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Product Instruction

Product Name:  Mildronate

CAS.:  76144-81-5

Molecular Weight: 146.18756

Molecular Formula: C6H14N2O2

EINECS:  682-135-0

Boiling point: 85-900C

Storage temp:  Refrigerator

Form: Powder

Color: white

Stability: Hygroscopic

Purity: 99%

 

Description

Meldonium (INN; trade name Mildronate, among others) is a limited-market pharmaceutical, developed in 1970 by Ivars Kalviņš at the USSR Latvia Institute of Organic Synthesis, and now manufactured by the Latvian pharmaceutical company Grindeks and several generic manufacturers. It is primarily distributed in Eastern European countries as an anti-ischemia medication.

Medical use

Meldonium may be used to treat coronary artery disease.  These heart problems may sometimes lead to ischemia, a condition where too little blood flows to the organs in the body, especially the heart. Because this drug is thought to expand the arteries, it helps to increase the blood flow as well as increase the flow of oxygen throughout the body.  Meldonium has also been found to induce anticonvulsant and antihypnotic effects involving alpha 2-adrenergic receptors as well as nitric oxide-dependent mechanisms. This, in summary, shows that meldonium given in acute doses could be beneficial for the treatment of seizures and alcohol intoxication.  It is also used in cases of cerebral ischemia, ocular ischemic syndrome and other ocular disease caused by disturbed arterial circulation and may also have some effect on decreasing the severity of withdrawal symptoms caused by the cessation of chronic alcohol use.

Physio-pharmacology

To ensure a continuous guarantee of energy supply, the body oxidises considerable amounts of fat along with glucose. Carnitine transports activate long-chain fatty acids (FA) 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 are mediated by the inhibition of the enzyme 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 highly oxygen-consuming process.  Treatment with meldonium therefore shifts the myocardial energy metabolism from fatty acid oxidation to the more favorable oxidation of glucose, or glycolysis, under ischemic conditions. It also reduces the formation of trimethylamine N-oxide(TMAO), a product of carnitine breakdown and implicated in the pathogenesis of atherosclerosis and congestive heart failure.

In fatty acid (FA) 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, the effects of the carnitine shuttle are reduced by meldonium, which competitively inhibits the SLC22A5 transporter. 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.  Because of its inhibitory effects on L-carnitine biosynthesis and its subsequent glycolytic effects as well as reduced acylcarnitine production, meldonium has been indicated for use in diabetic patients. In animal models and a very small clinical trial, meldonium has been shown to reduce blood glucose concentrations, exhibit cardioprotective effects and prevent or reduce the severity of diabetic complications. Long term treatment has also been shown to attenuate the development of atherosclerosis in the heart.

Its vasodilatory effects are stipulated to be due to the stimulation of the production of nitric oxide in the vascular endothelium. It is hypothesized that meldonium may increase the formation of the gamma-butyrobetaine esters, potent parasympathomimetics and may activate the eNOS enzyme which causes nitric oxide production via stimulation of the M3 muscarinic acetylcholine receptor or specific gamma-butyrobetaine ester receptors.

 Meldonium is believed to continually train the heart pharmacologically, even without physical activity, inducing preparation of cellular metabolism and membrane structures (specifically in myocardial mitochondria to survive ischemic stress conditions. This is done by adapting myocardial cells to lower fatty acid inflow and by activating glycolysis; the heart eventually begins using glycolysis instead of beta oxidation during real life ischaemic conditions. This reduces oxidative stress on cells, formation of cytotoxic products of fatty acid oxidation and subsequent cellular damage. This has made meldonium a possible pharmacological agent for ischemic preconditioning.

The mechanisms underlying the central nervous system effects of meldonium are unclear. In a study in a transgenic mouse model of Alzheimer's disease, meldonium increased cognition and mental performance by reducing amyloid beta deposition in the hippocampus.