Catching up with sports dopers: benzothiazepines

The drugs athletes use to gain an illegal edge in take one of two general forms: they are variants of (most often) steroids already known to, and tested for, by doping authorities, chemically modified to make them less detectable or undetectable in screenings; or they are drugs developed in order to treat familiar diseases, with their effects on strength, speed, and endurance being merely a happy and happenstance finding among “sports pharmacologists” who then deploy them well before testing authorities get wise.
The former “class” become more popular in the 21st century as technology on both the cheating and testing sides has become more elaborate–in the past, drugs use for doping were invariably drugs already on the market and developed for the purpose of treating illnesses. In the case of the latter, testers have an especially difficult job when the “drug” is actually a substance produced naturally in the body that has recently entered mass synthetic production thanks to recombinant technology. Perhaps the best-known example of the is erythropoetin (EPO), a hormone produced in the adrenal glands that stimulates the production of new red blood cells. Originally used to treat anemia, most often in people with chronic kidney disease or cancer, it quickly became a favorite of distance runners, Nordic skiiers, and cyclists because of its immediate and marked effects on aerobic capacity. It has spawned a number of synthetic cousins since the early 1990s, notably darbepoetin.


Other favorite natural-gone-synthetic performance enhancers include hGH, somatostatin, insulin. Meanwhile, in addition to the synthetic steroid-class variants noted above, there has been a recent surge in the use of, and positive tests for, newer stimulants such as modafinil, approved for the treatment of narcolepsy. (Until people start falling off their bikes in a sound slumber or passing out on top of their 200-meter-dash starting blocks, you can be fairly certain that anyone flagged for modafinil is not using it with a legitimate prescription.)
This post deals with an interesting twist–anti-doping authorities being aware of drugs showing promise to cheaters that have not yet even reached the market. This article mentions two such substances, currently known only as JTV-519 and S-107 and geared toward the treatment of cardiac abnormalities. These drugs, which exert their effects by increasing intracellular calcium through the stabilization of ion channels in muscle cells, have proven to increase endurance in mice. So, while their effects on humans have yet to be explored, there is already a test in place for these “benzothiazepines” (a potentially confusing designation; would-be cheaters, please be aware that popping Valium or Xanax is unlikely to help you shave minutes off your marathon time).
The article explains the biochemistry behind the test clearly and succinctly:

“As soon as these drugs enter human clinical trials, there is a huge potential for them to be misused in sports. This preventive research lets us prepare before these compounds are officially launched,” says Mario Thevis, Director of the Center for Preventive Doping Research at the German Sport University of Cologne, Germany, who led the research.
The researchers think the simple nature of the compounds means they are easy to make and sell to drug cheats as endurance boosters on the black market.
The study characterises the compounds according to their weight and molecular structure. This gives the researchers a molecular “fingerprint” by which to identify the compounds. Thevis and colleagues show that, using high resolution mass spectrometry, JTV-519 and S-107 can be detected in spiked urine at concentrations as low as 0.1 nanograms per millilitre.
“We used the common approaches that are employed for detecting anabolic agents. Our work showed that we could identify the right compounds and that we have a sensitive test,” says Thevis.
The next step is to look for the molecules created by the metabolic breakdown of the compounds once they have entered the human body. This will give researchers a wider scope of compounds by which to identify cheats when screening samples. However, the compounds can’t be given to humans until they have been approved for clinical trials, so the researchers must focus on bench studies using human microsomes. These are tiny vesicles that mimic cell metabolism and so can be used to predict how the drugs might be broken down.

The test will be described in detail on the launch issue of Drug Testing and Analysis, a journal to be published by Wiley & Sons beginning this month.

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  1. #1 by anon on January 8, 2009 - 4:57 pm

    There are other legitmate uses for Modafinil than Narcolepsy. Classic narcolepts are also unliley to be doing sprint events given the problems with excitement and cataplexy.
    The non-classic narcolepts or people with idiopathic hypersomnia, sleep apnea or shiftwork sleep disorder may well be on modafinil for legitimate reasons. International athletes could certainly make a convincing case that their jetlag may require modafinil treatment. It would be up to the appropriate authorities to make it clear that a presciption for this reason would still be illegtimate for the purposes of drug testing in sport (I hope they’ve done this already).

  2. #2 by anon on January 8, 2009 - 4:57 pm

    There are other legitmate uses for Modafinil than Narcolepsy. Classic narcolepts are also unliley to be doing sprint events given the problems with excitement and cataplexy.
    The non-classic narcolepts or people with idiopathic hypersomnia, sleep apnea or shiftwork sleep disorder may well be on modafinil for legitimate reasons. International athletes could certainly make a convincing case that their jetlag may require modafinil treatment. It would be up to the appropriate authorities to make it clear that a presciption for this reason would still be illegtimate for the purposes of drug testing in sport (I hope they’ve done this already).

  3. #3 by Scicurious on January 9, 2009 - 10:49 am

    Modafinil is also being proposed for use as a cognitive enhancer.
    And I love that they are calling the new drugs “benzothiazepines”. I’m sure they’re going to catch some high school athelete in trouble for popping his mother’s Valium, figuring he’s get increased cardiac capacity.

  4. #4 by Simon on January 13, 2009 - 1:46 pm

    Also confusingly, olanzapine (Zyprexa), an antipsychotic that does not bind GABA receptors, is a thienobenzodiazepine…

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