Drug Makers, in Shift, Join Fight Against Doping

[Tony T]

Drug Makers, in Shift, Join Fight Against Doping (http://www.nytimes.com/2013/02/19/business/drug-makers-increasingly-join-fight-against-doping.html?hpw)

The blood-enhancing drug EPO has improved the lives of millions of anemia patients, but Lance Armstrong and other top cyclists have turned the medicine into a byword for doping.

Now, a growing number of pharmaceutical companies are trying to prevent their drugs from experiencing the same fate by joining with antidoping officials to develop tests to detect the illegal use of their drugs among athletes.

The development reflects a significant shift from the days when drug makers paid little attention to how their products could be abused by athletes, said David Howman, the director general of the antidoping agency. In the past, drug makers “felt that any publicity in relation to antidoping control would be negative,” he said. “But what they discovered is the opposite happened.”

Still, Dr. Rabin and others said some companies needed persuading and did not return his calls. In those cases, he said, he uses peer pressure, reminding them that other companies are also participating.

“We know the progress of their drugs, and we know that at some point collaboration will naturally come,” he said. “We are a bit stubborn.”

[soulspinner]

The companies are beginning to put markers detectable by tests the companies develop.

[MattTuck]

The companies are beginning to put markers detectable by current drug testing..............

Hopefully these markers have a very long half-life.

[Joachim]

The companies are beginning to put markers detectable by tests the companies develop.

I did not read anything about markers in the article. They talk about "reagents to help identify the drug". While this can point to the development of a specific antibody against the drug which can subsequently be labeled with a fluorescent tag or use in either single or double Western Blotting (with isoelectric focusing in the case of 2D SDS PAGE), its not the same as a "marker" in the traditional sense of the word.

[Lewis Moon]

I did not read anything about markers in the article. They talk about "reagents to help identify the drug". While this can point to the development of a specific antibody against the drug which can subsequently be labeled with a fluorescent tag or use in either single or double Western Blotting (with isoelectric focusing in the case of 2D SDS PAGE), its not the same as a "marker" in the traditional sense of the word.

God loves a good chemist.

[false_Aest]

I did not read anything about markers in the article. They talk about "reagents to help identify the drug". While this can point to the development of a specific antibody against the drug which can subsequently be labeled with a fluorescent tag or use in either single or double Western Blotting (with isoelectric focusing in the case of 2D SDS PAGE), its not the same as a "marker" in the traditional sense of the word.

i like what you said but i don't really understand what you said.

learn this art major yo.

[Joachim]

i like what you said but i don't really understand what you said.

learn this art major yo.


Explained more clearly (I hope)... no talk of a marker being added to the drug. They talk about stuff to detect the drug. While some people think this is a marker, its not. Its a detection reagent. The general public sees a marker as something that is added to the drug and that is "what's in the bottle". This additional "marker" can then be detected.

However, companies will not add "markers" to their molecule/drug, merely for antidoping purposes since markers can influence how the drug works in the body (one of the many things that could happen is that the molecule gets "bigger" by addition of the marker, which could alter its biological profile). $1 billion to develop a drug and then worry about small fish like WADA and go through all the trials again because a marker is added? Not going to happen. Its a different case to share information that was gathered during the development of the drug (detection methods). What they are talking about in the article are the methods that were developed by the drug companies to detect the drug and/or its metabolites (ie after the drug/molecule entered the body). These methods, which could take very long to develop by anti-doping labs due to limited resources, are therefore immediately available and only need a little "tweaking" to make it usable in the anti-doping field. The companies, with A LOT more resources, develop these detection methods rapidly, since its required by the FDA to show the half life of the drug and metabolism/metabolites etc. Given that the molecules are often guarded secrets by the companies, these detection methods will normally only be available once the drug hits the market. By sharing the methods during development, the anti-doping labs have these tests ready before the drug hits the market.

[carpediemracing]

Here's a short answer on markers.

Markers are additions to the drug. It's like putting little smiley face molecules in the drug - if you see smiley faces in the pee then the rider is positive.

Problem is that the smiley face molecule may have some effect on people. Think red food dye (the bad kind). It's supposed to be harmless, it's just red dye, but it ended up bad for you.

If a company adds anything to their approved drug then they have to retest everything.

Not worth it.

Instead they figure out what kind of trace stuff their drugs leave behind and teach/tell others how to detect those traces.

Chemist, feel free to correct.

[Joachim]

Pretty much, I think all angles are covered. It will be really cool if I can see smiley faces in urine, but then I probably have been eating the wrong mushrooms :)

The fluorescent antibodies and western blotting I have been talking about in my earlier posts are examples of detection methods (similar to the current method to detect EPO).

[Lewis Moon]

Pretty much, I think all angles are covered. It will be really cool if I can see smiley faces in urine, but then I probably have been eating the wrong mushrooms :)

The fluorescent antibodies and western blotting I have been talking about in my earlier posts are examples of detection methods (similar to the current method to detect EPO).

A big thank you to Joachim for explaining this issue so completely. As a biologist, I tend to enjoy this type of 5#!+ talking.
It would be a HUGE step forward if drug companies start to "protect" their products in this way. What I still worry about is the micro scale "designer" end of the (black/grey) market (think: Owsley Stanley).
I also worry about the spectrum of issues This (http://articles.latimes.com/2012/oct/24/news/la-heb-gene-therapy-mitochondrial-dna-20121024) calls to mind.

[Joachim]

A big thank you to Joachim for explaining this issue so completely. As a biologist, I tend to enjoy this type of 5#!+ talking.
It would be a HUGE step forward if drug companies start to "protect" their products in this way. What I still worry about is the micro scale "designer" end of the (black/grey) market (think: Owsley Stanley).
I also worry about the spectrum of issues This (http://articles.latimes.com/2012/oct/24/news/la-heb-gene-therapy-mitochondrial-dna-20121024) calls to mind.

Interestingly (scary) is that there is A LOT of information out there regarding the developent of steroids in the 60's and 70's with their published chemical structures but never taken into clinical trials. Many of those are currently undetectable and are easily manufactured by "underground" labs. Then we have "endurance" drugs like AICAR which are available online and drugs like GW501516 (see http://en.wikipedia.org/wiki/GW_501516). The last time I chatted with a colleague at an anti-doping lab they were talking about developing mRNA chips to use at the London Olympics to detect autologous blood transfusions. I am not sure if that was ready on time and passed through the legal mumbo jumbo. With regards to gene doping, you still need a way to insert the gene into the sequence and hope the transcription performs without a hitch (PCR doping?). I've wondered many times if doping chemists will take more translational approach by targeting mRNA or microRNA's or try to go through posttranslational modification of proteins. Remember the body will also recognize the transfection with subsequent non-desired effects. In my lab we are currently working on drug to increase bone marrow progenitor cells (to limit the side effects of certain chemotherapies) and one of the effects is an increase in red blood cell production. The funny thing is that this drug is undetectable since it resembles an endogenous molecule and is used to alter the redox balance within cells.

[54ny77]

so much for the sales rep's healthy commissions to their favorite doctor customer.

oh, woops, does that really happen? no, can't be.

:rolleyes:

[Lewis Moon]

Interestingly (scary) is that there is A LOT of information out there regarding the developent of steroids in the 60's and 70's with their published chemical structures but never taken into clinical trials. Many of those are currently undetectable and are easily manufactured by "underground" labs. Then we have "endurance" drugs like AICAR which are available online and drugs like GW501516 (see http://en.wikipedia.org/wiki/GW_501516). The last time I chatted with a colleague at an anti-doping lab they were talking about developing mRNA chips to use at the London Olympics to detect autologous blood transfusions. I am not sure if that was ready on time and passed through the legal mumbo jumbo. With regards to gene doping, you still need a way to insert the gene into the sequence and hope the transcription performs without a hitch (PCR doping?). I've wondered many times if doping chemists will take more translational approach by targeting mRNA or microRNA's or try to go through posttranslational modification of proteins. Remember the body will also recognize the transfection with subsequent non-desired effects. In my lab we are currently working on drug to increase bone marrow progenitor cells (to limit the side effects of certain chemotherapies) and one of the effects is an increase in red blood cell production. The funny thing is that this drug is undetectable since it resembles an endogenous molecule and is used to alter the redox balance within cells.

Looks like we're in for as much of a "whack-a-mole" future as we had in the past.
So...how is the posttranslational modification of proteins affected? I'm an ecosystems ecologist (WAY on the other end of the spectrum). Use small words and speak slowly...

[Joachim]

I would say targeted. By targeting potential posttranslational sites on a protein, you can alter its function, activate and deactivate for one. If a small molecule, that is membrane permeable, can enter the cell and subsequent modify a protein (for example the EPO receptor) you can initiate a signaling cascade with a subsequent desired biological response (more red blood cells). In the cancer field, similar drugs have been in development for a long time, AKT inhibitors, Pim kinase inhibitors etc. GW501516 for example is a PARP (a nuclear hormone receptor) modulator. Bottom line is, you don't need a big molecule like EPO to do the same thing. Think of it in terms of get in, get out kind of approach.

[54ny77]

so much science!

http://3.bp.blogspot.com/-p5o81FzcDYk/UKuOiQJyA0I/AAAAAAAAAD8/HStWJquJxRk/s1600/doc+brown+thinking+cap+back+to+the+future.jpg

[Joachim]

Its witchcraft! I still think tubulars are better than clinchers.

[Lewis Moon]

I would say targeted. By targeting potential posttranslational sites on a protein, you can alter its function, activate and deactivate for one. If a small molecule, that is membrane permeable, can enter the cell and subsequent modify a protein (for example the EPO receptor) you can initiate a signaling cascade with a subsequent desired biological response (more red blood cells). In the cancer field, similar drugs have been in development for a long time, AKT inhibitors, Pim kinase inhibitors etc. GW501516 for example is a PARP (a nuclear hormone receptor) modulator. Bottom line is, you don't need a big molecule like EPO to do the same thing. Think of it in terms of get in, get out kind of approach.

As they always admonish grad students in the design phase of a study: keep it simple, keep it small, keep it low tech. It's amazing how, the more we know about a complex system, the less we need to do to affect changes to it.

[soulspinner]

Only reason I used the name markers is cause I read that Amgen was considering them and used the term.

[54ny77]

the preferred marker of riis/saiz/bruyneel, et al....

http://volokh.com/wp/wp-content/uploads/2011/04/crayola.jpg

[soulspinner]

QUOTE=54ny77;1297343]the preferred marker of riis/saiz/bruyneel, et al....

http://volokh.com/wp/wp-content/uploads/2011/04/crayola.jpg[/QUOTE]

:)