Revision Year: 2015 Publisher: AS GRINDEKS, Krustpils iela 53, Rīga, LV-1057, Latvia Tel.: +371 67083205 Fax: +371 67083505 E-mail: grindeks@grindeks.lv
Pharmacotherapeutic group: other cardiac preparations
ATC code: C01EB22
Meldonium is a structural analogue of a precursor of carnitine, gamma-butyrobetaine (GBB), which has one carbon atom replaced by nitrogen atom. Its effect on the body may be explained in two ways.
Effect on carnitine biosynthesis:
Meldonium, by reversibly inhibiting the activity of gamma butyrobetainhydroxylase, causes a decrease of carnitine biosynthesis and thus prevents long-chain fatty acid transport through the cell membranes. Accordingly, it prevents the accumulation of strong detergents, activated forms of un-oxidised fatty acids, in cells thus diminishing damage of the cells membranes.
Under the decrease of carnitine concentration in ischemic conditions, β-oxidation of fatty acids is inhibited and oxygen consumption in cells is optimized, the oxidation of glucose is stimulated and ATP transport from their sites of biosynthesis (in mitochondria) to the sites of consumption (in cytosol) is restored. Essentially, the cells are supplied with nutrients and oxygen, as well as the usage of these substances is optimized.
In turn, by increasing of biosynthesis of the precursor of carnitine i.e. GBB, NO-synthetase is activated, that results in improved blood rheological properties and reduced peripheral vascular resistance.
When meldonium concentration lowers, the carnitine biosynthesis is again intensified and the level of cell fatty acids is gradually restored.
It is considered that meldonium efficacy is based on enhancing cells tolerance to load (by changes in fatty acid level).
Mediator function in hypothetical GBB-ergic system:
A hypothesis was advanced that the organism has a neural signal transmission system, i.e. GBB-ergic system which ensures the transmission of nervous impulses to somatic cells. The mediator of this system is a direct carnitine precursor – GBB ester. As a result of GBB-esterase action this mediator gives up an electron to the cell, thus transmitting electric impulse, but itself transforms into GBB. Then the hydrolyzed form of GBB with participation of active transport enters the liver, kidneys and testicles, where it transforms into carnitine. Somatic cells in response to stimuli, synthesize new GBB molecules, thus providing signal spreading.
When carnitine concentration lowers, the GBB synthesis is stimulated, resulting in increased GBB ester concentration.
As indicated above, meldonium is a structural analog of GBB and is able to perform the functions of a hypothetical “mediator”, while GBB-hydroxylase does not “recognize” meldonium. Consequently, carnitine level does not increase but lowers. Thus meldonium both by replacing the “mediator”, and contributing to rise of GBB concentration, promotes the development of body’s response. As a result, the overall metabolic activity in other systems also, e.g. central nervous system (CNS), increases.
Animal studies have shown that meldonium has positive effect on myocardial contractility, it exerts myocardioprotective action (including that against catecholamines and alcohol), it can prevent heart rhythm disorders and reduce myocardial infarct zone.
The analysis of the clinical data on meldonium use in repeated courses for the treatment of stable effort angina pectoris shows that the medicine reduces the frequency and intensity of angina attacks, as well as intake of glyceryl trinitrate. The medicine has pronounced antiarrhythmic effect in patients with coronary heart disease (CHD) and ventricular extrasystoles, it is less effective in patients with supraventricular extrasystoles. Particularly important is the medicine’s ability to decrease oxygen consumption at rest, which is considered as efficacy criterion of antianginal therapy in CHD.
Meldonium favourably affects atherosclerotic processes in coronary and peripheral blood vessels by lowering total serum cholesterol levels and atherogenicity index.
A relatively large number of clinical trials analyzed the role of meldonium in the treatment of CHD-induced chronic heart failure, and marked its ability to increase the tolerance to physical loads, as well as the amount of doable work in patients with heart failure.
The efficacy of meldonium in the treatment of moderate heart failure (NYHA functional class II) was studied in cardiology institutes in Latvia and Tomsk. After the treatment with meldonium, 59-78% of patients with initially diagnosed functional class II heart failure were reclassified in functional class I group. It was found that meldonium improves myocardial inotropic function and increases tolerance to physical load, improves patients' life quality by causing no severe adverse effects.
Antihypoxic and brain perfusion improving effect of meldonium was noticed during the animal studies. Meldonium optimizes the volume of redistribution of cerebral blood flow for the benefit of ischemic lesions, increases neuronal resistance under hypoxic conditions. The medication has CNS stimulating activity – increase in movement activity and physical performance, stimulation of behavioural reactions. It has also antistress activity – stimulation of sympathoadrenal system, the accumulation of catecholamines in the brain and adrenal glands, protection against stress-related changes in the internal organs.
It has been demonstrated that meldonium is effective in complex therapy in the management of acute and chronic cerebrovascular disorders (ischaemic stroke, chronic cerebrovascular insufficiency). Meldonium normalizes brain capillary and arteriolar tone and resistance, restores their reactivity.
The effect of meldonium on the rehabilitation process in patients with neurological disorders (following cerebrovascular diseases, brain surgery, trauma, tick-borne encephalitis) has been studied.
The results of therapeutic efficacy test with meldonium show evidence of positive dose-dependent effect on patients' physical ability to work and functional self-support recovery during the convalescence period.
A positive effect on intellectual function recovery during the rehabilitation period was found while studying distinct and integral intellectual functional changes following medicine administration.
It has been established that meldonium improves quality of life in convalescent patients (most of all because of the recovered physical functions) and also contributes to elimination of mental disorders.
Meldonium has positive effect on regression of nervous system function disorders in patients with neurological deficit during the recovery period. General neurological status of patients improves (the diminishing of brain nerve damage and pathological reflexes, the regression of pareses, the improvement of movement coordination and vegetative functions).
The pharmacokinetics was studied in normal human subjects using meldonium intravenously and orally.
Following intravenous administration of multiple doses Cmax reached 25.50±3.63 μg/ml. The apparent bioavailability was increased in individuals with Cmax, AUC and t1/2 increases, in patients with liver cirrhosis and in patients with severe renal insufficiency. Administered intravenously, AUC following single and repeated doses of meldonium is different. These results suggest a possible meldonium accumulation of blood plasma.
Meldonium is rapidly distributed from the circulation to the tissues with high affinity to the heart. The plasma protein binding ratio increases depending on the time after dosing. Meldonium and its metabolites partially cross the placental barrier. Animal studies have shown that meldonium excreted into breast milk.
Metabolism studies in experimental animals have shown that meldonium metabolized mainly in the liver.
Renal excretion plays a substantial role in elimination of meldonium and its metabolites. After meldonium single dose of 250 mg, 500 mg and 1000 mg intravenous administration, early elimination half-life is 5.56-6.55 hours, terminal elimination half-life is 15.34 hours.
Meldonium dose should be reduced in elderly patients with hepatic or renal impairment in whom the apparent bioavailability is increased (see section 4.2).
Meldonium dose should be reduced in patients with renal impairment in whom the apparent bioavailability is increased (see section 4.2). There is meldonium or its metabolites (e.g. 3-hydroxymeldonium) interaction with renal reabsorption of carnitine, leading to increased renal carnitine clearance. Meldonium, GBB and meldonium/GBB combination does not have the direct action on rennin-aldosterone-angiotensine system.
Meldonium dose should be reduced in patients with hepatic impairment in whom the apparent bioavailability is increased (see section 4.2). During toxicity study in rats, in groups that were treated with meldonium dose more than 100 mg/kg, yellow coloration of liver and denaturation of fats were observed. Histopathological examination of animals after large doses of meldonium (400 mg/kg and 1600 mg/kg) received, revealed changes in lipids of liver cells. Abnormal changes of hepatic function in human at doses of 400-800 mg were not observed. The possibility of fat infiltration in liver cells cannot be excluded.
There are no data on meldonium safety and efficacy in children and adolescents (up to 18 years of age), therefore the medicine is contraindicated in children and adolescents (see section 4.3).
Meldonium is of low toxicity. LD50 after active substance oral administration to mice and rats was more than 18 000 mg/kg.
The body weight, blood count, biochemical blood and urine tests of the rats did not showed any adverse changes after a continuous administration of meldonium for more than six month period. 20, 100 or 500 mg/kg oral meldonium doses had no effect on haematopoiesis, functional status of liver and kidneys, and did not cause changes in the structure of tissue of internal organs.
The medicine has no mutagenic and carcinogenic properties.
Specific toxicity studies showed no teratogenic and embryotoxic action of meldonium. In reproductivity studies with adult experimental animals it was stated that there were no effects on the number of corpora lutea, estrous cycle, mating rate and conception rate that could have been caused by meldonium administration. From the results of the studies it was concluded that the dose that causes no toxicological effects is 400 mg/kg/daily, and the dose that causes no effects on reproductive function is 1600 mg/kg. Toxicity on foetal development has not been observed using doses exceeding 1600 mg/kg/daily.
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