Meldonium

Not to be confused with medronate or minodronate.
Meldonium
Systematic (IUPAC) name
2-(2-Carboxylato-ethyl)-1,1,1-trimethylhydrazinium
Clinical data
Trade names Mildronate, Mildronāts
Legal status
Legal status
  • US: Unscheduled
Identifiers
CAS Number 86426-17-7 YesY
ATC code C01EB22 (WHO)
PubChem CID 123868
ChemSpider 110405 YesY
UNII 73H7UDN6EC YesY
ChEBI CHEBI:131843 YesY
Synonyms THP, MET-8 Mildronāts or Quaterine
Chemical data
Formula C6H15N2O2+
Molar mass 147.19 g/mol
Physical data
Solubility in water >40 mg/mL mg/mL (20 °C)

Meldonium (INN), trade-named as Mildronate among others, is a limited-market pharmaceutical, developed in 1970 by Ivars Kalviņš, 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 January 1, 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.

Medical use

Meldonium maybe used to treat coronary artery disease.[4][5]

Pharmacology

Meldonium is believed to work through its ability to increase the size of blood vessels and therefore improve blood flow.[6]

Although initial reports suggested meldonium is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine;[7] further studies have identified that meldonium is a substrate for gamma-butyrobetaine dioxygenase.[8][9][10] 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.[11] 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."[11][10] The unusual mechanism is thought likely to involve a Steven's type rearrangement.[9]

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."[12][13] Meldonium is an example of an inhibitor that acts as a non-peptidyl substrate mimic.[14]

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).[15][16][13]

Physical and chemical properties

The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate.[17][18] It is a structural analogue of γ-butyrobetaine, with an amino group replacing the C-4 methylene of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.[19]

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][20] It was on the 2015 WADA's list of drugs to be monitored.[21][22] WADA classes the drug as a metabolic modulator, just as it does insulin.[23]

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.[24][25] Earlier the same day, Russian ice dancer Ekaterina Bobrova announced she had also tested positive for meldonium at the 2016 European Figure Skating Championships. Bobrova 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.[26]

Other athletes who are provisionally banned for using meldonium include Swedish Ethiopian-born middle-distance runner Abeba Aregawi,[27] Ethiopian long-distance runner Endeshaw Negesse,[28] Russian cyclist Eduard Vorganov,[29] and Ukrainian biathletes Olga Abramova[30] and Artem Tyshchenko.[31]

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.[32]

The World Anti-Doping Agency has recorded 124 positive samples with traces of meldonium since banning meldonium.[33] These include:[34]

Name Country Sport Where Consequences source
Maria Sharapova  Russia Tennis 2016 Australian Open Provisionally suspended [24][25]
Semion Elistratov  Russia Short track speed skating Provisionally suspended
Pavel Kulizhnikov  Russia Speed skating 2016 World Sprint Speed Skating Championships – Men Provisionally suspended
Alexander Markin  Russia Volleyball Unknown
Eduard Vorganov  Russia Cycling Unknown
Ekaterina Bobrova  Russia Figure skating 2016 European Figure Skating Championships Unknown
Eduard Latypov  Russia Biathlon Provisionally suspended [29]
Olga Abramova  Ukraine Biathlon Unknown [30]
Artem Tyshchenko  Ukraine Biathlon Unknown [31]
Davit Modzmanashvili  Georgia Wrestling Suspension temporarily lifted
Jekaterina Konstantinova  Russia Short track speed skating Unknown
Abeba Aregawi  Sweden Athletics Unknown [27]
Endeshaw Negesse  Ethiopia Athletics Unknown [28]
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—February 15 & 24 Unknown [35]
Nadezhda Sergeeva  Russia Bobsleigh Suspension temporarily lifted
Nadezhda Kotlyarova  Russia Athletics Cleared of fault by RUSADA [36]
Andrey Minzhulin  Russia Athletics Cleared of fault by RUSADA [37]
Gulshat Fazletdinova  Russia Athletics Cleared of fault by RUSADA [38]
Olga Vovk  Russia Athletics Cleared of fault by RUSADA [39]
Sergei Semenov  Russia Wrestling Cleared of fault by RUSADA [40]
Evgeny Saleev  Russia Wrestling Unknown [41]
Anastasia Chulkova  Russia Cycling Cleared of fault by RUSADA [42]
Pavel Yakushevsky  Russia Cycling Suspension temporarily lifted [43]
István Lévai  Slovakia Wrestling Unknown [44]
Gabriela Petrova  Bulgaria Athletics February 6, 2016 Suspension temporarily lifted [45]
Alexey Bugaychuk  Russia Water polo Unknown [46]
Pavel Kulikov  Russia Skeleton Suspension temporarily lifted [47]
Andrei Rybakou  Belarus Weightlifting Unknown [48]
Nikolai Kuksenkov  Russia Artistic gymnastics Unknown [49]
Denis Yartsev  Russia Judo Unknown [50]
Mikhail Pulyaev  Russia Judo Unknown [51]
Natalia Kondratieva  Russia Judo Unknown [52]
Yekaterina Valkova  Russia Judo Unknown [53]
Kirill Vichuzhanin  Russia Cross-country skiing Unknown [54]
Igor Mikhalkin  Russia Boxing (professional) 12 March 2016 2 year ban [55]
Ruth Kasirye  Norway Weightlifting Unknown
Petr Novak  Czech Republic Wrestling Unknown [56]
Elena Mirela Lavric  Romania Athletics 2016 IAAF World Indoor Championships Unknown [57]
Eva Tofalvi  Romania Biathlon Unknown [58]
Anastasiya Mokhnyuk  Ukraine Athletics Unknown [59]
Islam Makhachev  Russia Mixed martial arts Out of contest routine testing Provisionally suspended [60]
Beka Lomtadze  Georgia Wrestling Suspension temporarily lifted [61]
Davit Chakvetadze  Russia Wrestling Cleared of fault by RUSADA [62]
Armanto Vitkausko  Lithuania Football unknown [63]
Martyno Dapkaus  Lithuania Football unknown [64]

In addition it was reported that five Georgian wrestlers (this may or may not include Modzmanashvili)[65] and a German wrestler had tested positive for the drug although no further names have released.[66] 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.[67]

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".[68]

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.[69]

The drug was invented in the mid-1970s at the Institute of Organic Synthesis of the Latvian SSR Academy of Sciences by Ivars Kalviņš.[70][71][72] Kalviņš criticized the ban, saying that WADA had not presented scientific proof that the drug can be used for doping. According to him, meldonium doesn't 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 was made either out of bias against Eastern European athletes or to take out competition.[73][74] 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.[75]

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. It's 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 creatinine (a natural substance that, when taken as a supplement, is thought to enhance muscle mass).”[76] 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".[77]

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.[78][79]

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

Economics

Meldonium is manufactured by Grindeks, a Latvian pharmaceutical company, with offices in thirteen Eastern European countries[80] as a treatment for heart conditions.[81][82] The company identifies it as one of their main products.[83] It had sales of 65 million euros in 2013.[72]

References

  1. ↑ "Grindeks: We Believe that Meldonium Should not be Included in the List of Banned Substances in Sport". Grindeks. 9 March 2016. Retrieved 9 March 2016.
  2. 1 2 "Prohibited List". World Anti-Doping Agency. Retrieved 9 March 2016.
  3. ↑ "All About Meldonium, the Banned Drug Used by Sharapova". New York Times. Associated Press. March 8, 2016. Retrieved 8 March 2016.
  4. ↑ Sjakste, N; Gutcaits, A; Kalvinsh, I (2004). "Mildronate: an antiischemic drug for neurological indications.". CNS drug reviews 11 (2): 151–68. PMID 16007237.
  5. ↑ Dambrova, M; Makrecka-Kuka, M; Vilskersts, R; Makarova, E; Kuka, J; Liepinsh, E (2 February 2016). "Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity.". Pharmacological research. PMID 26850121.
  6. ↑ "Meldonium". Retrieved 19 April 2016.
  7. ↑ Galland, S; Le Borgne, F; Guyonnet, D; Clouet, P; Demarquoy, J (January 1998). "Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase". Mol. Cell. Biochem. 178 (1–2): 163–8. doi:10.1023/A:1006849713407. PMID 9546596.
  8. ↑ PDB: 3O2G​
  9. 1 2 Henry L, Leung IKH, Claridge TDW, Schofield CJ (August 2012). "γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement". Bioorganic and Medicinal Chemistry Letters 22 (15): 4975–4978. doi:10.1016/j.bmcl.2012.06.024. PMID 22765904.
  10. 1 2 Spaniol, M; Brooks, H; Auer, L; Zimmermann, A; Solioz, M; Stieger, B; Krähenbühl, S (March 2001). "Development and characterization of an animal model of carnitine deficiency". Eur. J. Biochem. 268 (6): 1876–87. doi:10.1046/j.1432-1327.2001.02065.x. PMID 11248709.
  11. 1 2 Leung, IK; Krojer, TJ; Kochan, GT; Henry, L; von Delft, F; Claridge, TD; Oppermann, U; McDonough, MA; Schofield, CJ (December 2010). "Structural and mechanistic studies on γ-butyrobetaine hydroxylase". Chemistry and Biology 17 (12): 1316–24. doi:10.1016/j.chembiol.2010.09.016. PMID 21168767.
  12. ↑ Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M (August 2010). "Crystal structure of human gamma-butyrobetaine hydroxylase". Biochemical and Biophysical Research Communications 398 (4): 634–9. doi:10.1016/j.bbrc.2010.06.121. PMID 20599753.
  13. 1 2 For a perspective from a Merck discovery biochemist on the clinical advantages of picomolar to nanomolar (i.e., thousand- to million-fold more potent) inhibitors, see Copeland, Robert A. (2005). "Tight Binding Inhibition; Potential Clinical Advantages of Tight Binding Inhibitors [Chapter 7, §7.8]". Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists. Methods of Biochemical Analysis, Vol. 46. New York, NY, USA: John Wiley. pp. 206–209. ISBN 0471723266. Retrieved 9 March 2016. [Quoting:] If one is beginning this pharmacological optimization with compounds displaying very high target affinity, more flexibility in compromising affinity for other parameters can be exercised. Thus, if the starting molecule has picomolar affinity for the target enzyme, and nanomolar affinity will suffice, the researcher can afford to give up 1000-fold in target affinity for the sake of pharmacological optimization. … high affinity of …tight binding inhibitors allows one to minimize the dose of drug to which patients are exposed, thus limiting off-target based toxicities.
  14. ↑ Rose, N.R.; McDonough, M.A.; King, O.N.; Kawamura, A. & Schofield, C.J. (2011). "Inhibition of 2-Oxoglutarate Dependent Oxygenases" (print, online review). Chemical Society Reviews 40 (8; August): 4364–4397. doi:10.1039/c0cs00203h. PMID 21390379. Retrieved 9 March 2011. (subscription required (help)).
  15. ↑ Jaudzems K, Kuka J, Gutsaits A, Zinovjevs K, Kalvinsh I, Liepinsh E, Liepinsh E, Dambrova M (December 2009). "Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism". Journal of Enzyme Inhibition and Medicinal Chemistry 24: 1269–75. doi:10.3109/14756360902829527. PMID 19912061.
  16. ↑ Wu D, Govindasamy L, Lian W, Gu Y, Kukar T, Agbandje-McKenna M, McKenna R (April 2003). "Structure of Human Carnitine Acetyltransferase Molecular Basis for Fatty Acyl Transfer". Journal of Biological Chemistry 278: 13159–65. doi:10.1074/jbc.M212356200. PMID 12562770.
  17. ↑ Pubchem. "Mildronate". nih.gov. Retrieved 9 March 2016.
  18. ↑ Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E (January 1988). "3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties". Biochemical Pharmacology 37 (2): 195–202. doi:10.1016/0006-2952(88)90717-4. PMID 3342076.
  19. ↑ Fraenkel G, Friedman S (1957). "Carnitine". Vitamins Hormones 15: 73–118. doi:10.1016/s0083-6729(08)60508-7. PMID 13530702.
  20. ↑ "2016 Prohibited List, Summary of Major Modifications and Explanatory Notes" (PDF). World Anti-Doping Agency. 16 September 2015.
  21. ↑ Associated Press (30 September 2015). "WADA updates list of banned substances". USA Today. Retrieved 7 March 2016.
  22. ↑ "WADA 2015 Monitoring Program" (PDF). wada-ama.org. WADA. 1 January 2016.
  23. ↑ "Prohibited List" (PDF). World Anti-Doping Agency. January 2016. S4:5.3. Retrieved 11 March 2016.
  24. 1 2 "Maria Sharapova admits to failing drug test, will be provisionally banned". CNN. Retrieved 7 March 2016.
  25. 1 2 "Sharapova drug scandal: what is Meldonium". NewsComAu. 7 March 2016. Retrieved 9 March 2016.
  26. ↑ "Top Russian ice dancer Bobrova fails doping test - report". The Big Story. Retrieved 7 March 2016.
  27. 1 2 "Preparatet som kan fälla Aregawi". dn.se Sport (in dn). Retrieved 29 February 2016.
  28. 1 2 "Ethiopian Tokyo Marathon winner Negesse reportedly fails drugs test for Meldonium". insidethegames. Retrieved 2 March 2016.
  29. 1 2 Rogers, Neal (2016-02-06). "Second positive test in 12 months could see Katusha sidelined up to 45 days". cyclingtips.com. Retrieved 2016-03-07.
  30. 1 2 "Ukrainian biathlete Abramova suspended in doping case". insidethegames. Retrieved 10 February 2016.
  31. 1 2 "Tyshchenko named as second Ukrainian biathlete to fail doping test in 2016". insidethegames. Retrieved 27 February 2016.
  32. ↑ "Russia replaces entire junior hockey team after drug scandal". Yahoo!. Retrieved 13 April 2016.
  33. ↑ "WADA: 123 failed meldonium tests since January ban". en.as.com.
  34. ↑ Cambers, Simon (2016-03-10). "Why was Maria Sharapova taking meldonium? Her lawyer responds". theguardian.com (London). Retrieved 2016-03-11.
  35. ↑ Craig Lord (21 March 2016). "Yuliya Efimova Tells Russia “I’m Innocent” Despite Two Meldonium Positives in 2016". SwimVortex.
  36. ↑ http://tass.ru/en/sport/871016
  37. ↑ http://tass.ru/en/sport/871016
  38. ↑ http://tass.ru/en/sport/871016
  39. ↑ http://tass.ru/en/sport/871016
  40. ↑ http://tass.ru/en/sport/871016
  41. ↑ "Два российских борца попались на мельдонии".
  42. ↑ http://tass.ru/en/sport/871016
  43. ↑ "Source: two Russian cyclists test positive for meldonium". Retrieved 1 April 2016.
  44. ↑ "Aj najlepší slovenský zápasník bral meldónium. Lévai do Ria asi nepôjde". Pravda (in Slovak). 30 March 2016. Retrieved 1 April 2016.
  45. ↑ "Хванаха с допинг най-добрата ни спортистка !". Topsport.bg. 27 March 2016. Retrieved 1 April 2016.
  46. ↑ "TASS: Sport - Russian water polo player tests positive for meldonium — source". TASS. Retrieved 1 April 2016.
  47. ↑ http://www.neveitalia.it/olimpiadi-invernali/news/pavel-kulikov-e-la-30-positivita-al-meldonium-dal-caso-di-maria-sharapova
  48. ↑ http://www.sport.ru/other/Belorusskiy_tyajeloatlet_Andrey_Rybakov_popalsya_na_meldonii/article306407/
  49. ↑ http://sport.segodnya.ua/others/gimnast-smenivshiy-ukrainu-na-rossiyu-popalsya-na-upotreblenii-meldoniya-704861.html
  50. ↑ http://ici.radio-canada.ca/sports/plussports/2016/04/04/004-pulyaev-russie-sharapova-meldonium-moutko.shtml
  51. ↑ http://ici.radio-canada.ca/sports/plussports/2016/04/04/004-pulyaev-russie-sharapova-meldonium-moutko.shtml
  52. ↑ http://ici.radio-canada.ca/sports/plussports/2016/04/04/004-pulyaev-russie-sharapova-meldonium-moutko.shtml
  53. ↑ http://ici.radio-canada.ca/sports/plussports/2016/04/04/004-pulyaev-russie-sharapova-meldonium-moutko.shtml
  54. ↑ http://www.gazeta.ru/sport/news/2016/04/08/n_8480807.shtml
  55. ↑ http://www.worldboxingnews.net/2016/04/11/news/european-champ-igor-mikhalkin-admits-taking-banned-drug-meldonium
  56. ↑ http://sports.yahoo.com/news/czech-wrestler-petr-novak-tests-positive-meldonium-081725576--spt.html
  57. ↑ http://rsport.ru/athletics/20160412/912658516.html
  58. ↑ http://www.sport1.de/wintersport/biathlon/2016/04/eva-tofalvi-des-dopings-mit-meldonium-ueberfuehrt
  59. ↑ http://sport.segodnya.ua/others/ukrainskaya-legkoatletka-anastasiya-mohnyuk-popalas-na-dopinge-708034.html
  60. ↑ "Islam Makhachev flagged for banned substance, UFC on Fox 19 matchup with Drew Dober canceled". MMAFighting.com.
  61. ↑ http://www.theguardian.com/sport/2016/apr/15/doping-suspensions-14-athletes-lifted-meldonium
  62. ↑ http://www.theguardian.com/sport/2016/apr/15/doping-suspensions-14-athletes-lifted-meldonium
  63. ↑ http://www.futbolas.lt/lt/naujiena/lff-nenustate-zaideju-kaltes-del-antidopingo-taisykliu-pazeidimo
  64. ↑ http://www.futbolas.lt/lt/naujiena/lff-nenustate-zaideju-kaltes-del-antidopingo-taisykliu-pazeidimo
  65. ↑ "Seis luchadores georgianos dan positivo por Meldonium" (in Spanish). El Dia.es. 15 February 2015. Retrieved 20 March 2016.
  66. ↑ "A German wrestler tests positive for meldonium". nzherald.co.nz. Mar 17, 2016. Retrieved 20 March 2016.
  67. ↑ "TASS: Sport - Two Russian Sambo wrestlers test positive for banned meldonium drug — executive". TASS. Retrieved 1 April 2016.
  68. ↑ Görgens, Christian; Guddat, Sven; Dib, Josef; Geyer, Hans; Schänzer, Wilhelm; Thevis, Mario (2015). "Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry.". Drug Testing and Analysis 7 (11-12): 973–979. doi:10.1002/dta.1788.
  69. ↑ "Meldonium Ban Hits Russian Athletes Hard". Nytimes.com. Retrieved March 9, 2016.
  70. ↑ "Scientific Board". osi.lv. Retrieved 9 March 2016.
  71. ↑ "Ivars Kalvins: A broad range of medicines based on natural compounds, spearheading a new generation of drugs". European Inventor Awards. Candidates in the Lifetime Achievement category. European Patent Office. Retrieved 9 March 2016.
  72. 1 2 Niiler, Eric. "The Quirky History of Meldonium". Wired (website). Retrieved 9 March 2016.
  73. ↑ "Изобретатель мельдония назвал две причины решения WADA" [Meldonium inventor named two reasons for WADA decision]. vesti.ru (in Russian) (Russia). Retrieved 9 March 2016.
  74. ↑ Kristīna, Hudenko (8 March 2016). "Mildronāta radītājs Ivars Kalviņš: meldonija pielīdzināšana dopingam ir cilvēktiesību pārkāpums" (in Latvian). Delfi. Retrieved 10 March 2016.
  75. ↑ "Antidopinga eksperte: Mildronāts iekļauts aizliegto vielu sarakstā" (in Latvian). Diena. 8 March 2016. Retrieved 10 March 2016.
  76. ↑ Rita Rubin. "Banned drug Sharapova took is widely used, study shows, despite little evidence that it boosts performance". Forbes. Retrieved 9 March 2016.
  77. ↑ Ford Vox. "Sharapova suspension: doping agency's unfair game of 'gotcha'?". CNN. Retrieved 14 March 2016.
  78. ↑ "Banned Drug Sharapova Took Is Widely Used, Study Shows, Despite Little Evidence That It Boosts Performance". Forbes.
  79. ↑ Görgens C, Guddat S, Dib J, Geyer H, Schänzer W, Thevis M (November–December 2015). "Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry". Drug Testing and Analysis 7 (11-12): 973–979. doi:10.1002/dta.1788.
  80. ↑ "Branches and Representative Offices". Grindeks. Retrieved 9 March 2016.
  81. ↑ "AS "Grindeks" ir vadošais zāļu ražotājs Baltijas valstīs." (in Latvian). Grindeks. Retrieved 9 March 2016.
  82. ↑ Niiler, Eric (9 March 2016). "The Original Users of Sharapova's Banned Drug? Soviet Super Soldiers". Science. Retrieved 9 March 2016.
  83. ↑ "Mildronate". Grindeks. 9 March 2016.

Further reading

This article is issued from Wikipedia - version of the Friday, April 22, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.