Mildronate

Description

Mildronate is a cardiac and neuroprotective drug. It is a compound with a new structure first developed by Latvia Institute of Organic Synthesis. It was first developed by Grindeks in the former Soviet Union in 1989. On the market, the drug is a structural analog of carnitine, which can compete with carnitine for γ-trimethylaminobutyrate hydroxylase, reduce the concentration of free carnitine and long-chain acetylcarnitine in cells, so it can inhibit Carnitine-dependent fatty acid oxidation. Meldonium was added to the WADA list of banned substances on January 1, 2016 because of "evidence of its use by athletes with the intention of enhancing performance."

Chemical Properties

White Crystalline Powder

Uses

Mildronate is a drug used to treat angina, myocardial infarction, and chronic heart failure. It is a novel pharmaceutical composition based on a reverse transcriptase inhibitor and meldonium.This compound generally contains a significant amount of water.

Definition

ChEBI: Mildronate is an ammonium betaine that is beta-alaninate in which one of the amino hydrogens is replaced by a trimethylamino group. A clinically used cardioprotective drug that is used for treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes. It has a role as a cardioprotective agent, a neuroprotective agent and an EC 1.14.11.1 (gamma-butyrobetaine dioxygenase) inhibitor.

General Description

Mildronate (3-(2,2,2-trimethylhydrazinium)propionate; MET-88; meldonium, quaterine) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. Mildronate was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acida-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Mildronate is efficient in the treatment of heart is chemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients’ mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non-carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the -butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via acetylcholine receptors or specific-butyrobetaine ester receptors.

Pharmacology

Mildronate is efficient in the treatment of heart is chemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients’ mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non-carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the butyrobetaine and its esters pools.

Side effects

Possible side effects of Mildronate treatment were an allergic reaction , weakness , headache , and discomfort in the epigastrium. According to the manufacturer of Mildronate GX, the commercial pharmaceutical product of meldonium, there are some rare adverse effects, including allergic reactions (redness and itchy skin, urticaria, rash, and/or angioedema), dyspepsia, tachycardia, and change (increase or decrease) in blood pressure.

Synthesis

The general procedure for the synthesis of Mildronate from 3-(2,2,2-trimethylhydrazine)-propionic acid methyl ester chloride is as follows: 1. 24 g of sodium hydroxide was suspended in 450 mL of ethanol, maintaining the temperature at 18-20 °C, and 136 g of methyl 3-(2,2,2-trimethylhydrazine)-propionate chloride was slowly added under stirring for 5-10 minutes. 2. the reaction mixture was stirred continuously at 18-20 °C until the saponification of the ester was complete (the progress of the reaction was monitored by thin layer chromatography TLC). 3. the reaction mixture is cooled to 2-4 °C and saturated with carbon dioxide gas until a pH of 8.1-8.5 is reached. 4. The precipitate formed was collected by filtration and the precipitate was washed with 3 x 10 mL of ethanol. 5. The filtrates were combined and concentrated by evaporation to give 91 g (95% yield) of a semi-crystalline solid product containing 95% of 3-(2,2,2-trimethylhydrazine) propionate. 6. recrystallizing the product using ethanol, isopropanol or other suitable solvent to obtain 3-(2,2,2-trimethylhydrazine) propionate dihydrate with a melting point of 85-87 °C (purity >99.5%).

Clinical claims and research

Mildronate (Grindeks, Latvia), an inhibitor of l-carnitine biosynthesis pathway via the inhibition of γ-butyrobetaine dioxygenase, is used for the treatment of myocardial ischemia in Eastern Europe and has shown a neuroprotective effect in several stroke models. Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats even though the infarct size did not decrease (Svalbe et al 2011). Analysis of cerebellar tissue extracts revealed significant decrease of concentration of l-carnitine and increase of γ-butyrobetaine. Russian studies have reported efficacy of the mildronate in treatment of patients with ischemic stroke. A randomized, double-blind, placebo-controlled phase II clinical trial in ischemic stroke patients is ongoing at the Xijing Hospital in China (ClinicalTrials. gov Identifier: NCT01800357).

Mode of action

Mildronate is a cardioprotective drug, the main mechanism of action of Mildronate is based on carnitine biosynthesis inhibition aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process.

References

[1] Patent: US2009/318731, 2009, A1. Location in patent: Page/Page column 3
[2] Patent: WO2008/28514, 2008, A1. Location in patent: Page/Page column 7