Talk:Meldonium

In need of a serious rewrite

This page is full of scandel trigger bait - not up to standards one would expect from an encyclopedia. Some of the readers are more interested in if it might be helpful (no longer patentable - thus not a research candidate in the USA ). This medicine may be effective for heart disease - nephropathy etc. As a potential treatment drug it is VERY interesting - not that anyone will see this from this poor quality page.

In the USA, if a drug is banned for use by athletes, or is illegal, it's because it can be damaging to the person taking it. In other words, because it could be fatal. Nowhere does this Wikipedia entry for Meldonium discuss the dangers of taking this drug. Any medication has at least one mild negative side effect. People who have contributed to this page seem to have decided that publicizing any negative side effects of this drug would hurt the sales of this drug.

I can see a short section on the sports ban - but there are more important things pushed out. What if this drug is actually more effective than the statins commonly prescribed? What if the effects on the NO system really matter?. There is material in research about this drug - might be a wonder drug hiding out in the Russian block - not used in the USA due to politics and ignorance. — Preceding unsigned comment added by 108.243.106.82 (talk) 19:44, 9 August 2020 (UTC)

Abuse

Can a suitably knowledgeable expert editor add a section explaining how this drug can be used to enhance athletic performance? --Ef80 (talk) 20:47, 7 March 2016 (UTC)

Not an expert, but here is some info:

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Herman RAM, director of the Netherlands doping-authority is adamant: There will be more athletes who will get caught for MELDONIUM. “Meldonium is an often used drug in Eastern-Europe, so a lot of people are taking it.”

“Enhances stamina” -- While doctors in the USA and the EU cannot prescribe the drug – Meldonium is not registered as a medicine- it’s often used in Eastern Europe by people with heart failure or pain in their chest whilst doing exercise. (…)

The Latvian pharmaceutics Grindeks in Riga praises the use also for healthy people. “Enhances the stamina and the brain function of heart patients and healthy people.”

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I think "enhances stamina" is quite clear. :) Some additional info is here - blood flow is mentioned: http://www.theguardian.com/sport/2016/mar/08/meldonium-maria-sharapova-failed-drugs-test Naki (talk) 08:30, 8 March 2016 (UTC)

It works similar to Ranolazine, which is a partial fatty acid oxidation inhibitor that "inhibits the late inward sodium current in heart muscle.[5] Inhibiting that current leads to reductions in elevated intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle." The part in bold is what would lead to the improved performance. Aglo123 (talk) 12:49, 8 March 2016 (UTC)

Thanks Aglo123 for the good info! :) Naki (talk) 13:14, 8 March 2016 (UTC)

The proposed mechanism of action by which meldonium enhances athletic performance is not clear in this article. Meldonium is chemically similar to butyrobetaine, the immediate precursor of L-carnitine. Meldonium may thus compete with butyrobetaine for the active site of the enzyme (gamma-butyrobetaine dioxygenase, BBD) and thus reduce the synthesis of L-carnitine. Since L-carnitine is required to transport activated fatty acids (acyl-CoA) into the mitochondria, we might reasonably infer that meldonium can inhibit fatty acid beta oxidation, which takes place in the mitochondrial matrix. BUT oxidation of acyl-CoA is a major source of NADH, which, in turn, powers ATP synthesis. Inhibiting ATP synthesis is clearly NOT a good way to enhance athletic performance. Yes, oxygen requirements for the muscle are reduced, but this is because the muscle is doing LESS work. Again, this is not a recipe for enhanced athletic performance. Perhaps Maria will actually defeat Serena now that she has stopped taking meldonium, assuming she ever gets to play another Australian Open. I think the original question asked by Ef80 is still important. What was the evidence that led the WADA to ban this drug? It's often important to reduce the work of the heart in patients with heart failure, but it's the opposite of what you want to do if you are an athlete. Rdphair (talk) 18:57, 8 March 2016 (UTC)

This part of our article seems to have as good an answer as any to the question of how an inhibitor of mitochondrial acyl-CoA oxidation can enhance cell metabolism:

"In the mitochondria, the effects of the carnitine shuttle are reduced by meldonium, which competitively inhibits the SLC22A5 transporter. This results in reduced transportation and metabolism of long-chain fatty acids in the mitochondria (this burden is shifted more to peroxisomes). The final effect is a decreased risk of mitochondrial injury from fatty acid oxidation and a reduction of the production of acylcarnitines, which has been implicated in the development of insulin resistance.[9][10] Because of its inhibitory effects on L-carnitine biosynthesis and its subsequent glycolytic effects as well as reduced acylcarnitine production, meldonium has been indicated for use in diabetic patients. Long term use has been shown to reduce blood glucose concentrations, exhibit cardioprotective effects and prevent or reduce the severity of diabetic complications.[11] Long term treatment has also been shown to attenuate the development of atherosclerosis in the heart."

Meldonium is alleged to shift acyl-CoA oxidation from the mitochondria to peroxisomes, and reduce the likelihood of mitochondrial injury and possibly insulin resistance. That's the rationale, anyway. We'd have to follow tagged meldonium through cultured muscle cell lines to confirm any of that. loupgarous (talk) 20:20, 19 February 2018 (UTC)

World Anti-Doping Agency

Could someone add to this article why this drug was added to the World Anti-Doping Agency's banned list? What exactly would this drug be used for to enhance performance? Kingturtle = (talk) 22:05, 7 March 2016 (UTC)

See my and Aglo123 comments, above. Naki (talk) 08:36, 8 March 2016 (UTC)

A review is available at PMID 26767774 "Annual banned-substance review: analytical approaches in human sports drug testing". LeadSongDog come howl! 21:29, 8 March 2016 (UTC)

Why does the article cite a study that it improved performance, then says "nevertheless", WADA banned the drug. Seems like this modifier only works if the results of that study were opposite. Perhaps we should edit out that word, or change it to "accordingly", or something? — Preceding unsigned comment added by 169.234.214.202 (talk) 07:16, 9 March 2016 (UTC)

A New York Times opinion piece says about meldonium: "The World Anti-Doping Agency banned the drug because it helps athletes by delivering more oxygen to muscles." The article cited in the Doping section ("A December 2015 study in the journal Drug Testing and Analysis argued that meldonium "demonstrates an increase in endurance performance of athletes, improved rehabilitation after exercise, protection against stress, and enhanced activations of central nervous system (CNS) functions".[38]") is an article about a method for measuring the drug or its metabolites. The article asserts in its conclusions section that meldonium "is known to have a positive effect on the endurance performance of athletes," but no reference for this statement is provided. Meldonium is an inhibitor of fatty acid beta-oxidation. Beta-oxidation produces NADH, which drives oxidative phosphorylation. It makes no sense that this drug enhances performance in any activity that requires ATP. Athletes may be using meldonium because they think it enhances performance, but what if meldonium is, instead, decreasing performance? Can anyone provide the reference to a scientific study that demonstrates meldonium increases performance?Rdphair (talk) 01:05, 12 March 2016 (UTC)

The reference to the Bayer AG company lobbying WADA only has a reference to the Bayer wiki page. Seems like this needs citation. Anyone? (sorry for the anon)68.43.112.179 (talk) 15:05, 12 March 2016 (UTC)

I have removed the claim which was added by an anon a couple of hours ago [1] given that not only is a wikipedia article not a reliable souce (although their sources could be), but it doesn't mention Meldonium. I'm pretty sure the WADA list doesn't mention lobbying and I couldn't find any source from a quick search (although I can't search non English or at least non latin sources very easily). So it's basically unsourced. Nil Einne (talk) 16:52, 12 March 2016 (UTC)

Neutrality of medicinal uses section

I read an article in the L.A. Times that quotes a doctor saying very negative things about the medicinal use of this drug. To wit: "I can tell you that in my roughly 18 years of practicing medicine, not once have I nor my medical colleagues ever prescribed this medication. It has no robust, randomized trials to support its clinical use from a cardiac perspective..." and so on. Howver, this Wikipedia article says only really, really good things about the medicinal uses. I've thereofre tagged that section as possibly non-neutral, given the quote of a likely reputable doctor and the oposite statements in the article. This probably requires the help of someone in the medicine field.HappyValleyEditor (talk) 05:36, 8 March 2016 (UTC)

It will be very strange if he did. It's not approved in USA, but in Russia it's common drug for heart diseases and other chronic illnesses. Read russian wikipedia article on it. — Preceding unsigned comment added by 95.90.185.82 (talk) 10:15, 8 March 2016 (UTC)

Just because a drug has not been approved by the FDA does not mean that the rest of the world does not recognize legitimate medical uses for that drug. — Preceding unsigned comment added by 172.243.194.166 (talk) 12:24, 8 March 2016 (UTC)

We have other drugs so we simply have no medical need for a drug like this in the US market to go to clinical trials would be my guess. That's not to say the drug sucks necessarily but it's not a wonder-drug of any sorts. I don't think it was biased at all. It merely states what it's used for and where it is marketed, how is that biased? Aglo123 (talk) 12:45, 8 March 2016 (UTC)

I did a PubMed search and I couldn't find a good clinical trial either. That means Phase III studies, not Phase II studies or animal tests. Without a Phase III study, they couldn't get it approved for sale in the EU or Japan either. I think the quote from Michael S. Lee is a good summary: "It has no robust, randomized trials to support its clinical use from a cardiac perspective in terms of any benefit regarding the treatment of cardiovascular disease like arrhythmia, heart failure or coronary artery disease." --Nbauman (talk) 15:53, 8 March 2016 (UTC)

I'm a physician, but not a cardiologist. There are no phase 3 studies for meldonium submitted to the F.D.A. to get approval in the U.S., and there are unlikely to be - it's an old drug, big pharma is unlikely to want it. That may simply be a financial decision, but it means that meldonium doesn't currently meet the criteria for safety and efficacy -- in the U.S. I don't know what the standards are in Latvia, Lithuania, or the Russian Federation, where it seems to be legal. I agree with Aglo123 - the statements presented seem accurate. However, they seem out of place in the section on 'medicinal use' because there is no medicinal use for it in the U.S. and Western Europe. Ira Leviton (talk) 16:52, 8 March 2016 (UTC)

It's greatly imrpoved in terms of balance, and it only took a dozen or so hours... thanks.HappyValleyEditor (talk) 20:24, 8 March 2016 (UTC)

More likely it is not approved for use in the US because Russian's have the rights to it. Completely political. SChalice 16:36, 8 June 2016 (UTC)

I came here to ask about the same thing - IMO that bit should be removed, because it gives too much attention to one man's opinion given that nothing in the LA Times article suggests that the guy is an expert on the particular drug, who has acctualy tested, if it is effective or not, rather they just appear to have consulted with a random doctor, who probably asked around, looked it up and came back with an answer that makes perfect sense considering that the drug is not approved for use in United States. Simply saying that the drug is not FDA approved, which the article allready does, should probably suffice ~~Xil (talk) 12:55, 9 March 2016 (UTC)

• I have one article from clinicaltrials.gov --213.10.103.106 (talk) 21:47, 9 March 2016 (UTC)

I removed that part as it just occured to me that given that he is commenting on Sharapova's doping case he likely just means that a person who has lived most of her life in US has no good reason for using a drug sold on other side of the World. ~~Xil (talk) 20:28, 10 March 2016 (UTC)

Meldonium is believed to exert its cardioprotective effects through its ability to cause vasodilation in the coronary arteries via increased nitric oxide synthesis, reducing blood glucose concentrations through increased oxidation of glucose and also by preconditioning the heart to handle ischaemic situations, among other effects. It also has been used to treat cerebral ischaemia. This is all done through its inhibition of carnitine synthesis.

Where does this come from? The vasodilation claim is probably only from the meldonium-author himself and the vasodilation connection with carnitine is complete and utter nonsense. Carnitine himself is a vasodilator, if you block it's synthesis, then there will be the opposing effect! I suggest to delete this part completely. --2A02:908:1964:BCA0:E9D4:8C2E:775C:FF91 (talk) 15:13, 17 October 2017 (UTC)

References

a “metabolic modulator”, similar to insulin?

Need someone to expand on this idea. Similar to insulin? In which ways? Does someone care to elaborate on this or cite sources where the two are compared? — Preceding unsigned comment added by Aglo123 (talk • contribs) 12:31, 8 March 2016 (UTC)

• nop. vasodilation action. Эээ (talk) 13:17, 8 March 2016 (UTC)

Molecular diagram isn't standard?

What is the "ME3" in the molecular diagram? Maybe this should be changed to a more standard looking diagram. — Preceding unsigned comment added by 2001:4898:80E8:C:0:0:0:3E9 (talk) 15:04, 8 March 2016 (UTC)

"-Me" is a common abbreviation for the methyl group (-CH₃) which I used to see more commonly, but I don't see it very often in scientific publications today. I think Me₃ would be 3 methyl groups. Somebody who knows more about chemistry than me should change it to a standard style sheet if necessary. --Nbauman (talk) 15:48, 8 March 2016 (UTC)

OK, thanks, that makes sense. Still, it is out of line with most other molecular diagrams (example: https://en.wikipedia.org/wiki/Dimethyl_sulfate). I've asked on the Help page on how to update the image. — Preceding unsigned comment added by 2001:4898:80E8:C:0:0:0:3E9 (talk) 16:10, 8 March 2016 (UTC)

External links modified

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Into Drugbox?

Change the infobox into {{Drugbox}}? It's a medicine, could use clinical data etc. -DePiep (talk) 10:12, 9 March 2016 (UTC)

 Done -DePiep (talk) 12:04, 9 March 2016 (UTC)

Political motivations?

Hm. This is becoming a bit political. Some people in Russia claiming that this is a Western attempt at sanctions due to political differences (see: [2], claim that the initiative to ban it started in the US), that this is "as ridiculous as banning aspirin". There's currently a scandal in Russia, as apparently the bureaucrats who should've objected to the banning of the drug on the international forum failed to do their job, and didn't take part in the debates at all, leading to an uncontested decision to ban it: [3]. Also, interesting Russian-language interview with a manufacturer of the drug here: [4], and French-language interview in Le Monde with the inventor, who steadfastly claims that "it's not a doping drug": [5]. Esn (talk) 07:57, 10 March 2016 (UTC)

This is very likely. Dutch top newspaper NRC Next confirmed today that the the effect of Meldonium on sporters is unclear, and that even the claim of it improving brain functions is dubious and was only mildly tested on rats. According to Harm Kuipers, who specializes in the subject of doping-related science, it was done due to political motivations. This simply has to be addressed in the article. Bataaf van Oranje (talk) 12:41, 10 March 2016 (UTC)

Russia's foreign minister Sergei Lavrov also suggests that this was done due to political motivations. See this interview (starting at about the 5-minute mark or a bit before). Esn (talk) 23:29, 18 March 2016 (UTC)

Well he would say that wouldn't he. If that becomes Russia's official line we'll look into it.©Geni (talk) 00:20, 20 March 2016 (UTC)

"Well he would say that wouldn't he." No, not necessarily. Lavrov is known for choosing his words very carefully (Putin too, for that matter), and even in this case I think he didn't quite say it directly. He did say that he wouldn't be surprised if the West next accuses Russia's diplomatic corps of doping in order to have a reason to ban all Russian delegations from international gatherings. Esn (talk) 02:38, 21 March 2016 (UTC)

I find it ironic that posters here state that the drug is not picked up by the FDA because it has no efficacy but yet the US bans the drug "because of evidence of its use by athletes with the intention of enhancing performance." This whole deal smells very fishy! SChalice 16:42, 8 June 2016 (UTC)

• @Schalice: Not sure what do you want FDA to do. FDA has no power to initiate drug approval process. It is the drug's manufacturer who should file for marketing authorisation. See, the process is very costly, this is not a newly discovered drug (short/no patent protection), and there is not much evidence from clinical trials - consequently the manufacturer, even if somehow miraculously granted marketing authorisation on the basis of existing efficacy data, is unlikely to receive marketing exclusivity in the US. Which means, the manufacturer won't likely make much money on the drug.

As the old wisdom goes, if it's unclear what's all about, it's all about money. — kashmiri ^TALK 18:41, 8 June 2016 (UTC)

There is an FDA program which allows market exclusivity for drug companies who sponsor clinical studies on old drugs either "grandfathered" in (such as colchicine for gout) or evaluated for new indications. That could be the objective of the team at Xijing Hospital which is testing efficacy of meldonium in patients who've had ischemic stroke. Of course, any indication for meldonium's a new one from the FDA's perspective. If meldonium performs as its manufacturer and the Eastern European medical community claim it does and its adverse effect profile is acceptably mild/low, then I would expect more studies to be sponsored and perhaps Big Pharma to work on functionally similar compounds to benefit from patent protection and market exclusivity in the US and Europe. That's what generally happens when you get an entire new functional class of drugs, Big Pharma companies start making "me too" drugs and prodrugs in order to get a good income stream for their trouble.

As far as sinister political motives, I have to call bullshit on that. WADA decides whether a drug's subject to abuse in doping. Not USFDA, and not any one country's Olympic committee. loupgarous (talk) 19:55, 19 February 2018 (UTC)

Adding a news source

I didn't see this specific article used in Wiki, so I'm adding it in case it comes in handy. It contains some information that may help with the evaluation of inventor's medical claims and MEDRS: https://edition.cnn.com/2016/03/21/health/maria-sharapova-drug-meldonium-cold-war-origins/index.htmlKC LV (talk) 11:33, 21 February 2018 (UTC)

The last part of article "Does meldonium enhance athletic performance?" is showing what's going on. British Medical Journal article sounds very scientific

• "meldonium might..." "drug may benefit" "could potentially" " "widespread use" of the drug suggests"
• But Nissen, the cardiologist at the Cleveland Clinic, said he wonders if perhaps it's all in the athletes' heads.

"The placebo effect is very powerful," he said. "I can imagine how this plays out in the athletic world, where you're operating at the 99th percentile of human performance. Someone says, 'I can give you something that's going to make you a little bit better.' It's very tantalizing to try it."

So we have some drug with hypothetical enhance of athletic performance. Cheap and believed to be safe. Nobody wants to make deeper investigations on drug. It's good ground for manipulation with "might may could". Andrey Smirnov (talk) 12:45, 28 February 2018 (UTC)

Removed sentence

I removed the following sentence from the doping section of the article because: (1) the source is no longer working (404 error) (2) the sentence is vague (banned by who?) (3) it contradicts one of the major examples which is in Tennis in which it was banned in 2016

"Based on the overall effects these drugs have, they have been banned since 2001 from men's competitions and 2005 for women's. ref: S4 Hormone and metabolic modulators. Antidoping Switzerland."

Lena Key (talk) 09:37, 26 October 2022 (UTC)