Meldonium — mildronate

Meldonium is an anti-ischemic drug, used primarily to treat angina, myocardial infarction and chronic heart failure. It is manufactured in Latvia under the commercial name of Mildronate and is one of the countries largest exports, with turnover reaching EUR 65 million in 2013 according to reports. This drug is not yet approved by the Food and Drug Administration for use in the United States.

Meldonium is a structural analogue of the carnitine precursor, gamma-butyrobetaine. Carnitine is a key regulator of fat metabolism, since it is required to transport fatty acids into the mitochondrial matrix for fatty acid breakdown. Carnitine binds to the fatty acid chains to form acylcarnitine, which can then cross the inner mitochondrial membrane.

Meldonium affects carnitine metabolism by inhibiting gamma butyrobetaine hydroxylase, which catalyzes the conversion of gammabutyrobetaine to carnitine. There is also evidence to suggest that meldonium inhibits the organic cation transporter-2 (OCTN2) (Dambrova et al, 2016) The function of OCTN2 is to maintain the tissue concentrations of organic cations, such as carnitine.

Together, inhibition of butyrobetaine hydroxylase and of OCTN2, decreases the tissue concentration of carnitine and increases its concentration in the urine.

The lowering of carnitine levels has two effects; (1) a shift of cell metabolism from highly oxygen-consuming fatty-acid oxidation to increased glucose oxidation and increased ATP generation per molecule of oxygen and (2), protection of mitochondria from an overload of fatty acid metabolites. Meldonium also increases gene expression related to glucose metabolism and thereby also directly stimulates the oxidation of glucose (Liepnish et al. 2008).

The increase in ATP generated per molecule of oxygen consumed could be of huge benefit under hypoxic conditions. The most apparent benefits have so far been seen in the treatment of ischemic heart disease, but it is suggested that meldonium could be equally beneficial under the low oxygen conditions experienced during intense exercise.

Brand name Meldonium, Mildronate

Meldonium History

Meldonium was initially developed in the mid-1970s for veterinary applications, due to proposed growth-promoting effects in animals, at the Latvian Institute of Organic Synthesis. It was designed by the Latvian chemist Ivars Kalvinsh, with the aim of inhibiting carnitine biosynthesis and preventing the accumulation of cytotoxic intermediates of fatty acid beta-oxidation. This function was then also noted to have a beneficial effect in ischemic tissues, where it blocks the highly oxygen-consuming process of beta-oxidation.

The main application of meldonium was initially as a treatment for myocardial ischemia, and this is still a widespread use for the drug. Meldonium has been clinically trialed for use in the treatment of myocardial ischemia and it was shown to improve ventricular systolic function, inhibit myocardial hypertrophy and dilation, increase peripheral blood circulation, improve exercise tolerance and ultimately improve patients' quality of life (Schobersberger et al, 2016).

Nowadays, meldonium is also prescribed in neurological clinics for its reported beneficial effect on cerebral circulatory disorders and CNS functions (N. Sjakste et al, 2005). That said, the clinical evidence that meldonium can improve neurological outcomes after ischemic brain injury is, at present, minimal.

In some reports, meldonium also appears to improve mood in patients; they reported as becoming more active, and have decreased motor dysfunction, asthenia, dizziness and nausea (Enina et al, 1991). In some eastern European countries, meldonium is therefore also recommended for improvement of reduced work capacity, as well as for physical and psycho-emotional overexertion and alcoholism.

Even more recently, meldonium has been widely used by elite athletes across a range of sports. For example, at the Baku 2015 European games, meldonium was found in 8.7% of all urine samples collected, and its use was detected in athletes competing in 15 of the 21 sports (Stuart et al, 2016). The drug was used by athletes competing in both power-based and endurance-based sports.

The evidence supporting the use of meldonium as a performance-enhancing drug is limited. The theory is that as exercise intensity increases, we shift our metabolism away from fat oxidation and towards carbohydrate oxidation (Romijn etal, 1995). L-carnitine is suggested to be the main regulator of fat oxidation in the transition from moderate to higher exercise intensities (Jeppesen et al, 2012). In principle, the effect of meldonium on carnitine may therefore allow the oxygen-sparing shift in metabolism to occur sooner, thereby improving exercise performance.

The one study investigating the effects of meldonium in sports people reported increased physical capacity in trained judokas (Kakhabrishvili et al, 2002). However, that study has an unreliable methodology, with a low number of participants, no clear validation of exercise tests and no statistical tests.

How is Meldonium Supplied

The clinically suggested dose is 500mg twice a day. The main manufacturer, Grindeks, a Latvian pharmaceutical company, sells the drug in capsule form. Meldonium is not approved by the FDA in the United States but it is registered and widely prescribed in Latvia, Russia, Ukraine, Georgia, Kazakhstan, Azerbaijan, Belarus, Uzbekistan, Moldova and Kyrgyzstan.

Meldonium Structural Characteristics

Meldonium is a structural analogue of the carnitine precursor, A-butyrobetaine, with an amino group replacing the C4 methylene on A-butyrobetaine. It has the chemical name 3-(2,2,2-trimethylhydrazinium)propionate.

Meldonium Side Effects

The side effects of meldonium, when taken as a performance enhancing supplement by healthy subjects, rather than as a cardioprotective drug, are very poorly characterized. The vast majority of human studies have focused on the effects of meldonium on patients with chronic coronary heart disease or diabetes. The effects of the drug in healthy subjects is thus unknown.

Drug labels from countries where meldonium is sold list side effects including increased blood pressure, tachycardia, and indigestion. Another Latvian manufacturer of the product - OlainFarm - lists headaches, agitation and skin irritation as side effects.

The toxicology of meldonium has been studied in various animal models. One study showed no changes in hematopoiesis,functional state of liver and kidneys, or any alterations in tissue structure of the inner organs after repeated oral daily administration of the drug for 6 months, in mice (Petersone et al, 1991). However, a different study reported liver steatosis in rats treated with meldonium (20 mg/100 g) during the 3rd or 6th weeks of administration (Spaniol etal,2001).

Meldonium Administration

The standard dose of meldonium is 500mg twice daily.

Meldonium Availability

Meldonium is not sold legally in the US because it is not approved by the FDA.

However, it is available to import from various suppliers in Eastern Europe. Following Maria Sharapova's announcement that she had taken meldonium, a popular Russian supplements website reportedly sold 150 packets of the drug in 24 hours, compared with 850 in the past 12 months.

The price for a pack of 40 250mg tablets ranges from from $20 to $30. Buying unlicensed drugs from abroad comes with no guarantee that the product is safe.

References

Wlliam Llewellyn (2017) - Anabolics

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