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Up to Speed on Meldonium

I will freely admit that I had never heard of meldonium (aka mildronate) until yesterday, when it made headlines across the sports pages (and cost Maria Sharapova a great deal of endorsement money). That’s probably because it’s never been approved in the US or anywhere in Western Europe. That category of drugs is a relatively small and very mixed bag. Very few countries have companies or institutes that actually develop new drugs, and once you get past North America, Western Europe, and Japan things thin out pretty rapidly. India and China have only started getting into from-the-ground-up drug discovery business relatively recently, so you have Israel, Australia, and not too many others once you get outside the three regions mentioned above.

But eastern Europe and the former Soviet Union are a case all by themselves. The division of Europe during the cold war era caused two parallel scientific worlds to develop, and there were two worlds in the pharmaceutical business as well. There were (and are) extremely capable chemists and biologists in Russia, Ukraine, the Baltic states, former Czechoslovakia, Hungary, East Germany, Poland, etc., and a lot of pharmaceutical R&D was done during the cold war years that never really mixed with the West. Those readers who remember the Warsaw Pact chemistry and biology journals know about the sheer volume of work that came out of these countries (although from what I’m told, there was often a justify-your-relatively-good-job-comrade aspect to all this publishing).

Meldonium is one of these. It came out of Latvia in the 1970s, and the only places where it’s an approved drug appear to be parts of the former Soviet Union. There can be several reasons for this sort of cold-war hangover in approval, but I have no problem invoking my standard answer to questions that start off with “I wonder how come they. . .”, which is “Money”. Drugs that were approved under the old government(s) in this region have by and large been carried over until today, and seeking approval in the EU or the US is an expensive proposition for something whose patentability is shot.

But there are other factors. An outstanding drug caught in that situation could easily be the subject of some research to produce a newer derivative or improved formulation that would be patentable, but when you haven’t seen that happen, it increases the chances that the drug itself is something that probably wouldn’t find much of a niche. Meldonium, though, has been the subject of recent clinical work in several countries, generally in people who’ve had heart attacks or strokes.  It’s prescribed for ischemia in cardiac patients, and the increased blood flow is surely the reason that it’s caught on among some athletes. Sharapova’s claim that she has been taking it for years for “medical reasons” doesn’t sound very plausible, at least at first, considering what the approved patient population looks like – they tend not to have very effective backhand strokes.

She claims to suffer from magnesium deficiency and a family history of diabetes, but I’m having trouble drawing a line from those to meldonium. Most of the time when people talk about a family history of diabetes they mean something like Type I or MODY, either of which would have presumably shown up long since in Sharparova’s case. And a professional athlete would seem to be at little risk of Type II, with its strong connection to weight gain and lack of exercise. As for magnesium deficiency, that’s a staple of “Could You Have This Common Disease?” columns, usually with reference to vague symptoms (tiredness!) that everyone feels. Magnesium is not a particularly rare element in a varied human diet and it can be easily supplemented. A true problem with its absorption is something that can be demonstrated clinically. Unless Sharapova has something to back that diagnosis up, it’s not very solid, either.

The compound – a very simple structure – appears to work as an inhibitor in the carnitine biosynthesis pathway, and may have several other activities. Landing in that pathway might well be enough all by itself; metabolically, there’s a lot going on at that intersection. The World Anti-Doping Agency has now banned it, on the basis of studies that say that it increases endurance, speeds recovery, protects against stress, and may have CNS effects as well. Unless more evidence comes to light, I’d say that this case is exactly what it looks like.

57 comments on “Up to Speed on Meldonium”

  1. steve

    “…increases endurance, speeds recovery, protects against stress, and may have CNS effects as well”. Sounds great! Where do I get some?

    1. Me in reply to steve

      Russia

      Agree with your assessment Derek – got straight on it as soon as I saw it.

      As a one-time neurodegeneratives researcher……….

      1. Robot in reply to Me

        Mandrake: l-carnitine have strong effect on Red Blood Cells (RBC), it increases the life span of RBC, allowing them to release oxygen effectively and to boost Sharapova endorsements. Is not it Design Monkey? Ops I forgot you may supplement RBC with tonnes of l-arginine to have similar effect?

        Gamma-butyrobetaine dioxygenase or BBOX1 also catalyses the oxidation of carnitine /Meldonium. https://en.wikipedia.org/wiki/Gamma-butyrobetaine_dioxygenase
        As oxy-2 oxygenase (2-OG) It requires α-Ketoglutaric acid similar to prolyl hydroxylase (PHD). Inhibitors of PHD is an attractive target for many companies, including Vertex Pharmaceutical? I am wondering if mildronate may speed up an discovery process as a rare example of a non-peptidyl substrate mimic inhibitor for 2-OG?

    2. Mark Thorson in reply to steve

      It’s all over the morning talk shows, mostly because of Sharapova endorsements being dropped. I predict a surge of interest in this heretofore obscure drug. If it’s possible to invest in the manufacturer, could be a good play. Assuming Shkreli doesn’t get there first.

  2. anoano

    The drug was banned only from this year. So, Sharapova was tested positive this year, but then what does it mean for pre-January 2016? It was legal before that date, and may have been used by a lot of professionals in tennis (it was at least used in other sport as some athletes have been found using it as well this year), but if one would have read the email from the agency during Christmas about the new doping list, they could have stopped just before new year.

    I found some of the reaction very eager towards putting her as a cheat, she may be one, but I think we can give some doubt for now until things settle down after all the media craziness.

  3. Zander

    Looks a bit like a trimethylated lysine… Perhaps it also influences gene expression (think about histone trimethylation).

  4. anchor

    I too on my part rushed to get some info. on this and in the process visited the company’s (Grindex) website that is based in Latvia but drew blank. Wikipedia has a structure and it turns out be a hydrazine analog! May be a good project for fledgling PI to write a proposal (NIH) as to how this works to reverse ischemic events for which it is prescribed.

  5. Mark Thorson

    I too was looking for some data about this drug, especially after reading in Wikipedia that it may have some value in treating Alzheimer’s. I found this paper, but I can’t get the full paper to download from researchgate:

    https://www.researchgate.net/publication/258856474_Mildronate_improves_cognition_and_reduces_amyloid-b_pathology_in_transgenic_Alzheimer's_disease_mice

    I’ve been having a lot of trouble with researchgate recently. It used to work great, but now downloads usually crap out after part of the file downloads. I’ve tried to download this file lots of times, and it always fails.

    Just judging by the abstract, there’s lots of other agents that look more promising than this one. Decreased amyloid deposition and better performance on mouse cognition tests suggest more research is warranted, but it’s not anything exciting yet.

    1. Me in reply to Mark Thorson

      *sci-hub*… sci-hub Sci-hub Sci-Hub SCIIIIIII HUUUUUUUUBBBBBBBB!!!!!!!!!!!

      1. alchemist in reply to Me

        You beat me to this one… 😉

        1. Me in reply to alchemist

          Yes – we both meant to say that use of Sci-Hub is a wanton breach of copyright law.

    2. Anonymous Researcher snaw in reply to Mark Thorson

      While I wasn’t able to make the download button on ResearchGate work, when I scrolled down in the preview window and clicked the Read Full Paper button the rest of the paper appeared there and I am reading it now. Basically, they tried the drug on mice with the Swedish Mutation (a popular AD model) and found some benefits in social recognition and water maze tests. As they note near the end of their discussion section, since mice of the age they used with the Swedish Mutation don’t show any tau pathology, it’s not clear whether these results would generalize to subjects with tau pathology.

      My take: a moderately interesting study, but I have seen many such studies. So far, none of them has translated to success in humans.

  6. Ash (Wavefunction)

    In old Soviet Union, meldonium consumes you.

    1. Better the meldonium that you know than the polonium that you don’t?

      I’ve linked a 2012 blog post featuring Maria, drug discovery and the Australian Open as the URL for this comment

  7. Dave

    In addition to the usual Type I and Type II Diabetes, and MODY, there’s also LADA, which some studies indicate may be a LOT more prevalent than previously thought (e.g., 50% of Type II Diabetes may be LADA!). It’s usually misdiagnosed as Type II Diabetes, based on the age at which it is first diagnosed, but the symptoms are closer to Type I Diabetes, consisting of failure of Islet of Langerhans cells, resulting in lowered Insulin production. Additionally, it doesn’t necessarily have the Insulin-resistance characteristics of Type II Diabetes, nor is associated with weight/fat issues.

    https://en.wikipedia.org/wiki/Latent_autoimmune_diabetes_of_adults

    1. ROBOT in reply to Dave

      Next generation meldonium drugs specifically designed with chemical evolution deal can significantly reduce therapy such as Orkambi since the costs of these drugs can be readily justified by the overall SAVINGS that breakthrough drugs can deliver thanks to reduced downstream costs and better health for patients in need. With magic of knowledge driven force of proteins evolution the targets can be switch off/on with single trick without PAINS by activating genes networks are capable to resolve metabolic demands.

  8. I also though meldonium is something you would show to your doctor, privately

    1. RB in reply to milkshake

      I thought that Meldonium was a East European country, either that or a musical instrument.

      1. Susan Solarz in reply to RB

        I thought it was a mental illness. ;- )

  9. The Latvian company that manufactures meldonium says the normal course of treatment for the drug is four to six weeks – not the 10 years that Maria Sharapova says she used the substance.

    1. Susan Solarz in reply to Chris Swain

      That’s an important fact that should be included in the reporting on the Sharapova ban and her appeal for a lighter penalty. Until I learned that the drug is not ever prescribed for long term use I was a little sympathetic because she’d been using it legally for such a long time. Now we know that she couldn’t possibly have been using it for a legitimate health concern. Sharapova took the drug as it would be taken to enhance athletic performance not as one would take it for a medical condition like angina.

  10. anon

    Of course she’s a cheat but not for the reason that people think.
    Based on her reading of Marvel Comics Issue 1132, Maria mistakenly
    believes that Meldonium gives here supernatural powers of being
    able to meld her mind with that of her opponent and having the
    ability to influence them into making critical errors.

    Who knew that she was simply increasing her
    endurance, speed of recovery and protecting herself against stress?

  11. pete

    I first heard about meldonium by following competitive road bicycling. Often it seems that some of those road racers are at the bleeding edge of testing new (& older) candidates for the growing PED lists. The 2016 WADA list is here:

    http://www.usada.org/wp-content/uploads/wada-2016-prohibited-list-en.pdf

    1. Sam P in reply to pete

      It’s relatively easy and inexpensive to put a reasonably accurate and somewhat precise power meter on a bicycle. Training with power meters has been widespread among cycling pros for perhaps more than a decade (first commercial system available over 20 years ago).

      Treadmills and rowing machines are comparable but aren’t something you can take with you into the outdoors.

      So cyclists testing for marginal gains is relatively easy and not as boring as for runners and rowers.

  12. a. nonymaus

    What I don’t get out of all this is how inhibiting fatty acid metabolism is supposed to help athletic performance. As I understand it, many of the inborn errors in fatty acid metabolism involve the likelihood of abruptly dying of hypoglycemia during exertion. Is it something to do with the relative oxygen demand for carbohydrate oxidation vs. fatty acid oxidation so long as you don’t run out of glucose?

    1. Design Monkey in reply to a. nonymaus

      Yep. Multiple mechanisms actually. One, chopping up sugars for energy indeed requires less oxygen than doing the same with lipids. Second, carnitine fatty acid esthers actually are surfactants. At increased demand of energy and deficit of oxygen, their concentration build up and they start to damage membranes of mitochondria. Third, there is also a bunch of other unclear and not very well explained effects, like blood flow increase, possibly mediated through interaction with NO system, and short term effects of single doses (carnitine lowering happens only fter regular use of week and more).

  13. Tuck

    “…although from what I’m told, there was often a justify-your-relatively-good-job-comrade aspect to all this publishing…”

    How is this is different from Western academic journals?

    1. Isidore in reply to Tuck

      A huge difference: In the former Soviet block an academic scientist published in order to satisfy the party commissars of his/her proper and productive use of funds dispensed by the government. In western countries an academic scientist publishes in order to demonstrate to grant review committee members his/her proper and productive use of funds dispensed by government-funded grant agencies. Hmm…

      1. Design Monkey in reply to Isidore

        You both haven’ t lived there, no wonder you don’ t understand. Still as a homework you can try to compare Lysenkoism with Weissmanism-Morganism- Mendelism and tell, if you see significant differences.

        1. dr nemo in reply to Design Monkey

          Design Monkey, I enjoyed reading your story about meldonium discovery – where did you find this information? In the interviews that one of the inventors, Ivar Kalvinsh, gave, he said that the discovery was serendipitous, but did not give all the details that you found. He did say it was first approved as a veterinary drug.
          Also, about Soviet science, but off-topic – you asked people to do a search on Lysenkoism etc., so I did. Last time I thought much about Lysenkoism was in my high school biology class circa 1982. What I did not understand then was why in the Soviet Union genetics had been treated as a corrupt and dangerous pseudoscience from 1930-ies to 1950-ies. (Frankly, I thought then the whole thing had been madly overblown). Today, looking at some of those old accusations, I suddenly realized they sounded quite familiar. I read something very much like it in the Wall Street Journal – several weeks ago.
          If you look up “The Progressive History of Eugenics” by Amity Shlaes, Feb 26, 2016, maybe you’d get a sense of perspective on how horrifying the practical implementation of genetics was in the US and in Western Europe in 1930-ies to 1940-ies.
          I apologize for the extensive quoting: “Civic Biology” advocated eugenics on the basis of race and flirted with the fallacy that acquired traits such as “shiftlessness” might be passed down the generations. Buck v. Bell, the 1927 case in which the Supreme Court upheld Virginia’s right to sterilize citizens it deemed mentally ill, somehow deficient or, indeed, shiftless. . Tens of thousands of inmates were duly sterilized, and state officials, far from hiding their work, trumpeted the news, so loud that they got the attention of Europeans, especially the Germans. Hard as it is to imagine, the Third Reich’s Law for the Prevention of Hereditarily Diseased Offspring, which led to the sterilization of hundreds of thousands, was crafted from a blueprint issued by a lab in Cold Spring Harbor, N.Y. It was only when the Nazis took eugenics to the extreme of genocide that the eugenic fervor in the United States began to abate”.
          So, given all that and the fresh memory of Soviet people declared to be untermensch and destroyed by the Nazis in the WWII, it really should not be shocking that in 1950-ies genetics was still seen as a dangerous heresy that needed to be wiped out. Once Nazism appeared firmly in check, it became possible to relax about genetics. I never thought about it this way – thank you for giving me a chance to get a sense of perspective.

          1. Design Monkey in reply to dr nemo

            Those details are local drinking time stories here in IOS. 🙂 Dr Kalvinsh still works here, and person, who was his lab assistant at that time and was first one to accidentally synthesize meldonium, too.

        2. Isidore in reply to Design Monkey

          Fair enough, Design Monkey.

  14. Sulphonamide

    Mention of carnitine and ischaemia together suggests an effect similar to carnitine palmitoyl transferase inhibitors like perhexiline which switch metabolism from fats to carbohydrates – preventing the fats from being transported into the mitochondria. Contrary to what I remembered about fats having more energy than carbs, carbs apparently give more ATP per unit oxygen (over 30% with perhexiline, but not sure we really know why it is quite so high) – more bang for the buck to support the struggling heart. Are CPT-1 inhibitors are banned for athletes too? As you say, as long as an athlete doesn’t run low on glucose, then maybe it is an obvious way to boost performance

    1. Robot in reply to Sulphonamide

      What’s the cost? Meldonium vs l-arginine is only “Money”. Nobody will ever patent beneficiary effect of Hydroxycitric acid since others derivatives are available.
      I would better satisfy WADA with only use of Meldonium than uncover whole story of Sharapova endorsements.

  15. Bruce Hamilton

    From Latvian media last year…

    ” The World Anti-Doping Agency (WADA) has added meldonium, commonly sold as Mildronats, an anti-ischemic drug produced in Latvia to its list of banned substances, LETA reported on Thursday.

    It seems that the fame of the drug has spread far and wide, as WADA says the drug was included in the updated list because of “evidence of its use by athletes with the intention of enhancing performance.”

    Developed in Latvia, meldonium has been used to treat ischemia, or lack of blood flow. Meldonium had previously been on WADA’s list of drugs to be monitored.

    Mildronats is one of the most successful medicinal exports from Latvia. In 2013, export turnover of the drug reached EUR 65 million. It is produced by the Latvian pharmaceutical company Grindeks. “

  16. Kling

    Why does athletic doping bother people? Super athletes are rarely normal people to start with, already mutant abilities.
    I am as good with Lance being sponsored by Amgen rather than the Postal Service. Both logos are blueish on his yellow shirt.

    1. Emjeff in reply to Kling

      Well, for one it’s cheating. Two, it encourages others to cheat in an attempt to compete effectively. Three, it encourages amateurs and young people to use potentially dangerous drugs in an attempt to reach the pro level.

    2. Sam P in reply to Kling

      There are some safety issues, Reportedly some EPO dopers died when their blood became too thick to circulate well. I suppose if PEDs were out in the open then careful monitoring would be more easily available. But I’ve read that some PEDs were filtering down to high school students.

      1. Isidore in reply to Sam P

        Quite so. And unlike professional athletes, who could easily have PEDs administered under medical supervision, high school and college athletes may suffer the ill effects of the unsupervised illegal administration of such.

  17. Mandrake

    Hydrazine alert!

    1. Design Monkey in reply to Mandrake

      Yep, hydrazine. Still it happens that such quaternized hydrazine mostly doesn’t metabolize in typical nasty hydrazine way. Also it was discovered in old times in soviets. And the way of discovery was approximately as this: 1. ppl are working on only partially drug oriented research 2. they run a certain reaction and get a totally unexpected product in huge white crystals. 3. hey, its stucture looks like plant product glycine betaine and also like herbicide Alar (daminozide). Let’s try it on plants, maybe it will be a new, pretty herbicide. 4. oops, instead of killing plants, it somewhat stimulates their growth. Not a herbicide then. Let’s try it on mice. 5. mice seems happy. Also it is impossible to establish acute oral LD50 on mice – it’s not possible to feed them enough to kill them. Intraperit tox data are not trustworthy as well, one has to inject such unholy amount of drug, that mice finally dies from sort of bursting, and not from drug itself. It’s easier to kill the mice by whacking them on head with bottle of this compound, than unsuccessfully trying tho poison them with it. In any case, it’s definitely less toxic than sugar or salt. 6. Now that product behaves funnier and funnier, it gets extended bio testing. 7. which results in cardio drug meldonium.

      1. Istvan in reply to Design Monkey

        I disagree. Many breakthrough drug discoveries were done just the way you described. Think about benzodiazepinesand even LSD-25. The discover of lidocaine is also a prime example:
        http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2085799

      2. pKa for deprotonation on NH may be relevant?

      3. Robot in reply to Design Monkey

        Just got it. Back to the roots. http://www.ncbi.nlm.nih.gov/pubmed/3342076
        2-OG story is much more interesting than you think. Isn’t it?

  18. arun sharma

    Why was she taking it if this drug was under monitoring by WADA. Does she have east european doctor to prescribe it? It appears to be a well thought out strategy. by her and her managers.

  19. Saiko

    Doesn’t sound plausible that shed been taking it for years? But it sounds plausible that she’d see it was now banned and then go ahead and just start taking it at that time? And that she’d do so going into a major where lots of testing instead of waiting for the time-off period after where there’s much less chance of being tested?

    Your “analysis” has the common error of focusing on only one factor at hand (in this case the drug itself) while ignoring the rest.

  20. Javaria

    “The World Anti-Doping Agency has now banned it, on the basis of studies that say that it increases endurance, speeds recovery, protects against stress, and may have CNS effects as well.”

    No, the reason WADA banned it is based on circumstantial evidence i.e., many athletes are using it so it probably is a PED.
    The only scientific research the president of WADA cited is about the prevalence of this drug among athletes and the ways that can be used to detect it.

    WADA has no scientific research to support their claim of this drug being a PED.

  21. Rachel Isabelle Jacobs

    I believe from researching it online, that I, as a heart-failure patient, need meldonium,DESPERATELY. I have been given lisinopril and lasix to treat the heart failure, I am wetting all over myself and still can’t breathe at night to sleep, even though my BP is that of a teenager, 110/70–so that doesn’t need adjustment. I have to strengthen my heart so I can have joint replacement surgery on both hips and knees. I have to use a walker and can hardly take a step without a joint trying to collapse on me, so I MUST have the joint replacements soon. Please help me find a place where I can get Meldonium: please. Rachel I. Jacobs

  22. Puddles

    Ebay is selling it, out of London, Eastern Europe or Russia. There are Russian pharmacies online, but I got a notice one was hacked and decided Ebay vendors were more reliable. The prices were about the same. It’s a class 5 drug, which is like a supplement, and the customs cost shouldn’t be much, if any. I’m sure the price is higher than if it were sold from a pharmacy in Europe or Russia, but what can you do if you want to give it a try? I’m interested in the increased circulation of oxygen in the brain, and waiting for the 60 capsule, 500 mg package to arrive around the end of the month. Good luck to you, Ms. Jacobs, it sounds like you are going through a difficult time.

  23. Anonymous Researcher snaw

    This drug was on the Watch List for some months before it was banned. Any competitive athlete should pay attention to the Watch List, because drugs on that list are likely to get banned in the near future.

    As for her claim that she was taking it for a medical issue, there is a mechanism for athletes with valid medical reasons for the use of a banned drug to get an exemption:

    https://www.wada-ama.org/en/what-we-do/science-medical/therapeutic-use-exemptions

    For instance, insulin is on the WADA banned list, but athletes with diabetes routinely get TUE approvals.

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