at in trying to construct a renal impairment defense. There's still a big jump between lab studies and a credible in vivo mechanism. Both of these studies were carried out using cell cultures. The first study, on bronchial epithelium, used concentrations of NSAIDs that the authors concede are far higher than in vivo plasma concentrations following the usual doses. The second study did not directly demonstrate an effect on salbutamol transport, but on a much simpler cation, tetraethylammonium. The effects were quite modest, and in fact their data suggest that at physiological doses there wouldn't be any effect at all. It should also be noted that this study transfected the transporters into the cells, i.e., inserted the appropriate gene. I think this was done to maximize the amount of transporter, so that it would be easier to detect changes produced by the NSAIDs.

I'm just speculating here, of course, but Froome may claim that after the crash on stage 12, he took paracetamol or some other NSAID or NSAID-like pain-killer for several days. The argument would be that this reduced uptake of salbutamol both in his lungs and in the kidneys, leading to elevated concentrations in the lungs and plasma. When he stopped taking the analgesic, this backlog of salbutamol was excreted.

This would require more than a week of analgesic, though, which seems unlikely, unless Froome wants to claim he was treating some additional problem. Also, of course, Froome has crashed before, as no doubt have other riders who take salbutamol, not to mention that pain-killers might be taken for some other problem. In any case, as supporting evidence, he would want to show that all his urine samples during this previous time period showed very low levels of salbutamol. And if he gave a blood sample at any point during that period, plasma concentration would be very informative. Though as noted before, all of this information has limited usefulness if Froome can't demonstrate how much salbutamol he was inhaling during this period.

 

[thehog]

NSAIDs are anti-inflammatory based drugs often coupled with a pain killer like ibuprofen or paracetamol. They are not pain killers on their own.

NSAID = Non-Steroidal Anti-Inflammatory Drug.

 

[Merckx index]

NSAIDs are anti-inflammatory based drugs often coupled with a pain killer like ibuprofen or paracetamol. They are not pain killers on their own.

NSAID = Non-Steroidal Anti-Inflammatory Drug.

Of course NSAIDs (including ibuprofen) are used to treat pain. Inflammation is painful (and there are other mechanisms). There are technical issues in the definition of NSAIDs, e.g., paracetamol is not actually a NSAID, but it works like one in some respects (which is why I said "NSAID-like"). The anti-inflammatory activity of NSAIDS results from inhibition of the cyclo-oxygenase (COX) enzymes, and paracetamol has this effect, but generally not in tissues where inflammation occurs.

 

[thehog]

NSAIDs are anti-inflammatory based drugs often coupled with a pain killer like ibuprofen or paracetamol. They are not pain killers on their own.

NSAID = Non-Steroidal Anti-Inflammatory Drug.

Of course NSAIDs (including ibuprofen) are used to treat pain. Inflammation is painful (and there are other mechanisms). There are technical issues in the definition of NSAIDs, e.g., paracetamol is not actually a NSAID, but it works like one in some respects (which is why I said "NSAID-like"). The anti-inflammatory activity of NSAIDS results from inhibition of the cyclo-oxygenase (COX) enzymes, and paracetamol has this effect, but generally not in tissues where inflammation occurs.

I won’t argue with any of that

 

[AussieGoddess]

But surely if NSAIDS did this - then more athletes would go over the limit much more often. Athletes take painkillers and NSAIDS all the time ... they crash, they hurt, they are sore and exhausted ... paracetomol and Ibprofen would be part of their regular diet

so how would the sky team be able to prove that it so happened just this once?

 

[Merckx index]

Re:

But surely if NSAIDS did this - then more athletes would go over the limit much more often. Athletes take painkillers and NSAIDS all the time ... they crash, they hurt, they are sore and exhausted ... paracetomol and Ibprofen would be part of their regular diet

so how would the sky team be able to prove that it so happened just this once?

Yes, I pointed this problem out above. But keep in mind that different individuals will react differently to drug interactions, so assuming there really is an effect, the magnitude of the effect will vary between individuals as well as at different times for the same individual. Any effect that did occur might not be enough, by itself, to raise urine levels above the threshold most of the time, but might combine with other causes in exceptional circumstances. E.g., if Froome took all of the maximum 800 ug allowed within a couple of hours of the finish, without urinating; if he was somewhat dehydrated; if NSAID use went on every day during a period when he was also taking near-maximum allowed amounts of salbutamol.

Any case his team develops is probably going to have to involve multiple factors. I still think it's a stretch, but this is the way it would probably be presented.

Edit: I should have mentioned above that while those studies show that salbutamol excretion can be inhibited by NSAIDs, this effect is not selective. Excretion of other substances, such as creatinine, would also be affected. So as someone pointed out previously, unless Froome's samples show a significant effect on markers like this, pointing to lower salbutamol levels probably wouldn't help him.

More edit: On looking at those studies more closely, I see that the effect of NSAIDs on organic cation transporters (OCTs; the class that would be relevant to salbutamol uptake and excretion) really is not that great; the needed concentrations are too high. They seem to be more potent at OATs, the anion transporters. But I found a very recent study--it was just accepted a few weeks ago--which reports effects of eighteen commonly used antibiotics on transporters. Again, the greater effect is generally on OATs, but there is a significant effect of several of these antibiotics on OCTs, i.e., effects at physiologically relevant concentrations.

http://sci-hub.la/10.1016/j.ejps.2018.01.002

There is irony in this approach, because to the extent that substances like NSAIDs or antibiotics inhibit excretion of salbutamol, they are in effect masking agents, much like probenecid, which Impey tested positive for. Indeed, now that I think about it, this is another possible explanation for Froome's positive. If he used a masking agent during the Vuelta--not to mask use of salbutamol, but of some other drug, such as a steroid--but then forgot to use it before stage 18, he could get a back-up of salbutamol that was later excreted in high concentration. In fact, he wouldn't even have had to forget to use it. If, with the end of the GT approaching, he decided he didn't need to use the steroid or whatever any longer, he would have also stopped using the masking agent, without realizing this could have an effect on salbutamol.

 

[Robert5091]

Re: Re:

[quote="Merckx index

There is irony in this approach, because to the extent that substances like NSAIDs or antibiotics inhibit excretion of salbutamol, they are in effect masking agents, much like probenecid, which Impey tested positive for. Indeed, now that I think about it, this is another possible explanation for Froome's positive. If he used a masking agent during the Vuelta--not to mask use of salbutamol, but of some other drug, such as a steroid--but then forgot to use it before stage 18, he could get a back-up of salbutamol that was later excreted in high concentration. In fact, he wouldn't even have had to forget to use it. If, with the end of the GT approaching, he decided he didn't need to use the steroid or whatever any longer, he would have also stopped using the masking agent, without realizing this could have an effect on salbutamol.[/quote]

The doc c**k up theory ... but his samples from 19 & 20 would show this?

 

[TheSpud]

Re:

But surely if NSAIDS did this - then more athletes would go over the limit much more often. Athletes take painkillers and NSAIDS all the time ... they crash, they hurt, they are sore and exhausted ... paracetomol and Ibprofen would be part of their regular diet

so how would the sky team be able to prove that it so happened just this once?

Wasn't Ibuprofen part of Lance's diet as advised by Ferrari?

I could imagine a paracetamol / ibuprofen being used quite a lot - as a combination its very good at pain relief, and also for relief from colds & flu.

Could be that Sky are using NSAIDs - perhaps prescription ones (in the UK at least) like Naproxen. Its an effective pain reliever and doesn't appear on any list as far as I know especially if they are no longer using Tramadol (although lets not confuse those two in terms of their potency).

 

[fmk_RoI]

Re: Re:

But surely if NSAIDS did this - then more athletes would go over the limit much more often. Athletes take painkillers and NSAIDS all the time ... they crash, they hurt, they are sore and exhausted ... paracetomol and Ibprofen would be part of their regular diet

so how would the sky team be able to prove that it so happened just this once?

Wasn't Ibuprofen part of Lance's diet as advised by Ferrari?

I could imagine a paracetamol / ibuprofen being used quite a lot - as a combination its very good at pain relief, and also for relief from colds & flu.

Could be that Sky are using NSAIDs - perhaps prescription ones (in the UK at least) like Naproxen. Its an effective pain reliever and doesn't appear on any list as far as I know especially if they are no longer using Tramadol (although lets not confuse those two in terms of their potency).

Wasn't paracetamol used in the middle years of Gen-EPO to help stop clotting? WRT Ibupfroen: yes, it's mentioned in the Reasoned Decision:

The ubiquitous references to "Schumi" demonstrate that Stefano is the middle man and go between for Armstrong to receive professional advice from his father. The advice and questions from Schumi to Armstrong continue to flow even during the Tour. For instance, on July 6, 2009 Armstrong receives the advice that, "Schumi suggests raising the saddle by 2 mm – try in the am and let us know how it feels?" On July 22, 2009, Armstrong is told, "Schumi asks if your TT bike has the same height as the road bike? If yes, he suggests raising it 2 mm. And, since you still look low on the road bike, only for the Ventoux stage, raise it another 2 mm. Tomorrow keep taking ibuprofen."

(It's in the Jack Robertson affidavit, screen shots of emails to/from Ferrari.)

 

[King Boonen]

Re: Re:

Wasn't paracetamol used in the middle years of Gen-EPO to help stop clotting?

That'd be asprin, paracetamol doesn't thin the blood/prevent clotting. They may have used it for another reason.

 

[buckle]

Re: Re:

Wasn't paracetamol used in the middle years of Gen-EPO to help stop clotting?

That'd be asprin, paracetamol doesn't thin the blood/prevent clotting. They may have used it for another reason.

Aspirin helps to unstick the blood but does not 'thin' it per se. In that sense it is useful and most people over 60 should consider 75mg once every couple of days in lieu of alcohol. In other words blood thickening agents are intrinsically dangerous and their side effects can it best be managed.

 

[King Boonen]

Re: Re:

Wasn't paracetamol used in the middle years of Gen-EPO to help stop clotting?

That'd be asprin, paracetamol doesn't thin the blood/prevent clotting. They may have used it for another reason.

Aspirin helps to unstick the blood but does not 'thin' it per se. In that sense it is useful and most people over 60 should consider 75mg once every couple of days in lieu of alcohol. In other words blood thickening agents are intrinsically dangerous and their side effects can it best be managed.

I'm well aware how asprin works, thanks.

 

[fmk_RoI]

Re: Re:

Wasn't paracetamol used in the middle years of Gen-EPO to help stop clotting?

That'd be asprin, paracetamol doesn't thin the blood/prevent clotting. They may have used it for another reason.

Apps for the confusions. All headache tablets are the same to me. You can see why I never got that Summer job in the chemist's round the corner from where I grew up...

 

[Merckx index]

All this evidence that NSAIDs inhibit drug excretion made me wonder, why not just use aspirin as a masking agent? Well, google that, and people do! There are several articles on the internet promoting it for that purpose. This is a home remedy, to be sure, but one backed by a lot of scientific evidence. The only problem with this as far as salbutamol goes is, as I said before, that NSAIDs primarily act on OATs, not OCTs. But it appears they might be effective masking agents for steroids and other drugs that probenecid is used for.

And though this seems to be a new area of research, some antibiotics might work to some extent on both classes of transporters, meaning they would be effective masking a much wider range of drugs. I have to wonder if some doctors advising riders haven't figured this out. This would be such a neat explanation for salbutamol positives. The rider is taking the antibiotic as a way of masking some PED, stops taking it when he stops taking the PED, and doesn't realize that it will have an effect on salbutamol as well.

Oh, and have to mention this. I found a comprehensive review of drugs that affect the various transporters, and one that inhibits OCTs is pyrimethamine, which is used as an alternative treatment for...schisto!

 

[Wiggo's Package]

All this evidence that NSAIDs inhibit drug excretion made me wonder, why not just use aspirin as a masking agent? Well, google that, and people do! There are several articles on the internet promoting it for that purpose. This is a home remedy, to be sure, but one backed by a lot of scientific evidence. The only problem with this as far as salbutamol goes is, as I said before, that NSAIDs primarily act on OATs, not OCTs. But it appears they might be effective masking agents for steroids and other drugs that probenecid is used for.

And though this seems to be a new area of research, some antibiotics might work to some extent on both classes of transporters, meaning they would be effective masking a much wider range of drugs. I have to wonder if some doctors advising riders haven't figured this out. This would be such a neat explanation for salbutamol positives. The rider is taking the antibiotic as a way of masking some PED, stops taking it when he stops taking the PED, and doesn't realize that it will have an effect on salbutamol as well.

Oh, and have to mention this. I found a comprehensive review of drugs that affect the various transporters, and one that inhibits OCTs is pyrimethamine, which is used as an alternative treatment for...schisto!

Asthmatics are advised not to take aspirin although that would only be of relevance to Froome if he is genuinely asthmatic

Same with ibuprofen which IIRC has been shown to block the recovery process in athletes so perhaps not a good choice in a GT

However just found this link not sure of the author's credentials but it refers to ibuprofen damaging the kidneys...

https://runnersconnect.net/ibuprofen-and-running/

 

[bigcog]

All this evidence that NSAIDs inhibit drug excretion made me wonder, why not just use aspirin as a masking agent? Well, google that, and people do! There are several articles on the internet promoting it for that purpose. This is a home remedy, to be sure, but one backed by a lot of scientific evidence. The only problem with this as far as salbutamol goes is, as I said before, that NSAIDs primarily act on OATs, not OCTs. But it appears they might be effective masking agents for steroids and other drugs that probenecid is used for.

And though this seems to be a new area of research, some antibiotics might work to some extent on both classes of transporters, meaning they would be effective masking a much wider range of drugs. I have to wonder if some doctors advising riders haven't figured this out. This would be such a neat explanation for salbutamol positives. The rider is taking the antibiotic as a way of masking some PED, stops taking it when he stops taking the PED, and doesn't realize that it will have an effect on salbutamol as well.

Oh, and have to mention this. I found a comprehensive review of drugs that affect the various transporters, and one that inhibits OCTs is pyrimethamine, which is used as an alternative treatment for...schisto!

Asthmatics are advised not to take aspirin although that would only be of relevance to Froome if he is genuinely asthmatic

Same with ibuprofen which IIRC has been shown to block the recovery process in athletes so perhaps not a good choice in a GT

However just found this link not sure of the author's credentials but it refers to ibuprofen damaging the kidneys...

https://runnersconnect.net/ibuprofen-and-running/

Ibuprofen and some other NSAIDs damaging kidneys is a well known side effect:

https://medlineplus.gov/ency/article/000482.htm

not saying that's what happened here mind.

This I suppose is relevant:
https://uk.reuters.com/article/us-h...dney-damage-in-ultramarathoners-idUKKBN1AO25N

 

[AussieGoddess]

Re: Re:

There is irony in this approach, because to the extent that substances like NSAIDs or antibiotics inhibit excretion of salbutamol, they are in effect masking agents, much like probenecid, which Impey tested positive for. Indeed, now that I think about it, this is another possible explanation for Froome's positive. If he used a masking agent during the Vuelta--not to mask use of salbutamol, but of some other drug, such as a steroid--but then forgot to use it before stage 18, he could get a back-up of salbutamol that was later excreted in high concentration. In fact, he wouldn't even have had to forget to use it. If, with the end of the GT approaching, he decided he didn't need to use the steroid or whatever any longer, he would have also stopped using the masking agent, without realizing this could have an effect on salbutamol.

plausible theory ... maybe.

but Froome lost time on the stage beforehand ... so to my mind its unlikely that he would be winding down the steriods at that point.

still - its an interesting point. Perhaps it wasnt an error in the salbutomol itself, but a change in another drug that changed the body/reaction

 

[Wiggo's Package]

Quote below from Kelner and Ingle of the Guardian

[Who as an aside are lighting up Twitter with surprise at having today been blocked by Froome (probably via Michelle) on Twitter - since when was it a smart move for an athlete under suspicion to antagonise journalists?]

https://www.theguardian.com/sport/2018/jan/30/chris-froome-plea-bargain-drug-test-untrue-sky

"It is understood Froome, his advisers at Team Sky and his lawyer, Mike Morgan, are still committed to finding a physiological reason to explain why he returned an adverse analytical finding to a urine test."

 

[Wiggo's Package]

Re: Re:

[lighting up Twitter with surprise at having today been blocked by Froome (probably via Michelle) on Twitter - since when was it a smart move for an athlete under suspicion to antagonise journalists?]
https://www.theguardian.com/sport/2018/jan/30/chris-froome-plea-bargain-drug-test-untrue-sky
"It is understood Froome, his advisers at Team Sky and his lawyer, Mike Morgan, are still committed to finding a physiological reason to explain why he returned an adverse analytical finding to a urine test."

Well, Mike Morgan doesn't get paid his attorney fees during a protracted defense, if he gets "bypassed" and immediately cut out of the picture now by Michelle. That part is self-explanatory, as to why he differs on the current approach. She is shrewd, and it wouldn't surprise me if the near-real-time feedback from social media has convinced her that the physiology argument is futile.
Clinic much ?
So yes, there seems to be a dissonance between wife-manager and attorneys, leaving Chris unsure who to believe right now

Good observation

I suspect there is also a dissonance between the wife and the husband (the latter who is after all out doing 7hr rides every day to try and game the AAF system - not a regime designed for intellectual engagement once you're back home on the sofa)

And I think it's a given that Michelle controls Chris' social media profile (with all that entails including no doubt lurking/posting in the Clinic, going loco on Twitter, etc - hello Michelle )

Plus it wouldn't surprise me in the slightest if Michelle (Chris' agent remember) has been freelancing (giving Chris plausible Twitter deniability) trying to get a sweetheart 6 month ban from the UCI

Brailsfraud has been hanging Froome out to dry on legal fees/lack of team support and that's gonna rub the Dawg's agent/wife up the wrong way

Meanwhile Morgan gets paid his hourly rate for the work he does. But I bet he's pulling his hair out right now. Ain't nothing worse than a client (or their spouse/agent) going rogue

 

[Merckx index]

What is Froome’s defense? It was reported a couple of weeks ago that he was going to claim his kidneys malfunctioned, resulting in a build-up of salbutamol that, when normal kidney function was restored, resulted in a very high level of the drug in the urine. Other reports, though, claimed this was only one possibility being considered, or that maybe it wasn’t being considered at all.

I think all of these reports could have some truth in them. Something like renal impairment—but not exactly--could be part of the explanation. Any single theory, though, would be unlikely to account for all of the elevated salbutamol level. It would be used, in conjunction with other factors, to explain that level. This could be why, according to some sources, one particular theory is said to be the focus of Froome’s defense, while other sources insist it is not the focus, or only part of the focus.

Let’s begin with the so-called renal impairment theory. I think this is a misnomer. My educated guess is that Froome’s team is not proposing that there was anything wrong with his kidneys. A much better explanation would be a theory of DDI, or drug-drug interaction; that is, the presence of some other drug in Froome’s system inhibited excretion of salbutamol. This theory has several advantages over the renal impairment explanation, including:

1. It doesn’t imply that Froome—he of the schisto, typhoid, asthma, urticaria, etc.-- has yet another pathology, one usually associated with much older individuals, and which would likely make it difficult for him to race at all. His kidneys were working normally; the presence of another drug caused the inhibition of salbutamol excretion.

2. It’s easier to explain a sudden change in salbutamol level. As long as the drug was present, it would suppress salbutamol excretion. When he stopped taking the drug, the inhibition would immediately be relieved. In contrast, it would be difficult to explain why Froome’s kidneys stopped working properly, and even more difficult to explain why they suddenly resumed normal function.

3. It potentially can be supported by better evidence. Salbutamol is excreted by certain mechanisms in the kidney, and there are drugs, of the kind Froome might very well have taken, that can interfere with these mechanisms. Specifically, one set of suspects seems to be antibiotics. We know that Froome has taken antibiotics in the past. One of them, azrithomycin, has been reported to be an inhibitor of the organic cation transporter (OCT) thought to be involved in excretion of salbutamol. That particular drug was used to treat typhoid, which he presumably has been cured of, but there are other potential antibiotics, such as erythromycin, he might have been given for respiratory problems related to asthma. If Froome claims he was taking one of these antibiotics, this might be directly confirmed by analysis of his urine (depending on the antibiotic; very little erythromycin is excreted via the kidneys), and if there were an inverse correlation between its urinary levels and those of salbutamol, this would be strong evidence that it was indeed interfering with salbutamol excretion. Of course, if Froome inhaled a variable amount of salbutamol from day to day, this would complicate analysis, but one might still see a general trend.

All this notwithstanding, a single cause of the high level is unlikely. If taking some antibiotic or some other drug could result in such a dramatic change in excreted salbutamol, one would expect that this problem would have arisen with other athletes in the past, maybe even Froome himself. Possibly it might explain some other positives, but positives are fairly rare. It’s more likely that this just contributed to higher salbutamol levels, along with other factors. This would be why “renal impairment” is only one possibility being considered. IMO, they’re not looking for a silver bullet, but several pieces of lead shot.

http://sci-hub.la/10.1016/j.ejps.2018.01.002

 

[Merckx index]

In my previous post, I outlined a possible way in which Froome’s salbutamol concentration could have been raised beyond the normal limits, first in the plasma, and eventually in the urine. This is an accidental scenario, something he didn’t realize was happening, and so could be used as an explanation for his positive.

But the same sort of process could occur intentionally, as a way of avoiding a positive test. In that case, we call it masking. AFAIK, no one has ever discussed the possibility of masking salbutamol use, but if it really has PE effects, then masking it would obviously be of value, and maybe something some clever trainer has considered. How would you do it?

Most of the masking agents on WADA’s banned list are substances that affect water/salt balance, and therefore have broad, non-selective effects on excretion. The main exception is probenecid (of Impey fame), which inhibits organic anion transporters (OATs), and thus selectively blocks excretion of acidic substances, including steroids. There do not seem to be any substances that block excretion of basic substances like salbutamol, via action on organic cation transporters (OCTs), though, which as far as I can tell opens the door to doing this with little risk of getting caught.

E.g., one potential masking agent for salbutamol would be cimetidine, a drug that is used for GI disorders such as reflux disease and peptic ulcers. That’s not on WADA’s list. There are even substances that everyone normally takes which, in high enough doses, might inhibit salbutamol excretion, such as thiamine, or vitamin B1.

So a rider who wanted to take salbutamol orally could increase his dose by using such a masking agent. As discussed here previously, the dose could also be effectively doubled by using the active S stereoisomer, rather than the usual 50/50 racemic mixture. Combining these two approaches, one could potentially get quite a benefit. Based on lab studies, one could probably take as much as two mg of salbutamol orally without exceeding the threshold. That could be doubled using the S form, and perhaps doubled again by masking. So a rider might conceivably take as much as 8 mg of salbutamol orally without testing positive.

This also suggests another possible explanation for Froome’s positive. Had he been orally dosing with salbutamol, and masking it, the plasma concentration would rise, putting him at risk for high urine levels if he suddenly stopped taking the masking agent. A rider like Froome, used to winning and therefore frequently being tested, would probably want to wait until after a race or GT before doing this, so you would not think he would make that kind of mistake. But there are enough variables here that one can think of several scenarios that would result in higher than expected urine levels.

 

[TourOfSardinia]

That why come here - kudos MI

 

[Red Rick]

Added poll in this thread to avoid getting too many threads on this

 

[Irondan]

I went with a nine-month ban mainly because I think the precedence has already been set with Ulissi and further back by the Petacchi ban for the same thing.

I know that Froome is going to fight this to the bitter end, that much we should all accept. He's going to drag cycling through this just as Contador did and just as Roman Kreuziger did not too long ago. These guys don't think in broad terms on what's good or bad for cycling, they're concern lies with what's good for them and their families, which if I were in their shoes I'd feel the same way.

Get ready for an interesting Giro, and then I'm sure it will drag on through the Tour when he appeals to the CAS. In the end, it will all be for naught and he'll have to serve a ban.

 

[bigcog]

Re:

I went with a nine-month ban mainly because I think the precedence has already been set with Ulissi and further back by the Petacchi ban for the same thing.

I know that Froome is going to fight this to the bitter end, that much we should all accept. He's going to drag cycling through this just as Contador did and just as Roman Kreuziger did not too long ago. These guys don't think in broad terms on what's good or bad for cycling, they're concern lies with what's good for them and their families, which if I were in their shoes I'd feel the same way.

Get ready for an interesting Giro, and then I'm sure it will drag on through the Tour when he appeals to the CAS. In the end, it will all be for naught and he'll have to serve a ban.

Haven't the regulations for this changed somewhat since Ulissi ? If so, could that not affect the length of the ban either way assuming he gets one.