Meldonium

Structural formula
Meldonium ( zwitterionic form)
General
Non-proprietary name	Meldonium
other names	2- (2-carboxyethyl) -1,1,1-trimethylhydrazine ( IUPAC ) 3- (2,2,2-trimethyldiazaniumyl) propanoate (WHO) Quater THP MET-88
Molecular formula	C 6 H 14 N 2 O 2
Brief description	white solid
External identifiers / databases
CAS number 76144-81-5 86426-17-7 (dihydrate) EC number 682-135-0 ECHA InfoCard 100.110.108 PubChem 123868 ChemSpider 110405 Wikidata Q4289752
properties
Molar mass	147.19 g · mol -1
Physical state	firmly
solubility	soluble in water (> 40 g l −1 , dihydrate)
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 315-319-335 P: 261-305 + 351 + 338
Toxicological data	7850 mg kg −1 ( LD 50 ,  mouse ,  ip ) 4430 mg kg −1 ( LD 50 ,  mouse ,  iv ) 18500 mg kg −1 ( LD 50 ,  mouse ,  oral ) 12000 mg kg −1 ( LD 50 ,  rat ,  ip ) > 20 g kg −1 ( LD 50 ,  rat ,  oral ) 8 g kg −1 ( LD 50 ,  rabbit ,  iv )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Meldonium is the international non-proprietary name for a drug that has an effect on the heart and circulation . It is produced and marketed by the Latvian pharmaceutical company Grindeks . It is approved as a drug in some Eastern European countries, for example Russia and Lithuania , but not z. B. in Germany or the United States .

Since January 1, 2016 it has been on the doping list of the World Anti-Doping Agency (WADA) as an illegal substance . Since then it has been proven in various athletes.

Mechanism of action

Meldonium inhibits the synthesis of carnitine in the organism , with which it has a high structural similarity, by blocking the enzyme γ-butyrobetaine hydroxylase . This increases the levels of γ-butyrobetaine (GBB), a precursor of carnitine , in the blood serum . A cardioprotective effect is ascribed to the increased GBB levels.

Medical indication

Meldonium is prescribed for angina and heart attacks in countries where it is approved . The concept behind this is the idea that the metabolism of the heart muscle in the case of ischemia, e.g. B. as a result of a coronary artery obstruction , should be switched from aerobic to anaerobic metabolism in order to still supply the heart muscle cells with the necessary energy despite the lack of oxygen.

Application forms

Meldonium is effective orally and is on the market in capsule and tablet form. There is also a 10% solution for intravenous injection.

Pharmacokinetics

After oral administration of Meldonium, maximum plasma levels are reached after 1 to 2 hours. It spreads quickly into the tissue. Meldonium and its metabolites partially cross the placental barrier ; animal studies have shown that meldonium is excreted in breast milk. Excretion is mainly renal after metabolism in the liver; the elimination half-life is around 4 hours.

Analytics

For the reliable qualitative and quantitative determination of meldonium, the coupling of HPLC with mass spectrometry is used after adequate sample preparation .

Doping use

On September 16, 2015, with effect from January 1, 2016, Meldonium was listed by WADA as a doping substance in group S4 (hormones and metabolic modulators) at position 5.3. It was previously on the watchlist. According to WADA, the effects of meldonium are comparable to those of insulin . It is said to increase blood supply and endurance. A doping researcher from the German Sport University Cologne stated that meldonium is usually taken in "high doses" and that it is "relatively" easy to detect using conventional methods. The substance causes a higher physical and mental resilience as well as a faster regeneration.

In February and March 2016, meldonium hit the headlines after it became known that many athletes had used the substance for doping purposes.

Trade names

Mildronate ( LT ), Mildronāts ( LV ), Мельдоний ( RU )

literature

• M. Dambrova, E. Liepinsh, I. Kalvinsh: Mildronate: cardioprotective action through carnitine-lowering effect. In: Trends in Cardiovascular Medicine. Volume 12, Number 6, August 2002, pp. 275-279, PMID 12242052 .
• N. Sjakste, A. Gutcaits, I. Kalvinsh: Mildronate: an antiischemic drug for neurological indications. In: CNS Drug Reviews. Volume 11, Number 2, 2005, pp. 151-168, PMID 16007237 .
• M. Dambrova, M. Makrecka-Kuka et al. a .: Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity. In: Pharmacological Research . February 2016, doi : 10.1016 / j.phrs.2016.01.019 , PMID 26850121 .

Individual evidence

1. ↑ ^{a b c d} data sheet Meldonium dihydrate from Sigma-Aldrich , accessed on February 18, 2018 ( PDF ).
2. ↑ ^{a b c d e f} Entry on Meldonium (INN) in the ChemIDplus database of the United States National Library of Medicine (NLM), accessed on March 8, 2016.
3. ↑ Homepage of Grindeks
4. ↑ Christian Görgens, Sven Guddat, Josef Dib, Hans Geyer, Wilhelm Schänzer , Mario Thevis: Mildronate (Meldonium) in professional sports - monitoring doping control urine samples using hydrophilic interaction liquid chromatography - high resolution / high accuracy mass spectrometry. . In: Drug Testing and Analysis . 7, No. 11-12, 2015, pp. 973-979. doi : 10.1002 / dta.1788 .
5. ↑ Meldonium (Mildronate®) at dopinginfo.de
6. ↑ ^{a b} E. Liepinsh, R. Vilskersts u. a .: Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. In: Journal of cardiovascular pharmacology. Volume 48, Number 6, December 2006, pp. 314-319, doi : 10.1097 / 01.fjc.0000250077.07702.23 , PMID 17204911 .
7. ↑ C. Sesti, BZ Simkhovich et al. a .: Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. In: Journal of cardiovascular pharmacology. Volume 47, Number 3, March 2006, pp. 493-499, doi : 10.1097 / 01.fjc.0000211732.76668.d2 , PMID 16633095 .
8. ↑ Y. Hayashi, T. Kirimoto et al. a .: Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. In: European journal of pharmacology. Volume 395, Number 3, May 2000, pp. 217-224, PMID 10812052 .
9. ↑ Technical information Mildronāts 250 mg / 500 mg hard capsules (AS Grindeks), as of November 2015.
10. ^ Yun-Feng Lu, Xin Hu, Kai-Shun Bi: Determination of mildronate in human plasma and urine by liquid chromatography - tandem mass spectrometry . In: Journal of Chromatography B . tape 852 , no. 1–2 , June 2007, pp. 35-39 , doi : 10.1016 / j.jchromb.2006.12.031 .
11. ↑ Yuriy V. Pidpruzhnykov, Valerii E. Sabko, Volodymyr V. Iurchenko, Igor A. Zupanets: UPLC-MS / MS method for bioequivalence study of oral drugs of meldonium . In: Biomedical Chromatography . tape 26 , no. 5 , May 2012, p. 599-605 , doi : 10.1002 / bmc.1703 .
12. ↑ PROHIBITED LIST - JANUARY 2016 World Anti-Doping Agency, accessed March 8, 2016.
13. ↑ dpa: New agent on doping list. In: FAZ.net . September 30, 2015, accessed March 8, 2016 . 
14. ↑ WADA 2015 Monitoring Program . WADA. January 1, 2016.
15. ↑ Suspected doping: Public prosecutors investigate wrestlers. In: Spiegel Online . February 24, 2016, accessed March 8, 2016 . 
16. ↑ Editor: Doping with Meldonium. In: Tennismagazin.de. March 8, 2016, accessed February 19, 2018 . 
17. ↑ Biathlon: Ukrainian Abramova causes doping case. In: Spiegel Online . February 9, 2016, accessed March 8, 2016 . 
18. ↑ Abeba Aregawi's B sample also positive. In: Leichtathletik.de. March 10, 2016, accessed March 11, 2016 . 
19. ↑ Sharapova's doping agent is a hit in Russia. In: welt.de . March 8, 2016, accessed March 8, 2016 . 
20. ↑ Next doping case: Swimming star Jefimowa also took Meldonium. In: Spiegel Online . March 17, 2016, accessed May 2, 2016 . 
21. ↑ Speed ​​skaters Kulischnikow doped with meldonium. In: Augsburger Allgemeine . March 8, 2016, accessed March 8, 2016 . 
22. ↑ Tennis: Sharapova tested positive for doping. In: Spiegel Online . March 7, 2016, accessed March 8, 2016 . 
23. ↑ Cases of doping with the substance meldonium. In: sueddeutsche.de . February 10, 2017, accessed August 28, 2020 . 
24. ^ Sid: Doping: Already seven meldonium cases this year. (No longer available online.) In: handelsblatt.com . March 8, 2016, archived from the original on March 8, 2016 ; accessed on March 8, 2016 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  

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