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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.
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.
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.
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.
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.
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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.
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.
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.
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.
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.