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Meldonium

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Not to be confused with medronate or minodronate.

Meldonium
Clinical data
Trade namesMildronate, Mildronāts
Other namesTHP, MET-8 Mildronāts or Quaterine
ATC code
Legal status
Legal status
  • US: Unscheduled
Identifiers
  • 2-(2-Carboxylato-ethyl)-1,1,1-trimethylhydrazinium
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.110.108 Edit this at Wikidata
Chemical and physical data
FormulaC6H14N2O2
Molar mass147.19 g/mol
3D model (JSmol)
Solubility in water>40 mg/mL mg/mL (20 °C)
  • C[N+](C)NCCC(=O)[O-]
  • InChI=1S/C6H14N2O2/c1-8(2,3)7-5-4-6(9)10/h7H,4-5H2,1-3H3
  • Key:PVBQYTCFVWZSJK-UHFFFAOYSA-N

Meldonium (INN), trade-named as Mildronate among others, is a limited-market pharmaceutical, developed in 1970 by Ivars Kalviņš, Latvian Institute of Organic Synthesis (USSR), and manufactured primarily by Grindeks of Latvia and several generic manufacturers. It is distributed in Eastern European countries as an anti-ischemia medication.[1]

Since 1 January 2016, it has been on the World Anti-Doping Agency (WADA) list of substances banned from use by athletes.[2] However, there are debates over its use as an athletic performance enhancer. Some athletes are known to have been using it before it was banned.[3] It is currently unscheduled in the US.

Don Catlin, a long-time anti-doping expert and the scientific director of the Banned Substances Control Group (BSCG) said “There’s really no evidence that there’s any performance enhancement from meldonium - Zero percent.”[4]

Medical use

Meldonium may be used to treat coronary artery disease.[5][6] These heart problems may sometimes lead to ischemia, a condition where too little blood flows to the organs in the body, especially the heart. Because this drug is thought to expand the arteries, it helps to increase the blood flow as well as increase the flow of oxygen throughout the body.[7] Meldonium has also been found to induce anticonvulsant and antihypnotic effects involving alpha 2-adrenergic receptors as well as nitric oxide-dependent mechanisms. This, in summary, shows that meldonium given in acute doses could be beneficial for the treatment of seizures and alcohol intoxication.[8] It may also have some effect on decreasing the severity of withdrawal symptoms caused by the cessation of chronic alcohol use.

Pharmacology

Meldonium is believed to work through its ability to increase the size of blood vessels and therefore improve blood flow.[9]

Although initial reports suggested meldonium is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine;[10][non-primary source needed] further studies have identified that meldonium is a substrate for gamma-butyrobetaine dioxygenase.[11][12][13] X-ray crystallographic and in vitro biochemical studies suggest that meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as an alternative substrate, and therefore a competitive inhibitor.[14][non-primary source needed] Normally, this enzyme's action on its substrates γ-butyrobetaine and 2-oxoglutarate gives, in the presence of the further substrate oxygen, the products L-carnitine, succinate, and carbon dioxide; in the presence of this alternate substrate, the reaction yields malonic acid semialdehyde, formaldehyde (akin to the action of histone demethylases), dimethylamine, and (1-methylimidazolidin-4-yl)acetic acid, "an unexpected product with an additional carbon-carbon bond resulting from N-demethylation coupled to oxidative rearrangement, likely via an unusual radical mechanism."[14][non-primary source needed][13][non-primary source needed] The unusual mechanism is thought likely to involve a Steven's type rearrangement.[12][non-primary source needed]

Meldonium's inhibition of γ-butyrobetaine hydroxylase gives a half maximal inhibitory concentration (IC50) value of 62 micromolar, which other study authors have described as "potent."[15][non-primary source needed][16] Meldonium is an example of an inhibitor that acts as a non-peptidyl substrate mimic.[17]

In further primary research reports, meldonium has been shown—by nuclear magnetic resonance—to also bind to carnitine acetyltransferase, a ubiquitous enzyme that plays a role in cellular energy metabolism; it also inhibits this enzyme, although even more weakly (inhibition constant, KI, of 1.6 millimolar).[18][non-primary source needed][19][non-primary source needed][16]

Chemistry

The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl) propionate.[20][21] It is a structural analogue of γ-butyrobetaine, with an amino group replacing the C-4 methylene of γ-butyrobetaine.[citation needed] γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.[22][better source needed][needs update] It has a molecular weight of 146.188. It is available as a white crystalline powder, as well as a capsule sold by Grindeks. The melting point is anywhere between 85-90 degrees Celsius.[23]

Society and culture

Doping

Meldonium was added to the World Anti-Doping Agency (WADA) list of banned substances effective 1 January 2016 because of evidence of its use by athletes with the intention of enhancing performance.[2][24] It was on the 2015 WADA's list of drugs to be monitored.[25][26] An alarmingly high prevalence of meldonium use by athletes in sport was demonstrated by the laboratory findings at the Baku 2015 European Games. 13 medallists or competition winners were taking meldonium at the time of the Baku Games. Meldonium use was detected in athletes competing in 15 of the 21 sports during the Games. Most of the athletes taking meldonium withheld the information of their use from anti-doping authorities by not declaring it on their doping control forms as they should have. Only 23 of the 662 (3.5%) athletes tested declared the personal use of meldonium. However, 66 of the total 762 (8.7%) of athlete urine samples analysed during the Games and during pre-competition tested positive for meldonium.[27]

WADA classes the drug as a metabolic modulator, just as it does insulin.[28] Metabolic modulators are classified as S4 substances according to the WADA banned substances list. These substances have the ability to modify how some hormones accelerate or slow down different enzymatic reactions in the body. In this way, these modulators can block the body's conversion of testosterone into oestrogen, which is necessary for females. Based on the overall effects these drugs have, they have been banned since 2001 from men's competitions and 2005 for women's.[29] On April 13, 2016 it was reported that WADA had issued updated guidelines allowing less than 1 microgram per milliliter of meldonium for tests done before March 1, 2016.[30] The agency cited that "preliminary tests showed that it could take weeks or months for the drug to leave the body".

Affected athletes

On March 7, 2016, former world number one tennis player Maria Sharapova announced that she had failed a drug test in Australia due to the detection of meldonium. She said that she had been taking the drug for ten years for various health issues, and had not noticed that it had been banned.[31][32] On June 8, 2016, she was suspended from playing tennis for two years by the International Tennis Federation (ITF).[33][34][35] Earlier the same year (March 7), Russian ice dancer Ekaterina Bobrova announced that she had also tested positive for meldonium at the 2016 European Figure Skating Championships. Bobrova said she was shocked about the test result, because she had been made aware of meldonium's addition to the banned list, and had been careful to avoid products containing banned substances.[36] In May 2016, Russian professional boxer Alexander Povetkin — a former two-time World Boxing Association (WBA) Heavyweight Champion— tested positive for meldonium. This was discovered just a week prior to his mandatory title match against World Boxing Council (WBC) Heavyweight Champion, Deontay Wilder. As a result, the match—scheduled to take place in Povetkin's native Russia—was postponed indefinitely by the WBC.[37]

Other athletes who are provisionally banned for using meldonium include Ethiopian-Swedish middle-distance runner Abeba Aregawi,[38] Ethiopian long-distance runner Endeshaw Negesse,[39] Russian cyclist Eduard Vorganov,[40] and Ukrainian biathletes Olga Abramova[41] and Artem Tyshchenko.[42]

The Ice Hockey Federation of Russia replaced the Russia men's national under-18 ice hockey team with an under-17 team for the 2016 IIHF World U18 Championships after players on the original roster tested positive for meldonium.[43]

The World Anti-Doping Agency has recorded 124 positive samples with traces of meldonium since banning meldonium.[44] These include:[45]

Name Country Sport Where Consequences source
Alexander Povetkin  Russia Boxing mandatory challenger, World Boxing Council Heavyweight Title match match canceled
Maria Sharapova  Russia Tennis 2016 Australian Open Banned for two years, backdated to 26 January 2016 [31][32]
Semion Elistratov  Russia Short track speed skating No fault [46]
Pavel Kulizhnikov  Russia Speed skating 2016 World Sprint Speed Skating Championships – Men No fault [46]
Alexander Markin  Russia Volleyball Unknown
Eduard Vorganov  Russia Cycling Unknown
Ekaterina Bobrova  Russia Figure skating 2016 European Figure Skating Championships No fault [46]
Eduard Latypov  Russia Biathlon Provisionally suspended [40]
Olga Abramova  Ukraine Biathlon Unknown [41]
Artem Tyshchenko  Ukraine Biathlon Unknown [42]
Davit Modzmanashvili  Georgia Wrestling Suspension temporarily lifted
Yekaterina Konstantinova  Russia Short track speed skating No fault [46]
Abeba Aregawi  Sweden Athletics Unknown [38]
Endeshaw Negesse  Ethiopia Athletics Unknown [39]
Alexey Mikhaltsov  Russia Rugby sevens Unknown
Alena Mikhaltsova  Russia Rugby sevens Unknown
Nataliia Lupu  Ukraine Athletics Unknown
Yuliya Yefimova  Russia Swimming Two out of competition tests— 15 & 24 February Unknown [47]
Nadezhda Sergeeva  Russia Bobsleigh Suspension temporarily lifted
Nadezhda Kotlyarova  Russia Athletics Cleared by RUSADA [48]
Andrey Minzhulin  Russia Athletics Cleared by RUSADA [48]
Gulshat Fazletdinova  Russia Athletics Cleared by RUSADA [48]
Olga Vovk  Russia Athletics Cleared by RUSADA [48]
Sergei Semenov  Russia Wrestling Cleared by RUSADA [48]
Evgeny Saleev  Russia Wrestling Unknown [49]
Anastasia Chulkova  Russia Cycling Cleared by RUSADA [48]
Pavel Yakushevsky  Russia Cycling Suspension temporarily lifted [50]
István Lévai  Slovakia Wrestling Unknown [51]
Gabriela Petrova  Bulgaria Athletics 6 February 2016 Suspension temporarily lifted [52]
Alexey Bugaychuk  Russia Water polo Unknown [53]
Pavel Kulikov  Russia Skeleton Suspension temporarily lifted [54]
Andrei Rybakou  Belarus Weightlifting Unknown [55]
Nikolai Kuksenkov  Russia Artistic gymnastics Unknown [56]
Denis Yartsev  Russia Judo Unknown [57]
Mikhail Pulyaev  Russia Judo Unknown [57]
Natalia Kondratieva  Russia Judo Unknown [57]
Yekaterina Valkova  Russia Judo Unknown [57]
Kirill Vichuzhanin  Russia Cross-country skiing Unknown [58]
Igor Mikhalkin  Russia Boxing (professional) 12 March 2016 2-year ban [59]
Ruth Kasirye  Norway Weightlifting Unknown
Petr Novak  Czech Republic Wrestling Unknown [60]
Elena Mirela Lavric  Romania Athletics 2016 IAAF World Indoor Championships Unknown [61]
Eva Tofalvi  Romania Biathlon Unknown [62]
Anastasiya Mokhnyuk  Ukraine Athletics Unknown [63]
Islam Makhachev  Russia Mixed martial arts Out of contest routine testing Provisional suspension lifted after 75 days [64]
Beka Lomtadze  Georgia Wrestling Suspension temporarily lifted [65]
Davit Chakvetadze  Russia Wrestling Cleared by RUSADA [65]
Armantas Vitkauskas  Lithuania Football unknown [66]
Martynas Dapkus  Lithuania Football unknown [66]
Andrii Kviatkovskyi  Ukraine Wrestling Provisionally suspended [67]
Alen Zasyeyev  Ukraine Wrestling Provisionally suspended [67]
Oksana Herhel  Ukraine Wrestling Provisionally suspended [67]
Varvara Lepchenko  United States Tennis ''no fault"

In addition it was reported that five Georgian wrestlers (this may or may not include Modzmanashvili)[68] and a German wrestler had tested positive for the drug although no further names were released.[69] On 25 March 2016 the Fédération Internationale de Sambo confirmed that four wrestlers under their governance (two from Russia and two from other countries) had recorded positive tests for the drug.[70]

Debates

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".[71][additional citation(s) needed] It is opposing to steroids in the sense that instead of making the athlete emotionally unstable and readily irritable, it keeps them in an elevated state of mind and keeps their emotions in a happier state. When referring to central nervous system enhancements, it better activates the neurons in the CNS. This improves the messaging system throughout the body and, therefore, can decrease (improve) reaction time for an athlete.

The manufacturer, Grindeks, said in a statement, that it did not believe meldonium’s use should be banned for athletes. It said the drug worked mainly by reducing damage to cells that can be caused by certain byproducts of carnitine. Meldonium “is used to prevent death of ischemic cells and not to increase performance of normal cells,” the statement said. “Meldonium cannot improve athletic performance, but it can stop tissue damage in the case of ischemia,” which is lack of blood flow to an area of the body.[72]

The drug was invented in the mid-1970s at the Institute of Organic Synthesis of the Latvian SSR Academy of Sciences by Ivars Kalviņš.[73][74][75] Kalviņš criticized the ban, saying that WADA had not presented scientific proof that the drug can be used for doping. According to him, meldonium does not enhance athletic performance in any way, and was rather used by athletes to prevent damage to the heart and muscles caused by lack of oxygen during high-intensity exercise. He contended that not allowing athletes to take care of their health was a violation of their human rights, and that the decision aimed to remove Eastern European athletes from competitions and his drug from the pharmaceutical market.[76][77] Liene Kozlovska, the head of the anti-doping department of the Latvian sports medicine center, rejected claims that the ban is in violation of athletes' rights, saying that meldonium is dangerous in high doses, and should only be used under medical supervision to treat genuine health conditions. She also speculated that Russian athletes may not have received adequate warnings that the drug was banned – due to the suspension of the Russian Anti-Doping Agency in late 2015.[78]

Forbes reported that anesthesiology professor Michael Joyner, at the Mayo Clinic in Rochester, Minnesota, who studies how humans respond to physical and mental stress during exercise and other activities, told them that "Evidence is lacking for many compounds believed to enhance athletic performance. Its use has a sort of urban legend element and there is not much out there that is clearly that effective. I would be shocked if this stuff [meldonium] had an effect greater than caffeine or creatine (a natural substance that, when taken as a supplement, is thought to enhance muscle mass).”[79] Ford Vox, a U.S.-based physician specializing in rehabilitation medicine and a journalist reported "there's not much scientific support for its use as an athletic enhancer".[80]

Packaging, showing 250 mg capsules and the injection 10% 5 ml

Approval status

Meldonium, which is not approved by the FDA in the United States, is registered and prescribed in Latvia, Russia, Ukraine, Georgia, Kazakhstan, Azerbaijan, Belarus, Uzbekistan, Moldova and Kyrgyzstan.[81][82][unreliable medical source?]

Economics

Meldonium is manufactured by Grindeks, a Latvian pharmaceutical company, with offices in thirteen Eastern European countries[83] as a treatment for heart conditions.[84][85] The company identifies it as one of their main products.[86] It had sales of 65 million euros in 2013.[75]

References

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Further reading

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