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Meldonium

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This is an old revision of this page, as edited by Abuelo jack (talk | contribs) at 22:03, 7 March 2016 (Clarified that Sharapova had been taking the drug for some years, when it was legal, and had not noticed that it had become banned as of this year.). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Not to be confused with medronate or minodronate.
Meldonium
Names
IUPAC name
2-(2-Carboxyethyl)-1,1,1-trimethylhydrazinium
Other names
Mildronate; THP, MET-8 Mildronāts or Quaterine
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.110.108 Edit this at Wikidata
UNII
  • InChI=1S/C6H14N2O2/c1-8(2,3)7-5-4-6(9)10/h7H,4-5H2,1-3H3
    Key: PVBQYTCFVWZSJK-UHFFFAOYSA-N
  • C[N+](C)(C)NCCC(=O)[O-]
Properties
C6H15N2O2+
Molar mass 147.19 g/mol
Appearance White to off-white powder
>40 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Meldonium (also known as Mildronate, THP, MET-88, Mildronāts or Quaterine[1]) is a clinically used anti-ischemic drug that is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia.[2] It is used in Lithuania and the Russian Federation,[3] but is not approved by the Food and Drug Administration for use in the United States.Meldonium can increase 'physical work capabilities'[4]

Medical use

Meldonium is clinically used to treat angina and myocardial infarction.[5][6][7] The first clinical trial testing the efficacy of using a combination of meldonium and lisinopril, an angiotensin-converting enzyme inhibitor, to treat chronic heart failure was reported in 2005.[8] The report demonstrated that the combined treatment of meldonium and lisinopril may improve the quality of life, exercise capacity and mechanisms of peripheral circulation of patients with chronic heart failure.[8] A later report in 2008 further demonstrated the efficacy of combined meldonium-lisinopril treatment by showing improved carotid baroreceptor reflex in patients with chronic heart failure.[9] In February 2010, the clinical trial testing the efficacy and safety of meldonium treatment in combination with standard exercise tolerance therapy on angina patients was successfully completed.[10] The studies revealed that meldonium treatment significantly improves the exercise tolerance of stable angina patients.[11][12] A phase II clinical trial on the efficacy and safety of meldonium for acute ischemic stroke was completed in August 2013 and the studies showed that meldonium is as effective and safe as cinepazide injection.[13][14]

Besides clinical trials, a number of scientific research projects have also been conducted to improve the efficacy of meldonium and its applicability to other diseases. For example, a report published by Vilskersts et al. suggested that the effect of mildronate treatment may be enhanced with co-treatment of other compounds such as orotic acid.[15]

Using animal models, the applications of meldonium, sometimes in tandem with other drugs such as metformin, have shown beneficial effects on neurological disorder[16][17] and diabetes.[18]

Meldonium may also be beneficial for the treatment of seizures and alcohol intoxication.[19]

Recent reports also suggest that meldonium may improve the ability of learning and memory, as the drug changes the expression of hippocampal proteins related to synaptic plasticity using rat model.[20]

Meldonium was reported to elevate the concentrations of γ-butyrobetaine hydroxylase in testes tissues;[6] in addition, long term (90 days) administration of meldonium was reported to improve sexual performance, sperm motility and concentration of testosterone in boars, although further studies are needed to confirm the potential of using meldonium as a sperm motility and sperm quality-enhancing agent.[21]

To date, meldonium is one of Latvia's most exported products, and can be readily obtained in countries including Russia, Ukraine, Moldova, Belarus, Azerbaijan and Armenia.[22][23][24]

Mechanism of action

The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate,[25][26] a structural analogue of γ-butyrobetaine, with a NH group replacing the CH2 at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.[27]

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.[28] γ-Butyrobetaine hydroxylase is an enzyme that belongs to the 2-oxoglutarate (2OG) oxygenase superfamily and catalyses the formation of L-carnitine from γ-butyrobetaine.[29][30] X-ray crystallographic and in vitro biochemical studies suggest meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as a competitive substrate/inhibitor to form malonic acid semialdehyde, dimethylamine, formaldehyde, 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid,[31][32] likely via a Steven's type rearrangement mechanism.[33] Mildronate is a potent γ-butyrobetaine hydroxylase inhibitor, with a half maximal inhibitory concentration (IC50) value of 62 μM.[34] Meldonium is an example of a non-peptidyl substrate mimic inhibitor for human 2OG oxygenase.[35]

Meldonium has also been shown by NMR to bind to carnitine acetyltransferase.[36] Carnitine acetyltransferase belongs to a family of ubiquitous enzymes that play pivotal roles in cellular energy metabolism.[37] Meldonium therefore may act as a regulator of energy metabolism. Meldonium is a relatively weak inhibitor to carnitine acetyltransferase (when compared to γ-butyrobetaine hydroxylase), with an inhibition constant (KI) of 1.6 mM.

Forms

Packaging of Mildronate showing 250 mg capsules and the Injection 10% 5 ml
  • 250 mg capsules N60[38]
  • 500 mg capsules N60
  • Injection 10% 5 ml N10

Doping

On 7 March 2016, former Wimbledon champion 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 some years for various health issues, and had not noticed that it had been added to the list of banned drugs as of 1 January 2016. Earlier the same day, Russian ice dancer Ekaterina Bobrova announced she had also tested positive for meldonium at the 2016 European Figure Skating Championships.[39] Other athletes who are on provisional banned list for using meldonium are Swedish Ethiopian born middle-distance runner Abeba Aregawi[40], Turkish middle-distance runner Gamze Bulut[41], Russian cyclist Eduard Vorganov[42], and Ukrainian Biathletes Olga Abramova[43] and Artem Tyshchenko.[44]

History

Meldonium was invented in the mid-1970s at the Institute of Organic Synthesis of the Latvian SSR Academy of Sciences by Ivars Kalvins.[45][46] Meldonium was presented as anti-ischemic drug.[45]

See also

References

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  5. ^ Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA (March 2006). "Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics". J. Cardiovasc. Pharmacol. 47 (3): 493–9. doi:10.1097/01.fjc.0000211732.76668.d2. PMID 16633095.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M (December 2006). "Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction". J. Cardiovasc. Pharmacol. 48 (6): 314–9. doi:10.1097/01.fjc.0000250077.07702.23. PMID 17204911.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N (May 2000). "Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction". Eur. J. Pharmacol. 395 (3): 217–24. doi:10.1016/S0014-2999(00)00098-4. PMID 10812052.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  12. ^ Dzerve V, MILSS I Study Group (2011). "A Dose-Dependent Improvement in Exercise Tolerance in Patients With Stable Angina Treated With Mildronate: A Clinical Trial "MILSS I"" (PDF). Medicina (Kaunas). 47 (10): 544–51. PMID 22186118. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  13. ^ 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 (2013). "Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial". Clin Drug Investig. doi:10.1007/s40261-013-0121-x. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
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  45. ^ a b http://www.osi.lv/en/scientific-council/
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