Mildronate dihydrate
[CAS# 86426-17-7]

Identification

• Classification: Biochemical >> Inhibitor >> Metabolism >> Hydroxylase inhibitor
• Name: Mildronate dihydrate
• Synonyms: 3-(2,2,2-Trimethylhydrazinium)propionate dihydrate
• Molecular Formula: C₆H₁₄N₂O₂.2(H₂O)
• Molecular Weight: 182.22
• CAS Registry Number: 86426-17-7
• EC Number: 695-494-3
• SMILES: C[N+](C)(C)NCCC(=O)[O-].O.O

Properties

• Solubility: H2O >40 mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

Mildronate dihydrate, also known as meldonium dihydrate, is a synthetic compound developed in the 1970s primarily in Latvia for medical use. It is classified as a metabolic agent and is used mainly to improve energy metabolism in cells under conditions of ischemia or hypoxia.

Pharmacologically, mildronate dihydrate acts by inhibiting the enzyme gamma-butyrobetaine dioxygenase, which is involved in the biosynthesis of carnitine. Carnitine is essential for the transport of long-chain fatty acids into mitochondria for beta-oxidation and energy production. By reducing carnitine synthesis, mildronate shifts energy metabolism from fatty acid oxidation to glucose oxidation, which requires less oxygen and produces ATP more efficiently under oxygen-limited conditions. This metabolic shift helps protect cells, particularly in the heart and brain, from ischemic damage.

Clinically, mildronate dihydrate has been used in the treatment of various cardiovascular diseases, including angina pectoris, chronic heart failure, and myocardial infarction recovery. It is also used to improve exercise tolerance and reduce fatigue in patients with ischemic conditions. Additionally, mildronate has found applications in neurology for the treatment of stroke and other cerebral ischemic conditions.

Mildronate dihydrate is administered orally in tablet form, and its pharmacokinetics indicate good absorption from the gastrointestinal tract. It is metabolized in the liver and excreted mainly via the kidneys. The elimination half-life is approximately 4 to 6 hours, supporting dosing schedules of one to three times daily depending on the clinical indication.

Adverse effects of mildronate dihydrate are generally mild and infrequent, including gastrointestinal discomfort and allergic reactions in some patients. It is considered to have a favorable safety profile when used according to prescribed guidelines.

Mildronate has also been studied for its potential performance-enhancing effects due to its role in improving energy metabolism and endurance, leading to its inclusion on the World Anti-Doping Agency’s prohibited substance list in competitive sports.

In summary, mildronate dihydrate is a metabolic agent that modulates energy metabolism by inhibiting carnitine synthesis, thereby enhancing cellular resistance to ischemic stress. It is used mainly in cardiovascular and neurological disorders to improve energy efficiency and protect tissues from damage, with a well-established clinical and safety profile.

References

1988. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochemical Pharmacology, 37(2).
DOI: 10.1016/0006-2952(88)90717-4

2021. Hyperpolarized magnetic resonance shows that the anti‐ischemic drug meldonium leads to increased flux through pyruvate dehydrogenase in vivo resulting in improved post‐ischemic function in the diabetic heart. NMR in Biomedicine, 34(4).
DOI: 10.1002/nbm.4471

2024. Meldonium, as a potential neuroprotective agent, promotes neuronal survival by protecting mitochondria in cerebral ischemia-reperfusion injury. Journal of Translational Medicine, 22(1).
DOI: 10.1186/s12967-024-05222-7