„Meldonium“ – Versionsunterschied

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'''Meldonium''' (auch '''Mildronate''', '''THP''', '''MET-88''' oder '''Mildronāts''') ist ein Herz- und Kreislaufmedikament, das von [[Grindeks]] <ref>[[http://www.grindeks.lv]]</ref>, [[Litauen]] entwickelt wurde und vertrieben wird. Als Medikament ist es in Osteuropa, nicht jedoch z.B. in Deutschland oder den [[USA]] zugelassen.<!--
{{Use dmy dates|date=March 2016}}
{{distinguish|medronate|minodronate}}
{{chembox
| ImageFile = Mildronate.png
| IUPACName = 2-(2-Carboxyethyl)-1,1,1-trimethylhydrazinium
| OtherNames = Mildronate; THP, MET-8 Mildronāts or {{Not a typo|Quaterine}}
| Section1 = {{Chembox Identifiers
| InChI = 1S/C6H14N2O2/c1-8(2,3)7-5-4-6(9)10/h7H,4-5H2,1-3H3
| InChIKey = PVBQYTCFVWZSJK-UHFFFAOYSA-N
| CASNo= 86426-17-7
| CASNo_Ref = {{cascite|correct|CAS}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 73H7UDN6EC
| PubChem = 123868
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID=110405
| SMILES = C[N+](C)(C)NCCC(=O)[O-]
}}
|Section2={{Chembox Properties
| Formula=C<sub>6</sub>H<sub>15</sub>N<sub>2</sub>O<sub>2</sub><sup>+</sup>
| MolarMass=147.19 g/mol
| Appearance= White to off-white powder
| Solubility= >40 mg/mL
}}
|Section3={{Chembox Hazards
| ExternalMSDS = [http://www.sigmaaldrich.com/catalog/product/sigma/m5199 MSDS]
}}
}}

'''Meldonium''' (also known as '''Mildronate''', '''THP''', '''MET-88''', '''Mildronāts''' or '''{{Not a typo|Quaterine}}'''<ref>Patent Number: 1429753. http://www.surechem.org/index.php?Action=document&docId=679316&db=EPB&tab=desc&lang=EN&db_query=2%3A0%3A&markupType=all (accessed 16 August 2012).</ref>) is a clinically used anti-[[Ischemia |ischemic]] drug that is currently manufactured and marketed by [[Grindeks]], a pharmaceutical company based in [[Latvia]].<ref>JSC Grindeks. http://www.grindeks.lv (accessed 17 May 2012).</ref> It is used in Lithuania and the Russian Federation,<ref>{{cite web | url = http://www.drugs.com/international/mildronate.html | title = Mildronate | publisher = drugs.com}}</ref> but is not approved by the [[Food and Drug Administration]] for use in the [[United States]].<!--
{{cite journal |url=http://onlinelibrary.wiley.com/doi/10.1002/dta.1788/full |vauthors=Christian Görgens, Sven Guddat, Josef Dib, Hans Geyer, Wilhelm Schänzer, Mario Thevis |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=November-December 2015}}
{{cite journal |url=http://onlinelibrary.wiley.com/doi/10.1002/dta.1788/full |vauthors=Christian Görgens, Sven Guddat, Josef Dib, Hans Geyer, Wilhelm Schänzer, Mario Thevis |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=November-December 2015}}
--> Seit Januar 2016 steht es als [[Doping]]mittel auf den Verbotslisten der [[WADA]]. Seitdem wurde es u.a. bei Athleten wie [[Marija Jurjewna Scharapowa|Scharapowa]]<ref>{{Cite web|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|access-date=7 March 2016}}</ref>, [[Jekaterina Alexandrowna Bobrowa|Bobrowa]]<ref>{{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|access-date=7 March 2016}}</ref>, [[Eduard Alexejewitsch Worganow|Worganow]]<ref>{{Cite web|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 {{!}} CyclingTips|website=cyclingtips.com|access-date=2016-03-07}}</ref> und [[Olga Walerjewna Abramowa|Abramowa]]<ref>{{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||access-date=10 February 2016}}</ref> entdeckt.
--> Since January 2016, it is on the [[World Anti-Doping Agency]] (WADA) list of substances banned from use by athletes.


==Medizinische Indikation==
==Medical use==
Meldonium wird bei [[Angina pectoris]] und [[Myokardinfarkt|Herzinfarkt]] verschrieben.<ref name="pmid16633095">{{cite journal | author = Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA | title = Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics | journal = J. Cardiovasc. Pharmacol. | volume = 47 | issue = 3 | pages = 493–9 |date=March 2006 | pmid = 16633095 | doi = 10.1097/01.fjc.0000211732.76668.d2 }}</ref><ref name="pmid17204911">{{cite journal | author = Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M | title = Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction | journal = J. Cardiovasc. Pharmacol. | volume = 48 | issue = 6 | pages = 314–9 |date=December 2006 | pmid = 17204911 | doi = 10.1097/01.fjc.0000250077.07702.23 }}</ref><ref name="pmid10812052">{{cite journal | author = Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N | title = Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction | journal = Eur. J. Pharmacol. | volume = 395 | issue = 3 | pages = 217–24 |date=May 2000 | pmid = 10812052 | doi = 10.1016/S0014-2999(00)00098-4 }}</ref>
{{POV section|date=March 2016}}
Meldonium is clinically used to treat [[angina]] and [[myocardial infarction]].<ref name="pmid16633095">{{cite journal | author = Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA | title = Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics | journal = J. Cardiovasc. Pharmacol. | volume = 47 | issue = 3 | pages = 493–9 |date=March 2006 | pmid = 16633095 | doi = 10.1097/01.fjc.0000211732.76668.d2 }}</ref><ref name="pmid17204911">{{cite journal | author = Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M | title = Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction | journal = J. Cardiovasc. Pharmacol. | volume = 48 | issue = 6 | pages = 314–9 |date=December 2006 | pmid = 17204911 | doi = 10.1097/01.fjc.0000250077.07702.23 }}</ref><ref name="pmid10812052">{{cite journal | author = Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N | title = Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction | journal = Eur. J. Pharmacol. | volume = 395 | issue = 3 | pages = 217–24 |date=May 2000 | pmid = 10812052 | doi = 10.1016/S0014-2999(00)00098-4 }}</ref> The first [[clinical trial]] testing the [[efficacy]] of using a combination of meldonium and [[lisinopril]], an [[ACE inhibitor|angiotensin-converting enzyme inhibitor]], to treat [[chronic heart failure]] was reported in 2005.<ref name="trial2005">{{cite journal | author = Dzerve V, Matisone D, Kukulis I, Romanova J, Putane L, Grabauskiene˙V, Skarda I, Berzina D, Strautmanis J | title = Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the first report) | journal = Semin Cardiol | volume = 11 | issue = 2 | pages = 56–64 | year = 2005 | month = | pmid = | pmc = | ISSN = 1648-7966 |url= http://www.seminarsincardiology.com/pdf/Seminars-2005-11-2-56-64.pdf | doi = }}</ref> The report concluded that the combined treatment of meldonium and [[lisinopril]] may improve the [[quality of life]], [[Aerobic_exercise#Aerobic_capacity|exercise capacity]] and mechanisms of [[Systemic circulation|peripheral circulation]] of patients with [[chronic heart failure]].<ref name="trial2005"/> A later report in 2008 concluded that combined meldonium-[[lisinopril]] treatment improved [[Baroreceptor|carotid baroreceptor reflex]] in patients with [[chronic heart failure]].<ref name="trial2008">{{cite journal | author = Vitols A, Voita D, Dzerve V | title = Mildronate improves carotid baroreceptor reflex function in patients with chronic heart failure | journal = Semin Cardiovasc Med | volume = 13 | issue = | pages = 6 | year = 2008 | month = | pmid = | pmc = | ISSN = |url= http://www.seminarsincardiology.com/pdf/SeminarsCVMed-2007-13-6.pdf | doi = }}</ref> In February 2010, the [[clinical trial]] testing the [[efficacy]] and [[Pharmacovigilance|safety]] of meldonium treatment in combination with [[Exercise_intolerance#Treatment|standard exercise tolerance therapy]] on [[angina]] patients was successfully completed.<ref name="trial1a">JSC Grindeks. http://www.grindeks.lv/en/for-investors/stock-news/mildronate_clinical_trial (accessed 17 May 2012).</ref> The studies concluded that meldonium treatment significantly improves the [[Exercise intolerance|exercise tolerance]] of [[Stable_angina#Stable_angina|stable angina]] patients.<ref name="trial1b">{{cite journal | author = Dzerve V, Matisone D, Pozdnyakov Y, Oganov R | title = Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial | journal = Semin Cardiovasc Med | volume = 16 | issue = | pages = 3 | year = 2010 | month = | pmid = | pmc = | ISSN = |url= http://www.seminarsincardiology.com/pdf/SeminarsCVMed-2010-16-3.pdf | doi = }}</ref><ref name="pmid22186118">{{cite journal | author = Dzerve V, MILSS I Study Group | title = A Dose-Dependent Improvement in Exercise Tolerance in Patients With Stable Angina Treated With Mildronate: A Clinical Trial "MILSS I" | journal = Medicina (Kaunas) | volume = 47 | issue = 10 | pages = 544–51 | year = 2011 | month = | pmid = 22186118 | pmc = | ISSN = |url= http://medicina.kmu.lt/1110/1110-04e.pdf | doi = }}</ref> A [[clinical trial|phase II clinical trial]] on the [[efficacy]] and [[Pharmacovigilance|safety]] of meldonium for [[Stroke|acute ischemic stroke]] was completed in August 2013 and the studies concluded that meldonium is as effective and safe as [[cinepazide]] injection.<ref name="trial2a">{{cite journal | author = Zhu Y, Zhang G, Zhao J, Li D, Yan X, Liu J, Liu X, Zhao H, Xia J, Zhang X, Li Z, Zhang B, Guo Z, Feng L, Zhang Z, Qu F, Zhao, G | title = Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial | journal = Clin Drug Investig | volume = | issue = | pages = | year = 2013 | month = | pmid = | pmc = | doi = 10.1007/s40261-013-0121-x }}</ref><ref name="trial2b">ClinicalTrials.gov A service of the U.S. National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01831011?rcv_d=14&lup_s=03%2F16%2F2013&lup_d=30 (accessed 21 August 2012).</ref>


==Verfügbarkeit==
==Non-clinical Research==
⚫
''Meldonium'' ist eines der wichtigsten Exportgüter von [[Litauen]] und in [[Russland]] sowie weiten Teilen Osteuropas verschreibbar.<ref>Biotech Intelligence. http://www.biotech-intelligence.com/html/html/pool_7/91cc83b0e3f8b4edbbda2a42ae43e1b1.html (accessed 17 May 2012).</ref><ref>PMR. Pharmaceutical, Healthcare and Medical Sector in Central and Eastern Europe: Industry News, Analyses and Market Data. http://www.ceepharma.com/63359/Grindex-names-Russian-manufacturing-partner-for-Mildronate.shtml (accessed 17 May 2012).</ref><ref>Evaluate Pharma. https://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=137196 (accessed 17 May 2012).</ref>
Besides [[clinical trials]], a number of [[scientific research]] projects have also been conducted using laboratory animal models.


==Availability==
==Packungsformen==
⚫
As meldonium is not approved for drug use by the US FDA, it is not available in the United States. Meldonium is one of [[Latvia]]'s most exported products, and can be readily obtained in countries including [[Russia]], [[Ukraine]], [[Moldova]], [[Belarus]], [[Azerbaijan]] and [[Armenia]].<ref>Biotech Intelligence. http://www.biotech-intelligence.com/html/html/pool_7/91cc83b0e3f8b4edbbda2a42ae43e1b1.html (accessed 17 May 2012).</ref><ref>PMR. Pharmaceutical, Healthcare and Medical Sector in Central and Eastern Europe: Industry News, Analyses and Market Data. http://www.ceepharma.com/63359/Grindex-names-Russian-manufacturing-partner-for-Mildronate.shtml (accessed 17 May 2012).</ref><ref>Evaluate Pharma. https://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=137196 (accessed 17 May 2012).</ref>

==Mechanism of action==
The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate,<ref>Sigma Aldrich. http://www.sigmaaldrich.com/catalog/product/sigma/m5199 (accessed 17 May 2012).</ref><ref>{{cite journal | author = 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 = Biochem. Pharmacol. | volume = 37 | issue = 2 | pages = 195–202 |date=January 1988 | pmid = 3342076 | doi =10.1016/0006-2952(88)90717-4 }}</ref> a structural analogue of γ-butyrobetaine, with a NH group replacing the CH<sub>2</sub> at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the [[carnitine biosynthesis|biosynthesis of carnitine]].<ref>{{cite journal | author = Fraenkel G, Friedman S | title = Carnitine | journal = Vitam. Horm. | volume = 15 | pages = 73–118 | year = 1957 | pmid = 13530702 | doi=10.1016/s0083-6729(08)60508-7}}</ref>

The mechanism of action of meldonium is to act as a [[fatty acid oxidation inhibitor]], presumably by [[Enzyme inhibitor|inhibiting enzymes]] in the [[carnitine biosynthesis]] pathway such as [[gamma-butyrobetaine dioxygenase|γ-butyrobetaine hydroxylase]].<ref>{{cite journal | author = Vaz FM, Wanders RJA | title = Carnitine biosynthesis in mammals | journal = Biochem. J. | volume = 361 | pages = 417–29 | year = 2002 | doi=10.1042/0264-6021:3610417}}</ref> [[Gamma-butyrobetaine dioxygenase|γ-Butyrobetaine hydroxylase]] is an [[enzyme]] that belongs to the [[2-oxoglutarate|2-oxoglutarate (2OG)]] [[oxygenase]] superfamily and catalyses the formation of [[L-carnitine]] from γ-butyrobetaine.<ref name="pmid9753662">{{cite journal | author = Vaz FM, van Gool S, Ofman R, IJlst L, Wanders RJ | title = Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase | journal = Biochem Biophys Res Commun | volume = 250 | issue = 2 | pages = 506–10 |date=Nov 1998 | pmid = 9753662 | pmc = | doi = 10.1006/bbrc.1998.9343 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: BBOX1 butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8424| accessdate = }}</ref> X-ray crystallographic and ''in vitro'' biochemical studies suggest meldonium binds to the substrate pocket of [[gamma-butyrobetaine dioxygenase|γ-butyrobetaine hydroxylase]] and acts as a competitive [[substrate (biochemistry)|substrate]]/[[Enzyme inhibitor|inhibitor]] to form malonic acid semialdehyde, [[dimethylamine]], [[formaldehyde]], 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid,<ref>{{cite journal | author = 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 = Chem. Biol. | volume = 17 | issue = 12 | pages = 1316–24 |date=December 2010 | pmid = 21168767 | doi = 10.1016/j.chembiol.2010.09.016 }}</ref><ref name="pmid11248709">{{cite journal | author = 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 = Eur. J. Biochem. | volume = 268 | issue = 6 | pages = 1876–87 |date=March 2001 | pmid = 11248709 | doi =10.1046/j.1432-1327.2001.02065.x }}</ref> likely ''via'' a [[Stevens rearrangement|Steven's type rearrangement]] mechanism.<ref name = "pmid22765904">{{cite journal | author = Henry L, Leung IKH, Claridge TDW, Schofield CJ | title = γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement | journal = Bioorg. Med. Chem. Lett. | volume = 22 | issue = 15 | pages = 4975&ndash;4978 |date=Aug 2012 | pmid = 22765904 | doi = 10.1016/j.bmcl.2012.06.024 }}</ref> Mildronate is a potent [[gamma-butyrobetaine dioxygenase|γ-butyrobetaine hydroxylase]] inhibitor, with a [[half maximal inhibitory concentration]] (IC<sub>50</sub>) value of 62 μM.<ref>{{cite journal | author = 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 = Biochem. Biophys. Res. Commun. | volume = 398 | issue = 4 | pages = 634–9 |date=August 2010 | pmid = 20599753 | doi = 10.1016/j.bbrc.2010.06.121 }}</ref> Meldonium is an example of a non-peptidyl substrate mimic inhibitor for human [[2-oxoglutarate|2OG]] [[oxygenase]].<ref name="pmid21390379">{{cite journal | author = Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ | title = Inhibition of 2-oxoglutarate dependent oxygenases | journal = Chem Soc Rev | volume = 40 | issue = 8 | pages = 4364–97 |date=August 2011 | pmid = 21390379 | doi = 10.1039/c0cs00203h }}</ref>

Meldonium has also been shown by [[NMR]] to bind to [[carnitine acetyltransferase]].<ref>{{cite journal | author = Jaudzems K, Kuka J, Gutsaits A, Zinovjevs K, Kalvinsh I, Liepinsh E, Liepinsh E, Dambrova M | title = Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism | journal = J. Enzyme Inhib. Med. Chem. | volume = 24 | pages = 1269–75 |date=December 2009 | pmid = 19912061 | doi=10.3109/14756360902829527}}</ref> [[Carnitine acetyltransferase]] belongs to a family of ubiquitous enzymes that play pivotal roles in cellular energy metabolism.<ref>{{cite journal | author = Wu D, Govindasamy L, Lian W, Gu Y, Kukar T, Agbandje-McKenna M, McKenna R | title = Structure of Human Carnitine Acetyltransferase Molecular Basis for Fatty Acyl Transfer | journal = J. Biol. Chem. | volume = 278| pages = 13159–65 |date=April 2003 | doi = 10.1074/jbc.M212356200 | pmid=12562770}}</ref> Meldonium therefore may act as a regulator of energy metabolism. Meldonium is a relatively weak inhibitor to [[carnitine acetyltransferase]] (when compared to [[gamma-butyrobetaine dioxygenase|γ-butyrobetaine hydroxylase]]), with an inhibition constant (''K''<sub>I</sub>) of 1.6 mM.

==Forms==
[[File:Packaging of Mildronate.jpg|thumb|right|Packaging of Mildronate showing 250 mg capsules and the Injection 10% 5 ml]]
[[File:Packaging of Mildronate.jpg|thumb|right|Packaging of Mildronate showing 250 mg capsules and the Injection 10% 5 ml]]
* 250&nbsp;mg capsules N60<ref>JSC Grindeks. http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate (accessed 17 May 2012).</ref>
* 250&nbsp;mg Kapseln N60<ref>JSC Grindeks. http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate (accessed 17 May 2012).</ref>
* 500&nbsp;mg capsules N60
* 500&nbsp;mg Kapseln N60
* Injection 10% 5 ml N10
* Injektion 10% 5 ml N10


==Doping==
==Doping==
Meldonium wurde am 16. September 2015 mit Wirkung zum 1. Januar 2016 von der WADA als Dopingsubstanz gelistet;<ref>https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf</ref> zuvor war es auf der Beobachtungsliste.<ref>{{cite news|url=http://www.usatoday.com/story/sports/olympics/2015/09/30/wada-updates-list-of-banned-substances/73073450/|title=WADA updates list of banned substances|author=[[Associated Press]]|date=30 September 2015|work=[[USA Today]]|accessdate=7 March 2016}}</ref><ref>{{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}}</ref> Laut WADA ist das Medikament mit [[Insulin]] vergleichbar.
Meldonium was added to the [[World Anti-Doping Agency]] (WADA) list of banned substances on 16 September 2015 effective starting 1 January 2016;<ref>https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf</ref> it was previously on WADA's list of drugs to be monitored.<ref>{{cite news|url=http://www.usatoday.com/story/sports/olympics/2015/09/30/wada-updates-list-of-banned-substances/73073450/|title=WADA updates list of banned substances|author=[[Associated Press]]|date=30 September 2015|work=[[USA Today]]|accessdate=7 March 2016}}</ref><ref>{{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}}</ref> WADA considers the drug to be a “metabolic modulator”, similar to insulin. 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.” <ref> Christian Görgens, Sven Guddat, Josef Dib, Hans Geyer, Wilhelm Schänzer and Mario Thevis. 2015. Drug Testing and Analysis. 7:973-979.</ref> 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.<ref>{{Cite web|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|access-date=7 March 2016}}</ref><ref>{{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}}</ref> 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, she stated that she had been aware of meldonium's addition to the banned list (on 1 January 2016) and had been careful to avoid products containing banned substances.<ref>{{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|access-date=7 March 2016}}</ref> Other athletes who are provisionally banned for using meldonium include Swedish Ethiopian-born middle-distance runner [[Abeba Aregawi]],<ref>{{Cite web|url=http://www.dn.se/sport/preparatet-som-kan-falla-aregawi/|title=Preparatet som kan fälla Aregawi|website=dn.se Sport|language=dn|access-date=29 February 2016}}</ref> Turkish middle-distance runner [[Gamze Bulut]],<ref>{{Cite web|url=http://spor.mynet.com/diger-sporlar/93691-gamze-bulutta-da-doping-cikti.html|title=Gamze Bulut'ta da doping çıktı!|website=mynet|access-date=2016-03-06}}</ref> Ethiopian long-distance runner [[Endeshaw Negesse]]<ref>{{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|access-date=2 March 2016}}</ref>, Russian cyclist [[Eduard Vorganov]],<ref>{{Cite web|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 {{!}} CyclingTips|website=cyclingtips.com|access-date=2016-03-07}}</ref> and Ukrainian biathletes [[Olga Abramova]]<ref>{{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||access-date=10 February 2016}}</ref> and [[Artem Tyshchenko]].<ref>{{Cite web|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|access-date=27 February 2016}}</ref> and as the latest case Maria Sharapova

== History ==
Meldonium was invented in the mid-1970s at the [[Latvian Institute of Organic Synthesis|Institute of Organic Synthesis]] of the [[Latvian SSR Academy of Sciences]] by Ivars Kalvins.<ref name="Ivars">http://www.osi.lv/en/scientific-council/</ref><ref>http://advertisementfeature.cnn.com/epo/nominees/2015/ivars-kalvinsh/</ref> Meldonium was presented as an anti-ischemic drug.<ref name="Ivars"/>


==See also==
* [[Carnitine]]
* [[Angina]]
* [[Myocardial infarction]]
* [[gamma-butyrobetaine dioxygenase|γ-Butyrobetaine hydroxylase]]


== Einzelnachweise ==
==References==
<references />
{{Reflist|2}}


[[Kategorie:Arzneistoff]]
[[Category:Drugs acting on the cardiovascular system]]
[[Kategorie:Doping]]
[[Category:Antianginals]]
[[Category:Ischemic heart diseases]]
[[Category:Latvian inventions]]
[[Category:Drugs in the Soviet Union]]

Version vom 8. März 2016, 09:47 Uhr

Meldonium (auch Mildronate, THP, MET-88 oder Mildronāts) ist ein Herz- und Kreislaufmedikament, das von Grindeks [1], Litauen entwickelt wurde und vertrieben wird. Als Medikament ist es in Osteuropa, nicht jedoch z.B. in Deutschland oder den USA zugelassen. Seit Januar 2016 steht es als Dopingmittel auf den Verbotslisten der WADA. Seitdem wurde es u.a. bei Athleten wie Scharapowa[2], Bobrowa[3], Worganow[4] und Abramowa[5] entdeckt.

Medizinische Indikation

Meldonium wird bei Angina pectoris und Herzinfarkt verschrieben.[6][7][8]

Verfügbarkeit

Meldonium ist eines der wichtigsten Exportgüter von Litauen und in Russland sowie weiten Teilen Osteuropas verschreibbar.[9][10][11]

Packungsformen

Packaging of Mildronate showing 250 mg capsules and the Injection 10% 5 ml
  • 250 mg Kapseln N60[12]
  • 500 mg Kapseln N60
  • Injektion 10% 5 ml N10

Doping

Meldonium wurde am 16. September 2015 mit Wirkung zum 1. Januar 2016 von der WADA als Dopingsubstanz gelistet;[13] zuvor war es auf der Beobachtungsliste.[14][15] Laut WADA ist das Medikament mit Insulin vergleichbar.


Einzelnachweise

  1. ↑ [[1]]
  2. ↑ Maria Sharapova admits to failing drug test, will be provisionally banned. In: CNN. Abgerufen am 7. März 2016.
  3. ↑ Top Russian ice dancer Bobrova fails doping test - report. In: The Big Story. Abgerufen am 7. März 2016 (amerikanisches Englisch).
  4. ↑ Second positive test in 12 months could see Katusha sidelined up to 45 days | CyclingTips. In: cyclingtips.com. Abgerufen am 7. März 2016.
  5. ↑ Ukrainian biathlete Abramova suspended in doping case. In: insidethegames. Abgerufen am 10. Februar 2016.
  6. ↑ Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA: Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. In: J. Cardiovasc. Pharmacol. 47. Jahrgang, Nr. 3, März 2006, S. 493–9, doi:10.1097/01.fjc.0000211732.76668.d2, PMID 16633095.
  7. ↑ Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M: Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. In: J. Cardiovasc. Pharmacol. 48. Jahrgang, Nr. 6, Dezember 2006, S. 314–9, doi:10.1097/01.fjc.0000250077.07702.23, PMID 17204911.
  8. ↑ Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N: Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. In: Eur. J. Pharmacol. 395. Jahrgang, Nr. 3, Mai 2000, S. 217–24, doi:10.1016/S0014-2999(00)00098-4, PMID 10812052.
  9. ↑ Biotech Intelligence. http://www.biotech-intelligence.com/html/html/pool_7/91cc83b0e3f8b4edbbda2a42ae43e1b1.html (accessed 17 May 2012).
  10. ↑ PMR. Pharmaceutical, Healthcare and Medical Sector in Central and Eastern Europe: Industry News, Analyses and Market Data. http://www.ceepharma.com/63359/Grindex-names-Russian-manufacturing-partner-for-Mildronate.shtml (accessed 17 May 2012).
  11. ↑ Evaluate Pharma. https://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=137196 (accessed 17 May 2012).
  12. ↑ JSC Grindeks. http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate (accessed 17 May 2012).
  13. ↑ https://wada-main-prod.s3.amazonaws.com/resources/files/wada-2016-prohibited-list-en.pdf
  14. ↑ Associated Press: WADA updates list of banned substances In: USA Today, 30 September 2015. Abgerufen im 7 March 2016 
  15. ↑ WADA 2015 Monitoring Program. In: wada-ama.org. WADA, 1. Januar 2016;.
Abgerufen von „https://de.wikipedia.org/w/index.php?title=Meldonium&oldid=152289957“