Meldonium
{{short description|Chemical compound}}
{{distinguish|medronate|minodronate}}
{{For|the similarly named reed organ occasionally referred to as a "melodeum"|Melodeon (organ)}}
{{Use dmy dates|date=September 2019}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{more science citations needed|date=March 2020}}
{{Infobox drug
| drug_name =
| type =
| IUPAC_name = 2-(2-Carboxylato-ethyl)-1,1,1-trimethylhydrazinium
| image = Meldonium.svg
| alt =
| image2 = Meldonium-from-xtal-3D-bs-17.png
| caption =
| pronounce =
| tradename = Mildronate, Mildronāts
| Drugs.com =
| MedlinePlus =
| licence_EU =
| licence_US =
| pregnancy_AU =
| pregnancy_AU_comment =
| pregnancy_category =
| legal_AU =
| legal_AU_comment =
| legal_CA =
| legal_DE =
| legal_NZ =
| legal_UK =
| legal_US = Unscheduled
| legal_UN =
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life =
| duration_of_action =
| excretion =
| CAS_number = 76144-81-5
| CAS_number_Ref = {{cascite|correct|CAS}}
| ATCvet =
| ATC_prefix = C01
| ATC_suffix = EB22
| PubChem = 123868
| DrugBank =
| ChemSpiderID = 110405
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII = 73H7UDN6EC
| UNII_Ref = {{fdacite|correct|FDA}}
| ChEBI = 131843
| ChEBI_Ref = {{ebicite|correct|EBI}}
| KEGG = D10504
| synonyms = THP, MET-8 Mildronāts or {{Not a typo|Quaterine}}
| C = 6
| H = 14
| N = 2
| O = 2
| SMILES = C[N+](C)(C)NCCC(=O)[O-]
| index2_label = dihydrate
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 86426-17-7
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 22DC15W645
| StdInChI = 1S/C6H14N2O2/c1-8(2,3)7-5-4-6(9)10/h7H,4-5H2,1-3H3
| StdInChIKey = PVBQYTCFVWZSJK-UHFFFAOYSA-N
| solubility = >40 mg/mL
| INN =
}}
Meldonium (INN; trade name Mildronate, among others) is a pharmaceutical developed in 1970 by Ivars Kalviņš at the USSR Latvia Institute of Organic Synthesis. It is now manufactured by the Latvian pharmaceutical company Grindeks and various generic producers. Primarily distributed in Eastern Europe, meldonium is used as an anti-ischemia medication.{{cite web |url=http://www.grindeks.lv/en/for-media/latest-news/Grindeks-meldonium-should-not-be-included-in-the-prohibited-list |title=Grindeks: We Believe that Meldonium Should not be Included in the List of Banned Substances in Sport |publisher=Grindeks |date=9 March 2016 |access-date=9 March 2016 |url-status=dead |archive-url=https://web.archive.org/web/20160312001639/http://www.grindeks.lv/en/for-media/latest-news/Grindeks-meldonium-should-not-be-included-in-the-prohibited-list |archive-date=12 March 2016 }}
Meldonium is prescribed for cardiovascular, neurological, and metabolic conditions due to its anti-ischaemic and cardioprotective effects, achieved by inhibiting β-oxidation and activating glycolysis. Athletes have used meldonium to enhance recovery and (controversially) performance, though these claims lack robust scientific support.{{cite journal | vauthors = Schobersberger W, Dünnwald T, Gmeiner G, Blank C | title = Story behind meldonium-from pharmacology to performance enhancement: a narrative review | journal = British Journal of Sports Medicine | volume = 51 | issue = 1 | pages = 22–25 | date = January 2017 | pmid = 27465696 | doi = 10.1136/bjsports-2016-096357 }}
Since 1 January 2016, meldonium has been listed as a banned substance by the World Anti-Doping Agency (WADA).{{cite web|url=https://www.wada-ama.org/en/what-we-do/prohibited-list|title=Prohibited List|date=14 November 2013|work=World Anti-Doping Agency|access-date=9 March 2016|archive-date=12 July 2017|archive-url=https://web.archive.org/web/20170712212817/https://www.wada-ama.org/en/what-we-do/prohibited-list|url-status=dead}} It functions as a metabolic modulator, altering enzymatic reactions in the body. While some athletes, including Maria Sharapova, used meldonium before its ban, its effectiveness as a performance enhancer remains controversial. Numerous athletes have since been suspended or disqualified for its use.{{cite news |title=All About Meldonium, the Banned Drug Used by Sharapova |url=https://www.nytimes.com/2016/03/09/sports/tennis/what-is-meldonium-maria-sharapova.html?_r=0 |access-date=8 March 2016 |agency=Associated Press |work=New York Times|date=8 March 2016}}
{{TOC limit|3}}
Medical uses
Meldonium, also known as Mildronate in Eastern Europe is primarily used for treating cardiovascular and neurological conditions.{{cite web | veditors = Wilson DR | vauthors = Newman T | date = 17 January 2019 | title = Why do people use meldonium? | url = https://www.medicalnewstoday.com/articles/309165 | work = Medical News Today }} It is prescribed for heart-related issues such as angina pectoris, heart failure, and coronary artery disease.{{cite journal | vauthors = Volynskyi D, Vakaliuk I | title = Use of meldonium in the treatment of patients with coronary artery disease and concomitant arterial hypertension. | journal = EUREKA: Health Sciences. | date = December 2019 | volume = 3 | issue = 6 | pages = 9–14 | doi = 10.21303/2504-5679.2019.001018 }} In some countries, particularly in Eastern Europe, meldonium is used to treat problems with brain circulation and has been reported to elevate mood and improve motor symptoms, dizziness, and nausea.
= Available forms =
File:Packaging of Mildronate.jpg
Meldonium is available in various pharmaceutical forms to suit different medical needs and administration routes. The most common form is oral capsules, typically containing 250 mg or 500 mg of the active ingredient.{{cite journal | vauthors = Berlato DG, Bairros AV | title = Meldonium: Pharmacological, toxicological, and analytical aspects. | journal = Toxicology Research and Application | date = March 2020 | volume = 4 | page = 2397847320915143 | doi = 10.1177/2397847320915 | doi-broken-date = 17 March 2025 }} For more rapid onset of action or in cases where oral administration is not feasible, meldonium is also produced as a solution for injection.
{{clear|left}}
Pharmacology
{{more medical citations|section|date=August 2024}}
=== Mechanism of action ===
The mechanism of action of meldonium is to act as a fatty acid oxidation inhibitor, presumably by inhibiting enzymes in the carnitine biosynthesis pathway such as γ-butyrobetaine hydroxylase.{{cite journal | vauthors = Vaz FM, Wanders RJ | title = Carnitine biosynthesis in mammals | journal = The Biochemical Journal | volume = 361 | issue = Pt 3 | pages = 417–429 | date = February 2002 | pmid = 11802770 | pmc = 1222323 | doi = 10.1042/bj3610417 }} Although initial reports suggested meldonium is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine;{{cite journal | vauthors = Galland S, Le Borgne F, Guyonnet D, Clouet P, Demarquoy J | title = Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase | journal = Molecular and Cellular Biochemistry | volume = 178 | issue = 1–2 | pages = 163–168 | date = January 1998 | pmid = 9546596 | doi = 10.1023/A:1006849713407 | s2cid = 23339575 }} further studies have identified that meldonium is a substrate for gamma-butyrobetaine dioxygenase.{{PDB|3O2G}}{{cite journal | vauthors = Spaniol M, Brooks H, Auer L, Zimmermann A, Solioz M, Stieger B, Krähenbühl S | title = Development and characterization of an animal model of carnitine deficiency | journal = European Journal of Biochemistry | volume = 268 | issue = 6 | pages = 1876–1887 | date = March 2001 | pmid = 11248709 | doi = 10.1046/j.1432-1327.2001.02065.x | doi-access = free }} 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.{{cite journal | vauthors = Leung IK, Krojer TJ, Kochan GT, Henry L, von Delft F, Claridge TD, Oppermann U, McDonough MA, Schofield CJ | title = Structural and mechanistic studies on γ-butyrobetaine hydroxylase | journal = Chemistry & Biology | volume = 17 | issue = 12 | pages = 1316–1324 | date = December 2010 | pmid = 21168767 | doi = 10.1016/j.chembiol.2010.09.016 | doi-access = free | author-link9 = Christopher J. Schofield }} 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." The unusual mechanism is thought likely to involve a Steven's type rearrangement.{{cite journal | vauthors = Henry L, Leung IK, Claridge TD, Schofield CJ | title = γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement | journal = Bioorganic & Medicinal Chemistry Letters | volume = 22 | issue = 15 | pages = 4975–4978 | date = August 2012 | pmid = 22765904 | doi = 10.1016/j.bmcl.2012.06.024 | author-link4 = Christopher J. Schofield }}
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."{{cite journal | vauthors = Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M | title = Crystal structure of human gamma-butyrobetaine hydroxylase | journal = Biochemical and Biophysical Research Communications | volume = 398 | issue = 4 | pages = 634–639 | date = August 2010 | pmid = 20599753 | doi = 10.1016/j.bbrc.2010.06.121 }} Meldonium is an example of an inhibitor that acts as a non-peptidyl substrate mimic.{{cite journal | vauthors = Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ | title = Inhibition of 2-oxoglutarate dependent oxygenases | journal = Chemical Society Reviews | volume = 40 | issue = 8 | pages = 4364–4397 | date = August 2011 | pmid = 21390379 | doi = 10.1039/c0cs00203h | author-link5 = Christopher J. Schofield }}
=Biochemistry=
File:Biosynthesis L-carnitine.png
To ensure a continuous guarantee of energy supply, the cell's energy-producing mitochondria oxidise considerable amounts of fat along with glucose. Carnitine transports long-chain fatty acids from the cytosol of the cell into the mitochondrion and is therefore essential for fatty acid oxidation (known as beta oxidation). Carnitine is mainly absorbed from the diet, but can be formed through biosynthesis. To produce carnitine, lysine residues are methylated to trimethyllysine. Four enzymes are involved in the conversion of trimethyllysine and its intermediate forms into the final product of carnitine. The last of these 4 enzymes is gamma-butyrobetaine dioxygenase (GBB), which hydroxylates butyrobetaine into carnitine.
The main cardioprotective effects of meldonium are mediated by the inhibition of GBB. By subsequently inhibiting carnitine biosynthesis, fatty acid transport is reduced and the accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues to produce energy is prevented, therefore blocking this oxygen-consuming process.{{cite journal | vauthors = Sjakste N, Gutcaits A, Kalvinsh I | title = Mildronate: an antiischemic drug for neurological indications | journal = CNS Drug Reviews | volume = 11 | issue = 2 | pages = 151–168 | date = 2004 | pmid = 16007237 | pmc = 6741751 | doi = 10.1111/j.1527-3458.2005.tb00267.x }}{{cite journal | vauthors = Dambrova M, Makrecka-Kuka M, Vilskersts R, Makarova E, Kuka J, Liepinsh E | title = Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity | journal = Pharmacological Research | volume = 113 | issue = Pt B | pages = 771–780 | date = November 2016 | pmid = 26850121 | doi = 10.1016/j.phrs.2016.01.019 }} Treatment with meldonium may shift the myocardial energy metabolism from fatty acid oxidation to the more favorable oxidation of glucose, or glycolysis, under conditions where oxygen is limited.
File:Acyl-CoA from cytosol to the mitochondrial matrix by carnitine.svg In fatty acid metabolism, long chain fatty acids in the cytosol cannot cross the mitochondrial membrane because they are negatively charged. The process in which they move into the mitochondria is called the carnitine shuttle. Long chain FA are first activated via esterification with coenzyme A to produce a fatty acid-coA complex which can then cross the external mitochondrial border. The co-A is then exchanged with carnitine (via the enzyme carnitine palmitoyltransferase I) to produce a fatty acid-carnitine complex. This complex is then transported through the inner mitochondrial membrane via a transporter protein called carnitine-acylcarnitine translocase. Once inside, carnitine is liberated (catalysed by the enzyme carnitine palmitoyltransferase II) and transported back outside so the process can occur again. Acylcarnitines like palmitoylcarnitine are produced as intermediate products of the carnitine shuttle.
In the mitochondria themselves, meldonium also competitively inhibits the carnitine shuttle protein SLC22A5. 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.{{cite journal | vauthors = Schooneman MG, Vaz FM, Houten SM, Soeters MR | title = Acylcarnitines: reflecting or inflicting insulin resistance? | journal = Diabetes | volume = 62 | issue = 1 | pages = 1–8 | date = January 2013 | pmid = 23258903 | pmc = 3526046 | doi = 10.2337/db12-0466 }}{{cite journal | vauthors = Lippi G, Mattiuzzi C | title = Misuse of the metabolic modulator meldonium in sports | journal = Journal of Sport and Health Science | volume = 6 | issue = 1 | pages = 49–51 | date = March 2017 | pmid = 30356593 | pmc = 6188923 | doi = 10.1016/j.jshs.2016.06.008 }}
Chemistry
File:Mildronate - 3D - Scaled-Ball-and-stick Model.pngThe chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl) propionate.{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/123868|title=Mildronate|author=Pubchem|work=nih.gov|access-date=9 March 2016}}{{cite journal | vauthors = Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E | title = 3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties | journal = Biochemical Pharmacology | volume = 37 | issue = 2 | pages = 195–202 | date = January 1988 | pmid = 3342076 | doi = 10.1016/0006-2952(88)90717-4 }} 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.{{cite journal | vauthors = Fraenkel G, Friedman S | title = Carnitine | volume = 15 | pages = 73–118 | year = 1957 | pmid = 13530702 | doi = 10.1016/s0083-6729(08)60508-7 | isbn = 9780127098159 | journal = Vitamins & Hormones }}{{better source needed|date=March 2016}}{{cite journal | vauthors = Paul HS, Sekas G, Adibi SA | title = Carnitine biosynthesis in hepatic peroxisomes. Demonstration of gamma-butyrobetaine hydroxylase activity | journal = European Journal of Biochemistry | volume = 203 | issue = 3 | pages = 599–605 | date = February 1992 | pmid = 1735445 | doi = 10.1111/j.1432-1033.1992.tb16589.x | doi-access = free }}
Meldonium is a white crystalline powder, with a melting point of {{Convert|87|C|F}}.[http://www.chemspider.com/Chemical-Structure.110405.html Meldonium | C6H14N2O2]. ChemSpider. Retrieved on 28 May 2016.
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.{{cite web |title=2016 Prohibited List, Summary of Major Modifications and Explanatory Notes |publisher=World Anti-Doping Agency |date=16 September 2015 |url=https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-summary-of-modifications-en.pdf}} It was on the 2015 WADA's list of drugs to be monitored.{{cite news|url=https://www.usatoday.com/story/sports/olympics/2015/09/30/wada-updates-list-of-banned-substances/73073450/|title=WADA updates list of banned substances|agency=Associated Press|date=30 September 2015|work=USA Today|access-date=7 March 2016}}{{cite web|url=https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2015-monitoring-program-en.pdf|title=WADA 2015 Monitoring Program|date=1 January 2016|website=wada-ama.org|publisher=WADA}} A 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.{{cite web|url=http://blogs.bmj.com/bjsm/2016/03/08/meldonium-use-by-athletes-at-the-baku-2015-european-games-adding-data-to-ms-maria-sharapovas-failed-drug-test-case/|title=Meldonium use by athletes at the Baku 2015 European Games|publisher=bmj.com|access-date=8 March 2016|date=8 March 2016}}
WADA classes the drug as a metabolic modulator, just as it does insulin.{{cite web |title=Prohibited List |date=January 2016 |publisher=World Anti-Doping Agency |url=https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf |at=S4:5.3 |access-date=11 March 2016}} 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.{{cite web|url=http://www.antidoping.ch/en/prevention/mobile-learning-programs/mobile-lesson-substances-and-methods/s4-hormone-and-metabolic|archive-url=https://web.archive.org/web/20140925014432/http://www.antidoping.ch/en/prevention/mobile-learning-programs/mobile-lesson-substances-and-methods/s4-hormone-and-metabolic|url-status=dead|archive-date=25 September 2014| title=S4 Hormone and metabolic modulators| publisher=Antidoping Switzerland}} On 13 April 2016 it was reported that WADA had issued updated guidelines allowing less than 1 microgram per milliliter of meldonium for tests done before 1 March 2016.{{cite news|url=https://www.nytimes.com/2016/04/14/sports/wada-meldonium-drug-testing.html|title=WADA Opens a Door for Athletes Who Tested Positive for Meldonium| vauthors = Reevell P |date=13 April 2016|newspaper=The New York Times}} The agency cited that "preliminary tests showed that it could take weeks or months for the drug to leave the body".
==Affected athletes==
On 7 March 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.{{cite news|url=http://www.cnn.com/2016/03/07/tennis/maria-sharapova-tennis-injuries/index.html|title=Maria Sharapova admits to failing drug test, will be provisionally banned|website=CNN|date=7 March 2016}}{{cite web|url=http://www.news.com.au/sport/tennis/maria-sharapovas-meldonium-drug-used-to-fight-heart-problems-diabetes-and-wild-boar-impotence/news-story/c3c51ff9c3ff0d622f669dffb5c030dd|title=Sharapova drug scandal: what is Meldonium|date=7 March 2016|work=NewsComAu|access-date=9 March 2016}} On 8 June 2016, she was suspended from playing tennis for two years by the International Tennis Federation (ITF), which was reduced to 15 months by Court of Arbitration for Sport after appeal.{{cite news|title=Maria Sharapova failed drugs test at Australian Open|url=https://www.bbc.com/sport/tennis/35750285|publisher=BBC|date=8 March 2016}}{{cite web |url=http://www.itftennis.com/news/225826.aspx |title=Press release: Tennis Anti-Doping Programme statement regarding Maria Sharapova |publisher=International Tennis Federation |date=7 March 2016 |access-date=15 March 2016}}{{cite news|title=Maria Sharapova banned for two years for failed drugs test but will appeal|url=https://www.bbc.com/sport/tennis/36482288|publisher=BBC|date=8 June 2016}} 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.{{cite web|url=http://www.bigstory.ap.org/article/a1371b6e5c614b56906436c2c20bda18/top-russian-ice-dancer-bobrova-fails-doping-test-report|title=Top Russian ice dancer Bobrova fails doping test – report|website=The Big Story|language=en-US|date=7 March 2016|access-date=7 March 2016|archive-url=https://web.archive.org/web/20160307205702/http://bigstory.ap.org/article/a1371b6e5c614b56906436c2c20bda18/top-russian-ice-dancer-bobrova-fails-doping-test-report|archive-date=7 March 2016|url-status=dead}} 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 Russia—was postponed indefinitely by the WBC.{{cite news| vauthors = Rafael D |title=Wilder-Povetkin called off after failed drug test|url=https://www.espn.com/boxing/story/_/id/15551134/wbc-postpones-deontay-wilder-alexander-povetkin-fight-failed-drug-test|date=16 May 2016|agency=ESPN.com}}
Other athletes who are provisionally banned for using meldonium include UFC flyweight Liliya Shakirova, Ethiopian-Swedish middle-distance runner Abeba Aregawi,{{cite news |url=https://www.dn.se/sport/preparatet-som-kan-falla-aregawi/ |title=Preparatet som kan fälla Aregawi |newspaper=Dagens Nyheter |department=Sport |language=sv |date=29 February 2016}} Ethiopian long-distance runner Endeshaw Negesse,{{cite web|url=http://www.insidethegames.biz/articles/1034922/ethiopian-tokyo-marathon-winner-negesse-reportedly-fails-drugs-test-for-meldonium|title=Ethiopian Tokyo Marathon winner Negesse reportedly fails drugs test for Meldonium|website=insidethegames|author=Butler, Nick |date=2 March 2016}} Russian cyclist Eduard Vorganov,{{cite news|author=Rogers, Neal|url=http://cyclingtips.com/2016/02/second-positive-test-in-12-months-could-see-katusha-sidelined-up-to-45-days/|title=Second positive test in 12 months could see Katusha sidelined up to 45 days|newspaper=Cyclingtips|date=6 February 2016}} and Ukrainian biathletes Olga Abramova{{cite web|url=http://bigstory.ap.org/article/062af7b9a5f34171b574caec7421811e/ukrainian-biathlete-abramova-suspended-doping-case|title=Ukrainian biathlete Abramova suspended in doping case |website=insidethegames|date=10 February 2016}} and Artem Tyshchenko.{{cite news|url=http://www.insidethegames.biz/articles/1034784/tyshchenko-named-as-second-ukrainian-biathlete-to-fail-doping-test-in-2016|title=Tyshchenko named as second Ukrainian biathlete to fail doping test in 2016|website=insidethegames|date=27 February 2016}}
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.{{cite web|url=https://sports.yahoo.com/blogs/nhl-puck-daddy/russia-replaces-entire-junior-hockey-team-after-drug-scandal-212538497.html|title=Russia replaces entire junior hockey team after drug scandal|website=Yahoo!|date=13 April 2016}}
More than 170 failed tests by athletes were identified in a relatively brief period after the ban on meldonium was imposed on 1 January 2016.{{cite news| vauthors = Ellingworth J |title=Q&A: Meldonium, the drug in Russia's Olympic doping case|url=https://www.apnews.com/84eea1b3c54b4b89ab8934a6bda7357b/Q&A:-Meldonium,-the-drug-in-Russia's-Olympic-doping-case|access-date=19 February 2018|work=The Associated Press|date=19 February 2018}} Many of the early cases were dropped when athletes claimed that they had ceased use in 2015. Notable athletes with positive samples include:{{cite news | vauthors = Cambers S |title=Why was Maria Sharapova taking meldonium? Her lawyer responds |url=https://www.theguardian.com/sport/2016/mar/10/maria-sharapova-meldonium-drugs-lawyer-explains |newspaper=theguardian.com |location=London |date=10 March 2016}}
In addition it was reported that five Georgian wrestlers{{cite web|url=http://eldia.es/agencias/8542488-LUCHA-GEORGIA-DOPAJE-Seis-luchadores-georgianos-dan-positivo-Meldonium|title=Seis luchadores georgianos dan positivo por Meldonium|date=15 February 2015|publisher=El Dia.es|language=es|access-date=20 March 2016}} and a German wrestler had tested positive for the drug although no further names were released.{{cite web|url=http://www.nzherald.co.nz/sport/news/article.cfm?c_id=4&objectid=11606863|title=A German wrestler tests positive for meldonium|date=17 March 2016|publisher=nzherald.co.nz|access-date=20 March 2016}} 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.{{cite web|url=http://tass.ru/en/sport/865236?utm|title=Two Russian Sambo wrestlers test positive for banned meldonium drug – executive|work=TASS|date=25 March 2016}}
== 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 activation of central nervous system (CNS) functions".{{cite journal | vauthors = Görgens C, Guddat S, Dib J, Geyer H, Schänzer W, Thevis M | title = Mildronate (Meldonium) in professional sports – monitoring doping control urine samples using hydrophilic interaction liquid chromatography – high resolution/high accuracy mass spectrometry | journal = Drug Testing and Analysis | volume = 7 | issue = 11–12 | pages = 973–979 | date = 2015 | pmid = 25847280 | pmc = 5066279 | doi = 10.1002/dta.1788 }} However the study itself presents no evidence for this claim, though it cited other studies that show performance enhancing effects, and focuses instead on describing two approaches for the reliable identification of meldonium.
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", the lack of blood flow to an area of the body.{{cite news|url=https://www.nytimes.com/2016/03/10/sports/tennis/meldonium-russian-athletes-maria-sharapova-doping.html|title=Meldonium Ban Hits Russian Athletes Hard|work=The New York Times|date=9 March 2016 |access-date=9 March 2016| vauthors = Reevell P }}
The drug was invented in the mid-1970s at the Institute of Organic Synthesis of the Latvian SSR Academy of Sciences by Ivars Kalviņš.{{cite web|url=http://www.osi.lv/en/scientific-council/|title=Scientific Board|work=osi.lv|access-date=9 March 2016}}{{cite web |title=Ivars Kalvins: A broad range of medicines based on natural compounds, spearheading a new generation of drugs |url=http://advertisementfeature.cnn.com/epo/nominees/2015/ivars-kalvinsh/ |publisher=European Patent Office |work=European Inventor Awards. Candidates in the Lifetime Achievement category.|access-date=9 March 2016 }} 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.{{cite news |title=Изобретатель мельдония назвал две причины решения WADA |language=ru |trans-title=Meldonium inventor named two reasons for WADA decision |location=Russia |url=http://www.vesti.ru/doc.html?id=2728666 |work=vesti.ru |access-date=9 March 2016}}{{cite news |url=http://www.delfi.lv/sports/news/other_kinds/other/mildronata-raditajs-ivars-kalvins-meldonija-pielidzinasana-dopingam-ir-cilvektiesibu-parkapums.d?id=47157855 |title=Mildronāta radītājs Ivars Kalviņš: meldonija pielīdzināšana dopingam ir cilvēktiesību pārkāpums | vauthors = Kristīna H |date=8 March 2016 |publisher=Delfi |language=lv |access-date=10 March 2016}} Liene Kozlovska, the former 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.{{cite news |url=http://www.diena.lv/latvija/zinas/antidopinga-eksperte-mildronats-ieklauts-aizliegto-vielu-saraksta-14132894?from-full |title=Antidopinga eksperte: Mildronāts iekļauts aizliegto vielu sarakstā |date=8 March 2016 |publisher=Diena |language=lv |access-date=10 March 2016}}
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 it 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)."{{cite news |url=https://www.forbes.com/sites/ritarubin/2016/03/09/study-finds-widespread-use-of-sharapovas-drug-despite-little-evidence-that-it-boosts-performance/#3727b1fd39a7 |title=Banned drug Sharapova took is widely used, study shows, despite little evidence that it boosts performance |author=Rita Rubin |work=Forbes |access-date=9 March 2016}} 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".{{cite news |url=http://www.cnn.com/2016/03/11/opinions/maria-sharapova-banned-drug-vox/|title=Sharapova suspension: doping agency's unfair game of 'gotcha'? |publisher=CNN|author=Ford Vox|access-date=14 March 2016}}
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".{{cite web|url=https://www.usatoday.com/story/sports/olympics/2016/04/05/meldonium-experts-wada-performance-enhancing-drug/82663156/|title=Experts say there's little evidence meldonium enhances performance|publisher=USA Today|access-date=8 April 2016}}
=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, Lithuania, Albania, and Kyrgyzstan.{{cite web|url=https://www.forbes.com/sites/ritarubin/2016/03/09/study-finds-widespread-use-of-sharapovas-drug-despite-little-evidence-that-it-boosts-performance/#3727b1fd39a7|title=Banned Drug Sharapova Took Is Widely Used, Study Shows, Despite Little Evidence That It Boosts Performance|work=Forbes}}
=Economics=
Meldonium is manufactured by Grindeks, a Latvian pharmaceutical company, with offices in thirteen Eastern European countries{{cite web |title=Branches and Representative Offices |publisher=Grindeks |url=http://www.grindeks.lv/en/contacts/branches-representative-offices |access-date=9 March 2016 |archive-url=https://web.archive.org/web/20160310012444/http://www.grindeks.lv/en/contacts/branches-representative-offices |archive-date=10 March 2016 |url-status=dead }} as a treatment for heart conditions.{{cite web|url=http://www.grindeks.lv|title=AS "Grindeks" ir vadošais zāļu ražotājs Baltijas valstīs.|language=lv |publisher=Grindeks|access-date=9 March 2016}}{{cite magazine|url=https://www.wired.com/2016/03/original-users-meldonium-sharapovas-banned-drug-soviet-super-soldiers/|title=The Original Users of Sharapova's Banned Drug? Soviet Super Soldiers|magazine=Wired|author=Niiler, Eric|date=9 March 2016|access-date=9 March 2016}} The company identifies it as one of their main products.{{cite web |url=http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate |title=Mildronate |publisher=Grindeks |date=9 March 2016 |url-status=dead |archive-url=https://web.archive.org/web/20160312213702/http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate |archive-date=12 March 2016 }} It had sales of 65 million euros in 2013.{{cite news| vauthors = Niiler E |title=The Quirky History of Meldonium|url=https://www.wired.com/2016/03/meldonium-became-doping-drug-choice/|access-date=9 March 2016|work=Wired}}
{{clear}}