Method of treating metabolic syndrome with using dopamine receptor agonists

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmacology. A method of treating of at least one vascular disease in a patient involving a stage of introduction into the patient suffering at least one vascular disease or manifesting its biomarkers of a therapeutically effective amount of a central dopamine agonist with said central dopamine agonist is effective for treating said at least one vascular disease in said patient; wherein said dopamine agonist is introduced so that the peak plasma concentration of the dopamine agonist is reached between 04:00 and 12:00 o'clock, while blood bioavailability of said dopamine agonist is reduced within approximately 50% of the peak plasma concentration approximately 2 to 6 hours after termination of a day peak or the steady-state plasma concentration of the dopamine agonist. According to one version of implementation, the central dopamine agonist represents bromocriptine optionally combined with a pharmaceutically acceptable carrier.

EFFECT: invention provides higher clinical effectiveness.

9 cl, 10 ex, 12 dwg

 

The level of technology

The technical field to which the invention relates

The present invention relates to methods for treating metabolic disorders and more specifically to methods for treating metabolic syndrome, its mixed variants manifestations of individual biochemical abnormalities associated with the risk of metabolic disorders, or metabolic syndrome, such as vascular inflammation and endothelial dysfunction, which leads to a predisposition of developing cardiovascular disease, peripheral vascular disease or cerebrovascular disease, and treatment of these diseases of the blood vessels by administration of a dopamine agonist with Central action, such as parlodel.

Description of the prior art

Metabolism is a complex ensemble of biochemical processes that occur between cells and tissues of the body, working together, ensuring the viability of the organism as a whole. The Central nervous system plays a major role in bringing this metabolic activity to maintain normal biological homeostasis of the organism. Caused by environmental or genetic causes of disorders of metabolism control from the Central nervous system can manifest as a variety of meta is omicheskikh violations. In addition, because the metabolic processes have strong effects on the whole organism, diseases and disorders affecting the metabolism, usually also affect other systems of the body. For example, individuals suffering from type 2 diabetes, there are violations of multiple organs and body systems. Usually when type 2 diabetes glucose levels in plasma increased in the resistance of a body to decrease the level of glucose the effects of a hormone called insulin, as well as a reduced ability to secrete appropriate amounts of insulin after a meal. Type 2 diabetes is associated with damage to different organs such as the eyes, nerves and kidneys. The disease is also associated with a significantly increased risk of cardiovascular disease (CVD), the leading cause of death in patients with type 2 diabetes. The spread of type 2 diabetes has reached epidemic dimensions in the United States and around the world.

In accordance with the guidelines of the American society for diabetes diagnosis of type 2 diabetes, the individual should have a fasting level of plasma glucose greater than or equal to 126 mg/DL or oral 2-hour test glucose tolerance (OGTT) the amount of glucose in the plasma is higher or equal to 200 mg/DL (Diabetes Care, 26: S5-S20, 2003). A related condition called prediabetes, determined is expressed as condition, when fasting glucose levels above or equal to 100 mg/DL but less than 126 mg/DL or 2-hour OGTT test the level of plasma glucose above 140 mg/DL but less than 200 mg/DL. Established evidence suggests that the condition of prediabetes may be a risk factor for development of cardiovascular disease (Diabetes Care 26:2910-2914, 2003).

Metabolic syndrome (MS), also denoted as syndrome X, is another metabolic disorder that affects other ways and systems of the body. Originally metabolic syndrome was defined as a set of metabolic disorders (including obesity, insulin resistance, hypertension and dyslipidemia, especially hypertriglyceridemia), which synergistically enhance cardio-vascular disease. Later (2001) national education program of the U.S. cholesterol (NCEP) has classified the metabolic syndrome as the occurrence of any three of the following five criteria: fasting glucose of at least 110 mg/DL, triglyceride levels in the plasma of at least 150 mg/DL (hypertriglyceridemia), HDL cholesterol below 40 mg/DL in men or below 50 mg/DL in women, blood pressure of at least 130/85 mm Hg (hypertension) and Central obesity, and Central obesity is defined as waist circumference on the abdomen above 101.6 cm for men and above 88,9 SMDS women. Currently, there are three other internationally recognized definitions of the metabolic syndrome from the following organizations: 1) the world health organization, 2) the American heart Association and national Institute of heart, lung, and blood (AHA/NHLBI) and (3) the international diabetes Federation (IDF). Definition of the metabolic syndrome who, AHA/NHLBI and IDF is very similar to the definition of the NECP, and all use the same metabolic parameters to define the syndrome, but who also includes assessing the levels of fasting insulin (Moebus S, et al., Cardiovascular Diabetology, 6: 1-10, 2007; Athyros VG, et al., Int. J. Cardiology, 117: 204-210, 2007). Still noticeable differences in the thresholds data metabolic parameters among these different definitions required for classification as having this syndrome can lead to different classification of a particular individual as having or not having the syndrome in accordance with these different definitions. In addition, the prevalence of cardiovascular disease (CVD) in MS vary depending on the definitions used (Moebus S, et al., Cardiovascular Diabetology, 6: 1-10, 2007; Athyros VG, et al., Int. J. Cardiology, 1 17: 204-210, 2007). Especially none of these widely used definitions of the MS ignores the Pro-inflammatory condition of the blood vessels, procoagulant state, prooxidant state or dysfunction of the endothelium when Oprah is the bookmark syndrome. However, these nametables biochemical disorders are often associated with MS. Later MS together with the pathophysiology of the blood vessels (described just above) was named by the term metabolic risk. The American diabetes Association determined that 1 out of every 5 people who are overweight suffer from metabolic syndrome.

Although these disorders, and diseases are related, it is clear that they are individual and different pathogenesis. For this reason, the drugs used to treat the same disorders (such as type 2 diabetes), may not be effective against other disturbance (namely the metabolic syndrome). For example, drugs that are effective in the treatment of type 2 diabetes or prediabetes, do not possess or have low effect on the effectiveness and safety in the metabolic syndrome. In addition, certain drugs used in the treatment of type 2 diabetes or prediabetes, can increase blood pressure (hypertension) or increase body mass in individuals taking these medications. For example, preparations of thiazolidinediones, used in the treatment of type 2 diabetes, causes growth of the body mass and have critical effects against hypertension. The other antidiabetic agent Metformin, also has critical effects in which the compared hypertension and hypertriglyceridemia. Insulin which is a hormone used to treat type 2 diabetes may exacerbate hypertension and increased body weight. Moreover, antihypertensive drugs do not necessarily treat dyslipidemia or obesity and many can worsen insulin sensitivity instead of improve it. Therefore, the conclusion that if the drug is effective as antidiabetic agents, it should be effective for the treatment of metabolic and/or nametables pathology, is not inevitable. As people with metabolic syndrome do not suffer from disease, and have biology which foreshadows the impending disease, safety criteria are also significantly higher when considering pharmacological tools for the treatment of this syndrome.

Because metabolic syndrome is diagnosed as having multiple criteria (as described above), he also covers vascular anomalies, such as endothelial dysfunction, Pro-inflammatory condition of blood vessels and procoagulant state of the vessels, the treatment of the metabolic syndrome according to the present invention further includes

a. Treatment of endothelial dysfunction associated with cardiovascular disease;

b. Treatment of hypertension, inflammatory condition of the blood vessels and so coagulants state vessels simultaneously. Examples of markers of blood for Pro-inflammatory condition include, but are not limited to: C-reactive protein, serum amyloid protein A, interleukin-6, interleukin-1, tumor necrosis factor-Alfa, homocysteine, and the number of leukocytes. Examples of markers of blood for procoagulant condition include, but are not limited to: endothelin-1, viscosity, hematocrit, erythrocyte aggregation, inhibitor-1 plasminogen activator, fibrinogen, factor von Willebrand's disease, factor VII, factor VIII and factor IX;

c. Treating at least two of hypertension, inflammatory condition of the blood vessels or procoagulant state at the same time; and

d. Treating at least one of hypertension, inflammatory condition of the blood vessels or procoagulant state.

The endothelium can modify circulating factors, as well as to synthesize and secrete factors that affect the cardiovascular system in health and disease. Endothelial dysfunction is characterized by changes in the modulation of the endothelium of the vascular network that facilitate or potentiate vasoconstriction, procoagulant state and/or Pro-inflammatory state, as well as other biochemical processes that all contribute to the initiation and progression of atherosclerosis (Am. J. Cardiol. 91(12A): 3H-11H, 2003; Am. J Cardiol. 115 Suppl 8A:99S-106S, 203) or arteriosclerosis (Nigam A, et al., Am. J. Cardiol. 92: 395-399, 2003; Cohn JN et al., Hypertension 46:217 to 220, 2005; Gilani M, et al., J. Am. Soc. Hypertens 2007) depending on the involved biochemical processes.

Various types of treatment are available for diseases associated with obesity, including type 2 diabetes. For example, U.S. patent No. 6506799 discloses methods for the treatment of cardiovascular disease, dyslipidemia, dyslipoproteinemia and hypertension, including the introduction of a composition comprising the ester compound. U.S. patent No. 6441036 reveals similar fatty acids, which can be used for the treatment and/or prevention of obesity, fatty infiltration of the liver and hypertension.

U.S. patent No. 6410339 discloses the use of agonist of cortisol to obtain a system for the diagnosis of metabolic syndrome and related conditions such as abdominal obesity, insulin resistance, including an increased risk of developing senile diabetes, i.e. of type II diabetes, high blood fat and high blood pressure, in this system, the dose of agonist cortisol is the interval at which the gain difference in the inhibitory effect produced by the body cortisol levels in individuals suffering from metabolic syndrome compared with normal values.

U.S. patent No. 6376464 discloses peptides and peptide analogs that mimic the structural and pharmacological properties of AP is A-1 person. Peptides and peptide analogs are used to treat a variety of disorders associated with dyslipidemia.

U.S. patent No.6322976 discloses, inter alia, methods for diagnosing diseases associated with defects in insulin action, glucose metabolism, fatty acid metabolism and/or action of catecholamines, by identifying mutations in the gene CD36.

U.S. patent No. 6197765 discloses the treatment of metabolic syndrome (syndrome X) and the resulting complications with the introduction of diazoxide.

U.S. patent No. 6166017 discloses a method of medical treatment of diabetes mellitus type II and countering the risk factors form part of the metabolic syndrome by administration of ketoconazole.

U.S. patent No. 6040292 discloses methods of treatment of diabetes, including type I, type II diabetes with insulin-resistance (both type I and type II). In the methods of the invention applies the introduction of complex rhIGF-I/IGFBP-3 to the individual suffering from the symptoms of diabetes. The introduction of rhIGF-I/IGFBP-3 to the individual suffering from the symptoms of diabetes, leads to relief or stabilization of symptoms of diabetes.

U.S. patent No. 5877183 reveals how the regulation and modification of the metabolism of fats and glucose, but not metabolic syndrome, by introducing individual D1 dopamine agonist, optionally in combination with D2 agony is that dopamine, alpha-1-adrenergic antagonist, alpha-2-adrenergic agonist or inhibitor of serotonin, or optionally in combination with D2 dopamine agonist, administered together with at least one of alpha-1-adrenergic antagonist, alpha-2-adrenergic agonist or inhibitor of serotonin and additional introduction of individual agonists 5HT1b. It is well known that the dopamine agonist are both activating and inactivating dopamine receptors, and thereby reduces dopaminergic neuronal activity.

U.S. patent No. 5741503 reveals the methods of regulating or improving lipid metabolism, which include the introduction or introduction at a certain time of day inhibitors beta-hydroxylase dopamine (DBH). However, this method is aimed only at reducing noradrenergic neuronal activity and does not increase dopaminergic neuronal activity, since DBH is not present in dopaminergic neurons, which are anatomically different from noradrenergic neurons, which is DBH.

In addition, several U.S. patents disclose the use of dopamine agonists such as parlodel, for use in the treatment of pathologies related to type II diabetes. See, for example, U.S. patent Nos. 6004972; 5866584; 5756513 and 5468755. Parlodel is also used for treatment of diabetes t is PA 2 or insulin resistance (Pijl H, et al. Diabetes Care, 23:1154, 2000; Meier AH et al., Diabetes Reviews, 4: 464, 1996).

A significant outcome of the complications in the treatment of metabolic disorders is that individual pathological conditions in the metabolic syndrome differ by their nature and significance, present or alone, or as part of this syndrome, so pathological conditions with this syndrome tend to have a synergistic effect, causing an increased risk of morbidity and mortality (Reviewed in GM Reaven, Diabetes, Obesity, and Metabolism, 4: (Suppl. 1) S13-S-18, 2002). In other words, the individual with metabolic syndrome have an excellent increased risk of cardiovascular disease as a result of his/her hypertension than is an individual with hypertension without metabolic syndrome. Currently, the Department for quality control of food products and medicines of the USA has not approved the use of any medication for the treatment of metabolic syndrome. The present definition of the metabolic syndrome NCEP and other definitions as described above, related to metabolic disorders and do not include aspects nametables biochemical abnormalities associated with the syndrome, such as procoagulant state, Pro-inflammatory state, a Pro-oxidant state or endothelial dysfunction. However, these namataba the practical biochemical disorders significantly contribute to cardiovascular disease through mechanisms, that may not necessarily involved in the deposition of lipids and the accompanying consequences in the form of plaque formation in an intim and internal media of the vascular walls (i.e. atherosclerosis). On the contrary, these nametables biochemical abnormalities may increase the process that leads to another type of damage to blood vessels, called arteriosclerosis (defined as thickening and increased arterial stiffness), which can have devastating effects on the health of blood vessels and increase vascular disorders, such as damage to large vessels, myocardial infarction, stroke and peripheral vascular disease (Safar ME Frohlich ED (eds) Atherosclerosis, Large Arteries and Cardiovascular Risk. McEniery CM, et al., Adv. Cardiol. Basel, Karger, vol. 44, pp. 160-172; Laurent S, et al., Eur. Heart J., 27: 2588-2605, 2006). These nametables biochemical pathology cause the predisposition of the individual to the increased rigidity of the vascular wall by changing the biochemical structure and architecture of the cell wall layers (i.e. extracellular matrix components such as collagen and elastin and so on) and by modifying contractility of its smooth muscle cells (Safar ME Frohlich ED (eds) Atherosclerosis, Large Arteries and Cardiovascular Risk. McEniery CM, et al., Adv. Cardiol. Basel, Karger, vol. 44, pp. 160 - 172). Such changes can cause damage to blood vessels, often in a much shorter time span than those metabolic is arsenia in the metabolic syndrome, which cause susceptibility to atherosclerosis. Moreover, these nametables violations can be complementary metabolic disorders, defined as the metabolic syndrome, aggravation of cardiovascular disease. And arteriosclerosis can cause a predisposition of an individual to atherosclerosis. Since arteriosclerosis is often precedes and enhances atherosclerosis, the ability to successfully treat arteriosclerosis or biochemical events leading to arteriosclerosis, enables medical intervention at an earlier time period in the chronology of CVD and to provide a better clinical outcome for the patient for a long time.

The mechanisms involved in nametables biochemical disorders in Pro-inflammatory condition of blood vessels, prooxidant state, procoagulant state and endothelial dysfunction, accelerating atherosclerosis and CVD, are extremely complex and very detailed in the reviews Nigam A, et al., Am. J. Cardiol. 92: 395-399, 2003; Cohn JN et al., Hypertension 46:217 to 220, 2005; and Gilani M, et al., J. Am. Soc. Hypertens 2007.

In previous studies described the use of a dopamine agonist, bromocriptine for the treatment of individual variants pathology of insulin resistance, hypertension, hypertriglyceridemia individually, but not in the composition, and also for the treatment of lipid nl the NIS with atherosclerosis (Meier AH et al., Diabetes Reviews, 4: 464, 1996; U.S. patent #s 5006526 and 5565454). However, as is known to applicants, there is no available literature that describes the applicability of bromocriptine or dopamine agonists for the simultaneous treatment of metabolic disorders MS and nematoblastic violations associated with MS, or for the simultaneous treatment of several nematoblastic violations associated with MS, or for the treatment of arteriosclerosis (as opposed to atherosclerosis) or to reduce existing adverse cardiovascular events such as myocardial infarction, stroke, angina or peripheral vascular disease (or the time to develop these adverse effects). Moreover, although the introduction at a certain time of day for any improvements to metabolic changes, such as diabetes type 2 and insulin resistance, as described (U.S. patent Nos. 6004972; 5866584; 5756513 and 5468755), the introduction of circadian synchronization for maximum effect of treatment with dopamine agonists when nametables biochemical activity that causes a predisposition to atherosclerosis and CVD, which are entirely different from those metabolic influences that previously described in the literature, is not defined. In fact, the available literature shows that treatment with dopamine agonists such as parlodel, associated with improving the adverse cardiovascular events, such as myocardial infarction, stroke and cerebrovascular complication (Ruch A et al., Obstet Gynecol 74: 448-451, 1989; Iffy L, et al., Med Law 15: 127-134, 1996; Katz M et al., Obstet Gynecol 66: 822-824, 1985; Iffy et al., Am J Ther 5: 111-115, 1998; Ddutt S et al., Aust N Z J Obstet Gynaecol 38: 1 16-117, 1998). In fact, the ability of dopamine agonists such as parlodel, to increase these adverse cardiovascular events was serious enough to put the management under the control over quality of food products and medicines of the USA on the labels for these pharmaceutical dopamine agonists warning, saying that their intake is associated with increased risk of hypertension, stroke, cerebrovascular complications and myocardial infarction (Physicians Desk Reference, leaflet in the packaging of parlodel). Absolutely the opposite of that described the relationship between increased exposure to a dopamine agonist and increased vascular diseases, the present invention demonstrates that, if the treatment with a dopamine agonist in a suitable dosage and at the right time of day so that its levels are not exceeded during the main part of the day, but limited to discrete diurnal period of the day, which is close to the natural diurnal circadian peak of dopaminergic activity in the Central nervous system in healthy individuals without any vascular diseases or above the established levels or metabolic nematoblastic biomarkers of vascular disease, and the agonist is given to an individual in need of treatment of cardiovascular disease, then treatment with a dopamine agonist in fact weakens vascular disease and adverse vascular events, rather than strengthens them. Such a method at a certain time of day of a dopamine agonist of the present invention to improve biomarkers of arteriosclerosis, atherosclerosis and CVD events is also done at this time of day, in order to reduce the excessive increase in Central noradrenergic tone that enhances these vascular disorders. And these favorable vascular effects of treatment with a dopamine agonist in certain times of the day are not the result of influences significantly reduced hyperglycemia, the levels of plasma triglycerides or blood pressure (see examples below).

The vascular endothelium is a dynamic tissue that responds to the humoral environment in which he shipped to influence the architectonics of the vessels and the contractile tone of blood vessels. Endothelial dysfunction can be defined as a biochemical condition in which the endothelium enhances vasoconstriction, inflammation of the layers of the intima and media of the vascular wall and the physical restructuring of the extracellular matrix of the vascular wall to potentiation thickening and stiffness of the wall. Among the humoral fact the ditch, known as biochemical stimulating the endothelial dysfunction, increased Pro-inflammatory factors, such as chemoattractant protein-1 monocytes (MCP-1), tumor necrosis factor alpha (TNF), interleukin-6 (IL-6) and C-reactive protein (CRP), stimulates in all cases, changes of the endothelium, which facilitates inflammation of the vascular wall, which, in turn, increases the rigidity of the vascular wall. Moreover, the reduction of plasma adiponectin, an anti-inflammatory factor of the vascular wall also facilitates endothelial dysfunction and inflammation of the endothelium, thereby potentsiruya rigidity of the vascular wall (i.e. atherosclerosis). Inflammation of blood vessels associated with the stiffness of the arteries and strengthens it (Yasmin MC et al., Arterioscler. Thromb. Vase. Biol. 24: 969-974, 2004; Duprez DA, et al., J. Hum. Hypertens. 19: 515-519, 2005; Booth A, et al., Arthritis Rheum. 50: 581-588, 2004).

Oxidative stress vessels may also contribute to the rigidity of the vascular wall. The increase in oxidative stress, which is called reactive oxygen species (ROS), may remove the nitric oxide, a strong stimulus for endothelial vasodilation and normal endothelial function. Reduced availability of vascular nitric oxide (NO) may enhance the rigidity of the walls of arteries, and revealed a direct correlation between the stiffness of arteries and endothelial dysfunction in the coronary vein and the peripheral circulation (Wilkinson IB, et al., irculation 105: 213 - 217, 2002; Schmitt M, et al., Hypertension 46: 227-231, 2005; Ichigi Y et al., J. Am. Coll. Cardiol. 45: 1461-1466, 2005; Ceravolo R, et al., J. Am. Coll. Cardiol. 41: 1753-1758, 2003). Endothelial dysfunction and reduced NO availability can occur due to a too low activity of NO-synthase or the hyperactive, but "unpaired" activity of NO-synthase. Paradoxically, the expression of NO synthase may be increased in conditions of endothelial dysfunction and vascular disease. The result is increased unpaired activity of NO-synthase vessels enzyme functions, producing elevated ROS and nitration tyrosine residues of proteins in the vascular wall, reducing at the same time, the number of available NO that collaboration enhances atherosclerosis of vessels (Upmacis RK et al., Am. J. Physiol. 293: H2878-2887, 2007; Ginnan R et al., Free It. Biol. Med., Jan 22, 2008; Landmesser et al., J. Clin. Invest., 111: 1201-1209, 2003; Munzel T, et al., Arterioscler. Thromb. Vase. Biol., 25: 1551-1557, 2005). In addition to its effect on inflammation described above adipokines (increased TNF and MCP-1 and decreased adiponectin and increased CRP may also increase the increase of ROS and nitration of proteins through changes of endothelial function and NO-synthase (Rong L, et al., Am. J. Physiol. 293: E1703-E1708, 2007; De Keulenger GW et al., Biochem. J. 329: 653-657, 1998). The increase of NO-synthase vascular endothelial (eNOS) (Kagota S, et al., Life Sciences 78: 1187-1196, 2006) and inducible NO synthase (iNOS) are observed in old rats SHR, which have increased stiffness of the arteries (Safar ME, In: Swales JD ed., Textbook of Hypertesion, London UK: Blackwell Scientific; 1994:85-102). In the case of high "unpaired" activity of NO-synthase unpaired NO-synthase actually produces higher local number superoxide by reducing NO production, thereby contributing to arteriosclerosis, and this process is, obviously, particularly increases in diabetes (Alp NJ, et al., J. Clin. Invest. 112: 725-735, 2003) and may contribute to atherosclerosis of diabetes and the subsequent increase in cardiovascular events (MI, stroke, and damage to peripheral vessels) diabetes compared with individuals without diabetes. A key sign of unpaired eNOS is the increase in the level or activity of eNOS with a concomitant decrease in the level or activity of soluble guanylate cyclase in the endothelium, as this enzyme is activated with NO induction favorable effects of NO on vascular network.

Procoagulant condition can also cause the predisposition of an individual to an increase in cardiovascular events. Relatively acute coronary syndrome, acute myocardial infarction and thrombotic stroke, a critical member of their occurrence is the procoagulant state, state, reinforcing the increase of the balance between the formation of blood clots and dissolution of blood clots favorable for the formation of blood clots. In procoagulant state involving many bio is imicheskih factors in the redistribution of body physiology, and increase factors that increase the formation of blood clots and/or inhibit the dissolution of blood clots, can work, not only accelerating acute CVD event, but can also function in facilitating mechanisms involved in atherosclerosis. Endothelin-1 is an example of such a factor. Endothelin-1 is a factor originating from the endothelium, which is significantly procoagulant and which functions also as a strong vasoconstrictor, can enhance the endothelial dysfunction (Halim A, et al., Thromb REs 72: 203-209, 1993; Iwamoto T, et al., Nephron 73: 273-279, 1996) and thereby lead to stiffening of the arteries. In the formation of a bunch of different factors, such as activated platelet inhibitor-1 plasminogen activator and fibrinogen, act synergistically, changing the endothelium and vascular wall in chronic hypercoagulative conditions that may lead to restructuring of the vascular wall, chronic vasoconstriction and arteriosclerosis.

Endothelial dysfunction, as described above, can be defined as a biochemical condition in which the endothelium enhances vasoconstriction, inflammation of the layers of the intima and media of the blood vessel walls and physical restructuring of the extracellular matrix of blood vessels with increased thickness and stiffness of the wall. Essentially dysfunction endotheli is, as defined in the present document makes a strong contribution to atherosclerosis and CVD (Nigam A, et al., Am. J. Cardiol. 92: 395-399, 2003; Cohn JN et al., Hypertension 46:217 to 220, 2005; Gilani M, et al., J. Am. Soc. Hypertens 2007). This distinction is important, because those biochemical abnormalities that affect atherosclerosis in contrast to atherosclerosis, should have a specific beneficial effect on the outcome of CVD. Arteriosclerosis is often an early sign of later CVD events, significantly earlier than become determinable any signs of atherosclerosis (Nigam A, et al., Am. J. Cardiol. 92: 395-399, 2003; Cohn JN et al., Hypertension 46:217 to 220, 2005; Gilani M, et al., J. Am. Soc. Hypertens 2007). Therefore, it may be possible prophylactic treatment of the individual with symptoms of atherosclerosis, such as endothelial dysfunction, Pro-inflammatory state, procoagulant state, or a Pro-oxidant state, all of which are easily evaluated clinically in an attempt to best prevent the development of atherosclerosis or CVD by affecting the problem at the time of the earliest foreshadowing signs. There are several simple tests for the measurement of endothelial dysfunction, Pro-inflammatory condition of the blood vessels, procoagulant state and prooxidant state. There are also a few available tests to assess the presence and degree of arteriosclerosis. It is also true that certain others the many biochemical abnormalities in the endothelium can also cause the predisposition of an individual to atherosclerosis, however, in the case of the present invention and as defined herein, endothelial dysfunction is a factor that enhances atherosclerosis. You should take into account that endothelial dysfunction should be characterized biochemical disorders of the endothelium, including, but not limited to, increased "unpaired" inducible NO synthase, "unpaired" NO-synthase endothelium, increased ROS, increased production of vasoconstrictor factors, such as endothelin-1, and/or the exposure time with them and the increased presence and activity of Pro-inflammatory or procoagulant factors.

Metabolic abnormalities that characterize the metabolic syndrome, as described above, differ in their impact on CVD from nematoblastic violations described above. Statins, drugs that lower total cholesterol synthesis and cholesterol low-density lipoprotein (LDL) by inhibiting the activity of HMG-CoA reductase inhibitor, fibrate, which reduce the levels of triglycerides in the plasma, as shown, reduce plaque in blood vessels and CVD events (Colhoun H, et al., Lancet 364; 685-696, 2004). Demonstrated that antihypertensive drugs reduce CVD events (Sever P, et al., Lancet 361: 1149-1158, 2003). However, cardiovascular disease is still currently the leading cause of disease is in the world and is the leading cause of mortality in individuals with cardiovascular disease in type 2 diabetes. Moreover, the population of patients with this type of diabetes CVD events increased in recent years, despite the availability of statins, fibrates, and antihypertensive drugs (Roglic G, et al., Diabetes Care, 28: 2130-2135, 2005). It is clear that these drugs are not completely effective and requires new ways of preventing CVD and treatment of CVD. In particular, the need for effective treatment of metabolic pathologies of the metabolic syndrome and nematoblastic pathologies associated with metabolic syndrome, for prevention, improvement, reducing the progression or regression of atherosclerosis and CVD. Necessary ways that reduce arteriosclerosis and atherosclerosis and biological amplifiers both of these vascular disorders. Moreover, these methods need individuals with type 2 diabetes. It is assumed that the present invention meets these needs.

Summary of the invention

In one aspect of the present invention is directed to a method of simultaneous treatment of hypertension, hypertriglyceridemia, inflammatory status and insulin resistance associated with metabolic syndrome, the method includes a step of introducing a patient suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for one the belt the treatment of hypertension, hypertriglyceridemia, inflammatory status and insulin resistance.

In another aspect of the present invention is directed to a method of simultaneous treatment of hypertension, hypertriglyceridemia, inflammatory status and insulin resistance associated with metabolic syndrome, the method includes a step of introducing a patient suffering from metabolic syndrome, a therapeutically effective amount of a pharmaceutical composition comprising parlodel and a pharmaceutically acceptable carrier, for simultaneous treatment of hypertension, hypertriglyceridemia, inflammatory status and insulin resistance.

In another aspect of the present invention is directed to a method of simultaneous treatment of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, and insulin resistance associated with metabolic syndrome, the method includes a step of introducing a patient suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for the simultaneous treatment of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, and insulin resistance.

In another aspect of the present invention is directed to a method of simultaneous treatment the Oia hypertension, proinflammatory state, procoagulant state and prooxidant state associated with metabolic syndrome, the method includes a step of introducing a patient suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for the simultaneous treatment of hypertension, proinflammatory state, procoagulant state, prooxidant state and any combination thereof. Prooxidant state is defined as a biochemical condition with increased reactive oxygen species or reactive nitrogen at the tissue level.

In another aspect of the present invention is directed to a method of simultaneous treatment of hypertension, proinflammatory state, and a procoagulant state, and the method includes a step of introducing a patient suffering from hypertension, proinflammatory state, and a procoagulant state, a therapeutically effective amount of a dopamine agonist with Central action for the simultaneous treatment of hypertension, proinflammatory state, procoagulant state, and any combination thereof.

In another aspect of the present invention is directed to a method of treating at least one condition of hypertension, proinflammatory state and procoagulant state or prooxidant the condition, associated with metabolic syndrome, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for treating at least one condition of hypertension, proinflammatory state, procoagulant state and prooxidant state.

In another aspect of the present invention is directed to a method of treating at least two States of hypertension, proinflammatory state, and a procoagulant state, and the method includes a step of introducing a patient suffering from at least one condition of hypertension, proinflammatory state, and a procoagulant state, a therapeutically effective amount of a dopamine agonist with Central action for treating at least one condition of hypertension, proinflammatory state, and a procoagulant state.

In another aspect of the present invention is directed to a method for the treatment of endothelial dysfunction associated with metabolic syndrome, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for the treatment of endothelial dysfunction.

In the other aspect of the present invention is directed to a method of treating endothelial dysfunction, associated with cardiovascular disease, the method includes a step of introducing a patient suffering from endothelial dysfunction, a therapeutically effective amount of a dopamine agonist with Central action for the treatment of endothelial dysfunction.

In another aspect of the present invention is directed to a method of simultaneous treatment of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, insulin-resistance, a Pro-oxidant state and endothelial dysfunction, associated or not associated with metabolic syndrome, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for the simultaneous treatment of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, insulin-resistance, a Pro-oxidant state and endothelial dysfunction.

In another aspect of the present invention is directed to a method of treating at least one of the metabolic disorders, consisting of insulin resistance or hypertriglyceridemia, or hypertension, and at least one of nematoblastic violations, consisting of a proinflammatory state, procoagulant state, Brookside the private state or dysfunction of the endothelium, moreover, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action to ensure at least one of the metabolic disorders, consisting of insulin resistance or hypertriglyceridemia, or hypertension, and at least one of nematoblastic violations, consisting of a proinflammatory state, procoagulant state, prooxidant state or endothelial dysfunction.

In another aspect of the present invention is directed to a method of treating at least one of nematoblastic violations, consisting of Pro-inflammatory condition of the blood vessels, procoagulant state, prooxidant state or endothelial dysfunction, associated or not associated with metabolic syndrome, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action to ensure at least one of nematoblastic violations, consisting of a proinflammatory state, procoagulant state, prooxidant state or endothelial dysfunction.

In another aspect of the present invention is directed to a method of treating, prophylact the key, postponement, delay or slowing of progression of atherosclerosis, the method includes a step of introducing a patient suffering or not suffering from metabolic syndrome, a therapeutically effective amount of a dopamine agonist with Central action for the treatment or prevention of arteriosclerosis.

In another aspect of the present invention is directed to a method of treatment, prevention, delay, delay or slowing of progression of vascular diseases, including cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, angina or peripheral vascular disease, including the state of the patient in need of such treatment, a therapeutically effective amount of a dopamine agonist with Central action to treat this disease. Unexpectedly, it was found that the magnitude of the favorable effect induced by this treatment with a dopamine agonist for vascular disease is very high (see example 3 below) and higher than one would predict from the available information about the effects of dopamine agonists on hyperglycemia or dyslipidemia, or hypertension.

In another aspect the invention relates to aspects of the treatment described above pathologies and disorders, simultaneously with the treatment of type 2 diabetes.

In another aspect of the present from retina directed to method a) simultaneous treatment of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, prooxidant status and insulin resistance, (b) concurrent treatment with three or more conditions of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, prooxidant status and insulin resistance, c) treatment of the metabolic syndrome, (d) simultaneous treatment of type 2 diabetes and metabolic syndrome, (e) simultaneous treatment of type 2 diabetes and one or more States of hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, prooxidant status and insulin resistance, f) treatment of endothelial dysfunction associated with metabolic syndrome, or g) treatment of endothelial dysfunction associated with cardiovascular disease, h) treatment of at least one of nematoblastic violations, consisting of Pro-inflammatory condition of the blood vessels, procoagulant state, prooxidant state or endothelial dysfunction, associated or not associated with metabolic syndrome, i) treating at least one of the metabolic disorders, consisting of insulin resistance or hypertriglyceridemia, or hypertension, and at least one of nematoblastic violations, consisting of prospaltella the state, procoagulant state, prooxidant state or endothelial dysfunction, associated or not associated with metabolic syndrome, j) of treatment, prevention, delay, delay or slowing of progression of arteriosclerosis, k) the treatment, prevention, delay, delay or slowing of progression of vascular diseases, including cardiovascular disease, myocardial infarction, cerebrovascular disease, stroke, angina or peripheral vascular disease, and the method includes a step of introducing the patient a therapeutically effective amount of a dopamine agonist with Central action, such as a pharmaceutical composition, comprising parlodel and a pharmaceutically acceptable carrier in the original predetermined time of day. Moreover, the present invention is directed to a method of treating the above conditions associated with vascular disease, where dopamine agonist with Central action enter thus, in order to induce a peak level of a dopamine agonist in plasma during the discrete period of the day, which is approaching the time of the daily peak hypothalamic dopaminergic activity in healthy mammal of the same species. Moreover, the present invention is directed to a method of treatment of a person with the above conditions, the de dopamine agonist with Central action enter so in order to induce a peak level of a dopamine agonist in plasma during the discrete period of the day from approximately 04:00 until 12:00 hours. The present invention also aims at a method of treatment of a person with the above conditions, where dopamine agonist with Central action enter thus, in order to induce a peak level of a dopamine agonist in plasma during the discrete period of the day from approximately 04:00 until 12:00 hours and then reduce its plasma levels up to approximately 50% of the peak plasma from approximately 2 to 6 hours after the daily peak or plateau level of a dopamine agonist in the plasma.

Defined in the present description, the term "nametables violation" refers to biomarkers of vascular diseases, including, but not limited to, proinflammatory state, procoagulant state, a Pro-oxidant condition or dysfunction of the endothelium. The additional biomarker is defined as a physiological state or a biological object (molecule(s)), with which diagnose or predict an increased risk of a condition associated with vascular disease in the future.

Defined in the present description, the term "treating" includes reducing the rate of progression or increase the time until the selected pathological status is I, and also reduced the need for surgical revascularization in a patient in need of such treatment.

These and other aspects will be described in more like in the following detailed description of the invention.

Brief description of figures

The invention will be more clear when further detailed description will be given in conjunction with the several figures in which:

Figure 1 is a histogram showing the concentration of insulin in plasma in groups of subjects;

Figure 2 is a histogram showing the analysis YOMAR-IR in groups of subjects;

Figure 3 is a histogram showing the concentration of triglycerides in plasma in groups of subjects;

Figure 4 is a histogram showing the pressure of blood plasma in groups of subjects;

Figure 5 is a histogram showing the concentration of CRP in plasma in groups of subjects;

Figure 6 is a histogram showing the concentration of fibrinogen in plasma in groups of subjects;

Figure 7 is a histogram showing an increase in weight per day in groups of subjects;

Figure 8 is a table showing the effects of treatment with bromocriptine on various metabolic parameters relative to placebo;

Figure 9 represent the possessing a different table, demonstrating the effects of treatment with bromocriptine on various metabolic parameters relative to placebo;

Figure 10 is another table showing the effects of treatment on various metabolic parameters bromocriptine relative to placebo;

Figure 11 is another table showing the effects of treatment on various metabolic parameters bromocriptine relative to placebo; and

Figure 12 is a histogram showing changes in blood pressure.

Detailed description

In accordance with this invention proposes a new method of treatment of metabolic syndrome (obesity, insulin resistance, hyperlipidemia and hypertension)associated with MS pathologies, non-metabolic (Pro-inflammatory state, procoagulant state, a Pro-oxidant state and endothelial dysfunction), and treatment of atherosclerosis and cardiovascular disease in individuals with or without type 2 diabetes. The method of treatment according to the invention also encompasses the simultaneous treatment of one or more metabolic disorders MS, including hypertension, hypertriglyceridemia, insulin resistance, and one or more non-metabolic disorders, often associated with MS, including Pro-inflammatory state, a state about what augustii, prooxidant state and endothelial dysfunction, which are not affiliated or associated with metabolic syndrome. The method of treatment according to the invention also covers the treatment of endothelial dysfunction associated with metabolic syndrome or cardiovascular disease. Treatment methods include the introduction in need of such treatment to the mammal a pharmaceutical composition, which simultaneously stimulates increased levels of Central dopaminergic neuronal activity (especially neurons Innervate the hypothalamus, and the hypothalamus and causes a decrease in Central noradrenergic neuronal activity (particularly in the brain stem area, which innervates the hypothalamus, and the hypothalamus). Unexpectedly, it was found that increase dopaminergic neuronal activity in the noradrenergic neuronal activity in the hypothalamus of the Central nervous system improves the condition of metabolic syndrome and/or type 2 diabetes, and hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, prooxidant status, insulin resistance and endothelial dysfunction, associated or not associated with metabolic syndrome. As defined in the present description, "neuronal activity" Rel which relates to the increase or decrease in synaptic neurochemical signal transmission from one neuron to another, influence the action potential. As defined in the present description, the term "Pro-oxidant state" refers to the increase in the oxidative capacity of the components or types of molecules in the blood or tissues.

In one embodiment, the method of the present invention includes an introduction to the individual in need of treatment of metabolic syndrome or type 2 diabetes pharmaceutical composition comprising (1) at least one compound that stimulates the increase in Central dopaminergic neuronal activity in the specified individual, and (2) at least one compound that causes a decrease in Central noradrenergic neuronal activity in the specified individual. In an alternative embodiment, the pharmaceutical composition may include a single connection, which stimulates the increase of the level of the Central dopaminergic neuronal activity, but also causes a reduction in the level of the Central noradrenergic neuronal activity. Also provides for the possibility of use in the pharmaceutical compositions of two, three, four or more such compounds, each of which is able to simultaneously encourage the improvement of Central dopaminergic neuronal activity, and also you shall Ivate the lower level of the Central noradrenergic neuronal activity. In all variants of implementation, however, the ratio of dopaminergic neuronal activity in the noradrenergic neuronal activity in the hypothalamus is reduced.

The increase in Central dopaminergic neuronal activity can be achieved using any mechanism. In preferred embodiments, the implementation of the higher level of the Central dopaminergic neuronal activity is provided by the inclusion in the pharmaceutical composition at least one compound that stimulates the increase in Central dopaminergic neuronal activity. Preferably such compounds include, but are not limited to, inhibitors of reuptake of dopamine, an inhibitor of the presynaptic dopamine Transporter, amplifiers presynaptic release of dopamine agonists postsynaptic dopamine receptors, stimulants of dopamine synthesis and/or catabolism inhibitors of dopamine. Examples of suitable compounds which stimulate the increase of the level of the Central dopaminergic neuronal activity, include, but are not limited to, GBR-12935 (known as l-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine); BDNF (derived neurotrophic factor from the brain), General ((4aR-TRANS)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH-pyrazolo[3,4-g]quinoline); SKF38393 (l-phenyl-7,8-dihydrox the -2,3,4,5-tetrahydro-lH-3 - benzazepine hydrochloride); deprenyl (also known as "selegiline"); apomorphine, pramipexol (sold under the name "mirapex"), GBR-12909 ("vanoxerine", l-2-(bis(4-forfinal)-methoxy)ethyl-4-(3-phenylpropyl)piperazine); and combinations thereof.

Inhibition of noradrenergic neuronal activity can also be achieved by any mechanism. In preferred embodiments, the implementation of the induction of the lower level of the Central noradrenergic activity is achieved by introducing at least one compound that causes a decrease in Central noradrenergic activity. Preferably such compounds include, but are not limited to, compounds that block postsynaptic noradrenergic receptors, inhibitors of the release of noradrenaline, inhibitors of the synthesis of norepinephrine, activators reverse presynaptic capture norepinephrine and activators of catabolism of norepinephrine into the presynaptic ending in the synapse. Examples of suitable compounds that reduce the level of Central noradrenergic activity, include, but are not limited to, prazosin (l-(4-amino-6,7-dimethoxy-2-hintline)-4-(2-fornicator)piperidin): propranolol (l-(isopropylamino)-3-(l-naphthyloxy)-2-propanol); clonidine (2-(2,6-dichloroaniline)-2-imidazolin); futurenow acid (5-butyl-2 - piridinkarbonovaya sour is a; 5-butalbitalbuy acid); dopamine; phenoxybenzamine; phentolamine, (3-[[(4,5-dihydro-lH-imidazol-2-yl)methyl](4-were)amino]phenol; 2-[N-(m-hydroxyphenyl-p-toluidine)imidazolin); capatin (sold under the trademark "TENEX"); and combinations thereof.

As noted above, the method of the invention may also include the introduction of a pharmaceutical composition, which includes a single or a separate connection, which simultaneously stimulates increased levels of Central dopaminergic neuronal activity and causes a decrease in the level of the Central noradrenergic neuronal activity. Examples of such compounds include modifiers of catecholamines, such as dopamine. This category can be classified as agonists of D2 receptor dopamine, because they stimulate postsynaptic D2 dopamine receptors and inhibit the presynaptic release of norepinephrine. However, the agonists of D2 receptor dopamine may need to be subjected to data demonstrate that differently modulated (reduced dopaminergic function) partly due to the binding of the D2 agonist with presynaptic sites D2 receptor dopamine in dopaminergic neurons, thus reducing the release of dopamine.

Compounds of the invention are preferably administered internally, for example, oral, subcutaneous, transdermal, sublingual, through the mucous and the and intravenous, in the form of conventional pharmaceutical compositions, e.g. conventional enteral or parenteral pharmaceutically acceptable fillers, containing organic and/or inorganic inert carriers, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, alcohol, vaseline or the like. The pharmaceutical compositions can be in conventional solid forms such as tablets, pills, suppositories, capsules or the like, or a conventional liquid forms such as suspensions, emulsions or the like. If desired, they may be sterilized and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizing agents, moistening agents, emulsifying agents, buffers or salts used to bring osmotic pressure. Pharmaceutical compositions can also contain other therapeutically active substances. The pharmaceutical compositions of the invention can be obtained by conventional methods known in the technical field of pharmaceutical production.

The pharmaceutical compositions of the invention should include the connection (connection) of the invention in amounts effective for the treatment of metabolic syndrome (obesity, insulin resistance, hyperlipidemia and hyperte the Zia), related with MS pathologies, non-metabolic (Pro-inflammatory state, procoagulant state, a Pro-oxidant state and endothelial dysfunction, atherosclerosis and cardiovascular disease in individuals with or without type 2 diabetes. Effective dose should depend on the severity of the disease and the activity of specific compounds (compounds), and, thus, the decision in respect of a particular mammalian host or another of the host body is within the competence of a person skilled in the art. The appropriate dose can, for example, be in the range of from about 0.001 to about 100 mg / kg for humans and more preferably from about 0.1 to about 50 mg / kg for humans.

The ratio of the compounds (compounds), which stimulates the increase of the level of the Central dopaminergic neuronal activity to the compound (compounds), which causes a decrease in Central noradrenergic neuronal activity, pharmaceutical compositions typically ranges from about 500:1 to about 1:500, based on the mass ratio (wt.:wt.) and more preferably from about 100:1 to 1:100 on the basis of the mass ratio (wt.:wt.).

In additional accordance with the method of the present invention was near the completion is detected, one or more metabolic abnormalities associated with metabolic syndrome can be treated by the introduction of centrally acting dopamine agonist (e.g., agonist of the D2 dopamine receptor with an agonist of D1 receptor dopamine or without him), in particular hypertension, hypertriglyceridemia, proinflammatory state, insulin-resistance and, not necessarily obese. The dopamine agonists used for the treatment of diseases such as Parkinson's and diabetes. However, it has been unexpectedly found that the introduction of dopamine agonists in patients suffering from metabolic syndrome, usually alleviates the symptoms. An important advantage of the present invention is the ability to treat many disorders associated with the syndrome, such as hypertension, insulin resistance, hypertriglyceridemia, proinflammatory state, and not necessarily obese.

As noted above, in one embodiment, the present invention is directed to a method of treating insulin resistance, hypertension, proinflammatory state, and hypertriglyceridemia. The levels of fasting glucose of at least 110 mg/DL, triglycerides, plasma at least 150 mg/DL, cholesterol below 40 mg/DL in men or below 50 mg/DL in women, blood pressure of at least 130/85 mm Hg are also si is Ptolemy, pointing to the metabolic syndrome.

In accordance with the method of the invention centrally acting dopamine agonist, preferably administered internally, for example, by enteral or parenteral administration, such as orally, through mucosa, sublingual, transcutaneous or intravenously, in the form of conventional pharmaceutical compositions, for example in conventional enteral or parenteral pharmaceutically acceptable fillers, containing organic and/or inorganic inert carriers, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, alcohol, vaseline or the like. The pharmaceutical compositions can be in conventional solid forms such as tablets, pills, suppositories, capsules or the like, or a conventional liquid forms such as suspensions, emulsions or the like. If desired, they may be sterilized and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizing agents, moistening agents, emulsifying agents, buffers or salts used to bring osmotic pressure. Pharmaceutical compositions can also contain other therapeutically active substances. The pharmaceutical compositions of the invention can be obtained tradition is nymi methods known in the technical field of pharmaceutical production.

Additionally, in accordance with the method of the present invention, the compounds or pharmaceutical compositions should include centrally acting dopamine agonist in an amount effective for the treatment of metabolic syndrome or hypertension, hypertriglyceridemia, proinflammatory state, procoagulant state, prooxidant status, insulin resistance and/or dysfunction of the endothelium, or associated with metabolic syndrome, independent of him, and manifestations of such metabolic abnormalities, including atherosclerosis, cardiovascular disease, peripheral vascular disease (including disease of the blood vessels of the kidneys), cerebrovascular disease or congestive heart failure. The effective dose of the pharmaceutical composition and/or centrally acting dopamine agonist should depend on the severity of the disease and the activity of specific compounds (compounds), and, thus, the decision in respect of a particular mammalian host or another of the host body is within the competence of a person skilled in the art. Suitable dose of centrally acting dopamine agonist can for example be in the range of from approximately 0.001 to approximately 0, mg / kg for humans and more preferably from about 0.01 to about 0.05 mg / kg for humans. For oral tablets regarding bromocriptine for media based on the mass ratio of approximately 1 mg of bromocriptine 90 mg tablets.

As for the treatment of cardiovascular disease, cerebrovascular disease or peripheral vascular disease, for individuals with such symptoms or diagnosed with such disorders, you can use this therapy with a dopamine agonist, for the inhibition of progression or treatment of a pathological consequences of these existing vascular disorders. Therefore, the use of centrally acting dopamine agonists for the treatment described in the present description of metabolic disorders is a continuum of possible intervention periods during the chronological development and deterioration of such metabolic and vascular disorders, beginning with the identification of the observed biomarkers approaching arteriosclerosis or vascular diseases (inflammatory condition, state of procoagulation, prooxidant state and/or dysfunction of the endothelium in the presence or absence of hypertension, hypertriglyceridemia, and insulin resistance) to overt vascular disease.

Multiple circadian Central nervous oscillations govern the regulation and coordination of many physical and the logical (for example, metabolic events in the periphery as a function of their relationship to circadian phase, described in the patent No. 5468755 and included in this description in full by reference. One such circadian rhythm, administrator of metabolism is Central (hypothalamic) circadian rhythm of dopaminergic activity. Previously it was shown that phase shift the circadian rhythm of dopaminergic activity has an impact on the condition of obesity or diabetes. However, it has been unexpectedly found that the phase shift away from healthy normal circadian rhythm Central or hypothalamic dopaminergic activity under the influence of environmental factors, diet, stress, genetic, and/or other factors somehow also affects quite a different and broader physiological regulatory system and strengthens and leads to multiple metabolic abnormalities of the metabolic syndrome and conditions associated with it, as described in the present description. Moreover, it was found that the recovery of these abnormal Central dopaminergic circadian rhythms to the rhythms of a healthy normal state leads to a simultaneous improvement in many complex pathologies of the metabolic syndrome and abnormalities associated with it, as described in the present description. As described above, the metabolic syndrome and related pathologies represent a pathology other than diabetes or obesity, the cause of which is unknown. However, in individuals with metabolic syndrome have a greater risk of developing cardiovascular disease compared with individuals without the syndrome. Because obesity and type 2 diabetes is not always associated with metabolic syndrome and Vice versa, it is clear that this is the main risk factor for health is a separate and unique state of metabolism with unique features. Normalization of circadian rhythm Central dopaminergic activity through various means can be used to suppress many of the abnormalities of this syndrome and related pathologies, for example, abnormal vascular tone, vascular, endothelial function, glucose metabolism and lipid levels, the immune system, especially affecting the vascular system, the actions of insulin and blood clotting. The same methodology restore circadian dopaminergic activity may be used to treat metabolic risk group physiological disorders common or different origin, which closed at an increased risk of cardiovascular disease. These risk factors include FA the Torah risk of metabolic syndrome, as well as inflammation, endothelial dysfunction, hypercholesterolemia, diabetes, obesity, Smoking, age and gender. Instead of simply increase dopaminergic activity by using Central dopamine agonists to improve metabolic syndrome, metabolic risk and related pathologies, it is better to influence these conditions by synchronizing the introduction of such a dopamine agonist with a daily peak of Central dopaminergic activity in healthy individuals of the same species to extract the most benefit from this therapy with a dopamine agonist in the treatment of these conditions.

Additionally in accordance with the invention the use of dopamine agonists for the treatment of metabolic syndrome (obesity, insulin resistance, hyperlipidemia and hypertension), nematoblastic pathologies associated with MS (Pro-inflammatory state, a state of procoagulation, prooxidant state and/or endothelial dysfunction, atherosclerosis and/or cardiovascular disease in individuals with or without type 2 diabetes, is applied during a specific day intervals to maximize the effectiveness of this treatment. The use of such a centrally acting dopamine agonists for the treatment of metabolic and nematoblastic vascular disorders described in this the Scripture, can be enhanced by putting them at the appropriate time(s) time of day. It has been shown that the circadian rhythms of dopaminergic activity in the Central nervous system and, in particular, the phase relationship of these dopaminergic neuronal rhythms with other types of circadian neuronal activity, such as serotonergic neuronal activity, regulate the metabolism of glucose and lipids at the periphery dependent on the phase of the daily peak circadian Central dopaminergic activity. Therefore, increased dopaminergic activity in some moments of the time of day in relation to other periods ensures maximum effectiveness in improving metabolic diseases and disorders, such as type 2 diabetes, obesity, susceptibility to diabetes, metabolic syndrome, metabolic risk, hypertension, dyslipidemia, insulin resistance, hyperinsulinemia, hepatic steatosis, kidney disease, cardiovascular disease, cerebrovascular disease and peripheral vascular disease and biomarkers coming vascular disease. In fact, maximized successful treatment of these above mentioned pathologies and abnormalities can be reached daily by the introduction at the appropriate time centrally acting agonist (agonist is in) dopamine. Since this therapy with a dopamine agonist is aimed at the root cause of these metabolic abnormalities (Central dysregulation of total peripheral metabolism), there is a possibility to cause improvements in several metabolic pathologies at the same time, which usually cannot be achieved by other conventional means, which are aimed at specific symptoms of metabolic disease, such as hypertension or high cholesterol levels or hyperglycemia, through the impact on a particular underlying peripheral targets, such as biochemical pathway in the liver or muscle. This therapeutic effect is currently not available on the General armament therapy of metabolic diseases. Moreover, treatment of Central dopamine agonist can be paired with therapeutic means acting directly or indirectly on the periphery, such as antidiabetic agents, antihypertensive agents, agents that reduce cholesterol, anti-inflammatory agents or agents against obesity, to obtain additive improvements in metabolic disease, such as obesity or type 2 diabetes or certain aspects of metabolic diseases, such as hypertension associated with obesity or type 2 diabetes.

Examples

The following examples are intended is received for illustration, and not to limit in any way the present invention.

Example 1

Four groups of animals with symptoms of the metabolic syndrome and/or type 2 diabetes treated with either saline as a control or activator (activator) Central dopamine neuronal activity inhibitor (inhibitors) Central noradrenergic neuronal activity and molecular substance or substances, which (who) is/are and activator of Central dopamine neuronal activity, and inhibitor of Central noradrenergic neuronal activity, respectively.

Compared with the control group dopaminergic neuronal activator/inhibitor noradrenergic neuronal activity shows the greatest improvement of metabolism (reducing obesity, dyslipidemia, hypertension, insulin resistance, hyperinsulinemia and/or hyperglycemia), which is also much better compared to groups or dopaminergic activator, or noradrenergic inhibitor. There is an unexpected synergism between the stimulator (stimulants) dopaminergic neuronal activity and inhibitor (inhibitors) noradrenergic neuronal activity in relation to their impact on improving the Metabo is practical syndrome and type 2 diabetes.

Example 2

Two groups of animals exhibiting metabolic syndrome, treated with either a dopamine agonist, such as parlodel, or vehicle (control) for around two weeks. Then determine the sensitivity to insulin, the level of plasma triglycerides, blood pressure, level (levels) procoagulant and proinflammatory factors in animals. Compared with the control group of animals treated with a dopamine agonist, has lower levels of triglycerides plasma level (levels) procoagulant and proinflammatory factors, blood pressure and insulin resistance.

Example 3: treatment Techniques associated with vascular disorders using agonists of dopamine receptors

Prior art. Daily administration of bromocriptine nelfinavir animal models of metabolic syndrome, improves insulin resistance, glucose intolerance, dyslipidemia, high blood pressure, proinflammatory state and excessive clotting. Clinical studies also showed that treatment with cycloset improves glucose intolerance, insulin resistance, glycemic control and dyslipidemia in individuals with obesity with insulin resistance or type 2 diabetes. However, the impact, if any, therapy cycle is set to the frequency of adverse cardiovascular events in individuals with type 2 diabetes not previously investigated in a large population. Therefore, in the present trial investigated the effect cycloset on the frequency of adverse cardiovascular events and severe adverse events due to all causes, individuals with type 2 diabetes receiving treatment at the present time in the form of diet, oral hypoglycemic agents and/or insulin.

Methods

This trial was a 52-week, double-blind, randomized 2:1, multicenter study of patients with type 2 diabetes treated diabetes, consisting of diet or no more than two hypoglycemic agents or insulin together with one additional oral agent, or without it, which randomized to treatment with CyclosetTM(titrated from 1.6 mg/day up to maximum permissible dose of 4.8 mg/day; n=2054) or placebo (n=1016) once daily in the morning soon after waking up. The first and second end points were the time to first severe adverse events caused by all causes (SAE) and cardiovascular SAE (sum of myocardial infarction, stroke, coronary revascularization, or hospitalization due to angina and congestive heart failure), respectively, which was made independent of the Supervisory Commission. At week 24 was also conducted an analysis of differences between treatment groups in HbA1c : the tion of individuals, treated with Metformin and a sulfonylurea and baseline HbA1c ≥7.5 and <10.

Results. 176 individuals receiving cycloset, and 98 individuals receiving placebo, suffered from SAE, which gives the ratio 0,88 at risk SAE for all causes 1,023 (96% one-sided confidence interval of 1.27). In the Cycloset groupTMoccurred 31 (1,5%) cardiovascular events SAE, and in the placebo group occurred 31 (3,0%) of such events, a reduction of cardiovascular outcomes in 42% of individuals treated with cycloset compared with individuals receiving placebo (HR=0,58, 95% CI: 0.35 to to 0.96; P <0,025). The ratio of the frequency of cases for each of the components of a mixture of cardiovascular disorders was less than 1.0. In a pre-selected subpopulation of individuals treatment cycloset (n=121) caused a reduction in HbA1c equal -0,674 compared with baseline, whereas placebo (n=71) caused an increase equal to 0,015 that gave given the placebo change compared with the initial level -0,69 (P<is 0.0002). Among these were treated with cycloset individuals in 39% (compared with 11% of placebo group) was achieved the goal of ADA with HbA1c ≤7,0 (P<0,0007) and 53% (compared to 21% of the placebo group) there was a minimal decrease in HbA1c of 0.7 with respect to the initial level (p<0,0001).

Discussion

Cycloset significantly reduced the risk of pre-defined and the progress of cardiovascular adverse events, and its effect on all other adverse events for the entire study population was comparable with the effect of placebo. In a pre-selected subset of individuals with inadequate control Metformin and sulfonylurea 24-week treatment cycloset has greatly improved the control of glycemia compared with placebo. These results indicate that properly designed time-daily treatment with a dopamine agonist simultaneously reduces the risk of microvascular complications due to better control of glycemia and also reduces macrovascular events during one year of therapy. The ability to significantly reduce microvascular and macrovascular disease in individuals with type 2 diabetes is a favorable and very unique therapeutic profile for one of the pharmaceutical agents.

Example 4

In patients with type 2 diabetes have an increased risk of cardiovascular disease (CVD). Available data suggest that the calculated time introduction cycloset, agonist of the D2 receptor has a Central action, increasing dopaminergic activity in the early morning of individuals with diabetes, which in turn improves many cardio-metabolic abnormalities such as hypertension, insulin resistance, hypertri glyceridae and inflammation. Safety testing cycloset was a prospective, multicenter, double-blind, placebo controlled 52-week study 3070 individuals with type 2 diabetes. Individuals randomized 2:1 to treatment with cycloset or placebo, respectively, in addition to other lowering glucose and cardiovascular medicines. Cycloset had a statistically significant favorable impact on a predefined composite CVD outcome, consisting of myocardial infarction (MI), stroke, replacement, coronary blood vessels, hospitalization for angina or congestive heart failure (risk reduction [RR]42%; p=being 0.036). This analysis includes secondary analysis of test security cycloset, which assesses the impact cycloset on the length of time to first occurrence of major adverse cardiovascular events (MACE), defined as consisting of MI, stroke and death from CVD, and additionally planned analysis of the impact cycloset on composite CVD outcome, complicated the median HbA1c. The assessment of the risk of CVD was defined as a measure of risk [HR] and 95% confidence interval [CI], based on the Cox proportional hazards regression risks.

Cycloset had a statistically significant beneficial effect on the risk of myocardial infarction, stroke and death from CVD (55% RR; p=,049). Individuals with HbA1c ≤7,0 had fewer CVD events with the introduction of cycloset (15, n=1219) compared with placebo (18, n=615). Individuals with HbA1c >7,0 also had fewer CVD events with the introduction of cycloset (16, n=830) compared with placebo (12, n=400). HR composite CVD outcome for individuals with baseline HbA1c ≤7,0 or >7,0 amounted to 0.48 (95% CI 0.24 to 0,95) or of 0.74 (95% CI 0.35 to 1,56) respectively. In addition, a favorable reduction in the composite outcome of CVD was observed regardless of age, gender or race. Cycloset significantly reduced the risk of myocardial infarction, stroke and death from cardiovascular disease. Reduction of macrovascular risk in relation to a pre-defined cardiovascular composite outcome was obvious even individuals with good glycemic control.

Effects calculated at the time of treatment with bromocriptine on CVD events described for populations of individuals in examples 3 and 4, are extremely surprising and unexpected given the magnitude response and a short period of exposure with timed bromocriptine for the induction of this response. This answer relates to most severe, if not the most pronounced responses reduction of cardiovascular events (composite or all of CVD events or major events, consisting of myocardial infarction, stroke and death from CVD) during the period of one year, ever obsesses in a wide randomizirovannom clinical trial testing the drug, calling reduction of pre-defined CVD outcomes for this population of patients. It should be noted that these individuals were under good metabolic control of blood pressure, blood glucose level, triglyceride plasma levels of total cholesterol and LDL cholesterol in the beginning of the test, because most of them received drugs aimed at these metabolic parameters (statins, antidiabetics and antihypertensive agents). However, cycloset (composition bromocriptine nelfinavir with quick release)taken once in the morning, was still able to reduce CVD events up to magnitude from 42% to 55%, compared with individuals treated with placebo. Other treatments for the treatment of CVD, such as treatment with statins or antihypertensive treatment does not lead to such strong results during the one-year time period of exposure (for example, Colhoun H, et al., Lancet 364; 685-696, 2004) in a similar population of patients. Moreover, these effects cycloset can not be explained by a significant decrease in defined MS metabolic parameters such as blood pressure, triglycerides, glucose, or cholesterol (total, HDL or LDL), since none of these parameters were not changed to such an extent as to affect CVD. Blood pressure was decreased by 1-2 mm RT.) - Rev. so, and triglycerides, cholesterol (total, HDL or LDL) and glucose clinically unchanged after treatment cyclonetm compared with placebo. These data are well in line with the basic doctrine of the present invention lies in the fact that the calculated time therapy with a dopamine agonist affects nametables parameters, such as Pro-inflammatory condition of blood vessels, a Pro-oxidant state, procoagulant state and endothelial dysfunction in the presence or absence of effects on hypertriglyceridemia plasma, high cholesterol, high glucose levels or high blood pressure, which can cause a significant reduction in CVD events, probably through effects on atherosclerosis. Again, these data and conclusions consistent with the observation that drugs that dramatically reduce plasma lipids and blood pressure (35-50%) and 10-15 mm Hg, respectively), do not cause such a significant reduction in CVD events in just one year, the period of exposure. Considered as a composite, these data cycloset together with data about the impact of reducing lipids and blood pressure medications on the incidence of CVD events indicate that the calculated time therapy with a dopamine agonist, is able to simultaneously treat hypertriglyceridemia, hypertension, and insulin resistance, acts and on the other point, in addition to those that have a beneficial effect on CVD events, defined metabolic syndrome.

Example 5

There have been several studies on hypertensive male SHR rats with insulin resistance in older men (age 16 weeks), which are known to differ in stiffness of the arteries, to determine the effect calculated at the time of the introduction of bromocriptine on blood pressure, obesity, insulin resistance, hyperlipidemia, biomarkers of Pro-inflammatory state, a Pro-oxidant state, procoagulant state of the endothelial dysfunction and the stiffness of the arteries (a marker of atherosclerosis). It is noteworthy that these animals do not show signs of atherosclerosis, so the effect on arteriosclerosis, if any, cannot be in any way confused with the impact on atherosclerosis. These animals were provided free access to food and drink when the content when the 12-hour daily photoperiod and randomized them into different groups for treatment with bromocriptine (10 mg/kg) or 1 h after lights on (HALO), 7 HALO, 13 HALO or HALO 19, or the carrier within 14 days. The treatment effect was tested in animals for blood pressure, obesity, insulin resistance, hyperlipidemia, biomarkers of Pro-inflammatory state, a Pro-oxidant condition is, procoagulant state of endothelial dysfunction and stiffness of the arteries (a marker of arteriosclerosis) from 12 to 14 days after beginning treatment. It was found that treatment with bromocriptine 13 HALO (offensive rhythm of locomotor activity in these nocturnal rodents) reduces high systolic and diastolic blood pressure (approximately 15%), obesity (42%), insulin (55%), glucose (11%), insulin resistance (approximately 50%), hyperlipidemia (approximately 10%), Pro-inflammatory condition of blood vessels (reduction of TNFalpha protein in adipose tissue relative to fat mass in the cell at 40% and protein MCP-1 in adipose tissue relative to the weight fat in the cell at 42%, the level of CRP plasma by approximately 10% and increase the level of adiponectin plasma 10-30%), a Pro-oxidant state (decrease elevated protein level of eNOS in the aorta by 22% and the level of iNOS protein in the aorta 17%), procoagulant state (increased clotting time and decrease the levels of endothelin-1 (30%) and plasma fibrinogen) and endothelial dysfunction (decrease elevated protein level of eNOS in the aorta 22% and 16% increase in the protein level of soluble guanylate cyclase in the aorta). In accordance with such data and the importance of having this treatment also significantly reduced the stiffness of the arteries (arteriosclerosis), measured in the aorta of these animals only after 14 days of treatment. The value of food and the length of such effects cannot be invoked by treatment with bromocriptine in any other tested time of day. Thus, therapy with a dopamine agonist at the onset of locomotor activity in comparison with other moments of the day in animal models of atherosclerosis have shown the most effective favorable influence on nametables violations of arteriosclerosis, and the arteriosclerosis. Important : to achieve maximum favorable response to dopamine agonist above metabolic and nematoblastic parameters need to dopamine agonist was largely removed from the blood stream within about 6-12-hour window from the time of the peak concentration in the blood after its introduction.

Example 6

Based on the data of previous experiments showing that dopamine agonists are the most effective in the treatment of high blood pressure (hypertension), obesity, insulin resistance, hyperlipidemia and biomarkers of Pro-inflammatory state, a Pro-oxidant state, procoagulant state, endothelial dysfunction and stiffness of the arteries (a marker of atherosclerosis), when they are administered at the onset of the rhythm of locomotor activity in rats (13 HALO)conducted additional studies with a variety of agonists dopamine receptor, administered at the same time of day (13 HALO) different groups of hypertensive resistant to insulin in rats SHR with the stiffness of artery (arteriosclerosis), respectively. Different groups of SHR rats were treated with bromocriptine (10 mg/kg) alone or together with SKF8393 (1 mg/kg), pergolid (0.1 mg/kg), terguride (2 mg/kg), talipexole (0.3 mg/kg), Cinelerra (0.15 mg/kg) or a carrier for 9 to 14 days. At the end of the processing carried out analyses of high blood pressure (hypertension), obesity, insulin resistance, hyperlipidemia and biomarkers of Pro-inflammatory state, a Pro-oxidant state, procoagulant state, endothelial dysfunction and stiffness of the arteries (a marker of atherosclerosis). It was found that although these different dopamine agonists are active to varying degrees (largest) in the treatment of high blood pressure (hypertension), obesity, insulin resistance, hyperlipidemia and biomarkers of Pro-inflammatory state, a Pro-oxidant state, procoagulant state, endothelial dysfunction and stiffness of the arteries (a marker of arteriosclerosis) relative to each other, each of them was generally effective in the treatment of high blood pressure (hypertension), obesity, insulin resistance, hyperlipidemia and biomarkers of Pro-inflammatory state, a Pro-oxidant state, procoagulant state, endothelial dysfunction and stiffness of the arteries (a marker of arteriosclerosis compared with controls with carriers. The lowering of the rigidity arter the th, caused by dopamine agonists, was very pronounced. It was found that terguride is particularly strong antihypertensive agent, reducing systolic and diastolic blood pressure by 30%. As you can see from the structures of these molecules are presented below, they are very different from the original alkaloid of ergot, Ergoline, have structures that are not associated with connection from ergot, related benzazepine. The main common feature is probably the only significant common feature is that they are agonists of dopamine receptors D2 and/or D1.

(+)-2-Bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl " ergotamine-3',6'-18-trione methansulfonate salt

(+)-Bromocriptine methanesulfonate salt

2-Bromo-α-ergokriptina methansulfonate salt

S(+)-N,N-Diethyl-N'([8α]-6-methylergoline-8-yl)urea

S(+)-Terguride (5R, 8S, 10R)

S(+)-Terguride

(5aR-TRANS)-5,5a,6,7,8,9,9a,10-Octahydro-6-propylpyridine[2,3-g]hinzelin-2-amine the dihydrochloride

Kinelory the dihydrochloride

8β-[(Methylthio)methyl]-6-propylalanine methansulfonate salt

Of pergolid methansulfonate salt

Of pergolid mutilata salt

5,6,7,8-Tetrahydro-6-(2-propenyl)-4H-thiazol[,5-d]azepin-2-amine the dihydrochloride

Talipexole

B-HT 920 dihydrochloride

(±)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride

(±)-SKF-38393 hydrochloride

Agonist D1 receptor dopamine

Substituted 1-phenyl-3-benzazepine form a class of compounds having a high selective affinity for the receptor D1 DA. 7,7-Dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin (SKF 38393) and its 6-halogenated analogues are strong and selective agonists of the receptor D1.

Example 7: Effect of treatment with bromocriptine clinical disorders and pathologies associated with metabolic syndrome in humans

This example shows that treatment of patients with metabolic syndrome bromocriptine (agonist of dopamine D2 receptor) at the onset of locomotor activity in the morning at the same time reduces insulin resistance, hypertriglyceridemia, markers giperpopuljarnogo conditions associated with increased cardiovascular risk and blood pressure.

Methods

Individuals with obesity, type 2 diabetes, poorly controlled treatment with sulfonylurea, gave informed written consent to participate in a double-blind, placebo-controlled trial of the effects of bromocriptine to improve glycemic control, randomized to treatment with either bromocriptine or placebo and Le the or within 24 weeks. Individuals were included only if they were supported by receiving a stable dose of sulfonylurea and hyperlipidemics drugs for 60 and 30 days prior to randomization, respectively. Individuals in tables 1 and 2 were subjected to either a) maximal doses of sulfonylurea, glipizide 15 mg/day, gliburida-10 mg/day,chlorpropamide-350 mg/day and tolbutamide 500 mg/day or (b) less than or equal to the maximum dose of a sulfonylurea, respectively. Individuals in this analysis met the criteria of metabolic syndrome (any three of the following: fasting glucose >/=110 mg/DL, triglycerides fasting >/=150 mg/DL, HDL on an empty stomach <40 for men and <50 for women, blood pressure >/=130/>/=85 and obesity). In the beginning of the study individuals 0.8 mg of bromocriptine in tablet or pill placebo in the morning after you Wake up within 1 week. Each subsequent week for 5 weeks number of tablets increased by 1 per week until reaching the maximum allowable dose of between 1.6 and 4.8 mg per day while saving time dose upon awakening in the morning. Individuals then supported on the maximum dose of bromocriptine or placebo during the rest of the tests before the end of 24 weeks after the date of randomization. Before the introduction of dose and then at the end of the studied what I had taken and blood samples for analysis % glycated hemoglobin (HbA1c) fasting, insulin, glucose, triglycerides, and the number and percentage composition of subfractions of leukocytes (WBC); recorded the blood pressure. These individuals at the beginning and at the end of the test was also conducted by the definition of insulin resistance and features of insulin secretion. Insulin resistance was determined by the method HOMA-IR [fasting glucose (mmol/l)*fasting insulin (ua/ml)/22,5], and the function of insulin secretion was determined by the method HOMA-B [20*fasting insulin (ua/ml)/fasting glucose (mmol) of 3,5].

Results

Table 1 shows the effects of treatment with bromocriptine relative to placebo on various metabolic parameters including HbA1c blood, fasting plasma glucose, triglycerides, number and percentage composition of subfractions WBC and blood pressure in individuals with metabolic syndrome with type 2 diabetes. This table also includes determining differences between the treatment of individuals with bromocriptine and placebo for HOMA-IR and HOMA-B.

The results show that treatment with bromocriptine during the 24 weeks of the individuals with metabolic syndrome, type 2 diabetes at the same time improves glycemic control (as evidenced by the decrease of HbA1c levels) and improves (reduces) hyperglycemia, insulin resistance (reduces the value of HOMA-IR), blood pressure, plasma triglycerides and the number of WBC and lymphocyte blood relation is sustained fashion control with placebo. The reduction in the number of WBC and lymphocytes remains within the clinically normal range.

Discussion

Metabolic syndrome is a combination of metabolic abnormalities, which converge at increased cardiovascular risk. In such individuals, insulin resistance, hypertriglyceridemia, high blood pressure and the presence of Pro-inflammatory immunological conditions may interact with accelerating the development and progression of cardiovascular disease. Although it is important to treat each of these pathologies, it would be advantageous from an economic, clinical and practical points of view to be able to treat this combination of abnormalities using a single effective therapy. The results of this study show that the actual means of achieving this goal is the introduction of centrally acting dopamine agonist, such as parlodel.

Treatment with bromocriptine reduced the value of HOMA-IR with 13,057 to 12,272 compared with an increase with 11,626 to 15,841 in control with placebo, which clearly indicates that in response to treatment improved insulin sensitivity compared to control with placebo. Simultaneously with this action, this treatment also improved the response of insulin secretion (the ability of beta cells to adequately secrete insulin in response to glucose levels in venom line) (HOMA-B increased c 51,125 to 55,202 individuals, treated with bromocriptine, compared with a decrease from 50,579 to 49,928 in control with placebo). You can also expect that induced by bromocriptine improved triglycerides reduces other atherogenic factors in the blood of these individuals and reduces the risk of CVD. High blood pressure is a well known risk factor for CVD, and therapy with bromocriptine decreased and systolic and diastolic blood pressure in these individuals compared with controls. Finally, subclinical increase in the number of WBC in the blood line and populations of lymphocytes were asked to consider as markers of Pro-inflammatory stimulation of CVD. Treatment with bromocriptine reduced the number of WBC and lymphocytes in the blood line when saving it within the normal range, and it can be expected that this is associated with reduced risk of CVD in individuals with metabolic syndrome.

Example 8: Effect of treatment with bromocriptine on disorders and pathologies associated with metabolic syndrome, hypertension, insulin-resistant rats SHR

Introduction

Male rats SHR well characterized as a model of hypertension in rodents. When these animals are subjected to the action "close to the Western" diet, consisting of compositions with a high content of fat and simple sugars, they develop severe insulin-resi is tentest and hypertriglyceridemia on top of existing hypertension. Using this induced by the diet of the animal model system, hypertension and insulin resistance, applicants describe a method for simultaneously improving (reducing) insulin resistance, hypertriglyceridemia, proinflammatory factors that increase cardiovascular risk, and procoagulant state by centrally acting dopamine agonist.

Methods

Male SHR rats at 4-5 weeks of age were placed 2 per cage and were accustomed to the premises by the animal care applicants and close to a Western diet for 4 weeks prior studies with medication. The animals were provided free access to food ("close to the Western" diet; Research Diets Inc. # D12079B; 41% fat, 29% sucrose) and water at will and kept them at 72°F (22°C) for 14-hour daily photoperiod (lights on at 06:00) during periods of adaptation and research. After a period of adaptation (4 weeks) animals randomized to handle media or bromocriptine (5-10 mg/kg/day) over 13 hours after lights on (the onset of the circadian rhythm of locomotor activity) and were treated for 28 days. On the seventeenth day of the study measured blood pressure in approximately 12 hours after the lights are switched on. On the twenty-ninth day of the test animals was anestesiol the (pentobarbital sodium 90 mg/kg) before heart puncture for blood collection and then squashed the addition of excessive doses of pentobarbital (180 mg/kg). Plasma blood samples were analyzed levels of glucose, insulin, triglycerides, C-reactive protein and fibrinogen.

Results

Control animals were manifested state of the metabolic syndrome, such as hypertension, hyperglycemia and hypertriglyceridemia, and insulin resistance.

The figure 1 shows that treatment with bromocriptine reduces the level of insulin in plasma by 59% compared to control animals.

The figure 2 shows that treatment with bromocriptine reduces HOMA-IR by 55% compared to control animals.

The figure 3 shows that treatment with bromocriptine reduces the level of triglycerides in the plasma at 24% compared to control animals.

The figure 4 shows that treatment with bromocriptine reduces systolic blood pressure by 14% and diastolic blood pressure by 19% compared to control animals.

The figure 5 shows that treatment with bromocriptine reduces the level of C-reactive protein in plasma by 16% compared to control animals.

In figure 6 it is shown that therapy with bromocriptine decreases the level of fibrinogen in plasma by 11% compared to control animals.

In figure 7 it is shown that therapy with bromocriptine reduces weight gain of 29% compared to control animals.

Discussion

Therapy promoclip the other every day at the same time improved hyperinsulinemia, insulin resistance (as indicated by the decrease in HOMA-IR), hypertriglyceridemia, systolic and diastolic blood pressure, C-reactive protein plasma (figure inflammatory condition), plasma brinogen level (figure coagulants capacity of the blood), and weight gain. Decrease insulin resistance, hypertriglyceridemia, proinflammatory state and hypercoagulative condition of simultaneous image should enhance protective effect against progression of cardiovascular disease. Induced by bromocriptine reduction of plasma brinogen level in this study is consistent with other, similar studies in rats, SHR, in which treatment with bromocriptine in 2-4 weeks (5 mg/kg) increased the clotting time (blood from the incision the distal part of the tail) compared with the control treated with carrier animals. Collectively, these data show that centrally acting dopamine agonist, such as parlodel, can act at the same time reducing the weight gain, insulin resistance, hypertriglyceridemia, high blood pressure, proinflammatory state and hypercoagulation condition in animals with type metabolic syndrome. Moreover, these effects do not depend on calorie restriction and the special nutritional diet. Indeed, these results were observed despite a diet known that it strengthens these pathologies ("close to the Western" diet). That is, this treatment suppresses the action close to the Western diet full induction of these pathologies.

Example 9: Influence of time of day on the action of bromocriptine on blood pressure

Methods

Male SHR rats aged 8 weeks were placed 2 per cage and were accustomed to the premises by the animal care applicants within 4 weeks prior studies with medication. The animals were provided free access to food (food for rodents, Harlan) and water at will and kept them at 72°F (22°C) for 14-hour daily photoperiod (lights on at 06:00) during periods of adaptation and research. After a period of adaptation (4 weeks) animals randomized to handle media or bromocriptine (1 or 5 mg/kg/day) after 1 or 13 hours after lights on (the onset of the circadian rhythm of locomotor activity) and were treated for 7 days. On the eighth day of the study measured the blood pressure of approximately 5 hours after lights on.

Results

Compared with the corresponding control animals treated with 5 mg/kg/day of bromocriptine in 13 HALO compared with 1 HALO, there was more red eye reduction is of blood pressure (figure 12). More importantly, the reduction in blood pressure in 13 HALO was maintained for 16 hours after administration, which is unusual for such responses on parlodel, suggesting that the effect of treatment in 13 HALO was a response to chronic treatment was prolonged. The lower blood pressure in 1 HALO was observed only after 4 hours after administration of bromocriptine.

Discussion

These data suggest that daily changes in sensitivity to centrally acting dopamine agonists such as parlodel, in the treatment of hypertension and, consequently, hypertensive individuals with metabolic syndrome can be decisive and have not yet been assessed in clinical practice.

Example 10:Effects of treatment with bromocriptine metabolic disorders in individuals with type 2 diabetes

Methods

Individuals with obesity and type 2 diabetes, which resisted treatment with sulfonylurea and gave informed written consent to participate in a double-blind, placebo controlled trial of the effects of bromocriptine to improve glucose control, were randomized to treatment with either bromocriptine or placebo and treated for 24 weeks. Individuals were selected only if they randomization received supportive therapy stable is osoi sulfonylureas and drugs for hyperlipidemia for 60 and 30 days, respectively. Individuals in tables 3 and 4 received either (a) the maximum dose of a sulfonylurea; glipizide 15 mg/day, gliburid - 10 mg/day, hlorpropamid - 350 mg/day and tolbutamide 500 mg/day or (b) less than or equal to the maximum dose of a sulfonylurea, respectively. At the beginning of the study individuals took the tablet 0.8 mg of bromocriptine or pill placebo in the morning after you Wake up within 1 week. Each subsequent week for an additional 5 weeks number of tablets increased by 1 per week until reaching the maximum allowable dose of between 1.6 and 4.8 mg per day while maintaining the reception time in the morning upon awakening. Individuals then were maintained on the maximum dose of bromocriptine or placebo for the remaining testing time before it expires after 24 weeks from a randomized date. Before the initial reception and then again at the end of the study were selected blood samples for analyses % glycated hemoglobin (HbA1c) fasting insulin, glucose, triglycerides, and the number of leukocytes (WBC) and percent of subfractions; recorded also measuring blood pressure. These individuals were also the definition of insulin resistance and insulin secretory function at the beginning and end of the test. Insulin resistance was determined using the method of HOMA-IR [glucose natosha the (mmol/l)* fasting insulin (ua/ml)/22,5] and insulin secretory function was determined using the method HOMA-B [20*fasting insulin (ua/ml]/fasting glucose (mmol)for 3,5].

Results

In tables 3 and 4 presents the effect of treatment with bromocriptine compared with placebo on various metabolic parameters including HbA1c, fasting plasma glucose, triglycerides, the number of WBC and the percent of subfractions and on blood pressure in individuals with metabolic syndrome and type 2 diabetes. These tables also include determining differences in treatment outcomes between individuals in the treatment of bromocriptine and placebo for HOMA-IR and HOMA-B.

The results show that treatment with bromocriptine for 24 weeks in individuals with type 2 diabetes at the same time improves the monitoring of glucose levels (as evidenced by lower levels of HbA1c) and improves (reduces) hyperglycemia, insulin resistance (reduces the value of HOMA-IR), blood pressure, triglycerides plasma and WBC and blood lymphocyte count compared with placebo controls. The reduction in the number of WBC and lymphocytes remains within the normal clinically acceptable range.

Discussion

These results show that treatment with a dopamine agonist, bromocriptine, can improve the course of type 2 diabetes, hypertension, hypertriglyceridemia, insulin resistance and improve biomarkers of Pro-inflammatory state.

Example 11

Hypertensive status with obesity represents substantially the th risk for development of cardiovascular disease. This condition is strongly associated with insulin-resistance and humoral anti-inflammatory/vascular condition. Previous studies implied the important role of circadian-dependent phase increase hypothalamic dopaminergic tone in maintaining the state of decreased sensitivity to insulin. In this study, therefore, examined the effects of introducing at a certain time of day bromocriptine, a D2 agonist of the dopamine receptor, hypertension and humoral markers of Pro-inflammatory state in addition to the effects on the level of fat reserves of the body and insulin-resistance in SHRs. SHRs age sixteen weeks, supported 12-hour daily photoperiod, was administered daily for 16 days parlodel (10-15 mg/kg/b) or media for 1 hour before the onset of the light period. The blood pressure measurement was performed 14 days after this treatment, 4 hours after the onset of the light period (16 hours after the last injection of bromocriptine) and animals were scored on day 16 of the study to analyze the level of fat stock body and metabolic and humoral immune factors. The introduction of bromocriptine reduced systolic and diastolic blood pressure from 211 to 172 (P=0,025) and 159 to 119 (P=0,059), retroperitoneal fat of the body by 33% (4,54 to 3.03 grams is a, P=0.004), the plasma insulin level by 45% from 289 to 160 pmol/l (P=0,0003), plasma glucose with 150 to 111 mg/DL (P=0.05) and HOMA-IR c to 15.8 6.5 the ua/ml*mmol/l (P=0,0015) compared with controls treated with the carrier. C-reactive protein plasma was reduced from 7 to 6.1 mg/l (P=0,0083). The level of plasma leptin was also reduced by 58% (from 971 to 412 PG/ml, P<0,0001) as a result of receiving bromocriptine. Moreover, in some studies with similar design with SHRs at the stern for rodents or diet with high fat and sucrose treatment with bromocriptine has also increased the level of adiponectin in plasma by 31% and 42% (from 10.0 to 13.1, P=0,035, and from 12.2 to 17.3 P=0,034, ng/ml), respectively. These data show that in spontaneously hypertensive rats, daily administration of bromocriptine at a certain time of day makes a favorable contribution in a number of different metabolic and nematoblastic pathophysiological indicators that cause predisposition to atherosclerosis and cardiovascular disease. These additional data suggest that therapy with a dopamine agonist at a certain time of day can make a favorable contribution simultaneously in metabolic disorders and nametables violations of the metabolic syndrome and, respectively, associated disorders. The above examples show that treatment at a certain time of day DOPA agonist is ina has the ability to simultaneously treat a) a number of metabolic disorders, including hypertension, hypertriglyceridemia and insulin resistance, and (b) the number of nematoblastic violations, including Pro-inflammatory condition of blood vessels, procoagulant state, a Pro-oxidant state and endothelial dysfunction, (c) metabolic syndrome, (c) type 2 diabetes, and may also favorably affect the progression of arteriosclerosis and cardiovascular disease. Significant scope and magnitude of these aspects of treatment at certain times of the day with a dopamine agonist was unknown. In aspects of the available evidence up to the present disclosure actually argues against these data in relation to effects on vascular disease.

1. A method of treating at least one disease in a patient, comprising the stage of the patient suffering from at least one disease or manifesting its biomarkers, a therapeutically effective amount of a dopamine agonist with a Central action and the specified dopamine agonist with Central action is effective for treatment of the specified at least one cardiovascular disease in a specified patient;
where specified, the dopamine agonist is administered such that the peak level of a dopamine agonist in plasma is between 04:00 and 12:00 hours, and the bioavailability of the specified dopamine agonist in the blood red eye reduction which is within about 50% of the peak values of the plasma is from about 2 to 6 h after the end of the afternoon peak or plateau agonist of dopamine in plasma.

2. The method according to claim 1, where the specified vascular disease selected from the group consisting of cardiovascular disease, microvascular disease, macrovascular disease, peripheral vascular disease, and cerebrovascular disease.

3. The method according to claim 2, where the specified cardiovascular disease selected from the group consisting of arteriosclerosis, myocardial infarction, stroke, angina and congestive heart failure.

4. The method according to claim 1, where the specified patient is suffering from one or more of the metabolic syndrome, endothelial dysfunction or type 2 diabetes, and this method of treatment also aims to metabolic syndrome and/or type 2 diabetes.

5. The method according to claim 1, where dopamine agonist with Central action is selected from agonists of D2 dopamine receptor and/or agonists D1 receptor dopamine.

6. The method according to claim 1, where the specified dopamine agonist selected from the group consisting of bromocriptine, e.g., dihydroergotoxine, dihydro-alpha-ergokriptina, terguride and their combinations.

7. The method according to claim 1, where the specified dopamine agonist is administered in combination with at least one other antidiabetic agents, anti-obesity, antihypertensive, anti-inflammatory agents or means of reducing the cholesterol level.

8. The method according to claim 1, which indicated the first method further includes the treatment of obesity.

9. The method according to claim 1, where the specified therapeutically effective amount of a dopamine agonist with Central action is in the range of from 0.001 mg per kg of body weight up to 2.0 mg per kg of body weight.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a method of treating the patients with metabolic syndrome involving patient's staying in the low atmospheric pressure environment at heights of 1000, 1500 m above sea level with underlying basic therapy combined with the oral administration of a therapeutic beverage, differing by the fact that a hypoxia adaptation course is two-staged; the first stage involves staged climbing at height of 1000, 1500, 2000 and 2500 m above sea level; at the second stage, from the fifth session, a "working height" is 2500 metres with climbing up and down at speed 4-5 m/s at partial oxygen pressure 20-35 mm Hg, chamber pressure 75.5 kPa for 15-20 minutes within the therapeutic course of 12-14 daily procedures; the therapeutic beverage is mare's milk of weak or medium strength of permanent Turner acidity 71-100° in dose of 200-250 ml three times a day before meals of the length of 24 days.

EFFECT: invention provides improved clinical values, haemodynamics, carbohydrate and lipid metabolism, higher tolerance to physical activity.

2 cl, 2 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology, particularly to obtaining a modified growth hormone, and can be used in medicine. By recombination, a polypeptide is obtained, which has antagonistic effect on the growth hormone receptor.

EFFECT: invention enables to obtain a polypeptide which is effective when treating conditions caused by excess growth hormone in the body of the patient.

11 cl, 19 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely neurology, and concerns treatment and prevention of neurodegenerative diseases, particularly Alzheimer's disease with the use of gene therapy. That is ensured by the introduction of a composition containing one or more nucleic acids inducing cell immune response. The nucleic acids to be introduced code one or more cytokines specified in a group consisting of IL-4 (interleukine-4), IL-10 (interleukine-10) and TGF-β (transforming growth factor beta).

EFFECT: method provides reduced cerebral accumulations of amyloid formations.

16 cl, 7 ex, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely obstetrics and gynaecology, and may be used for treating benign hyperplastic processes of the female reproductive system. That is ensured by the introduction of gonadotropin-releasing hormone agonist for 6 months once monthly in a combination with the oral administration of the preparation for hormonal replacement therapy. It is preceded by specifying the initial metabolic, vegetative and gynaecologic status of the patient which along with an age group provides a basis to assess an adequacy of initiating hormonal add-back therapy. If the patient belongs to the age group of under 40 years of age, and in case of observing additional burdening of the metabolic and vegetative status, the introduction of gonadotropin-releasing hormone agonist with no hormonal add-back therapy prescribed. For the purpose of preventing potential negative symptoms, it is combined with underlying prescription of a complex of phytoestrogens and vitamins with required intake of calcium and vitamin D3. Each injection of gonadotropin-releasing hormone agonist, starting with the second one, is followed by clinical assessment of hypestrogenism symptoms and blood chemistry analysis, and if observing hypestrogenism symptoms, additional hormonal add-back therapy is prescribed. If the patient appears to belong to the age of 40 years old and more, and in case of observing the presence of burdened metabolic and vegetative status regardless of the age group, 2 years after the first injection of gonadotropin-releasing hormone agonist, hormonal add-back therapy is started. When selecting the preparation included in the hormonal add-back therapy regimen: there are differentiated: if the patient belongs to a younger group under 35 years of age, a therapeutic add-back preparation is presented by a combine oral contraceptive containing ethinyl estradiol 30 mg and dienogest 2 mg in each tablet. The oral contraceptive is prescribed 1 tablet a day in the continuous regimen which is recommended to be used after termination of the therapeutic course with gonadotropin-releasing hormone agonist if pregnancy prevention is required. If the patient belongs to the age group of 35 years and older, a therapeutic hormonal add-back preparation is presented by a preparation for hormonal replacement therapy containing micronised 17-p estradiol 1 mg and dydrogesterone 5 mg or a preparation containing drospirenone 2 mg instead of dydrogesterone in each tablet 1 tablet a day in the continuous regimen. An initial or underlying tendency to increase of blood pressure, a combined preparation for hormonal replacement therapy containing drospirenone is prescribed. The therapeutic course is followed by recommended administration of the preparation of hormonal replacement therapy if the patient belongs to the age group of 50 years and older in the continuous regimen.

EFFECT: method enables providing an evident therapeutic effect that is manifested in stable elimination of estrogenic deficiency symptoms accompanying gonadotropin-releasing hormone agonist therapy with preserved clinical effectiveness and improved patient's quality of life.

2 ex

FIELD: medicine.

SUBSTANCE: invention provides using a prepared compound of a ghrelin splicing version for preparing an effective drug preparation activating body weight and food intake gain and/or stimulating growth hormone release, as well as for treating or preventing cachexia, lipodystrophy and muscle atrophy.

EFFECT: higher clinical effectiveness.

6 cl, 6 dwg, 13 ex

FIELD: medicine.

SUBSTANCE: invention provides using a prepared compound of a ghrelin splicing version for preparing an effective drug preparation activating body weight and food intake gain and/or stimulating growth hormone release, as well as for treating or preventing cachexia, lipodystrophy and muscle atrophy.

EFFECT: higher clinical effectiveness.

6 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamides, method for production thereof, use thereof to produce a medicinal agent which inhibits MR activity.

EFFECT: improved method.

11 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: stable fat emulsion contains prostaglandin as an active ingredient and phospholipids containing phosphatidylcholine and phosphatidyl glycerol in mass ratio 85:15 to 99.7:0.3. The fat emulsion under the invention and its active ingredient (prostaglandin) possess physical and chemical stability thereby increasing shelf life to approximately two years, and/or extended range of storage temperature to 10°C as compared with a commercially available fat prostaglandin emulsion.

EFFECT: fat emulsion under the invention enables satisfactory effectiveness even in the introduction of a low amount.

25 cl, 10 tbl, 12 ex

FIELD: veterinary medicine.

SUBSTANCE: method includes injection of the preparation "FSH-super" and the preparation of prostaglandin F2α. On the day of artificial insemination the cows-donors are additionally injected with homeopathic preparation "Ovariovit" at the dose of 4.9-5.1 ml per head in a single dose.

EFFECT: method enables to obtain a greater number of embryos and to improve their quality.

5 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: to reduce tachycardia in such patients used is ivabradin (coraxan) in dose 5-7.5 mg for 7-14 days with further supporting course in dose 5 mg to the moment of when preoperative reparation is finished.

EFFECT: application of ivabradin in preoperative period in case of manifest thyrotoxicosis instead of traditional beta-adrenoblockers makes it possible to weaken sympathetic impact on sinus node and increase chronotropic myocardium reserve, avoiding at the same time undesirable cardioplegic effects, characteristic of beta-adrenoblockers.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: present invention refers to pharmaceutics and medicine, and concerns the use of 40-O-(2-hydroxyethyl)rapamycin for treating renal angiomyolipoma, lymphangioleiomyomatosis, subependimal astrocytoma and/or giant cell astrocytoma and a based pharmaceutical composition.

EFFECT: invention provides higher clinical effectiveness.

3 cl

FIELD: medicine.

SUBSTANCE: invention relates to veterinary medicine. Method of obtaining preparation for stimulation of non-specific resistance and metabolism in animals includes mixing succinic acid with tissue preparation ADS F-2 (antiseptic Dorogov's stimulator fraction-2), sodium nucleinate and wastes of biological industry, obtained after cultivation of quail fibroblasts on primary culture medium, which includes synthetic medium MEM (minimal Eagle medium), synthetic medium 199 and cattle blood serum in the following component ratio, g/l: succinic acid - 6-7 ADS F-2 - 30-35, sodium nucleinate - 20-25, wastes of biological industry, obtained after cultivation of quail fibroblasts - to 1 l, succinic acid and sodium nucleinate are preliminarily subjected to ultraviolet irradiation.

EFFECT: invention ensures obtaining preparation, which produces expressed stimulating action on metabolism, possesses antioxidant properties and increases natural resistance of animal organism.

9 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary medicine. Method of obtaining preparation for stimulation of non-specific resistance and metabolism in animals includes mixing succinic acid with tissue preparation ADS F-2 (antiseptic Dorogov's stimulator fraction-2), sodium nucleinate and wastes of biological industry, obtained after cultivation of quail fibroblasts on primary culture medium, which includes synthetic medium MEM (minimal Eagle medium), synthetic medium 199 and cattle blood serum in the following component ratio, g/l: succinic acid - 6-7 ADS F-2 - 30-35, sodium nucleinate - 20-25, wastes of biological industry, obtained after cultivation of quail fibroblasts - to 1 l, succinic acid and sodium nucleinate are preliminarily subjected to ultraviolet irradiation.

EFFECT: invention ensures obtaining preparation, which produces expressed stimulating action on metabolism, possesses antioxidant properties and increases natural resistance of animal organism.

9 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary. Method includes application of anti-protozoa medication and immunomodulator. As anti-protozoa medication applied is Neosidin M in a single injection intramuscularly in dose 2.0 mg/kg of animal body weight (in terms of active substance). As immunomodulator applied is Ribotan in a single injection subcutaneously in dose 1 ml per an animal.

EFFECT: method is highly efficient in treatment and prevention of reindeer babesiosis, ensures reduction of parasites in blood of animals and protection against spontaneous babesiosis for a long term.

2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of veterinary. Composition includes n-tetradecyl(tri-n-butyl)phosphonium-chloride and 5,7-bis-(m-nitroanilino)-4,6-dinitrobenzofuroxane as active components and glucose as auxiliary substance with weight ratio of active components 1:10.

EFFECT: composition is not toxic, possesses high therapeutic efficiency.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention includes compositions and methods for obtaining activated polymer nanoparticles for targeted delivery of medication. Nanoparticle includes biocompatible polymer and amphiphilic stabilising agent, non-covalently bound with linker, which includes, at least, one elecrophile, selectively reacting with any nucleophile on targeting substance, and places targeting substance on external surface of biodegradable nanoenvelope, active substance being loaded into nanoenvelope. Biocompatible po;ymer includes one or several polyesters, selected from group, containing polylactic acid, polyglycolic acid, copolymer of lactic and glycolic acids and their combinations. Amphiphilic stabilising agent includes polyol. Active substance represents anti-cancer medication, preferably, curcumin.

EFFECT: invention ensures delivery of therapeutic substance to the place of its action.

27 cl, 11 dwg, 2 tbl

FIELD: food industry.

SUBSTANCE: invention relates to food industry, in particular, to dietary compositions based on food fibres. The dietary composition includes 48% - 90% (weight/weight) of glucomannan, 5% - 20% (weight/weight) of xanthan gum and 5% - 30% (weight/weight) of alginate, and at least one lipid or a lipid mixture. The lipid or lipid mixture is present at a ratio of the fibres composition to the lipid or lipid mixture equal to 50:50 (weight/weight) - 60:40 (weight/weight). The dietary composition has viscosity from nearly 1 to nearly 3500 centipoises after 5 minutes in water and, at least, nearly 90 000 centipoises after 5 minutes under bowel conditions. Additionally, one proposes a method for reduction of the food product glycaemic index which involves addition of the said dietary fibres composition to the food product before consumption in an amount of nearly 2.5-7.5 per 50 g of the food product digestible carbohydrate. The glycaemic index of the food product is reduced by, at least, 5 glycaemic index units. Additionally, the dietary composition is used for reduction of glycaemic variability with a person in need thereof. Additionally, the method for preparation of the said dietary composition is disclosed.

EFFECT: invention allows to significantly decrease the food product glycaemic index, reduce glycaemic variability with a person, reduce the level of blood glucose and cholesterol which, in its turn, promotes appetite suppression and body weight loss with a person suffering from body overweight.

27 cl, 26 dwg, 53 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to acids which are suitable for use in medicine, having links of formulae (I) and (II) where n equals 1 or 2; A1 is selected from O or NR5, R5 is H or C1-4alkyl; A2 is O; R3 and R4 are selected from H, NH4 or an alkali metal; R1 and R2 are selected from C1-10alkyl, C6-20aryl, NH4, an alkali metal and an agent: taxane, camptothecin, doxorubicin, an acridine, coumarine, rhodamine, xanthene, cyanine or pyrene dye, a magnetic resonance imaging agent, a polydentate ligand or precursor thereof of formulae where R7 is selected from H, NH4 or an alkali metal, provided that one of R1 and R2 is said agent, conjugated with a polymer directly or through a linker group, and the ratio of the agent to the polymer conjugate ranges from 1 to 50% (wt/wt).

EFFECT: compared to a polyglutamic acid conjugate, the novel biodegradable conjugate has high solubility and provides the solution with high optical transparency in a wide pH range.

53 cl, 29 dwg, 38 ex, 3 tbl

Antibiotic peptides // 2472805

FIELD: chemistry.

SUBSTANCE: peptides and peptide derivatives have general formula Sub1-X1NX2X3PVYIPX4X5RPPHP-Sub2, where Sub1, X1, X2, X3, X5, Sub2 are given in the claim. The disclosed peptides or peptide derivatives have at least one of the following advantages compared to natural apidecine peptides: (i) longer half-life in mammal serum owing to higher protease stability, (ii) high antimicrobial activity with respect to one or more bacterial strains, particularly human pathogens or fungi, or other microbial infections, (iii) demonstrate a wide range of antimicrobial activity, (iv) cause slower development of resistance in microorganisms and (v) are not toxic for human cells, including erythrocytes.

EFFECT: improved properties of peptides.

21 cl, 8 dwg, 7 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to obstetrics and gynecology and can be used for prevention and treatment of intrauterine growth retardation syndrome. For this purpose medications are administered to pregnant women of risk group in terms of pregnancy, determined in accordance with the critical period of fetus development. At term of pregnancy, equal to 14-18 weeks, administered is natural micronised progesterone in dose 200 mg intravaginally 2 times per day in 30-day course, complex of polyunsaturated fatty acids of family omega-3 in 30-day course, dry water extract of fresh artichoke leaves in dose 2 tablets 3 times per day in 14-day course, levocarnitin in dose 8 drops 3 times per day in 30-day course, instenon 5.0 ml on 5% dextrose in dose 500 ml intravenously 10 injections every second day per course, deproteinised hemoderivate from calf blood with low-molecular peptides and derivates of nucleic acids 5.0 ml on 5% dextrose in dose 500 ml intravenously every second day 10 injections per course, combined polyvitamin complex with micro- and macro-elements and potassium iodide in dose 200 mg per day daily until fetus birth. After that, at pregnancy term 20-24 weeks and 30-34 weeks, respectively, administered is complex of polyunsaturated fatty acids of family omega-3 in 30-day course, levocarnitin in dose 8-10 drops 3 times per day in 14-day course, calcium nadroparin in dose 0.3 ml subcutaneously in 30-day course, dry water extract of fresh artichoke leaves in dose 2 tablets 3 times per day in 14-day course, instenon on 5% dextrose in dose 500 ml intravenously 10 injections every second day per course, deproteinised hemoderivate from calf blood with low-molecular peptides and derivates of nucleic acids 5.0 ml on 5% dextrose in dose 500 ml intravenously 10 injections every second day per course.

EFFECT: method ensures considerable reduction of number of obstetric complications in pregnancy and labour, prevents perinatal loss, increases quality of individual health of born babies.

2 ex, 1 tbl

Up!