Mildronate - Use of Correctors of Cell Metabolism Under Hypoxia

Treatment of diseases caused by arteriosclerosis, especially coronary heart disease (CHD) and cerebro-vascular disease, over long periods of time was considered from the standpoint of improving blood flow and reduction of ischemic tissue oxygen requirements.

However, ATP Survey (Angina Treatment Patterns) study conducted under the auspices of the working group of the European Society of Cardiology, which examined the results of drug therapy of angina, it was shown that the appointment of a sick modern combination therapy hemodynamic effect of the drug does not lead to the complete elimination of angina attacks . TIBET study that compared Atenolol effects of Nifedipine SR, and combinations thereof, has not revealed the benefits of combining these drugs monotherapy before each of them. It turned out that drugs hemodynamic actions and means of neuro-hormonal blockade enough influence on the metabolism of target organ cells, so their use is not always possible to achieve sufficient positive dynamics. Besides, they have limitations, contraindications and side effects, particularly in terms of their combined use.

Thus, despite the introduction of new medicines and the successes achieved in the pharmacotherapy of ischemic heart disease, cerebro-vascular disease, and other clinical conditions associated with tissue ischemia, the effectiveness of their treatment is inadequate, and the mortality from them - high [3]. In this regard, in recent decades the attention of pharmacists and clinicians was aimed at the creation and implementation into medical practice cytoprotectors - tools that are capable of reducing disturbances of cellular metabolism and function of cell membranes, particularly cardiomyocytes, preventing the development of irreversible processes in them.

The origins of metabolic therapy can be considered the use of glucose-insulin-potassium mixture that in 1962 a group of scientists led by D. Sodi-Pallaris applied for the first time for the treatment of patients with acute myocardial infarction and established its positive impact on the dynamics of the ECG and early survival of patients [5]. Later attempts were made to use of Adenosine Triphosphate (ATP), Riboxinum intermediate substrates of the Krebs cycle, which have not been successful, as these substances do not penetrate the cell membrane and mitochondrial.

Currently, the main focus in improving energy use cardio-cytoprotectors infarction is able to adjust the energy and metabolic processes in the myocardium. The latter include drugs that improve the tolerability of myocardial ischemia periods, and retains the functional activity of the myocardium during hypoxia.

It is found that for an adequate blood supply to the myocardium ATP synthesis is mainly done by fatty acid oxidation, which requires a large amount of oxygen. In pathological conditions associated with chronic hypoxia-ischemia and infarction, activates the glycolytic pathway for the formation of adenosine triphosphate, and in severe ischemia of the main possible the synthesis of adenosine triphosphate mechanism becomes anaerobic glycolysis to produce ATP and simultaneous accumulation of lactate and pyruvate. When oxygen deficiency occurs in cardiomyocytes, inhibition of pyruvate dehydrogenase, pyruvate utilization disturbed, whereby it is converted to lactate. Last accumulates in the cytosol and leads to a reduction of intracellular pH and structural and functional disorders of cardiomyocytes. Tissue acidosis contributes to the uncoupling of oxidative phosphorylation and excess calcium ions in cardiomyocytes. This results in the activation of lipid peroxidation and damage to membrane structures of cardiomyocytes.

When myocardial hypoxia impaired fatty acid oxidation and the formation of intermediate products of their metabolism, which inhibit the enzyme systems that ensure the transfer of high-energy phosphates, exacerbating an energy deficit in the myocardium and promotes the buildup of acidosis. Accumulates in the mitochondria of cardiomyocytes large amount of oxidized fatty acids has a destructive effect on cell membranes. Thus, the lack of oxygen promotes the accumulation of fatty acids in mitochondria, and the increase in the intracellular concentration of the fatty acids leads to the inhibition of glucose utilization and production rate of adenosine, promotes an increase in membrane permeability to calcium ions enhances the b-adrenergic response infarction. fatty acid damaging effect is realized in several ways: inhibition of glucose utilization and formation of adenosine triphosphate speed uncoupling oxidation and phosphorylation in the electron-transport chain in the mitochondria, disturbance membrane enzymes properties, increased membrane permeability to calcium ions and its associated gain b-adrenergic response.

Thus, when the myocardium becomes ischemic appropriate restriction fatty acid oxidation in mitochondria cardiomyocytes. In this regard, in the arsenal of tools to positively influence the metabolism of myocardium in ischemia, new drugs - partial fatty acid oxidation inhibitors (partial fatty acid oxidation inhibitors - p-FOX), which belongs to the class of antianginal drugs. Representatives of this group of drugs or retard the rate of fatty acid oxidation in mitochondria (Trimetazidine), or restrict their transport into mitochondria. The latter belongs to the original drug Mildronate (Meldonium) production of JSC "Grindeks" (Latvia).

Mildronate is reversible limits the rate of biosynthesis of Carnitine from its predecessor - the gamma-butyrobetaine. Consequently, the broken-carnitine mediated transport of long chain fatty acids across the mitochondrial membrane, without affecting the metabolism of short chain fatty acids. Before the drug Mildronate unlike trimetazidine in mitochondria does not increase the concentration of oxidized intermediates of fatty acid metabolism of foods that can be a source of formation of toxic lipid peroxides.

Partial blockage of fatty acid oxidation includes an alternative energy system of education - the oxidation of glucose, which is much more efficient use of oxygen for ATP synthesis. Oxidation of glucose metabolic chain synthesis requires ATP per molecule of ATP 35-40% less oxygen than fatty acid oxidation, said oxygen savings is provided not only by the metabolic characteristics of glucose oxidation cycle (up to 20%), but also by lack of need for receipt of fatty acids into the mitochondria (about 15-20%), active transport requires ATP deficient in hypoxic conditions.

The mechanism of the effect of the drug Mildronate is based on the transport of fatty acids into the mitochondria.

Discuss another mechanism of action of the drug Mildronate is the ability to reduce the rate of inactivation of nitric oxide free radicals.

The ability of the drug Mildronate influences on metabolic energy chain provides the full functionality of the cells under hypoxic conditions, which is achieved by reducing the activity of costly oxygen oxidation of fatty acids and activation of a more favorable glycolytic pathway of energy production, the effect of preconditioning (improving the heart's ability to adapt to by the biochemical 'willingness to hypoxia conditions "without serious consequences to withstand longer periods of ischemia), induction of biosynthesis of nitric oxide and decrease peripheral vascular resistance.

Mildronate improves energy metabolism in the myocardium, that allows the use of the drug for chronic forms of coronary artery disease, chronic heart failure of ischemic origin, for the correction of metabolic disturbances by the target organs in arterial hypertension (AH). It should be noted that the process of left ventricular remodeling in patients with arterial hypertension accompanied by changes in geometry of the heart chambers, impaired systolic and diastolic functions of the myocardium and the subsequent development of heart failure [28-32]. High levels of free radicals in patients with hypertension and coronary heart disease negatively affects the clinical course of the disease, activating the processes of coagulation, inhibiting the synthesis of nitric oxide, reducing the sensitivity of baro-receptor NO- and the vascular wall. In addition, free radical modification of low density lipoproteins and membranes of endothelial cells in ischemic heart disease and hypertension has a strong pro-atherogenic effect and contributes to the progression of atherosclerosis.

Of great interest is the ability Mildronate described the drug to enhance the effectiveness of antihypertensive therapy in the treatment of angiotensin converting enzyme inhibitors, improve the circadian blood pressure profile in patients with hypertension, reduce the severity of vascular endothelial dysfunction, reduce the number of people with the most dangerous in terms of stroke nighttime blood pressure profiles ( " Knight-picker "," over-dipper "). With prolonged use of Mildronate remodeling speeds of the left ventricle on the background of achieving the target level of blood pressure. Mildronate due to the unique characteristics of its mechanisms of action in these clinical situations is the drug of choice among other cardio-metabolic means [13, 33-35].

The clinical studies demonstrated the efficacy of cytoprotector Mildronate to patients with stable angina, in particular, its positive effect on exercise tolerance, reduction of clinical manifestations of angina, reduction in nitrates requirements. These positive clinical effects have been associated with the ability of the drug to improve the functional state of the vascular endothelium and inhibit the processes of free radical oxidation. Feasibility of drug Mildronate destination is based on the fact that inhibition of the synthesis of carnitine leads to an accumulation of y-butyrobetaine, able to stimulate acetylcholine receptors, resulting in the synthesis of nitric oxide is activated that causes the vasoprotective effects and antioxidant drug Mildronate.

Established that Mildronate reduces peripheral vascular resistance, eliminates the vasospasm induced by epinephrine and angiotensin II, Meldonium inhibits platelet aggregation. As shown by in the early 2000s, research, application Mildronate (Meldonium) for hypertension in combination with basic therapy helped to reduce blood pressure levels, an increase in the number of people with target blood pressure numbers. Hypertensive patients with stable angina drug at the same time reduces the number of angina attacks and nitroglycerin amount received per day, increased exercise tolerance. There is evidence of the effectiveness of Mildronate in treatment of chronic heart failure, myocardial infarction, stroke.

Given the nature of the drug pharmacodynamics Mildronate and universal complex effect on ischemic myocardium and the vascular wall, the local comprehensive detailed randomized studies have been made of its clinical efficacy in patients with cardiovascular disease. Comparative evaluation of efficacy Mildronate to CHD patients with stable angina showed that its use in chronic coronary artery disease traditional therapy helped improve the effectiveness of anti-anginal therapy, significantly reduce the dose of short-acting sublingual nitro-preparations.

Of particular interest are the results of a recently completed international, multicenter, randomized, double-blind, placebo-controlled clinical trial MILSS II, which has been shown that taking Mildronate drug in the treatment of stable angina in combination with standard therapy leads to a significant improvement of patient's condition and improve his quality of life. The main objective of the study was to assess the effectiveness of the drug Mildronate against coronary heart disease and the effect of the drug Mildronate symptoms on exercise tolerance in patients with stable angina. Research MILSS II was conducted in accordance with the rules of Good Clinical Practice (ICH / GCP) and the requirements of the regulations of the European Union of 37 research centers of four countries - Latvia, Lithuania, Russia and Ukraine. The study involved 278 patients with chronic ischemic heart disease (stable angina II and Class III, Canadian Cardiovascular Society). The period of the study was 13 months, 4 weeks preparation period and 12 months of randomized treatment - double-blind treatment. The main objective method for studying the tolerance of patients is velo-ergometry method was chosen to exercise stress. All patients received standard antianginal treatment (beta-blockers, aspirin, statins, angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist). MILSS II study results showed that standard therapy in combination with Mildronate drug improves patient tolerance to physical activity, increases the time to occurrence of angina attack and before the emergence of ST-segment depression, and improves patients' quality of life.

Improving the energy exchange in the myocardium in patients receiving the drug Mildronate® in stable angina combined with improved systolic and diastolic function of the left ventricle of the heart: an increase in left ventricular ejection fraction, and a decrease in pulmonary artery pressure. In patients with coronary artery disease Mildronate use of the drug in a daily dose of 1000 mg for 6 weeks on a background of basic therapy leads to a significantly more pronounced compared to the control group, an increase in test distance with a 6-minute walk test, ejection fraction, stroke volume and velocity of circulatory contraction of the myocardium fibers left ventricle.

Of particular importance the use cardioprotectors gains in coronary angioplasty as percutaneous coronary intervention and coronary artery bypass grafting is associated with the development of complications of the cardiovascular system - myocardial dysfunction with the development of the syndrome of "stunned myocardium", accompanied by a violation of local contractility of the left ventricle, impaired hemodynamics and various arrhythmias. According to modern concepts, ischemic and reperfusion myocardial changes, including during coronary revascularization, developed as a result of violations of cardiomyocyte metabolism. Going normal metabolism to anaerobic pathway in ischemia, as well as the accumulation of excessive amounts of free fatty acids in the reduction of coronary blood flow contribute to a number pathobiochemical and pathophysiological changes leading to disruption of myocardial contractility, changes in the bioelectric activity of cardiomyocytes, and the development of dangerous cardiac arrhythmias . To correct the above pathological changes of great importance is the normalization of metabolism of cardiomyocytes, which was confirmed by the results of a clinical study carried out on the basis of GOU VPO "Russian State Medical University." The study involved 149 patients with stable angina FC II and III at the age of 41 to 75 years who underwent coronary artery bypass grafting with cardiopulmonary bypass or percutaneous coronary intervention. Patients of the first group (n = 79 people) for 10-15 days prior to revascularization to drug therapy, used to treat stable angina (nitrates, beta-blockers, aggregation inhibitors, angiotensin converting enzyme inhibitors, antiarrhythmics), was added Mildronate ( Meldonium) at a dosage of 750 mg per day for three days, and then - 750 mg a day, two times a week. The results of the above work Mildronate demonstrate the ability of the drug to reduce the degree of myocardial hibernation in chronic ischemia, as evidenced by the increase in overall and local contractility of the left ventricle. When coronary angioplasty inclusion Mildronate drug in the preoperative and postoperative therapy can accelerate the recovery of the contractile function of the myocardium on the background of improving coronary blood flow and thus increases the efficiency of coronary revascularization. Clinically it seems justified introduction cytoprotectors in pre- and postoperative period during routine angioplasty in patients with angina for the correction of reperfusion arrhythmias. It proved that Mildronate more than trimetazidine, reduces the level of lipid peroxides in the blood due to the activation of enzymes antioxidant and improves the functional activity of the myocardium in the postoperative period.

Currently, one of the key problems of the world of medicine is a comorbidity. There is a widespread combination of coronary artery disease, hypertension, diabetes mellitus (DM) type 2 and chronic heart failure (CHF). These diseases have a close pathogenetic relationship. They are characterized by endothelial dysfunction with marked predominance of vasoconstrictor and prothrombotic responses, microcirculatory disorders, ischemia of organs and tissues, metabolic disorders.

Diabetes mellitus is one of the leading risk factors of progression of lesions of the cardiovascular system, which is based on the intracellular metabolic disorders. Diabetes significantly complicates the course of coronary artery disease and hypertension, contributing to the rise of endothelial dysfunction, accelerate the development of atherosclerosis and coronary artery trunk, worsening hypoxia in the myocardium, activation of free radical oxidation, oxidative stress weighting on the background of significant decrease of the activity of enzyme systems of antioxidant protection. Disorders of carbohydrate metabolism are largely reflected in the course of chronic heart failure. In this regard, the use of correctors of metabolism in patients with cardiovascular diseases in conjunction with diabetes seems justified. Proof of this are the results of a randomized trial, which was attended by 100 patients aged 45-70 years suffering from ischemic heart disease with CHF II and III functional class classification PRAs (2002) and diabetes type 2 in the stage of compensation or subcompensation carbohydrate metabolism. A

ll patients suffering from chronic heart failure, received basic therapy with Enalapril, Bisoprolol, aspirin, simvastatin. If necessary, prescribed diuretics and nitrates. For correction of disorders of carbohydrate metabolism was carried out mono- or combination therapy with Metformine and Gliclazide. Half of the patients treated supplemented Mildronate drug in a daily dose of 1000 mg for 3 months. It was noted that the downward trend under the influence of the drug Mildronate (Meldonium) glycated hemoglobin in the blood. The positive effect of the drug Mildronate as part of a combined treatment of chronic heart failure in patients with type 2 diabetes on lipid profile, which was reflected in the reduction of triglycerides and very low density lipoproteins, while the control group had no significant changes were observed in lipid profile parameters. The study found that taking the drug Mildronate accompanied by a slight increase in activity of key antioxidant enzymes in red blood cells - catalase and superoxide dismutase; comparing the variations in the group activity of these enzymes is detected. The dynamics of the activity of antioxidant enzymes was accompanied by a decrease in the blood level of peroxidation products: in the main group the concentration of diene conjugates was reduced by 41% in the control group - only 20%. Assessing the impact of the drug Mildronate (Meldonium) the clinical course of ischemic CHF in patients with type 2 diabetes with cardiac autonomic neuropathy showed that basic therapy Mildronate after 16 weeks of treatment contributed to a decrease in the variability of cardiac arrhythmias.

Much attention is paid to the study of antiarrhythmic drug effectiveness Mildronate to CHD patients: in a number of studies demonstrated the ability of the drug on background of Mildronate is conventional antianginal therapy including beta-blockers, to reduce the frequency and duration of periods of arrhythmias, predominantly ventricular arrhythmia. The greatest effect of the drug was observed in patients without previous myocardial infarction and post-infarction left ventricular aneurysm.

One of the serious complications of comorbidity is acute cerebral circulatory distress. Use of the drug Mildronate in acute ischemic stroke in a daily dose of 1000 mg for 20 days, has a statistically significant positive impact on the severity of neurological disorders. In the treatment of drug Mildronate by single photon emission computed tomography found an increase in cerebral perfusion in areas of its original reduction, the relevant ischemic lesion. The most significant improvement was observed in cerebral blood flow in patients with ischemic stroke, the type of cardiogenic embolism, ie, in the absence of intracerebral lesions of small or major cerebral arteries. Use of the drug contributed to the enhanced activity and attention. In patients with increased tempo of assignments re-switchievness, improves memory, which was due to the improvement of neurodynamic background [64]. It was found that the use of Mildronate drug in the treatment of ischemic stroke accelerates the recovery of motor, sensory and coordinatorical functions, contributes to the normalization and restoration of mnemonic abilities, reduces the severity of focal neurological deficits, domestic and social exclusion, improve disease outcome [64]. In chronic vascular encephalopathy Mildronate improves neurodynamic and regulatory functions of the brain.

Important from the point of secondary prevention of cardiovascular disease and cardiovascular disease is one of the pleiotropic effects of the drug Mildronate- lipid corrective action, that is, the ability of some to reduce blood levels of triglycerides and low density lipoprotein. lipid corrective activity of the drug Mildronate proved as an experimental model of atherosclerosis in laboratory animals and in clinical trials, and the uniqueness of the drug Mildronate confirmed by the fact that a number of other cyto-protectors appreciable effect on the blood lipid profile of people does not have.

It is very important, especially in terms of comorbidity, and antioxidant properties of Mildronate (Meldonium) drug that improve cardiac performance against the background of combined ischemic and diabetic cardiomyopathy.

Promising is the use of the drug Mildronate in CHF, which is a universal complication of cardiovascular disease and having the basis of its formation disorders of energy metabolism in conjunction with chronic oxidative stress. Positive effects of the drug Mildronate to patients with CHF are expressed in increasing exercise tolerance, improved systolic and diastolic function of the left ventricle of the heart, in reducing the severity of inflammatory activation in a significant reduction of CRP and TNF-α levels, reducing serum N- terminal brain natriuretic peptide in improving endothelial function, and in a combination of cardiovascular disease with diabetes type 2 - to further reduce levels of hyper-insulinemia and insulin resistance.

Cytoprotectors play an important role in the treatment of acute coronary syndrome. Especially effective is their introduction in the early stages from the beginning of anginal attacks with the use of parenteral (intravenous) drug forms. Currently Mildronate having ampouled form for intravenous administration, it is one of the most used cardio-cytoprotectors in acute coronary syndrome due to its ability to improve the prognosis in hospital period of acute coronary disease. At the same time, according to an international multicenter study EMIP-FR (2000), intravenous administration of trimetazidine in acute myocardial infarction did not have a significant effect on the course, the incidence of complications and outcomes, and therefore parenteral forms of trimetazidine is not available.

In 2010, "Grindeks" has completed a number of clinical trials of the drug Mildronate (Meldonium), among them - MILSS I (MILSS I), MILSS II (MILSS II) and MI & CI. Studies have confirmed the efficacy and safety of Mildronate drug in the treatment of patients with coronary heart disease and peripheral arterial disease.

Important results were obtained in the study, MI & CI, which used Mildronate (Meldonium) in diseases of the peripheral arteries. It reported statistically significant increase in the indicator of absolute distance of intermittent claudication, the increase in the initial distance of intermittent claudication patients, regardless of age. These effects persisted 1 month after discontinuation of the drug. The data obtained during this study allow us to consider Mildronate as a promising drug in patients with peripheral arterial disease, including in diabetes type 2, when obliterating atherosclerosis of the lower limbs occurs 3-4 times more frequently than in the general population.

Given the pronounced antioxidative effects of Mildronate drug, its ability to inhibit platelet aggregation, stimulating the synthesis of nitric oxide and reduce endothelial dysfunction, there are objective prerequisites for its extensive use in the treatment of a large number of diseases. It is currently under clinical trials efficacy of Mildronate in various fields of internal medicine, and there are good reasons to think that the triumph of the corrector cell metabolism, has a unique mechanism of action and multiple organ effects occur in the near future, when a thorough evidence base significantly expand the scope of use.

Mildronate - Treatment Of Cardio-Neurological disorders during ischemia and hypoxia

Cerebrovascular pathology has long moved from the category of a single medical problem in the social problem. Progression of vascular lesions of the brain results in significant disability, and in the later stages interfere with the ability to self-service and significantly reduces the quality of life. The key link is ischemic brain damage, or glutamate, cascade, which many researchers believe trigger excitotoxic damage and a major cause of neuronal death. One important component of effective control of sequellae of ischemic disorders is complex neurocytoprotective therapy. To correct sequellae of both acute and chronic ischemia of the brain need it’s necessary to act effectively in several directions simultaneously, normalizing metabolic changes, eliminating the cytokine imbalance transcription violations, reducing the severity of oxidative stress and excitotoxicity.

Cerebrovascular pathology has long been moved from the category of a single medical problem into a social problem. The progression of vascular lesions of the brain leads to significant disability, and in the later stages impairs the ability to self-service and greatly reduces the patient's quality of life. A key element is the ischemic brain damage, or glutamate cascade, which many researchers consider the trigger of excite-toxic damage, and the main cause of neuronal death. One of the important components of an effective correction of the consequences of ischemic disorders is complex of neuro-cytoprotective therapy. To correct for the effects of both acute and chronic brain ischemia is necessary to work effectively in several directions simultaneously, normalizing metabolic changes, eliminating the cytokine imbalance of transcription violations, reducing the severity of oxidative stress and excitotoxicity. Unfortunately, the ideal neuro-cytoprotective capable of simultaneously affect all of the above processes of today is not found, however neuro-cytoprotective complex is used in clinical practice. Of the large number available in the market must select neuro-cytoprotective Mildronate is the original drug, which has long been effectively used in cardiology, whereas in neurologic practice it has been applied recently, demonstrating its effectiveness as with acute and chronic cerebral ischemia. Efficiency of Mildronate is in the practice of treating patients with acute and chronic vascular disease was confirmed in studies carried out on the basis of major neurological centers in Russia. Now it is considered appropriate to use the combined neuro-protective treatment regimens using Mildronate (Meldonium).

Mildronate is preparation, correcting metabolism and energy supply of tissues, refers to a group cytoprotectors / antihypoxants, provides protection and power supply of different cells of the body in conditions of ischemia and increased payload. Because the primary indication for use has been and remains Mildronate® cardiac pathology, look at how it works on the example of pathophysiological disorders that occur in the heart during ischemia and hypoxia. The aging process of the body, as well as the aging of individual organs, including myocardium, accompanied by certain changes in the structure and functions that contribute to the spread of heart failure in the elderly and are responsible for the increased role of diastolic dysfunction in its pathogenesis. In addition, it is necessary to take into account the presence of the syndrome of mutual burdening age factors and cardiovascular disease.

Among the primary mechanisms of the progression of heart failure and its main etiological factors are hypertension and coronary heart disease – it is now recognized as the leading state of violation of neuro-humoral regulation of endothelial and who acquire the greatest value in people of older age groups due to the growing imbalance of the regulatory systems in the aging process.

Energy phosphates (Adenosine triphosphate (ATP) and creatine phosphate), among other convertible forms of energy represent major energy reserves in the cells. Cardiac muscle, like many other tissues, for ATP synthesis uses two basic types of substrates: glucose and free fatty acid (FA). In addition, the heart can use oxidized products secreted by the cells of other organs - lactic acid, ketone bodies, which increases the stability of the heart as compared to other organs.

The choice of substrate depends on its concentration in the blood, and the intensity of the heart. In normal operation of the heart cardio-myocytes fatty acid is preferably used, and with increased functional load when it is required to accelerate the process of ATP synthesis, glucose is used, in which the oxidation of 1 mole of oxygen produced 14% more ATP than fatty acid oxidation.

When cells experiencing a shortage of oxygen, that is in conditions of hypoxia, myocardial metabolism varies. Short-chain and long-chain fatty acids into the mitochondria come, but for the oxidation of oxygen in the cell is lacking. As a result, oxidized in cardiomyocytes accumulate oxidized active form of fatty acids in the form of acyl-carnitine and acyl- coenzyme A. These metabolites capable of damaging cell membranes and block the delivery of already synthesized ATP cell organelles. As a result, there can come death of the cells. Oxidized products of long chain fatty acids - and acylcarnitine atsilkoenzim A - blocking Ca2 + -ATP ase of the sarcoplasmic reticulum (calcium pump), N + -, K + -ATPase sarcolemma (sodium and potassium pumps) adeninnukleotidtranslokazu (ATP-pump). Accumulation of fatty acid in oxidized conditions of oxygen deficiency blocks and glucose oxidation, as it happens in the case of myocardial ischemic reperfusion. The long chain acylcarnitine can cause contracture ischemic myocardium. The intensive oxidation of fatty acids in the myocardium in the post-ischemic period drastically reduces the possibility of heart function.

In acute stress, including pain, myocardial ischemia, there are significant changes in the content of biomolecules in blood. Thus, in the blood level of 36-72 hours increases norepinephrine and epinephrine, free fatty acids, for 3 hours or more - and glucose steroid hormones. At the same time increases the cellular uptake and intensity of the oxidation of free fatty acids, which entails an increase in oxygen consumption. At the same time capture cardiomyocytes glucose, lactate and pyruvate decreases. Reduced rate of conversion of pyruvate into acetyl coenzyme A, and its subsequent oxidation in the Krebs cycle. All this leads to a decrease in production macroergs. Thus, to preserve the viability of tissue ischemia all available methods must restrict release of fatty acids in the blood and their entry into the mitochondria, thereby reducing the rate of oxidation of free fatty acids. But it is necessary for the survival of cardiomyocytes at the same time to ensure the supply of high amounts of glucose into the cells to activate its oxidation and ensure the involvement of pyruvate in the Krebs cycle.

Thus, in ischemia and hypoxia body constantly experiences a power shortage, which can be exacerbated by attempts to normalize its own energy homeostasis using energy addition of glucose and other energy-intensive substrates, primarily free fatty acids. More often such attempts are caused by our unsustainable pharmacological effects such as the use of stimulants, beta-oxidation, to what concerns carnitine.

The oxidation of the free fatty acid although it provides a large amount of energy, but requires 30% more oxygen, which in the conditions of hypoxia on cell dooms even greater oxygen debt and injure it. Carnitine, as a kind of transporter, fatty acid contributes to the penetration into the cell, where the process of oxidation. Thus, under ischemic conditions necessary to limit the intake of fatty acids (FA) to the site of their oxidation. This can be accomplished by blocking the synthesis of LC transporter - carnitine.

Mildronate is a blocker beta-oxidation (oxidation LCD) has a multicomponent action on the following energogomeostaz stabilizing mechanisms. Mildronate in its chemical structure is an analogue of gamma-butyrobetaine (GBB) - substance having vasodilating properties, which is in every cell of the human body. Mildronate is inhibiting the activity of gamma-butyrobetaine hydroxylase blocks the biosynthesis of carnitine (conversion of gamma-butyrobetaine in Carnitine), transport of long-chain fatty acids across the membrane of cells and carnitine dependent oxidation of fatty acids. Mildronate’s secondary effect consists in reducing the transport of free fatty acids into mitochondria and formation acyl-coenzyme A that prevents an adverse effect on cells.

In the cell, glucose is used instead of the starting fatty acids and spent for this process is much less oxygen than to use the LCD. Consequently, Mildronate helps the cell to save oxygen, which is important in conditions of ischemia.

Due to the complex mechanism of action in conditions of ischemia and hypoxia Mildronate restores the balance of oxygen delivery and consumption processes in the cells, to prevent violations of transport ATP; It eliminates the accumulation of toxic products of metabolism in the cells, protecting them from damage; also has a tonic effect. At the same time it activates glycolysis, which proceeds without the use of supplemental oxygen. The main difference of Mildronate from other medicines, that it used to correct metabolism, is the presence of additional therapeutic effects which open broad opportunities for use of the drug. Competing for the receptors of the gamma-butyrobetaine hydroxylase, Mildronate by 40% reduces the concentration of Carnitine, and GBB level thus increased tenfold. As a result of the similarity of the geometry of GBB and acetylcholine activates endothelial acetylcholine receptors, which ultimately leads to the induction of the synthesis of nitric oxide (NO).

NO molecule on guanylate cyclase mechanism reduces intracellular calcium. This leads to the relaxation of vascular muscle not striated cells and therefore reduce peripheral vascular resistance (and vessels in extremities and, in the brain), thus steal syndrome arises as Mildronate does not affect vessels unchanged tonus. Also, there is an improvement of microcirculation and endothelial function. All these processes are very important in the pathology of the cardiovascular system, especially in the early stages of the disease. In addition, it is proved that Mildronate is able to activate genes that are responsible for protecting the body from stress. Activating antistress same genes, the ability to produce an additional amount of energy compounds increase efficiency, allow the body to better cope with the increased loads. Due to a similar mechanism of Mildronate action indispensable for increased mental stress, work in extreme situations. To increase the efficiency, Mildronate is taken by high-class athletes, students in preparation for exams. By improving cerebral blood flow Mildronate eliminates functional disturbances of the nervous system in patients with chronic alcoholism, reduces symptoms of withdrawal syndrome and intoxication.

Complex mechanisms of action determined by the variety of pharmacological effects of the drug: increased efficiency, reduction of symptoms of mental and physical stress, activation of tissue and humoral immunity, cardioprotective effect.

- In the treatment of: acute and chronic circulatory disorders of the brain (ischemic stroke, cerebro-vascular insufficiency);

- In the treatment of: acute circulatory disorder in the retina, hemophthalmus and retinal hemorrhages of different etiologies, thrombosis of the central retinal vein and its branches, retinopathy of various etiologies (including diabetic and hypertensive) - only for para-bulbar administration;

- In the complex therapy of ischemic heart disease (angina, myocardial infarction, chronic heart failure, cardiomyopathy dyshormonal);

- Peripheral arterial disease;

- Abstinence syndrome in chronic alcoholism (in combination with specific alcoholism therapy);

- Reduced performance, mental and physical stress (including athletes).

Dosage and administration of the drug for medical use according to the instructions:

1. Cardiovascular disease: in the complex therapy - 0,5-1 g (1-2 tablets) per day, singly or in 2 divided doses. The course of treatment - 4-6 weeks.

2. Cardialgia on background dyshormonal myocardial dystrophy - 500 mg per day. The course of treatment - 12 days.

3. Violation of cerebral circulation: the acute phase of cerebrovascular pathology - intravenously at 500 mg 1 time a day for 10 days, then the drug is prescribed inside of 500-1000 mg per day. The course of treatment - 4-6 weeks.

4. Chronic ischemic attack: the interior of 500 mg 1 time per day, preferably in the morning. The course of treatment - 4-6 weeks. Repeated courses (2-3 times a year) are possible after consultation with the doctor.

5. Peripheral artery disease - a daily dose of 1000 mg (500 mg 2 times a day).

6. The mental and physical overload (including the athletes) - into 1000 mg per day. The course of treatment - 10-14 days. If necessary, repeat the treatment after 2-3 weeks. Athletes - inside of 0.5-1 g, 2 times a day before training, preferably in the morning. The duration of the preparatory period - 14-21 days, during the period of competition - 10-14 days.

7. Alcohol abstinence syndrome (in combination with specific therapy) - 500 mg four times a day. The course of treatment - 7-10 days.

8. Chronic alcoholism - into 500 mg four times a day intravenously 500 mg 2 times a day. The course of treatment - 7-10 days.

9. Ophthalmopathology (hemophthalmus and retinal hemorrhages of varying etiology, central retinal vein thrombosis and its branches, retinopathy of various etiologies (diabetic, hypertensive)) - parabulbarly 0.5 mL solution for injection (0.5 g / 5 ml) for 10 days. It can be used in a combination therapy.

Precautions to keep in mind and which should be followed, especially during prolonged Mildronatom therapy:

- In acute coronary syndrome Mildronate is not a first-line drug;

- Caution should be exercised when prolonged use Mildronate by patients with chronic diseases of the liver and kidneys;

- Because of the possible development of the stimulating effect of the drug Mildronate recommended in the morning;

- No evidence of adverse effects on the reaction rate Mildronate that enables its use in the relevant categories of persons in the period of work;

- Have no experience with children;

- It enhances the action of the drug vasodilatig and some antihypertensive drugs, cardiac glycosides;

- Can be combined with antianginal drugs, anticoagulants, antiplatelet, anti-arrhythmic drugs, diuretics, bronchodilators. Since Mildronate can cause the development of mild tachycardia and hypotension, caution should be exercised when combined with antihypertensive drugs, nitroglycerin, nifedipine, - and ß-blockers, peripheral vasodilators.

Mildronate is ideal for the treatment of cardiovascular diseases, cerebro-vascular diseases and the other, as above-mentioned components affect the metabolic processes. Clinical practice has since proved the correctness of these patho-physiological concepts. Thus, the combined use in the treatment of patients with arterial hypertension Mildronate and enalapril contributes to a more rapid normalization of free radical oxidation, correction of endothelial dysfunction and a daily profile of blood pressure, improves the morphological and functional state of the left ventricle. Effect of combination therapy Mildronatom and enalapril on the state of the myocardium and intracardiac hemodynamics persists for 2 months. after the abolition of cytoprotector.

In early 2010, successfully concluded an international, multicenter, randomized, double-blind, placebo-controlled clinical trial of the drug Mildronate (MILSS II), which was conducted in 37 study centers in Latvia, Lithuania, Russia and Ukraine.

The study investigates the influence of Mildronate on exercise tolerance in patients with stable angina. A study carried out in strict accordance with the standards of good clinical practice (GSR). The results clearly demonstrated that the standard therapy in combination with Mildronate patients increases tolerance to physical activity, increases the time to occurrence of angina attack, improves the quality of life of patients.

Conducted a double-blind, placebo-controlled study clearly confirmed the results of previously conducted numerous studies, according to which the inclusion of Mildronate in the complex therapy of chronic heart failure significantly improved the efficiency of basic therapy in patients with middle-aged to 73%, the elderly - to 69%, senile age - up to 63% reduction by accelerating the functional class of patients of cardiological profile for 3-4 days, potentiation of antihypertensive and anti-ischemic effect of basic therapy.

Supplementation Mildronate to the means of basic therapy helped to reduce intramyocardial tension, normalization of endothelial and humoral regulation. It showed an increase in serum levels of NO metabolites and a significant decrease - in the erythrocytes, indicating normalization of metabolism of nitric oxide. There was also approaching indicators of vascular endothelial function to the values of healthy people.

Since the mechanisms of cell apoptosis resulting from energy starvation and inevitable gain beta-oxidation, the same for all tissues Mildronate used in the treatment of patients with acute and chronic neurological vascular pathology.

Studies have confirmed the effectiveness of Mildronate in the practice of the treatment of patients with acute and chronic vascular neurological disorders, held in major neurological centers and clinics of the Russian Federation.

Mildronate at a dose of 1000 mg (10 ml of 10% solution) intravenously for 20 days, has a statistically significant effect on the severity of neurological disorders in patients with ischemic stroke in the acute stage of its development. In this case, the biochemical basis of therapeutic action Mildronate is its pronounced antioxidant activity. Mildronate significantly reduces oxidative damage lipoprotein patterns of neuronal membranes, as well as restores the activity of endogenous antioxidant system. Given the mechanism of action of the drug, it is advisable as early as possible its use in patients with ischemic stroke, ie, use during the therapeutic window in the early hours and days, which significantly improves the clinical efficacy of the therapy.

In the early recovery period of ischemic stroke parenteral administration of Mildronate contributes to the overall activity and attention. In patients with increased tempo of assignments re-swithcing, improves memory. Conducted neuropsychological studies suggest that Mildronate therapy has a definite positive impact on mental processes in patients with circulatory encephalopathy.

Excellent, good and satisfactory results of such treatment were observed in 69.7% of patients with circulatory encephalopathy. The greatest effect was observed in patients with mood instability, violation of emotional and volitional, memory and ability to concentrate. The majority of patients with circulatory encephalopathy during treatment Mildronatom improvement occurs by both subjective and objective neurological symptoms, with the most precise dynamics undergo cochle-vestibular, astheno-neurotic cephalgic syndromes and diseases. Confirmed by experimental data on the antioxidant effect of Mildronate, which is realized by increasing endogenous antioxidant status of the organism. The clinical effect is manifested Mildronate to 4-5-th day of treatment, it is most pronounced in the 10 th day and continues to increase up to 6 weeks of treatment. After discontinuation of the drug is observed aftereffect that persists for several weeks.

Thus Mildronate is a drug effective in almost all forms of vascular pathology syndromes accompanied by ischemia and hypoxia.

In the case of acute ischemic myocardial injury Mildronate slows the formation of necrotic areas, shorten the rehabilitation period. In heart failure - increases myocardial contractility, increases exercise tolerance, reduces the frequency of angina attacks. In acute and chronic ischemic disorders of cerebral circulation - improves blood circulation to the ischemic focus, promotes redistribution of blood to the ischemic area. It is effective in the case of vascular and dystrophic pathology of the ocular fundus. It is also characteristic of the drug tonic effect on the central nervous system, elimination of functional disturbances of somatic and autonomic nervous system in alcoholics during abstinence. On the Ukrainian market there is a form of injectable and oral forms of the original drug Mildronate (JSC «Grindeks», Latvia). The injectable form of Mildronate - 1 ampoule contains 5 ml (500 mg) Meldonium. The package - 10 vials. Among the oral forms of the most interesting new form of oral - Mildronate GX (Meldonium phosphate) Tablets. 500 mg ¹ 60. This innovative formula, which has the features of: rapidly absorbed from the gastrointestinal tract, bioavailability of approximately 78%, the maximum concentration reached in 1-2 hours after administration, a daily dose of 1000 mg may be used singly, metabolized in the body into two major metabolites are excreted by the kidneys. The main indications for use Mildronate according to the medical use of the drug instructions

Applacation of Mildronate in treatment of acute and chronic cerebrovascular accident

Mildronate is an anti-ischemic, metabolic and antioxidant agent which is used to treat ischemic damage of organs. It was established that its therapeutic effect during acute and chronic disorders of brain circulation is associated mainly with an increase in the body content of NO, vasodilating properties of which contribute to the increase in cerebral blood flow and oxygenation of the brain. In case of ischemic stroke Mildronate® reduces the severity of neurological deficit, improves cognitive functions, reduces asthenia and dysphoria, improves quality of life. In case of dyscirculatory encephalopathy additionally it reduces the severity of cephalgia, vestibular-ataxic syndrome and dyssomnia. The pilot studies confirm the value of the drug in the treatment of transient ischemic attacks. Accumulated to date data require further confirmation in larger, placebo-controlled international studies.

Mildronate (Meldonium) was developed at the Latvian Institute of Organic Synthesis and refers to a group of agents used for the treatment of ischemic organ damage. Initially, the clinical application of Mildronate (Meldonium) associated with the treatment of cardiovascular diseases such as heart failure, angina pectoris, myocardial infarction. It has been found that the leading mechanism of drug action in these diseases is the ability to inhibit the synthesis of carnitine - transport molecules transferring long chain fatty acids into the mitochondria. The fact that it is in a healthy myocardium b-oxidation of fatty acids is the main energy source (to provide 70% of the heart needs to adenosine triphosphate (ATP)). However, this process requires large expenditures of oxygen. With the defeat of the myocardium associated with ischemia, oxygen delivery to the heart is reduced. Under these conditions, b-oxidation is less effective fatty acids, which leads to reduced formation of ATP. Furthermore, oxidized intermediates accumulate rendering a cytotoxic effect. Mildronate, disrupting the synthesis of carnitine, prevents the entry of fatty acids into the mitochondria, resulting in a lockup b-oxidation. Cage is forced to switch to another energy source - glucose. For its oxidation requires less oxygen, which is important in terms of ischemia, and, moreover, no cytotoxic products formed. This effect makes Mildronate a valuable drug for the treatment of cardio-patologic flowing with myocardial ischemia.

In further studies, it was found that Mildronate is also effective in acute and chronic disorders of cerebral circulation - ischemic stroke, vascular encephalopathy and transient ischemic attacks. However, the leading mechanism of drug action in the central nervous system (CNS) was different, different from the switching carbohydrate lipid metabolism, since in normal neurons as the principal source of energy use glucose. This brief review of the reader presents modern views on the mechanisms of action of Mildronate (Meldonium) in ischemic pathologies of the nervous system, as well as historical data about its clinical efficacy in these states.

Mechanism of Mildronate Action in ischemic pathology of nervous system

The mechanisms of Mildronate action in the CNS continue to be refined, but the studies performed to date, make it possible to introduce them as follows.

Biosynthesis of carnitine in the body occurs in several steps, the latter reaction - the conversion of gamma-butyrobetaine (GBB) in carnitine - occurs in the presence HBB-hydroxylase enzyme.

Mildronate (meldonium) inhibits the work of this enzyme, thereby disrupting formation of carnitine and increasing plasma concentrations of gamma-butyrobetaine. The latter, in turn, is subjected to esterification to form the ethyl ester of gamma-butyrobetaine. This material affects the M acetylcholine receptors and / or their own specific receptors, which leads to activation of NO-synthase - enzyme synthesizing nitric oxide (NO). As is known, NO is one of the main body of the molecules responsible for vasodilation (vasodilation).

Thus, Mildronate treatment associated with an increased content of NO in the body, vasodilator properties that determine the therapeutic effect in ischemic stroke, vascular encephalopathy and transient ischemic attacks.

The review cited by us are Mildronate and other mechanisms of action, providing assistance for acute and chronic disorders of cerebral circulation. The authors divide them into: 1) vasoprotection mechanisms, which in addition to improving myocardial metabolism, and NO-dependent vasodilation also include improved blood rheology, inhibition of atherosclerosis processes, improved glucose transport and the potentiation of insulin action; 2) neuroprotection mechanisms, which include the improvement of neuronal metabolism at the level of mitochondria and prevent mitochondrial damage, inhibition of lipid peroxidation and increase the activity of the endogenous antioxidants normalizing the expression of proteins involved in neurodegeneration, inflammation and apoptosis, restoration of the integrity of the blood brain barrier, gain regeneration of neural tissue , improving cholinergic transmission of nerve impulses.

Clinical Verification of Mildronate Capacity to Strengthen cerebral blood flow

Ability of Mildronate (Meldonium) enhances cerebral blood flow has been demonstrated in earlier studies. Thus, in 1991, in patients with ischemic stroke using tetra and bipolar rheoencephalography and inhalation method of xenon was detected amplification of cerebral hemodynamics, and the drug has been recommended for the treatment of ischemic brain disorders. In much more recent study, the same authors confirmed their earlier findings using Doppler ultrasound.

Another study in 1991 patients with circulatory encephalopathy degree II-III according echo-pulsegraphy Mildronate also showed a trend toward normalization of parameters of cerebral circulatory dynamics.

Mildronate ability has been confirmed in recent studies to enhance cerebral blood flow. In 2003, it was to assess the ability of the drug to affect brain blood flow in patients with circulatory encephalopathy due to stenosis of cerebral arteries. Using Doppler ultrasound extra- and intracranial arteries was revealed a positive impact on the performance of Mildronate® cerebral circulatory dynamics.

The authors of the study in 2007 reported that on hemodynamics in intracranial vessels is significantly affected by the speed of blood flow in the extra-cranial segments of the internal carotid artery and vertebral artery. Therefore, their work was valued linear blood flow velocity, and indices of peripheral vascular resistance in the extra-cranial arteries in these patients with circulatory encephalopathy atherosclerotic receiving Mildronate treatment . As a result, it was found that a drug contributed to the normalization of parameters of the internal carotid and vertebral artery blood flow.

The authors also reported that according to the test hypo-perfusion, made finger pressing of the internal carotid artery in the neck, including Mildronate medical complex in patients with circulatory encephalopathy atherosclerotic significantly improves the blood supply to the compensation. Thus, the test preparation increases the number of patients with compensated perfusion type.

A number of patients after acute ischemic cerebrovascular accident Mildronate reduced peripheral resistance index in the middle cerebral artery on the affected side as determined by Doppler ultrasound, indicating an improvement of microcirculation in ischemic brain regions.

The method of single photon emission computed tomography in patients with ischemic stroke in the acute stage of its development during Mildronate treatment found an increase in cerebral perfusion in areas of its original reduction, the relevant ischemic lesion on magnetic resonance imaging. The most clear improvement in cerebral blood flow was observed in patients with ischemic stroke, the type of cardiogenic embolism, ie in the absence of lesions or intracerebral small cerebral arteries [2, 8].

In the literature, there are reports that Mildronate enhances regression of brain damage by increasing the consumption of oxygen by the brain. In the study, SN Salnikov (2002) has confirmed the effectiveness of a course of the drug to improve cerebral oxygenation, while his one-time administration did not cause the therapeutic effect. However, other authors have observed positive effects and the occasional injection of the drug – Mildronate (Meldonium) improved cerebrovascular reactivity around the hearth ischemic cerebral lesions.

Efficiency of Mildronate during ischemic stroke

Clinical efficacy Mildronate in ischemic stroke (or during the formation of mixed groups of patients with ischemic stroke and traumatic brain injury) has been studied in trials. As a result, the effect of the drug was observed on a number of syndromes and symptoms of ischemic stroke.

Mildronats reduces the neurological deficit, fatigue, dysphoria, Meldonium improves cognitive function and quality of life.

In particular, Mildronate reduced the severity of neurological disorders in the acute (mostly) and subacute phase of stroke. While taking this drug noted improvement in cognitive functions such as memory, attention, speed of execution of tasks.

The drug was accompanied by a decrease in the severity of asthenic syndrome. The decrease was accompanied by dysphoria increased positive staining emotional experiences.

On improving the quality of life evidenced by the increase of the total activity of patients, their mobility and self-care ability.

In one study, it was further reported that the severity of reactive Mildronate (Meldonium) reduced inflammatory response, as evidenced by the reduction in the level of circulating immune complexes, reduced severity of endogenous intoxication was confirmed that content decreasing average molecular weight, and had a lipolytic activity.

Mildronate is an important feature is the absence of "robbing effect" to improve therapeutic results in the treatment of ischemic stroke.

Efficiency of Mildronate in encephalopathy

Clinical efficacy Mildronate with vascular encephalopathy I-III degrees of various origins (atherosclerosis, hypertension), with co-morbidities (diabetes) or without and in different age groups (including elderly patients) was studied. As a result, the effect of Meldonium was observed on a number of syndromes and symptoms of vascular encephalopathy.

As in the case of ischemic stroke, Mildronate reduced the severity of neurological disorders, as well as a positive effect on cognitive functions such as memory and attention.

The drug reduces the severity of asthenic syndrome, which was accompanied by a decrease in exhaustion and increasing the mobility of nervous processes. At the same time there was a decrease in the severity of cephalgic syndrome (headaches).

The Mildronate treatment reduces the severity of vestibular-atactic syndrome, as evidenced by a decrease in dizziness, nausea, increased stability when walking. Effect on myotonic syndrome manifested by normalization of night sleep.

Meldonium improves the quality of life of patients, which manifested an increase in the overall activity of the patients, their mental and physical performance.

Studies have shown the advantage of continuous Mildronate therapy compared with the exchange rate, because only with continuous treatment showed improvement of all assessed cognitive performance.

Efficiency of Mildronate in transient ischemic attack

Currently, researchers evaluated the possibility of using Mildronate for the treatment of transient ischemic attack. In one of these pilot studies, in the process of examination and treatment of 40 patients studied the dynamics of clinical status, psychometric data and indicators of free radical oxidation of lipids. Our study showed that in 24 patients with transient ischemic attacks after Mildronate treatment noted steady improvement in subjective status, as well as the improvement of memory and attention.

CONCLUSION

As of today, holds a large number of studies evaluating the effectiveness of Mildronate® (Meldonium) in the treatment of acute and chronic disorders of cerebral circulation. Their results suggest that the appointment of Mildronate (Meldonium) accelerates and improves the rehabilitation of patients with ischemic stroke and circulatory encephalopathy. Pilot studies also point to the value of the drug at a transient ischemic attacks.

Cumulative to date data requires further confirmation in larger, placebo-controlled international studies.

Mildronate and Multiple Sclerosis

In 2008, led by Professor T. Matveeva (Kazan), work was undertaken to study the possibility of using Mildronate as an antioxidant in complex therapy of different variants of multiple sclerosis (MS). The study included patients with MS (cerebrospinal form) of both sexes, average age 40,2 ± 2,7 years, mean disease duration 7,20 ± 1,58 years.

The treatment regimen consisted of:

- Mildronate 500 mg / day / m (group 1) within 10 days;

- Mildronate (Meldonium) 500 mg / day / m (group 2) for 10 days, 21 days further inwards;

- Mildronate 500 mg / day / m + GCS scheme (Dexamethasone) (group 3) within 10 days;

- Mildronate (Meldonium) 500 mg / day / m + GCS scheme (Dexamethasone) (Group 4) for 10 days, 21 days further inwards;

- Control group - GCS scheme (Dexamethasone) without Mildronats.

As a result of this work was concluded:

1. The value of the degree of disability of MS patients resulting in decreased Mildronate therapy compared with the control group, with Mildronate application regimen / m + Mildronate inside was more effective.

2. A significant reduction in the degree of disability in Mildronate group recorded with relapsing-remitting nature of MS, while the figure swelled in the control group.

3. Application Mildronate reduced the value of the EDSS during the 1st and 2nd stage of MS.

4. it was found that the use of Mildronate (Meldonium) reduces performance in pyramidal, cerebellar and sensory systems In assessing functional for Kurtske systems.

5. Application Mildronate in conjunction with Gluco-cortico-steroids (GCS) for the relief of acute MS reduced the degree of disability of MS patients, with a significantly increased gap between the initial and final degree of disability as compared to a group of corticosteroids without Mildronate.

6. Comparison of treatment regimens Mildronate / m + Mildronate PER os + GCS and Mildronats PER os + GCS revealed that the application form Ampouled Mildronate followed by a continuation of oral administration is more efficient compared with the scheme Mildronate (amp.) + Corticosteroids.

7. Mildronate is more effective with a favorable type of MS, while the degree of disability in unfavorable type has remained virtually unchanged.

8. Mildronate therapy improved quality of life, physical and mental health of people with MS.

9. Mildronate (Meldonium) treatment has an impact on all components of the health of patients.

Mildronate and Acute diseases of the CNS of VARIOUS GENESIS

One of the fundamental studies on the impact of Mildronate on rehabilitation processes (in the early period - up to 6 months) and improvement in the quality of life of neurological patients was the work on assessing the safety and tolerability of the drug in the recovery period after acute CNS disorders of various origins.

In a randomized, double-blind, placebo-controlled study included patients after acute ischemic and hemorrhagic cerebrovascular events after traumatic brain injury and patients with focal forms of tick-borne encephalitis (comorbidities: hypertension, coronary vessels of the heart (including myocardial infarction ) rhythm disturbances or without and signs of heart failure, diabetes mellitus, acute viral and bacterial infections, gynecological and / or urological disorders, intracranial surgery). Exclusion criteria were: severe disorders of consciousness and memory, severe heart, kidney and liver failure, bleeding disorders, signs of venous brain circulation.

The treatment regimen consisted of:

- Mildronate 300 mg 2 times a day orally (Group 1) for 4 weeks (against the background of basic therapy, except nootropics, CNS stimulant drugs and anabolic steroids);

- Mildronate 500 mg 2 times a day orally (Group 2) for 4 weeks (against the background of basic therapy, except nootropics, CNS stimulant drugs and anabolic steroids);

- Mildronate 1000 mg 2 times a day orally (3rd group) for 4 weeks (against the background of basic therapy, except nootropics, CNS stimulant drugs and anabolic steroids);

- The placebo group (Group 4) - only basic therapy.

The results significantly (p <0.05) showed that Mildronate (Meldonium) helps to improve the quality of life in the early period of rehabilitation after acute CNS diseases, which arise as a result of focal lesions of the brain. The improvement seen in the significant increase in physical performance and recovery of functional independence. Mildronate promotes regression of focal brain lesions in patients with symptoms of neurological deficit, is effective in the treatment of chronic heart failure, does not cause serious side effects, is safe. Mildronats recommended to include in the combination therapy of neurological patients, especially in the period of rehabilitation after acute diseases; optimal daily dose - 1000 mg per day.

Mildronate and Long-Term Effects Of Traumatic Brain Injury

Using of Mildronate was evaluated in the AU in the correction of complex long-term effects of cerebral blood flow and brain injuries in 2007.

The treatment regimen consisted of:

- Mildronate (Meldonium) 1000 mg / day orally for 6 weeks, in combination with basic therapy in the treatment of patients with circulatory encephalopathy stage II and post-traumatic encephalopathy.

As a result, the work proved a significant improvement in a number of indicators of life (mobility, self-care, household activities); significant improvement in motor and speech functions; significant improvement in attention, memory, language and numeracy; It found lipolytic and detoxifying action Mildronate.

On the basis of the Republican Scientific and Practical Center of Neurology and Neurosurgery (Minsk) series of works under the direction of professor was held in 2007, In which the open comparative purpose was to study the clinical efficacy antiischemic Mildronate in complex therapy for patients with brain injuries verified II-III type antineoplastic after operations (and supratentorial subtentorial).

The treatment regimen consisted of:

- Mildronate 1000 mg / day in / infusion (Group 1) 7-14 days in the complex therapy;

- Control group - placebo (group 2) in the complex therapy.

As a result of the work normal levels of consciousness and neurologic function (Glasgow Coma Scale and pressure indicators cerebrospinal fluid) was noted earlier as compared to control (in the 6th and 10th day, respectively). Introduction Mildronate contributes to the normalization of intracranial pressure and improve the process of functional recovery of damaged brain. The drug, which has a multi-component anti-hypoxic and anti-oxidant effect, it is advisable to use at different cerebral posthypoxic and endotoxin violations for neuroprotective therapy.

Mildronate and Acute Ischemic Stroke, the period of early rehabilitation

Evaluating the effectiveness of treatment of patients with ischemic stroke Mildronate it was carried out by Professor SM Vinichukom back in 1991 year.

The treatment regimen consisted of:

- Mildronate 500 mg / day intravenously for 10 days, then orally (duration of treatment is 2-3 weeks) jet (Group 1);

- Control group (Group 2) - Cavinton 10 mg, 100 mg of Pentoxifylline.

The results showed that the effect of a course of Mildronate treatment on total cerebral blood flow (OOMK) depended on the initial state of the regional hemodynamics. When brain tissue hypoperfusion and indicators rheoencephalography OOMK amplitude increases, hyperperfusion - decreased. Advancing stabilization tone resistant vessels of the brain, as evidenced by normalization of cerebral peripheral vascular resistance. Positive therapeutic effect Mildronate can be recommended in complex treatment of patients with acute cerebral blood flow by ischemic type. Efficacy of Mildronate on hemodynamics is due not only to a positive inotropic effect on the myocardium, but also the property of the normalization of cerebral vascular reactivity of the microvasculature, which improves cerebral hemodynamics in the post-ischemic brain gipo-perfuzione zone.

The study of clinical efficacy in patients Mildronate lacunar strokes were the spent ZA Suslina et al. in 2005 and a number of the authors, the purpose of which was to evaluate the effect of the drug on the dynamics of neurological deficit, the state of lipid peroxidation and cerebral hypoperfusion.

The treatment regimen consisted of:

- Mildronate 500 mg / day intravenously (Group 1) within 21 days (if necessary - anti-hypertensive and cardiac drugs, but excludes nootropic therapy, psychotropic drugs, antiplatelet agents and anticoagulants).

Results of the study was significantly (p <0.01) showed that treatment with Mildronate a significant proportion of patients with lacunar stroke in the acute phase of the disease there is a positive dynamics of subjective disorders and focal neurological deficits, improved cognitive function, reduction in lipid peroxidation intensity and an increase in activity endogenous antioxidants. Neuropsychological study showed a significant shortening of the execution time of the serial accounts (the study of intellectual activity) and improved memory (reproduction numerical series in reverse order). It was concluded that the inclusion of Mildronate in the course of therapy lacunar stroke, thanks to its antioxidant and neuroprotective properties, is appropriate and pathogenetically justified.

Evaluation of Mildronate application in the treatment of patients with ischemic stroke was conducted by a research team led by Professor GB Kabdrakhmanov (2005). The aim of the study was to investigate the efficacy of Mildronate in complex treatment of patients with ischemic stroke in the carotid or vertebrobasilar basin evaluation, not only the dynamics of neurological status, and level indicators of lipid peroxidation and antioxidant defense system.

The treatment regimen consisted of:

- Mildronate 1000 mg / day intravenously (Group 1) within 10 days against the background of basic therapy;

- Control group (Group 2) - only basic therapy.

The results of the study showed that in the group using Mildronate proved that recovery of neurological deficit in a shorter time with regression cerebral symptoms of vestibular and speech disorders; according to a study of mnemonic functions: a rapid increase in retained material (learning curve); According to laboratory tests showed a significant reduction in lipid peroxidation indices in comparison with the control group. Regression of neurological symptoms, a positive effect on cellular metabolism that underlies one of the most important parts of the pathogenetic mechanisms of acute cerebrovascular events, have shown the feasibility of incorporating Mildronate in combination therapy of neurological patients.

Given that stroke risk factors contribute to more frequent and rapid development of cerebral accident, work was carried out in 2006 (BA Duschanova, Abbasov GA, et al., 2006) to study the efficiency of use of clopidogrel in combination with at Mildronate patients in the recovery period of ischemic stroke.

The treatment regimen consisted of:

- Clopidogrel 75 mg po and Mildronate 1000 mg / day intravenously for 10 days followed by administration of clopidogrel 75 mg and 1000 mg Mildronate orally for 1 year.

The results showed that the rate of combined treatment with clopidogrel and Mildronate (Meldonium) has a stronger influence on the processes of lipid peroxidation and antiradical activity in patients in rehabilitation period of ischemic stroke.

Cognitive impairment and Mildronate

The problem of the relationship with arterial hypertension and cognitive impairment is becoming increasingly important for the following reasons: 1) age of the population increases the number of patients with isolated systolic hypertension (ISAH) and stroke as well as observed age-related cognitive decline, and therefore develop synergies pathological processes, significantly increases the risk of dementia; 2) it is a distinctive feature of the pathogenesis of early and marked reduction in the elasticity of arteries, with increased systolic blood pressure (SBP) creates a favorable background for the development of disorders of vascular genesis; 3) in clinical practice, and a combination ISAH cognitive impairment is common (incidence of dementia of 1: 1000 at age 40-65 years, 1: 20, 70-80 years, 1: 5 - 80 years of age), as the proportion of the population increases elderly and very elderly.

Mild cognitive impairment of vascular genesis many authors considered as prognostically unfavorable, since mortality in this group of patients is 2.4 times higher than that of persons of the age group in the population. Interesting data G. Frisoni et al. (2006) that during the observation period of 32 ± 8 months of death due to various causes occurred in 30% of patients with vascular mild cognitive impairment and vascular dementia, while during this period did not die of any one patient among patients with mild cognitive impairment primary degenerative genesis. Even more impressive results were obtained by observing the duration of 40 months, when during this period 50% of patients died with vascular mild cognitive impairment and vascular dementia. Thus, the problem of cognitive impairment in hypertensive patients is multidisciplinary in its decision involved not only neurologists and cardiologists and internists. Given these facts, it is appropriate and important in clinical practice to evaluate the effectiveness and to develop optimal treatment of these patients. In this regard, a group of researchers (Statsenko ME, et al., 2005) conducted a study which assessed the impact of the exchange rate and constant Mildronate therapy patients with cognitive impairment on the background of arterial hypertension in the elderly. In an open, randomized, placebo-controlled comparative study in parallel groups included 180 elderly patients with cognitive impairment to hypertension, which were divided into 3 groups at a ratio of 1: 1: 1 (Mildronate DC / Mildronat ESP / control (placebo). to assess cognitive impairment in the course of medical treatment, all patients were neuropsychological testing to identify and assess cognitive disorders, namely:. impaired memory, attention, concentration, mental performance and psychomotor functions to do this the following tests were used: the MMSE test Reitan test, test . Robert Wexler test for speech activity, memory (10 words) and serial account, the kinetic test, scale MFI-20 (for the assessment of fatigue severity) to assess depression severity was used Beck depression Inventory, and anxiety -. Taylor was received credible as a result of (p <0.01) improvement in MMSE index by 9.2% in the continuous therapy group Mildronate (against 0.4% - course therapy Mildronate and 2.3% in the control group). Improving indicators and Wechsler test Reitan in the continuous therapy group and the course of therapy Mildronate was respectively 16.6; 11.2 and 18.1; 7.5 and 5.5% versus 3.9% in the control group. Continuous therapy and course Mildronate almost equally reduced the severity of fatigue (respectively 10.5 and 10.6% vs. 2.2% in the control group). Improving performance on a scale of depression and anxiety scale in the continuous therapy group and the course of therapy Mildronate was respectively 15.6; 9.8 and 12.2%; 5.7% versus 1.3, 0.3% in the control group. It was concluded that continuous therapy Mildronate was the only mode of therapy, which significantly improved all parameters of cognitive function compared to baseline and to the control group.

First, you need to pay attention to the fact that the majority of patients with hypertension and cognitive impairment is a combination of vascular and neurodegenerative processes. If proven positive effect of long-term antihypertensive therapy on cognitive function in patients with arterial hypertension, for example, the elderly additional appointment Mildronate capable of an even greater extent to ensure their safety. Identified the main mechanisms through which is realized the positive effect of the drug on cognitive function: the activation of the central nervous system; stimulation of physical performance; regression of symptoms of neurological deficit; the trend towards normalization of cerebral circulation; redistribution of blood flow in favor oligemicheskoy zone; increase local blood flow; normalization of bioelectric activity of the brain; pronounced antioxidant effect.

The treatment regimen consisted of:

- Mildronate 500 mg / day orally (Group 1) continuously for 52 weeks;

- Mildronate 500 mg / day orally (group 2) in a course of therapy for 52 weeks.

As a result of this work it proved that continuous Mildronate therapy at a dose of 500 mg daily for 52 weeks significantly improves cognitive function in patients with hypertension and cognitive impairment; Mildronate course therapy is less effective than its continuous reception; continuous and course Mildronate therapy have expressed anti-astenic and antidepressant effects on the elderly patients with hypertension and cognitive impairment.

In another study conducted by IV Damulin et al. in 2006 on the effect of Mildronate on motor and cognitive function in elderly patients with chronic cerebrovascular insufficiency, also used Mildronate.

The treatment regimen consisted of:

- Mildronate 500 mg / day orally (Group 1) for 3 months;

- Meldonium 500 mg / day orally (group 2) in techenie1,5 month, then 1.5 months of 1000 mg / day inside.

It is important to note that the patients did not receive other metabolic, nootropic and vascular therapy, in addition to the previously chosen treatment with antihypertensive drugs, and antiplatelet agents. As a result, the work was revealed significant improvement in motor (sustainability and walk) and cognitive (memory and attention) functions, as well as parameters P300 KVP (p <0.05). A more significant benefit of increasing the dose Mildronate to 1000 mg / day was achieved in patients with ischemic stroke in history.

Mildronate and Chronic Brain Ischemia, burdened by diabetes mellitus

The defeat of the brain as a target organ for hypertension and diabetes mellitus (DM) is a serious medical and social problem. In the assessment of cognitive functions and features of the autonomic regulation of the heart rhythm in patients with hypertension orthostatic disturbances on the background of diabetes type 1 the feasibility of a comprehensive drug correction has been proven.

It is shown that combination therapy with Enalapril and Mildronate improves cognitive function, promotes the regression of clinical symptoms, normalize the emotional status. Mildronate has no effect on hemodynamic parameters, it is not conducive to a reduction of orthostatic insufficiency and does not change the heart rate variability). Mildronate effect evaluated on the dynamics of clinical status, parameters of lipid peroxidation and psychometric parameters in patients with chronic brain ischemia patients (HIM) in the presence of concomitant type 2 diabetes for more than 5 years.

The treatment regimen consisted of:

- Mildronate 500 mg / day intravenously for 21 days (as background therapy, all patients received hypoglycemic agents from the group of the sulfonylureas or biguanides, administered antihypertensives and other cardiovascular drugs if necessary).

As a result of the work, according to the assessment of the severity of the clinical syndrome, showed a significant improvement in the form of easing symptoms such as headache, dizziness, fatigue, sleep disturbance, and emotional lability. Dynamics of LPO processes: a significant decrease in the maximum intensity of lipid peroxidation, which indicates a decrease in the ability of lipoprotein oxidation structures; decrease in blood glucose levels more than 1.2 times. Thus, the addition of Mildronate (500 mg / day) to the basal glucose lowering therapy resulted in an increase of serum lipoprotein peroxidation resistance. Hypoglycemic ability of Mildronate possible to reduce the dose of antidiabetic drugs in patients with HIM, aggravated diabetes.

Other work on the use of Mildronate (Meldnium) to patients with diabetes was held in Perm State Medical Academy, which evaluated the effect of the drug in patients with diabetes type 1 in hypertension, for a chronic cerebrovascular accident combined with orthostatic disorders.

The treatment regimen consisted of:

- Mildronate 500 mg / day intravenously for 10 days, then orally for 2 weeks (as background therapy, all patients were treated with insulin and intensify antihypertensive therapy (Enalapril / Indapamide + Enalapril)).

The study showed good tolerability Mildronate (Meldonium) and its high efficacy in the treatment of this pathology. The drug has a mild stimulating effect on the cognitive functions, reduces anxiety, and emotional lability, promotes regression of clinical symptoms.

Mildronate and chronic brain ischemia

A key element of hypoxic brain injury is ischemic or glutamate cascade that many researchers consider the trigger excitotoxic damage, and the main cause of neuronal death.

Glutamate is an excitatory neurotransmitter and is found in most neurons of the brain. Under normal conditions, neurons and glia cells absorb excess glutamate from the extracellular space. In ischemic conditions, violation of energy-dependent processes reuptake of glutamate leads to its accumulation in the extracellular space. Develops a cascade of metabolic disorders, among which the leading role played by the processes of free radical oxidation of proteins, nucleic acids and lipids, responsible for direct damage to neurons and lead to the launching mechanism of apoptosis.

The importance of oxidative stress in the pathogenesis of vascular diseases of the brain determines the feasibility of using antioxidants as drugs. Mildronate has cyto-protective and immunoregulatory properties, so is widely used in treatment of ischemic stroke in the treatment of chronic cerebrovascular disease. Mildronate increases the effectiveness of treatment cephalgic syndrome vestibulopathy, improves physical and mental performance in patients with chronic brain ischemia, improves the condition of higher mental functions. The results of clinical studies of the effectiveness of the drug Mildronate with chronic cerebrovascular insufficiency.

The treatment regimen consisted of:

- 10% Mildronate solution intravenously with 5 ml (1 group) daily for 10 days, then orally for 20 days (during treatment – vaso-active inotropic agents, anti-hypertensives, vitamin therapy, magnetic therapy, aeronoterapiya, hydrotherapy, massage );

- Only vasoactive and nootropic drugs, antihypertensives, vitamin therapy, magnetic therapy, aeronoterapiyu, hydrotherapy, massage (Group 2 - control group).

The results showed a significant (p <0.01) the feasibility of introducing Mildronate in the therapeutic range for chronic cerebrovascular diseases.

The use Mildronate in the treatment of patients with circulatory encephalopathy in the background stenotic lesion cerebral arteries studied the effectiveness of Mildronate in treatment.

The treatment regimen consisted of:

- Mildronate 1000 mg / day, intravenously for 10 days, then 20 days orally.

As a result of this work was a statistically significant decrease in the severity of symptoms associated with damage to the cerebral hemispheres - pyramidal symptoms, aphasic disorders, as well as the subcortical symptoms, severity vestibulopathy. There was a statistically significant positive changes in the dynamics of indicators of operational, visual and motor memory. When receiving Mildronate decreases the severity of neurological symptoms, optimized performance of the brain electrical activity, there are positive developments in the state of cerebral hemodynamics.

In 2004, the work was carried out to assess the state of higher brain functions in patients with circulatory encephalopathy in the Mildronate treatment: open non-randomized comparative study on the effect of Mildronate on neuropsychological function and cerebral blood-treatment in patients with stage II DE atherosclerotic.

The treatment regimen consisted of:

- Mildronate 1000 mg / day (500 mg IV in the first half of the day + 500 mg orally in the second half of the day) for 10 days.

As a result of the work done by ultrasound duplex scanning and a significant increase in the average maximum blood flow velocity was obtained at the front (left and right) cerebral artery, as well as the maximum blood flow velocity in the middle cerebral artery, right; there was a significant decrease in headache, dizziness, cerebellar-vestibular disorders, sleep disorders. Using Mildronate contributed to the improvement of higher brain functions (memory, attention), decrease exhaustion and improve the mobility of the nervous processes.