Meldonium

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.

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.

Since 1 January 2016, meldonium has been listed as a banned substance by the World Anti-Doping Agency (WADA). 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.

Medical uses

Meldonium, also known as Mildronate in Eastern Europe is primarily used for treating cardiovascular and neurological conditions. It is prescribed for heart-related issues such as angina pectoris, heart failure, and coronary artery disease. 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

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. For more rapid onset of action or in cases where oral administration is not feasible, meldonium is also produced as a solution for injection.

Pharmacology

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. Although initial reports suggested meldonium is a non-competitive and non-hydroxylatable analogue of gamma-butyrobetaine; further studies have identified that meldonium is a substrate for gamma-butyrobetaine dioxygenase. 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. 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.

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." Meldonium is an example of an inhibitor that acts as a non-peptidyl substrate mimic.

Biochemistry

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. 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.

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.

Chemistry

The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl) propionate. 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.

Meldonium is a white crystalline powder, with a melting point of 87 °C (189 °F).

Society and culture

Doping

Concern over Meldonium was first raised when it was found to match a mass spectrometry peak seen in some but not all of a set of athlete urine samples.

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. It was on the 2015 WADA's list of drugs to be monitored. 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.

WADA classes the drug as a metabolic modulator, just as it does insulin. 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. It is important to note that meldonium does not have this effect - it is not an Aromatase Inhibitor (which is a different sub-type of S4 drug.) 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. The agency cited that "preliminary tests showed that it could take weeks or months for the drug to leave the body".