Meldonium Dihydrate

Meldonium, also called mildronate, MET-88 or THP (3-(2,2,2-trimethylhydrazinium)propionate), is a synthetic compound that lowers tissue carnitine. A 1988 paper from the Institute of Organic Synthesis in Riga, Latvia, now the Latvian Institute of Organic Synthesis, described it as a novel inhibitor of gamma-butyrobetaine (GBB) hydroxylase, an enzyme of carnitine biosynthesis (Simkhovich et al., 1988).

Those figures, the structure and the aliases other than THP are from PubChem CID 6918082 (dihydrate) and CID 123868 (meldonium). Meldonium is about 80 percent of the dihydrate's mass.

Published work on meldonium falls into five areas. Each summary below states the model used. A 2017 review noted that few clinical studies exist despite wide use (Schobersberger et al., 2017).

Carnitine biosynthesis and the shift away from fatty-acid oxidation

The 1988 Riga paper described meldonium as a noncompetitive inhibitor of GBB hydroxylase from rat liver. Rats given 150 mg/kg orally for 10 days had 63.7 percent less free carnitine and 74.3 percent less long-chain acylcarnitine in the heart, and fatty-acid oxidation fell (Simkhovich et al., 1988). An Oxford crystal structure showed meldonium competing with GBB in the enclosed active site of this enzyme, which completes carnitine biosynthesis, and the enzyme also oxidized it as a substrate (Leung et al., 2010).

Riga researchers also call meldonium the most potent clinically used inhibitor of the carnitine transporter OCTN2 (Liepinsh et al., 2017). In an independent Oxford study, 3 weeks at 100 mg/kg a day raised cardiac pyruvate dehydrogenase flux 3.1-fold in diabetic rats and 1.2-fold in controls, suggesting more glucose oxidation (Savic et al., 2021). Models: enzyme preparations and rats.

Cardiac ischemia models in rats

Rats given 200 mg/kg a day for 10 days before 45 minutes of coronary occlusion and 2 hours of reperfusion had infarcts covering 43 percent of the area at risk, against 57 percent in controls (p=0.004), with no difference in heart rate, arterial pressure or arrhythmias (Sesti et al., 2006). Two of its four authors co-wrote the 1988 Riga paper.

In hearts isolated from rats given 100 mg/kg for 14 days, L-carnitine fell 69 percent, GBB rose 6-fold and infarcts were smaller; with L-carnitine added, carnitine, mitochondrial fatty-acid respiration and infarct size showed no significant change (Kuka et al., 2012). In rats with heart failure after coronary ligation, a Japanese company laboratory reported that MET-88 at 100 mg/kg a day extended median survival from 79 to 103 days and prevented left ventricular cavity expansion, similar to captopril (Hayashi et al., 2000). Models: rats and isolated rat hearts.

Clinical studies in angina, heart failure and stroke

MILSS I, a randomized, double-blind, placebo-controlled phase 2 trial led from Riga, enrolled 512 people with stable angina at 72 centers in 4 countries, adding placebo or one of four daily amounts of mildronate to standard care for 12 weeks. The primary endpoint, change in total time on a bicycle ergometer stress test, did not differ from placebo at the two lowest amounts, rose at the third (p=0.002) and rose less at the highest (Dzerve et al., 2011).

In a randomized trial published in Russian, 65 people with heart failure after myocardial infarction received basic therapy alone or with trimetazidine or meldonium dihydrate for 6 months. Both drugs lowered functional class, but only trimetazidine raised ejection fraction, and the authors preferred it (Vasiuk et al., 2007).

In a Chinese double-blind phase II trial in 227 people with acute ischemic stroke, mildronate and the active comparator cinepazide showed no significant differences in modified Rankin Scale scores at 3 months or in NIHSS and Barthel Index scores at 15 days (Zhu et al., 2013). Models: human trials.

The anti-doping record

At the Baku 2015 European Games, 66 of 762 athlete urine samples (8.7 percent) contained meldonium, while only 23 of 662 tested athletes had declared it (Stuart et al., 2016).

Model: anti-doping surveillance data.

Detection and elimination studies

In 10 healthy volunteers studied by a Cologne anti-doping group, urine stayed above the 10 ng/mL quantification limit for up to 65 days after a single oral amount and 117 days after 6 days of repeated amounts, with nonlinear, biphasic excretion (Görgens et al., 2017).

In mice, carnitine or GBB given during washout sped elimination but the diuretic furosemide did not; the Riga authors tied the long elimination to OCTN2 uptake into muscle and slow diffusion out (Liepinsh et al., 2017). Models: healthy volunteers and mice.