Materials and methods for metabolism modulation

FIELD: medicine.

SUBSTANCE: invention concerns treatments of the conditions caused by pathological metabolism of glucose and lipids. That is ensured by administration of cystamine or its salt in effective doses.

EFFECT: invention provides normalisation of such factors as C-peptide, uric acid, microalbumin, adiponectin.

17 cl, 11 tbl, 6 ex, 10 dwg

 

This application claims the priority of provisional application U.S. No. applications 60/567899 and 60/637618, registered on may 3, 2004 and December 20, 2004, which are included in the present invention by reference in their entirety, including any numerical data, tables, or drawings.

The prior art inventions

Cholesterol is a natural presence in the body of the substance required to perform normal biological functions. For example, it is used for the synthesis of bile acids in the liver, to build and repair cell membranes, vitamin D and synthesis of steroid hormones. There are both exogenous and endogenous sources of cholesterol. For example, the average U.S. daily consume about 450 mg of cholesterol, and additionally in the liver and other tissues formed from 500 to 1000 mg of cholesterol. Another source are undergoing reabsorption approximately 50 percent from 500 to 1000 mg of cholesterol daily bile secreted into the intestine (enteropathic circulation).

Circulation of cholesterol in the bloodstream is carried out by means of plasma lipoproteins, which are particles of a complex of lipid and protein composition, providing transfer of lipids in the blood. There are certain types of lipoproteins, cholesterol, and immunoliposomes low density (LDL), the high-density lipoprotein (HDL) and triglycerides.

Approximately 75 percent of circulating blood cholesterol is usually found in the form of LDL. It is believed that LDL is responsible for delivery to extrahepatic tissues of cholesterol from the liver, where they are synthesized or obtained from dietary sources. The term "reverse transfer of cholesterol" means the transfer of cholesterol from extrahepatic tissues to the liver, where it is decomposed and eliminated.

There are three important metabolic consequences of the accumulation in the cell free cholesterol released from LDL. First a decrease of the synthesis of HMG-COA-reductase (hydroxymethylglutaryl-coenzyme a-reductase), the enzyme that regulates the synthesis of cell cholesterol de novo. Secondly, there is activation of the enzyme alliancepartners (ACAT), which atrificial free cholesterol to complex ester of cholesterol, which is a form of accumulation of cholesterol in the cell. Thirdly, the accumulation of cholesterol inhibits cellular synthesis of new LDL receptors. This feedback mechanism reduces the capture cage LDL from the bloodstream.

On the other hand, it is believed that HDL particles in plasma play a major role in the mechanism of reverse migration, acting as catalysts of tissue cholesterol. HDL also responsible for the pressure of the circulating blood lipids reholstering origin, oxycholesterol and other oxidized products. It is assumed that high levels of HDL in the plasma are not only protection against coronary artery disease, but in fact may promote regression of atherosclerotic plaques (for example, see Badimon et al. Circulation 86: (Suppl. III) 86-94 (1992); Dansky and Fisher, Circulation 100:1762-3 (1999)).

Currently, presumably 105 million of U.S. adults have undesirable high cholesterol levels, namely total cholesterol levels in the blood, components 200 milligrams per deciliter (mg/DL) and above. Among this number, 42 million people have cholesterol levels of 240 mg/DL or higher and are considered a population with a high risk factor. (Publications of the Centers of disease control: national Center for health statistics, according to the American Association of heart disease, history of heart attacks and strokes (Centers for Disease Control: National Center for Health Statistics as published by the American Heart Association, Heart and Stroke Statistics - 2003 Update. Dallas, TX: AHA, 2002.)

The characteristic that makes the useful cholesterol for cell membranes, namely its insolubility in water, at the same time makes this a sign of a potentially fatal when circulating in the blood of large quantities of cholesterol. For example, high cholesterol is usually associated with an increased risk of myocardial infarction, atherosclerosis and the infringement of the mi blood circulation. In addition, violations of cleavage of cholesterol cause various diseases such as gall-stone disease, atherosclerosis, hyperlipidemia, and some diseases of accumulation of lipids.

Atherosclerosis, for example, is a slowly progressive disease characterized by the accumulation of cholesterol inside the arteries. Presents clear evidence regarding the role of oxidized LDL in the occurrence of atherosclerotic lesions (Chisolm, Clin. Cardiol. 14:I-25 TO I-30 (1991)). When oxidized LDL, their properties and mechanisms of interaction with cells vary considerably. These changes are caused by the damaging effects of oxidized LDL on different levels of development of atherosclerotic lesions.

Numerous data indicate that the decrease undesirable cholesterol levels will reduce or prevent atherosclerotic complications. In addition to a diet that supports a healthy body weight and to minimize the concentration of lipids in the plasma, the strategy of therapy to lower cholesterol include eliminating factors that contribute to high cholesterol and drug administration for reducing the concentration of lipoproteins in the plasma as by reducing the production of cholesterol and by increasing the efficiency of removing them from the PLA who we are. For example, recent studies have shown that the use of antioxidants, such as vitamin E or beta-carotene reduces the risk of myocardial infarction in some patients, presumably by preventing LDL oxidation (see NY Times, R. A9, cols. 1-6, Nov. 19, 1992).

Additional ways to maintain desirable/useful levels of serum cholesterol include use of funds to reduce cholesterol (i.e lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin). Several trials prolonged exposure to drugs that reduce cholesterol in patients showed reduced morbidity and mortality from myocardial infarction (see Lipid Research Clinics Investigators, Arch Intern Med. 152:1399-1410 (1992)). Despite the fact that these drugs can cause a significant reduction of cholesterol level in serum, most of them, if not all, have undesirable side effects.

Despite the identified beneficial effects of estrogen on the level of LDL in serum, long-term estrogen therapy had consequences in the form of various disorders, including increased risk of uterine cancer, and possibly breast cancer. The recently proposed scheme of treatment aimed at reducing the risk of cancer, such as the introduction of a combination of progesterone and estrogen cause re warnie bleeding in patients which is unacceptable for most older women. Also, apparently, the combination of progesterone with estrogen smoothes the effect of estrogen on reducing serum cholesterol. Concern about the significant adverse effects associated with estrogen therapy, dictates the need to develop alternative treatment to reduce undesirable cholesterol levels, have a positive impact on the level of LDL in the serum, but does not cause unwanted effects.

Diabetes, which is often associated with high cholesterol levels, is a chronic, incurable disease. Currently, some of 18.2 million or 6.3% of the population in the United States have diabetes. According to approximate estimates, the diagnosis detected in 13 million patients, however, a rough estimate don't know about your disease 5.2 million people. The annual cost of diabetes is the 6th leading cause of death from disease in 2000 cost the U.S. health care system 132 billion $. National Diabetes Information Clearinghouse, NlH Publication No. 04-3892, November 2003. More serious than diabetes-related economic costs are reduced quality of life, serious complications health/effects and deaths associated with diabetes.

Diabetes is vidosu is the cause of new cases of blindness in adult patients aged 20 to 74 years, that is about 12,000 to 24,000 new cases each year. Diabetes is also the leading cause of end-stage renal disease, accounting for about 44% of new cases annually. Only in 2001, about 42,800 people began treatment for end-stage kidney disease (renal failure) due to diabetes. About 60-70 percent of people with diabetes have diabetic nerve damage in severity from mild to severe forms, which, if severe, can lead to amputations of the lower limb. In fact, diabetic patients spend more than 60% of nontraumatic amputations of the lower limb. In 2002-2003 diabetic patients were held over 82000 nontraumatic amputation of the lower extremities. In patients with diabetes the risk of stroke from 2 to 4 times higher. In addition, patients with diabetes adults have mortality rates from heart disease about 2 to 4 times higher than adults who are not suffering from diabetes.

Diabetes is a group of diseases characterized by high blood glucose levels, which are caused by defects of insulin production, insulin action, or both defect simultaneously. Because diabetes may remain undiagnosed for several years, many people learn that they have diabetes, only once again in the development of one of its life-threatening complications. Although the cause of diabetes remains unknown, it is generally accepted that the important factors are genetic factors, and environmental factors, such as obesity and lack of physical activity.

One group of diabetes, type 1 diabetes (or insulin-dependent diabetes, or juvenile diabetes)develops when the body's immune system destroys the pancreatic cells that produce the hormone insulin, which regulates glucose levels in the blood. Type 1 diabetes usually occurs in children and young adults; however, onset may occur at any age. Type 1 diabetes is about 5 to 10 percent of all diagnosed cases of diabetes. Risk factors for development of type 1 diabetes include autoimmune, genetic factors and environmental factors. People diagnosed with type 1 diabetes need daily delivery of insulin by injection or pump.

Another group of diseases diabetes mellitus type 2 (or non-insulin-dependent diabetes, or diabetes of adults)is a metabolic disorder caused due to the inability of the body to a sufficient extent to produce or properly use insulin. This disease usually begins as insulin resistance, the EU is ü with violations in which cells do not use insulin properly, and with the increased demand for insulin, the pancreas gradually loses its ability to produce insulin. Type 2 diabetes is the most common form of the disease, which constitutes 90-95% of diabetes cases. Type 2 diabetes is nearing epidemic size due to the increase in the number of Americans older age and higher prevalence of obesity and sedentary lifestyle.

Gestational diabetes refers to a form in which there is no tolerance to glucose, which is diagnosed in pregnant women. Treatment of diabetes pregnant women during pregnancy it is necessary to normalize the glucose level in the blood of the mother, to avoid complications in the fetus. After pregnancy, a certain percentage of women with diabetes during pregnancy (5-10%) have type 2 diabetes. Women with diabetes, pregnant women have a history of a chance of developing diabetes in the next 5-10 years, amounting to 20-50 percent.

Hyperinsulinemia refers to the excessive production of insulin by pancreatic cells. Often hyperinsulinemia occurs as a result of insulin resistance, which is the condition which is determined by the resistance of cells to insulin. Insulin resistance, as defined above, is with the standing/violation, in which the normal amount of insulin produces insufficient biological (metabolic) reactions. For example, it is believed that in patients with diabetes treated with insulin, insulin resistance is always present when a therapeutic dose of insulin exceeds the level of insulin secretion in healthy humans.

Arterial hypertension is associated with hyperinsulinemia. Among other effects, the action of insulin is to stimulate cell growth of blood vessels and increase the delay of sodium in the kidneys. The last of these functions can be performed without affecting glucose levels and is a known cause of hypertension. The growth of the peripheral vasculature, for example, can cause narrowing of peripheral capillaries, while sodium retention increases blood volume. Thus, reduced levels of insulin in hyperinsulinemia can prevent the abnormal growth of blood vessels and sodium retention in the kidneys caused by high levels of insulin, and thus relieve arterial hypertension.

Violation of homeostasis (or metabolism) glucose refers to the condition in which the blood sugar levels higher than normal but not high enough to be classified as diabetes. There are two categories that are considered risk factors for RA the development of diabetes and cardiovascular disease. Reduced glucose tolerance (IGT) occurs when glucose levels after a 2-hour oral test for glucose tolerance ranges from 140 to 199 mg/DL. PTH is a major risk factor for development of type 2 diabetes and can be detected in approximately 11 percent of the U.S. adult population, or approximately 20 million people. About 40-45 percent of people aged 65 years or older have type 2 diabetes and IGT. Impaired fasting glucose (IFG) occurs when glucose levels during the 8-hour test glucose in the fasting plasma are higher than 110 but less than 126 mg/DL.

Characteristics of patients with diabetes are early development of atherosclerosis and increased cardiovascular diseases and diseases of the peripheral vessels. Hyperlipidemia is an important precipitating factor in the development of these diseases. Hyperlipidemia is a condition usually characterized by pathological increase in circulating lipids in the serum and is an important risk factor for development of atherosclerosis and heart disease. Overview of lipid metabolism disorders can be found, for example, Wilson, Z. et al. (ed.), Disorders of Lioid Metabolism, Chapter 23, in Textbook of Endocrinology, 9thEdition, (W. C. Sanders Company, Philadelphia, Pa. U.S.. 1998).

The serum lipoproteins are carriers of lipids circulate in the her blood. Their classification is based on their density: they are divided into: chylomicrons; lipoproteins, very low density lipoproteins (VLDL), LDL, intermediate density (BOB); low-density lipoprotein (LDL) and high density lipoprotein (HDL). Hyperlipidemia is usually classified as primary or secondary hyperlipidemia. The cause of primary hyperlipidemia usually are genetic defects, whereas the secondary hyperlipidemia is usually caused by other factors, such as various pathological conditions, medication and dietary factors. Alternatively, the plasma may be due to a combination of both primary and secondary causes of hyperlipidemia. High cholesterol levels are associated with several pathological conditions, including coronary artery disease, angina, disease, carotid artery disease, strokes, cerebral arteriosclerosis and xanthoma.

Often diabetics diagnosed dyslipidaemia or abnormal levels of lipoproteins in blood plasma, which is one of the main components of a high prevalence of coronary disease and mortality among subjects with diabetes (for example, see Joslin, E. Ann. Chim. Med, (1927) 5: 1061-1079). Epidemiological studies since then have confirmed the relationship and showed several times higher incidence smart the STI from coronary disease among subjects with diabetes compared with subjects, not suffering from diabetes (for example, see Garcia, M. J. et al. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study," Diabetes, 23:105-11 (1974); and Laakso, M. and Lehto, S., "the Epidemiology of risk factors for cardiovascular disease in diabetes and impaired glucose tolerance," Atherosclerosis, 137 Suppl: S65-73 (1998)). Some of the lipoprotein abnormalities have been described in subjects with diabetes (Howard C., et al., "Lipoprotein composition in diabetes mellitus," Artherosclerosis, 30:153-162 (1978)).

Hyperglycemia, which is a common feature of diabetes, is caused by decreased utilization of glucose by the liver and peripheral tissues and increased production of glucose in the liver. Glucokinase (GK), which is the main glucosephosphate enzyme in β-cells of the liver and pancreas, plays an important role in the regulation of glucose homeostasis in the blood. Significantly the levels of this enzyme are reduced in patients with type 2 diabetes (Caro, J. F. et al. Hormone metabolic Res., 27; 19-22, 1995) and in some animal models of diabetes (Barzilai, N. and Rossetti, L J. Biol. Chem., 268:25019-25025, 1993).

As justified above, diabetes damages virtually every organ system of the body. Complications can include blindness, kidney failure, heart disease, stroke, amputation, loss of sensitivity of nerves, early tooth loss, high risk pregnancy and the birth of children with congenital defects. Currently, insulin injections are the only way of treatment, up to the available for more than 1.5 million patients with type 1 diabetes, and a potential method of treatment for many of the more than 16 million patients with type 2 diabetes in the United States. Treatment of type 2 diabetes usually consists of a combination of diet, exercise, oral means to reduce the level of sugar in the blood, such as preparations of thiazolidinediones, and in more severe cases, insulin. However, clinically available funds reduce blood sugar levels, can have side effects that limit their use, or the tool may be ineffective for a particular patient.

In the case of type 1 diabetes insulin is usually the primary treatment. Despite the recent discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and preparations of thiazolidinediones, such as troglitazone, rosiglitazone or pioglitazone as an oral means of lowering the level of sugar in the blood, treatment of diabetes remains less than satisfactory. A major influence on the cost associated with diabetic using long-term treatment will be diet therapy, positive impact on the uptake of glucose, even in the absence of insulin.

Adiponectin or Acrp30 (Hu, E. et al, "AdipoQ is as novel adipose-specific gene dysregulated in obesity," J. Biol, Chem., 271:10697-10703 (1996)) is the ow obtained from the adipocyte hormone with multiple biological functions. It has been described that obesity, type 2 diabetes and coronary heart disease associated with reduced levels of adiponectin in plasma, and that adiponectin may have alleged anti-atherogenic properties in vitro (Ouchi, N., et al. "Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class And scavenger receptor expression in human monocyte-derived macrophages," Circulation, 103:1057-1063 (2001), Yokota, T., et al. "Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages," Blood, 96:1723-1732 (2000)).

It was also reported that the sharp increase in the level of circulating Acrp30 reduces the production of glucose in the liver (Berg, A. N. et al., "The adipocyte-secreted protein Asgr enhances hepatic insulin action," Nat. Med., 7:947-953 (2001), Combs, T. P. et al. "Endogenous glucose production is inhibited by the adipose-derived protein Asgr™ J. Clin. Invest., 108:1875-1881 (2001)). In addition, there are reports that globular Asgr increases fatty acid oxidation in muscle and causes weight loss in mice (Fruebis, J. et al., "Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice," Proc. Natl. Acad. Sci. USA, 98:2005-2010 (2001)). Additionally, it was reported that treatment with adiponectin, consisting solely of globular domains (globular adiponectin, or gAd), increases fatty acid oxidation in muscle, increasing, thus, insulin resistance in mice with lipoatrophy and in mice with obesity, whereas treatment depressirovano adiponectin also causes improvement, although Enisei, than with gAd (Yamauchi, T. et al. "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity," Nat. Med., 7:941-946 (2001)).

Recently published that adiponectin dramatically activates AMP-kinase (AMPK - AMP-activated protein kinase in skeletal muscle, thus activating fatty acid oxidation and glucose intake (Yamauchi, T. et al. "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase," Nat. Med., 8:1288-1295 (2002)), and that adiponectin constantly activates α-receptor peroxisome proliferator-activated PPARα, which leads to increased oxidation of fatty acids, but lower content of tissue triglycerides in muscle, while these effects are higher with gAd than reprezentirovanii adiponectin (Yamauchi, T. et al. "Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis," J. Biol. Chem., 278:2461-2468 (2002)). Interestingly, the only reprezentirovanii adiponectin in the liver rapidly activates AMPK, causing the recovery associated with gluconeogenesis molecules and activating fatty acid oxidation, and, besides, the only reprezentirovanii adiponectin constantly activates AMPK, activating fatty acid oxidation and reducing tissue levels of triglycerides in the liver. All these changes are aimed at improving insulin sensitivity in vivo (Yamauchi, T. et al. Nat. Med., 8:1288-1295 (2002); Yamauchi, T. et al. J. Biol. Chem., 278:2461-2468 (2002)).

The above results suggest potentialyno the involvement of adiponectin in obesity, cardiovascular disease and diabetes. Production and concentration of circulating adiponectin are reduced in mice and people suffering from obesity (Hu, et al. J. Biol. Chem., 271:10697-107032 (1996); Arita, et al., "Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity," Biochem. Biophys. Res, Commun., 257:79-83 (1999)). Low levels of adiponectin in plasma may be a risk factor for development of coronary heart disease, and also significantly reduced its concentration with type 2 diabetes (Ouchi, et al. Circulation. 100:2473-2476 (1999); Hotta, et al. Diabetes, 50:1126-1133 (2001)). It is assumed that the ability of adiponectin to reduce glucose levels and make reversible insulin resistance may be used as a medicine against diabetes (Yamauchi, et al., Nat. Med. 7;941-946 (2001); Berg, et al. Nat. Med. 7:947-953 (2001)). In addition, it is shown that proteoliticeski splintered fragment of adiponectin causes weight loss in animals with obesity (Fruebis et al., Proc, Natl. Acad. Sci. USA. 98:20(15-2010 (2001)). This protein is directly or indirectly affected by at least four types of cells. Adiponectin modulates NF-Kappa b-mediated signals in the endothelial cells of the aorta person, perhaps explaining their reduced adhesion to monocytes (Ouchi, et al. "Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through and cAMP-dependent pathway," Circulation, 102:1296-1301(2000)). Protein suppresses the differentiation of myeloid precursor cells and has Diskretn the e impact on two monocytic cell lines (Yokota, Blood. 96:1723-1732 (2000)). Also adiponectin may induce metabolic changes in hepatocytes (Yamauchi, et al., 2001; Berg, et al. 2001).

As far as we know, has not previously been reported that cysteamine compounds are useful for the modulation of biological factors, such as levels of adiponectin and the levels of uric acid in the blood, with the goal of therapy of metabolic functions (i.e. glucose metabolism or lipid).

A brief summary of the invention

The present invention provides materials and methods for modulating at least one biological factor by introducing cysteamine compounds for the treatment of a biological condition, such as abnormal glucose metabolism or lipid. Consider biological factors, modulated in accordance with the present invention include insulin-like growth factors (such as insulin-like growth factor 1 or IGF-1)levels of blood sugar, insulin levels, the levels of C-peptide, triglyceride, levels of free fatty acids, uric acid levels in the blood, levels of microalbuminuria, the expression vector of glucose, the levels of adiponectin, total cholesterol in serum levels of high density lipoprotein (HDL) levels and low-density lipoprotein (LDL), but are not limited to the above.

RA is Krivaya in the present invention is the biological state, which can be treated by introducing cysteamine compounds include hypercholesterolemia, hyperinsulinemia; dysglycemia; hyperuricemia; high levels of triglycerides (including high levels of HDL cholesterol), obesity, cardiovascular disease; hypertension; hyperglycemia; the absence of glucose tolerance; low levels of HDL cholesterol; diabetes (types 1 and 2); and any other symptoms, complications, condition or disease associated or high cholesterol, or diabetes, but not limited to the above. According to the present invention the introduction of the patient cysteamine connection may slow down or even prevent the development of biological conditions (such as diabetes or high cholesterol) and any related symptoms, complications, conditions or diseases associated with the specified biological condition.

The present invention provides methods of treatment and/or prevention of disorders of lipid metabolism or prevent, slow growth and/or treatment of complications associated with impaired lipid metabolism. More specifically, the present invention provides materials and methods for the treatment and/or prevention of high cholesterol or hypercholesterolemia or prevent, slow growth and/or treatment develop the s complications, associated with hypercholesterolemia (or high cholesterol), through the introduction of patient cysteamine connection. Specifically, the present invention provides examples of the use of cysteamine connection to reduce total cholesterol levels in the blood levels of free fatty acids, levels of LDL and/or triglyceride. Additionally, cysteamine connection can be used to improve the patient's levels of HDL.

The present invention further provides materials and methods for the treatment of diabetes. In preferred embodiments, the implementation of the present invention provides unique materials and techniques for the treatment and/or prevention of concomitant diabetes symptoms, and preventing or slowing the development of concomitant diabetes complications, conditions or diseases. For example, can be prevented or treated by administration of cysteamine compounds according to the present invention, complications, condition or disease, such as background diabetic retinopathy, macular edema, cataracts, necrobiosis lipoidica, obesity, hyperinsulinemia, hypertension, hyperglycemia, diabetic dermopathy, fungal infections, cardiovascular disease, congestive heart failure, kidney disease, dysglycemia, hyperuricemia, high is the same as a serviceable triglycerides, high levels of HDL cholesterol, obesity (especially abdominal type) and diabetic neuropathy, all of which are typically associated with diabetes.

In preferred embodiments, the implementation cysteamine compound is administered to a patient not having the symptoms observed biological state, but with the detection of predisposition to develop biological state (hereinafter in the present invention such patients classified as "high risk patients"). In a particular embodiment, before the introduction of cysteamine compounds assess the patient to determine the risk of development of type 2 diabetes. Recently been identified by different markers that represent important markers prior to clinical manifestations of type 2 diabetes. Immunological markers that can be identified using methods known to experts in this field to identify patients at risk for type 2 diabetes include autoantibodies to insulin (IAA), glutamic acid decarboxylase (GAD) and autoantibodies to insulation (S), such as representatives of insulation receptor type collection tyrosinemia called IA-2, but are not limited to the above. Identification of patients at risk for type 2 diabetes by identifying such markers, which can be used according to the of the present invention, include the methods according to U.S. patent No. 6391651 and 6316209, but not limited to.

In another embodiment, before the introduction of cysteamine compounds assess the patient to determine the risk of developing high cholesterol. Recently identified the various markers that represent important markers prior to the beginning of clinical symptoms high cholesterol (hypercholesterolemia or hyperlipidemia). Markers that can be identified using methods known to experts in this field to identify patients at risk for high cholesterol include C-reactive protein (CRP) (see Yeh, ET C-reactive protein is an essential aspect of cardiovascular risk factor t op," Can J Cardiol., 20 (Suppl):93-96 (Aug 2004); apolipoprotein C and homocysteine levels in plasma (see Geisel, J et al. "The impact of hyperhomocysteinemia as and cardiovascular risk factor in the prediction of coronary heart disease," Clin Chem Lab Med., 4l(11):1513-7 (2003), but is not limited to the above. Ways to identify patients at risk for high cholesterol levels (hypercholesterolemia or hyperlipidemia) through the identification of markers that can be used according to the present invention, include patent application U.S. No. 2004/0198656, but are not limited to it.

Additional factors that can be used as a sole is e or in combination, to determine the predisposition of the patient's risk for developing hypercholesterolemia include, without limitation, heredity (i.e. familial hypercholesterolemia), high blood pressure, intensity of Smoking, alcohol consumption, diabetes, obesity, physical inactivity, age and gender (i.e. women in postmenopausal women over the age of 50 years) and stress.

In the used method cysteamine compound is administered to the patient before or after the diagnosis of biological condition (i.e. diabetes or high cholesterol) for treating, slowing the onset of symptoms or improve the symptoms associated with the biological condition and/or complications related to biological condition. According to the present invention to obtain therapeutic effect of the composition according to the present invention can be entered at any time (such as not provided for by the scheme is the introduction of time or indefinitely).

According to the present invention was first identified that the introduction of cysteamine connection to the patient may increase the expression vector of glucose (glut4) in liver, muscle, adipocytes and other tissues. In addition, the introduction of the patient cysteamine connection reduces levels of insulin-like growth factor 1 (IPF-1), reduces the level of C-peptide level is uric acid in the blood, reduces levels of microalbuminuria and increases levels of adiponectin. Modulation of these and other biological factors by introducing cysteamine connection can increase the sensitivity of the patient to insulin, reduce hyperinsulinemia, reduce the value assessment model of homeostasis (HOMA), to reduce hyperglycemia and reduce intolerance to glucose.

Also according to the present application, it was noted that the introduction of cysteamine connection to a patient to modulate the biological factors that can display or develop complications or conditions associated with diabetes or high cholesterol levels. As stated above, it was found that the introduction cysteamine connection to the patient can affect the levels of insulin, glucose or sugar levels in the blood, the levels of C-peptide, insulin-like growth factors, levels of uric acid in the blood levels of free fatty acids, the levels of adiponectin, glut4 expression, the levels of triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and levels of microalbuminuria in patients. In particular, the introduction of cysteamine connection to the patient is able to reduce hyperinsulinemia, reduced insulin-like growth factor 1 (IPF-1), to reduce the levels of C-peptide increase expression of glut4 in the tissues, to reduce the levels of W is rnie acids, to reduce the levels of uric acid in the blood, increase levels of adiponectin, reduce triglyceride levels, reduce the levels of LDL, increase HDL levels and reduce levels of microalbuminuria.

Since all of these biological factors associated with the diagnosis and/or development of symptoms associated with diabetes or high cholesterol levels, complications or conditions (see Reist, GC et al. “Changes in IGF activities in human diabetic vitreous,” Diabetes, 53(9):2428-35 (Sept. 2004); Janssen JA and Lamberts, SW, “The role of IGF-I in the development of cardiovascular disease in Type 2 diabetes mellitus: is prevention possible?” Eur J Endocrinol., 146(4):467-77 (2002); Chakrabarti, S et al. “C-peptide and retinal microangiopathy in diabetes,” Exp Diabesity Res., 5(1):91-6 (Jan-Mar 2004); Gottsater, A. et al. “Plasma adiponectin and serum advanced glicated end-products increase and plasma lipid concentrations decrease with increasing duration of Type 2 diabetes,” Eur J Endocrinol., 151(3):361-6 (Sept 2004); Tseng, CH., “Independent association of uric acid levels with peripheral arterial disease in Taiwanese patients with Type 2 diabetes,” Diabet Med., 21(7):724-9 (July 2004); Liese AD, et al., “Microalbuminuria, central adiposity and hypertension in the non-diabetic urban population of the. MONICA Augsburg servey 1994/95,” J Hum Hupertens., 15(11):799-804 (2001); and Wollesen, F. et al., Peripheral atherosclerosis and serum lipoprotein(a) in diabetes,” Diabetes Care., 22(1):93-8 (1999), introduction cysteamine compounds can be used as described for the treatment of concomitant diabetes or high cholesterol complications and conditions, and to prevent the development of such biological conditions in the high-risk patients. Consider the complications that are necessary in order to treat or prevent according to the present invention, include the following complications: hyperinsulinemia, dysglycemia, hyperuricemia, high levels of triglycerides, cholesterol HDL, hypertension, obesity, atherosclerosis, cardiovascular disease, cerebrovascular thrombosis or bleeding, stroke, angina, coronary thrombosis, coronary heart disease (i.e. heart failure), intermittent claudication and lower limb ischemia, but not limited to the above.

According to the present invention the introduction cysteamine connection to the patient before the diagnosis or diabetes may alter the metabolism of the patient so that diabetes or high cholesterol was not developed or evolved to a lesser extent than if the observations were carried out in the absence of cysteamine connection. Modulating the above-mentioned biological factors, materials and methods of the present invention can treat and/or prevent biological condition (such as diabetes or high cholesterol) and related symptoms, as well as to treat and/or prevent related biological States of complications or conditions. For example, in subjects with impaired glucose metabolism or insulin resistance, but without pronounced diabetes (e.g., obese patients),should not develop diabetes due to improved absorption of glucose and insulin resistance in cysteamine activity (i.e. observed cysteamine modulation vectors and glucose metabolism adiponectin and lipid).

According to the present invention, the daily number of doses cysteamine connection, enter the patient diagnosed with diabetes or suffering from complications, conditions or diseases associated with diabetes ranged from approximately 0.1 mg to 1,000 mg cysteamine compound per kg of body weight of the patient (W).

In one embodiment, the group probably facilitates administered to the patient daily without assigned time scheme for the treatment of diabetes, with a therapeutically effective amount of the group probably facilitates approximately from 0.1 mg to 400 mg per kilogram WATTS patient or an equivalent molar quantity cysteamine connection. In another embodiment, the group probably facilitates hydrochloride administered daily to a patient without the appointed scheme for the treatment of diabetes, with a therapeutically effective amount of the group probably facilitates hydrochloride is from about 1.0 mg to 600 mg/kg BW or an equivalent molar quantity cysteamine connection. Preferably for the treatment of diabetes according to the present invention, the patient is given a daily dose group probably facilitates component of less than about 30 mg/kg BW, or an equivalent molar quantity cysteamine connection.

In the embodiment of the present invention, the daily number of doses cysteamine connection is to be placed, enter the patient for treatment and/or prevention of hypercholesterolemia or to slow down the development of concomitant hypercholesterolemia complications can range from about 1 mg/kg to 300 mg/kg body weight. Preferably cysteamine compound is administered in a dose from about 5 mg/kg to 150 mg/kg of body weight a day without assigned schema. In a more preferred embodiment, every day the patient is administered from about 10 mg to 100 mg group probably facilitates hydrochloride per kilogram of body weight or an equivalent molar quantity cysteamine connection.

Cysteamine connection, you can enter as a single or in conjunction with other known means or methods of treatment to reduce cholesterol. Consider means of reducing cholesterol levels or methods of treatment include, without limitation, changes in eating, increased physical activity, weight reduction, replacement hormone therapy in postmenopausal women and drugs (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, resins bile acid, nicotinic acid or Niacin and fibrates).

In another embodiment, the present invention cysteamine compound is administered to a patient diagnosed with diabetes for diabetes, as well as before the rotation and/or reduce the severity of concomitant diabetes complications. In a related embodiment, cysteamine compound is administered in combination with other known means used for the treatment of diabetes (i.e. insulin, sulfonylurea, biguanides, inhibitors of α-glucosidase preparations, thiazolidinediones, meglitinides, D-phenylalanine), for the prevention and/or treatment of diabetes and related diabetes complications.

In another embodiment, provided compositions of the present compounds containing cysteamine connection, which include enabling connection of the primary material, fixing gases, liquids or compounds as inclusion complexes for processing in solid form and to facilitate subsequent release (that is, the allocation in an alkaline medium under the action of the solvent or by melting).

Brief description of drawings

Figure 1 shows the path of the group probably facilitates metabolism.

Figure 2 shows the group probably facilitates as a component of coenzyme A.

Figures 3-5 show the results of oral tests, glucose tolerance, performed in the mouse model, proving the effectiveness of the materials and methods of the present invention.

Figure 6 shows the results of tests of the levels of glucose, performed in the mouse model, proving the effectiveness of the materials and methods of the present invention.

Figure 7-10 who have serologic test results, performed in the mouse model, proving the effectiveness of the materials and methods of the present invention.

Detailed disclosure of the invention

The present invention provides materials and methods for modulating at least one biological factor by introducing cysteamine compounds for the treatment of a biological condition, such as a violation of the metabolism of glucose or lipids. Consider biological factors, modulated in accordance with the present invention include insulin-like growth factors (such as insulin-like growth factor 1 or IPF-1), the levels of blood sugar, insulin levels, the levels of C-peptide, triglyceride, levels of free fatty acids, uric acid levels in the blood, levels of microalbuminuria, the expression vector of glucose, the levels of adiponectin, the levels of high density lipoprotein (HDL) levels and low-density lipoprotein (LDL), but are not limited to the above.

Preferably the present invention provides materials and methods to treat or prevent high cholesterol (hypercholesterolemia or hyperlipidemia) the patient and/or treatment or delay/prevent complications, conditions or diseases associated with high cholesterol (hypercholesterolemia, eligibilities). The present invention also preferably treats and/or prevents the development of diabetes and related diabetes symptoms and complications, conditions and/or diseases associated with diabetes.

Used in the present invention the term "treatment" or any of its variants (i.e. to treat, treatment and so on) refers to any treatment of a patient diagnosed with biological conditions, such as hypercholesterolemia or diabetes, using materials and/or methods of the present invention. Used in the present invention, the term treatment includes: (i) prevent or delay the onset of symptoms patient risk associated with the biological condition of interest, which nevertheless revealed the symptoms associated with the biological condition; (ii) improvement of symptoms associated with the biological condition of interest in a patient diagnosed with biological condition; (iii) prevent, delay or improve the symptoms associated with complications, conditions, or diseases associated with the biological condition of interest (i.e. hypercholesterolemia and/or diabetes) as the patient risk groups and patients with diagnosed biological condition; and/or (iv) facilitation of the state (i.e. the mod is th reverse development of hypercholesterolemia and/or diabetes or related complications, conditions or diseases).

Used in the present invention, the term "hypercholesterolemia" (also known as high cholesterol, hypercholesteremia, hyperlipidemia or hypercholesterinemia) refers to a condition characterized by levels of total serum cholesterol or LDL and/or triglycerides, which are higher than levels that are considered normal by ordinary experts in this field. For example, the National institutes of health indicate that normal or optimal levels of total serum cholesterol be less than 200 mg of cholesterol per DL of blood, and normal or optimal LDL levels are less than 100 mg on LDL DL blood. According to some variants of implementation of the present invention hypercholesterolemia includes a condition in which the total cholesterol levels of approximately 200 mg/DL or higher; and the levels of LDL is 100 mg/DL or higher. As suggested by qualified experts in this field, the characteristics used for the diagnosis of hypercholesterolemia, are subject to change and you can apply the latest standards, such as disclosed by the National institutes of health, to identify hypercholesterolemia according to the present invention.

Identification of patients in need of treatment for hypercholesterolemia, surely falls within the scope of knowledge and competence in this area. For example, individuals with levels of serum cholesterol or cholesterol levels LPN identified clinical laboratory tests, which is higher than considered normal by experts in the field, are patients in need of treatment of hypercholesterolemia. Using the following example, clinical specialist, knowledgeable in this area can be easily identified by means of clinical tests, physical examination and medical/family history, patients suffering from hypercholesterolemia and patients predraspolozhena to the development of hypercholesterolemia, and, thus, easily determining whether an individual was a patient in need of treatment for hypercholesterolemia.

Used in the present invention, the term "atherosclerosis" refers to the state of the disease characterized by the development and growth of atherosclerotic lesions or plaques. Identification of patients in need of treatment for atherosclerosis, steadily falls in the scope of the knowledge and abilities of the person skilled in the art. For example, patients suffering from clinically significant atherosclerosis and components risk of atherosclerosis development as a result of hypercholesterolemia, sitouts the patients need treatment from complications associated with hypercholesterolemia.

Used in the present invention, the term "diabetes" is intended to refer to all diabetic conditions, including without limitation, diabetes, gestational diabetes, type 1 diabetes, type 2 diabetes and gestational diabetes. The term "diabetes" also refers to a chronic disease characterized by relative or absolute deficiency of insulin, which results in a lack of tolerance to glucose. Type 1 diabetes also refers to insulin-dependent diabetes mellitus (IDDM) and also includes, for example, juvenile diabetes mellitus. Type 1 diabetes occurs primarily due to destruction of β-cells of the pancreas. Diabetes type 2 also applies to non-insulin-dependent diabetes mellitus (NIDDM) and partly characterized by impaired release of insulin after a meal. Insulin resistance may also be a factor leading to the occurrence of diabetes type 2. Genetic diabetes occurs due to mutations that affect the function and regulation of β-cells.

Also used in the present invention, the term "diabetes" is the value of the level of fasting blood glucose, constituting approximately 130 mg/DL or more, or the value of the level of glucose in the plasma status is engaged in approximately 180 mg/DL or more when measuring levels approximately 2 hours after oral administration of glucose load in a dose of about 75 g or after a meal. By assumption experts in the field of technology characteristics used to identify diabetes, are subject to change and you can apply the latest standards, such as disclosed by the world health organization, to identify diabetes according to the present invention.

The term "diabetes" also implies the inclusion of individuals with hyperglycemia, including chronic hyperglycemia, impaired glucose homeostasis or tolerance and insulin resistance. Glucose levels in the plasma of individuals with hyperglycemia include, for example, glucose concentration, which is higher than normal, as determined by reliable diagnostic indicators. Such individuals with hyperglycemia are at risk or predisposed to the development of overt clinical symptoms of diabetes.

Used in the present invention, the term "complications (complications) hypercholesterolemia" refers to medical/clinical problems that occur more frequently in patients diagnosed with hypercholesterolemia than in the population as a whole. The present invention complications associated with hypercholest what anemia, include, without limitation, cardiovascular diseases (arteriosclerosis, atherosclerosis, stroke, high blood pressure, angina, heart attack/failure, cardiac arrhythmia), pancreatitis, diabetes, obesity and cerebrovascular disease (i.e. hemorrhagic stroke).

Used in the present invention, the term "diabetic complications (complications)" refers to medical/clinical problems that occur more frequently in patients diagnosed with diabetes. The present invention diabetic complications include medical/clinical problems that are caused by changes in the blood vessels and/or nerves as a result of diabetes. They include the condition of the skin (ie, bacterial infection, fungal infection, diabetic dermopathy, diabetic necrobiosis lipoidica (i.e. diabetic bladder), eruptive xanthomata, allergic skin reactions, finger sclerosis, disseminated rularuu granuloma and acanthosomatidae), gum disease, pathology of the eye (i.e. glaucoma, cataracts, retinopathy), kidney disease, neuropathy (i.e. system neuropathy, distal systemic neuropathy, proximal neuropathy, femoral neuropathy, the neuropathic arthropathy, cranial neuropathy,autonomic neuropathy, compression neuropathy and diabetic amyotrophy), hyperinsulinemia, dysglycemia, hyperuricemia, obesity, hypercholesterolemia, cardiovascular diseases/disorders (i.e. hypertension, heart disease, myocardial infarction, stroke) and is not limited to the above.

Under used in the present invention, the term "patient" refers to organisms, including mammals, have provided treatment compositions according to the present invention. Mammal species for which the disclosed methods of treatment are useful include apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals (i.e. Pets)such as dogs, cats, mice, rats, Guinea pigs and hamsters, but are not limited to the above.

The terms "co-administration" and "concurrently enter"used in the present invention include introducing the compound or treatment method that is suitable for use with the methods of the present invention (introduction cysteamine compounds for modulation of biological agents for the treatment of a particular biological state. In some embodiments, the implementation cysteamine compound is administered in conjunction with additional therapeutic agent known in ka is este useful for the treatment of diabetes or hypercholesterolemia. For example, according to the present invention cysteamine compound can be administered simultaneously with treatments or therapies useful for the treatment of hypercholesterolemia (i.e. increasing physical activity, change in consumption of a diet, reducing/stopping alcohol consumption and Smoking, the use of therapeutic agents, such as lovastatin, pravastatin, simvastatin, fluvastatin, and atorvastatin) or for treatment of concomitant hypercholesterolemia complications, conditions or diseases.

In other embodiments, implementation cysteamine compound can be administered simultaneously with at least one additional therapeutic agent suitable for use in the treatment of diabetes (insulin and/or compound that lowers the level of sugar in the blood) or for the treatment of diabetes-related complications, conditions or diseases.

According to the present invention, therapeutic agent may be provided in a mixture with cysteamine connection, for example, in the pharmaceutical composition; or the tool and the group probably facilitates can be provided as separate compounds, such as, for example, separate pharmaceutical compositions that are applied sequentially, simultaneously or at different times. Preferably, if cysteamine connection and know what tool (or treatment) for the treatment of hypercholesterolemia and/or diabetes used separately, they are not so distant from each other by the time that cysteamine connection and the connection is not known can interact with.

Used in the present invention, the reference to "cysteamine connection" includes the group probably facilitates various cysteamine salts, which include pharmaceutically acceptable salts cysteamine connection and cysteamine predicate, which can, for example, be metabolised in the body for the formation of the group probably facilitates. Also in the scope of the present invention is enabled analogs, derivatives, conjugates and metabolites group probably facilitates which can, as described in the present invention to modulate biological factors in the treatment of a biological condition, prevention of biological conditions in the high-risk patients or in the treatment of complications, condition or disease associated with interest biological condition. Various analogs, derivatives, conjugates and metabolites group probably facilitates are well known and easily applied by specialists in this field and include, for example, the compounds, compositions and methods of delivery, as set forth in U.S. patent No. 6521266; 6468522; 5714519 and 5554655.

The present invention cysteamine compound includes compounds that are known kakuyama endogenous production group probably facilitates includes Pantothenic acid. Pantothenic acid is a naturally occurring vitamin, which in mammals is converted into coenzyme A, which is the substance essential for many physiological reactions. The group probably facilitates is a component of coenzyme a, and increasing the level of coenzyme And leads to increased levels of circulating group probably facilitates. Alkali metal salts, such as rejonowy phosphate magnesium and sulfur magnesium (Epsom salt), increase the formation of coenzyme A. in Addition, the collapse of coenzyme a to group probably facilitates increases in the presence of a reducing agent, such as citric acid. Thus, the combination of Pantothenic acid and alkali metal salts leads to an increase in the production of coenzyme a, parallel group probably facilitates. Accordingly, in one embodiment, the present invention can be achieved provide the benefits of group probably facilitates formulated in the present invention, promoting endogenous development group probably facilitates through the natural process of metabolism, such as, for example, through action of coenzyme a or as a metabolite of cysteine (see Figures 1 and 2) or through the introduction of Pantothenic acid.

Used in the present invention, the term "pharmaceutically acceptable salt" refers to any salt cisteni the new connection, which is pharmaceutically acceptable and is not strongly reducing or inhibiting the activity cysteamine connection. Suitable examples include acid additive salts of organic or inorganic acids, such as acetate, tartrate, triptorelin, lactate, maleate, fumarate, citrate, methane sulfonate, sulfate, phosphate, nitrate or chloride.

Used in the present invention, the term "effective amount" refers to the amount necessary to achieve the desired biological response. According to the present invention an effective amount cysteamine connection represents the amount necessary to ensure a visible effect in at least one biological factor (i.e. a marked increase in the level of adiponectin) for use in the treatment of biological conditions (such as lowering total cholesterol levels in the blood of patients diagnosed with hypercholesterolemia or to prevent the onset of diabetes in a patient at risk). The effective amount may include an amount necessary to reduce to 1%-85% of the total cholesterol in serum or glucose in the blood. In specific embodiments, the effective amount allows the reduction of 5%, 10%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% and 00% severity of complications, associated with the biological condition (i.e complications associated with diabetes or hypercholesterolemia, such as obesity, retinopathy, glaucoma, cataracts, heart disease, stroke, hypertension, neuropathy, dermopathy, gum disease, etc).

The present invention first provides useful materials and methods for the modulation of various biological factors by introducing cysteamine connection. In one embodiment, the materials and methods of the present invention treat hypercholesterolemia and/or complications associated with hypercholesterolemia, and diabetes and/or complications associated with diabetes, through the introduction of patient cysteamine connection. In particular in the present invention example presents an introduction cysteamine connection to the patient before or after diagnosis of hypercholesterolemia and/or diabetes. In a preferred embodiment, the group probably facilitates hydrochloride (and/or its analogs, derivatives and predicate) is administered to a patient for the treatment of hypercholesterolemia, diabetes, or complications, conditions, or diseases associated with hypercholesterolemia, and diabetes. Preferably the introduction cysteamine connection (such as a group probably facilitates hydrochloride) is conducted without a specific schemes on time is.

Cysteamine compound can be administered simultaneously with other known means, and/or treatment methods used to treat diabetes (that is, with insulin, sulfonylurea, biguanides, inhibitors of α-glucosidase, preparations of thiazolidinediones, meglitinides, D-phenylalanine) and/or for the treatment of hypercholesterolemia and/or diabetes-related complications. In other embodiments, implementation of the present invention cysteamine compound can be administered simultaneously with the materials and/or methods used to treat hypercholesterolemia, including, without limitation, adjustments in food intake (i.e. the reduction of saturated fat and cholesterol in the diet); increasing physical activity, weight loss, reduction or cessation of alcohol/Smoking, substitutive hormone therapy and drugs that reduce the level of cholesterol (it has the means, which increases the secretion of bile acid, nicotinic acid and fibrin acid).

In other embodiments, implementation cysteamine compound can be administered simultaneously with the materials and/or methods used to treat complications associated with hypercholesterolemia, including, without limitation, drugs and methods of treatment of cardiovascular diseases (i.e. lifestyle changes (consumed is e food physical activity, reduction or Smoking cessation, use of beta-blockers, benazepril, ramipril and/or torsemide), arteriosclerosis (i.e. lifestyle changes, the use of alpha-blockers), atherosclerosis (i.e. lifestyle changes, the use of aspirin or ACE inhibitors), stroke (i.e. the use of antiplatelet agents, anticoagulation funds), high blood pressure (i.e. lifestyle changes, the use of antihypertensive drugs), pancreatitis (i.e. the use of antibiotics, blocker H2receptors), diabetes (i.e., the use of insulin) and obesity (i.e., the change in food intake).

Cysteamine compound can be administered simultaneously with insulin to treat type 1 diabetes, type 2 diabetes and related conditions and symptoms. When type 2 diabetes, insulin resistance, hyperinsulinemia, diabetes-hypertension, obesity or the lesion of blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin, connective tissue, or immune system cysteamine compound can be administered simultaneously with hypoglycemic connection instead of insulin. Alternatively, cysteamine compound can be administered simultaneously with insulin and hypoglycemic compound for the treatment of diabetes 2 t is PA, insulin resistance, hyperinsulinemia, diabetes-hypertension, obesity or destruction of blood vessels, eyes, kidneys, nerves, autonomic nervous system, skin, connective tissue, or immune system. Additional compounds and/or drugs, with which you can enter cysteamine connection, include, without limitation, drugs for genetic engineering basis; insulin and methods of insulin administration (i.e. insulin pump for subcutaneous infusion of insulin, introduction via nebulizer); sulfonylureas (i.e gliburid, glipizide, glimepiride, tolbutamide, chlorpropamide); a means of enhancing insulin secretion (i.e. Repaglinide, nateglinide); alpha-glucosidase inhibitors (i.e acarbose, miglitol); biguanide and preparations of thiazolidinediones (rosiglitazone, pioglitazone).

Compositions of the present invention can be derived by various routes of administration, including, for example, forms of oral administration such as tablets, capsules or the like, or by parenteral, intravenous, intramuscular, transdermal, buccal, subcutaneous routes of administration, in the form of suppositories, or in other ways. Such compositions are referred to in the present invention in General as "pharmaceutical compositions". Usually they may have Itsa in a standard dosage form, namely in the form physically discrete units suitable as a single dose for human consumption, with each dose contains a specified quantity of active ingredient calculated to produce the desired therapeutic effect in combination with one or more other pharmaceutically acceptable components, such as diluent or carrier.

Cysteamine compound of the present invention can be produced according to known methods to prepare pharmaceutically useful compositions. In some sources described formulations, which are known and readily available to specialists in this field. For example, in the publication "Remington''s Pharmaceutical Science (Martin EW [1995] Eastor Pennsylvania, Mack Publishing Company, 19thed.) describes formulations that can be used in connection with the present invention. Formulations suitable for parenteral administration include, for example, sterile aqueous solutions for injection, which may contain antioxidants, buffers, bacteriostatic and dissolved substances, which render the formulation isotonic with the blood of the recipient, intended for introduction; and aqueous and non-aqueous sterile suspensions that can include suspendresume tools and thickeners. The formulations may be presented in a package for a single dose or in packaging the La and repeated administration, for example sealed ampoules and vials and may be stored in the dried state, with the necessary condition for the existence of the sterile liquid carrier, for example water for injection before use. Extemporally injection solutions and suspensions can prepare from sterile powders, granules, tablets, etc. Need to understand that in addition to the components, in particular to the aforementioned ingredients, the formulations of the present invention may include other means conventional in the art having regard to the type of the considered formula.

In one embodiment, compositions are provided containing cysteamine connection and media, such as starting materials compounds of inclusion. Described in the present invention, the source material connection enable interact with cysteamine connection to increase the water solubility, increased chemical stability and/or enhance delivery of a drug (such as cysteamine connection) to biological membranes and through them. It is believed that by providing media, such as starting materials compounds include, you can safely delivered to the patient stable molecule cysteamine connection in the dose that will not cause toxicity. To omnitele, materials such media may include covering materials (i.e. intersolubility floor)that allow the dissolution of the coating in an alkaline environment, such as in the intestine.

Source material connection switching, which can be used according to the present invention include the materials disclosed in the patent application U.S. No. 20040033985 included in the present invention in its entirety. Consider starting materials compounds include include proteins (such as albumin), crown-ethers, polyoxyalkylene, polysiloxane, zeolites, cholestyramine, colestipol, colesevelam, colestimide, sevelamer, derivatives, cellulose derivatives, dextran, starch, starch derivatives and their pharmaceutically acceptable salts. Consider derivatives of cellulose and derivatives of dextran include DEAE-cellulose (diethylaminoethyl-cellulose), guanidinoacetate or DEAE-Sephadex. Preferred starches or starch derivatives for inclusion in compositions of the present invention include cyclodextrin, retrograding starch decomposed starch, a combination of retrograding and decomposed starch, hydrophobic starch, amylase, the starch-diethylaminoethylamine and 2-hydroxyethylated-starch.

According to the present invention, the preferred source is e materials compounds include include cyclodextrin and/or its derivatives (i.e. methyl-β-cyclodextrin (M-β-CD), hydrodiuril-β-cyclodextrin (HP-β-CD), hydroethyl-β-cyclodextrin (β-CD), polycyclohexylene, ethyl-β-cyclodextrin (E-β-CD) and branched cyclodextrin, but are not limited to the above. According to a specialist in this field can be used according to the present invention any cyclodextrin or a mixture of cyclodextrins, cyclodextrine polymers or modified cyclodextrins. Cyclodextrins are available from Wacker Biochem Inc., Adrian, Michigan or company Cerestar USA, Hammond, Indiana, as well as from other suppliers. The formation of inclusion complexes using cyclodextrin or its derivatives, protects the component (i.e. cysteamine connection) from losses due to evaporation from destruction by oxygen, acids, visible and ultraviolet light and from intramolecular and intermolecular reactions.

The General chemical formula cyclodextrin is a (C6O5H9)n. The contents of the source materials of the compounds included in the compositions of the present invention can vary from about 1 to 80% by weight. Preferably the content of the source material compounds incorporating the present invention ranges from about 1 to 60% by weight. The actual amount of used raw materials connection is switched on it will largely depend on the actual with the holding cysteamine compounds and therapeutic tools if any, used in cooked compositions of the present invention.

Introduction cysteamine compounds according to the present invention can be accomplished in any suitable way and the technology available now or in the future known to specialists in this field of technology. In preferred embodiments, the implementation cysteamine connection form in patentable and easy-to-use oral formulation such as a capsule, tablet, toffee, chewing gum, beverage, etc. Its use, therefore, takes place during, before or after diagnosis of hypercholesterolemia and/or diabetes.

According to the present invention the compositions contain as an active ingredient an effective amount cysteamine compounds and one or more non-toxic, pharmaceutically acceptable carrier or diluent. Examples of such carriers used in the present invention include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, sorbitol, Inositol, xylitol, D-xylose, mannitol, powdered cellulose, microcrystalline cellulose, talc, colloidal silicon dioxide, calcium carbonate, magnesium carbonate, calcium phosphate, aluminum silicate-calcium, aluminium hydroxide, sodium starch phosphate, lecithin and is equal to the n carriers and diluents.

To ensure the introduction of such dosages for the desired therapeutic effect of the composition of the present invention to NCEP will usually contain from about 0.1% to 95% of the total composition including carrier or diluent, and diabetes will usually contain from about 0.1% to 45% of the total composition including carrier or diluent. The applied dose can be modified depending on the age, weight, health status or gender of the individual in need of treatment.

In some embodiments, implementation of the present invention assessing the patient to identify the risk of developing insulin-dependent diabetes mellitus (IDDM) before the simultaneous application of cysteamine connection and at least one additional therapeutic agent (i.e. exercise, improve consumed diets and weight loss). Recently been identified by different markers as important markers prior to clinical symptoms of IDDM. Immunological markers that can be identified using methods known to the person skilled in the art technique for assessing the predisposition to diabetes in the absence of symptoms in patients, include auto-antibodies to insulin (IAA); decarboxylase glutamic acid (GAD); and auto-anti the ate to insulation (ICA), such as representatives of insulation receptor type collection tyrosinemia called IA-2, but are not limited to the above. How to identify asymptomatic patients with a predisposition to diabetes by identifying such markers, which can be used according to the present invention include methods according to U.S. patent No. 6391651 and 6316209, but not limited to.

In one embodiment, the dose cysteamine connection, input the patient to modulate a single biological factor is approximately 1 mg/kg body weight to 1000 mg/kg of body weight a day without some schemes in time. Preferably group probably facilitates hydrochloride administered daily at a dose of less than about 30 mg/kg of body weight for the treatment of a biological condition. In one embodiment, the group probably facilitates administered daily to a patient without a specific schemes on time for the treatment of diabetes, with a therapeutically effective amount of the group probably facilitates approximately from 0.1 mg/kg to 400 mg per kilogram of body weight of the patient WATT or equivalent molar quantity cysteamine connection. In another embodiment, the group probably facilitates hydrochloride administered daily to a patient without a specific schemes on time for the treatment of diabetes, with a therapeutically effective to the number of group probably facilitates hydrochloride is from about 1.0 mg to 600 mg/kg BW or an equivalent molar quantity cysteamine connection. Preferably the patient for treatment of diabetes according to the present invention is administered daily dose group probably facilitates or equivalent molar quantity cysteamine compounds comprising less than about 30 mg/kg BW.

In one embodiment of the present invention, the daily number of doses cysteamine connection, enter the patient for treatment and/or prevention of hypercholesterolemia or slow the development of related complications of hypercholesterolemia, may be from about 1 mg/kg body weight to 300 mg/kg body weight. Preferably cysteamine compound is administered in a dose from about 5 mg/kg body weight to 150 mg/kg of body weight a day without some schemes in time. In a more preferred embodiment, from about 10 mg to 100 mg group probably facilitates hydrochloride per kilogram of body weight or an equivalent molar quantity cysteamine connection daily administered to the patient.

Below are examples that illustrate how the implementation of the present invention. These examples should not be construed as limiting the scope of the present invention. All the above percentages are weight percentages, and all the proportions of soluble mixtures specified by volume, unless otherwise indicated.

Example 1

Nineteen male rats Goto-Kakizaki l the Wistar Institute (GK rats) with a body weight of 300±20 g were kept in steel cages for 3-4 rats in the same cage. Cells were changed every two days. Supported internal temperature and relative humidity, respectively, at 23±3°C and 65±1%. Provided food and drinking water. The GK rats given the opportunity to adapt within one month. When GK rats showed symptoms of diabetes (that is, frequent meals, frequent drinking, frequent urination, and a high level of plasma glucose, and insulin resistance), was randomly divided into 3 groups: the control group consisted of 7 rats; 6 rats was each of the treatment groups I and II.

During the preliminary stage.

One day before the experiment, at 17:00, removed all food from all groups, but drinking water is not removed. On the second day at 09:30, all GK rats was measured by the level of plasma glucose on an empty stomach. 10:00 conducted the test for tolerance to glucose (2 g/kg BW) and the level of plasma glucose was measured in all GK rats. On the third day of GK rats of the control group orally injected with saline (2 ml/rat) and GK rats in treatment groups I and II oral injected with a solution of Metformin (17 mg/kg body weight (W), 2 ml once per day at 09:30). This mode is observed in the next few days. On the ninth day measured the levels of plasma glucose on an empty stomach and again performed oral test for glucose tolerance in all GK rats in all groups.

The period of the middle stage is.

On the tenth day mode for GK rats in the treatment group II was replaced by oral administration of Metformin with group probably facilitates hydrochloride (Metformin at a dose of 17 mg/kg BW, group probably facilitates hydrochloride at a dose of 15 mg/kg BW) in the next 6 days, while the mode for the control group and the treatment group 1 remained unchanged. This mode was observed for six days.

The period of the final stage.

Six days after the change of regime was measured by the glucose level in plasma glucose and conducted tests for glucose tolerance, and taking samples of blood and tissue samples (liver, duodenum, pancreas, fat and muscle) from all GK rats from all groups. Blood samples were kept at 4°C for three hours and centrifuged for ten minutes at 3500 rpm Then selected the serum and kept at -20°C. tissue Samples immediately after collection were placed in liquid nitrogen and then kept at -80°C.

Ongoing trials on glucose tolerance included the stages of starvation GK rats during the night. The next day at 09:30 measured the levels of plasma glucose on an empty stomach. 10:00 oral injected with a glucose solution (2 mg/kg BW). Blood samples were collected from the tail vein after 0, 0,5, 1, 2 and 3 hours and then on the test equipment analyzed the level of glucose in plasma.

Serological methods the study included the phases of the ISM is rhenium levels of insulin in serum radioactive measurement and measure cholesterol levels, free fatty acids and triglycerides, using the known test kits and Protocol.

The results of oral tolerance test glucose in GK rats from all groups during the preliminary phase, middle phase and the final phase of the Example shown in Tables 1, 2 and 3 and Figures 3, 4 and 5, respectively. Changes in the levels of plasma glucose on an empty stomach in the periods shown in the tables and are summarized in Figure 6. These results show that oral administration of a single Metformin, to some extent, reduces duodenal levels of plasma glucose and insulin resistance. However, when Metformin is administered simultaneously with group probably facilitates hydrochloride, watched unexpectedly superior results. Specifically, when introduced, and Metformin, and group probably facilitates hydrochloride, levels of insulin and free fatty acids in plasma (diabetes) was lower than the levels when injected alone Metformin (or cysteamine connection) (see Figure 7-10). Additionally, it is assumed that if both Metformin and cysteamine connection enter only the lower levels of insulin and free fatty acids in plasma will be maintained over a long period of time after termination of the introduction of Metformin/group probably facilitates hydrochloride.

Table 1
Test for glucose tolerance, conducted during the preliminary stage
On an empty stomach0.5 hours1 hour2 hours3 hours
The control groupby 5.8715,57shed 15.3710,917,31
The treatment Ibetween 6.0815,7416,7611,47,82
Treatment II6,0215,2816,711,387,6

Table 2
Test for glucose tolerance, held during the middle stage (6 days after oral administration of Metformin)
On an empty stomach 0.5 hours1 hour2 hours3 hours
The control group5,0317,0418,4611,58,59
The treatment Ito 4.9815,6815,9310,558,5
Treatment II5,0315,6515,810,55of 8.37

Table 3
Test for glucose tolerance, held during the middle stage (6 days after oral administration of Metformin + group probably facilitates hydrochloride)
On an empty stomach0.5 hours1 hour2 hours3 hours
The control group5,2712,83 of 14.5710,817,52
The treatment I4,7512,9813,428,6to 6.67
Treatment II4,7711,7512,378,176

Example 2

The effects of simultaneous administration of Metformin and cysteamine connection nediabeticescoy rats

Thirty-two male Wistar rats (purchased in Central Shanghai laboratory animal Slaccas Laboratory Animal Center) at the age of about 13 weeks and weighing approximately 300 g were allowed to adapt to the conditions of detention for two weeks in individual cages. Feed and water were provided ad libitum.

Wistar rats were randomly divided into 4 groups, each group of 8 rats. Group 1 (control, n=8) were injected with saline via a stomach tube (2 ml/rat); Group 2 (group probably facilitates hydrochloride DC 15, n=8) were injected group probably facilitates hydrochloride via a stomach tube (15 mg/kg body weight (W) in 2 ml tap water); Group 3 (DC 22,5, n=8) took group probably facilitates hydrochloride via a stomach tube (22,5 mg/kg BW in 2 ml tap water); Group 4 (DC 30, n=8) were injected qi is teamine hydrochloride via a stomach tube (30 mg/kg BW in 2 ml tap water). All animals were treated with the indicated doses at 10:00 for 27 days.

Four groups of animals were kept in the same room in different cells from the bottom of the wire mesh to reduce coprophagia during the experiment. Rats were subjected to fasting throughout the night on the 28th day from 22:00 to 9:30 the next day. Rats were injected glucose in a dose of 2 g/kg BW in 2 ml of tap water and the blood was collected from the tail vein over 2 hours after administration of glucose.

The concentration of glucose in plasma were determined using equipment Glucotrendr2 (Roche Diagnostics, Basel, Switzerland), the Concentration of insulin in plasma were determined by radioimmunoassay analysis (Insulin RIA Kit, NO:0410 purchased at a Research Institute in Shanghai Radioimmunoassay). Effects on glucose levels in the plasma of fasting and the effects on insulin levels in the fasting plasma are shown in Table 4. Reducing STD denotes the variability of the data in relation to the average or "standard deviation". Reducing p denotes the significance level of the results.

Table 4
Dose-dependent effects of group probably facilitates hydrochloride on the levels of glucose and insulin in plasma fasting in normal Wistar rats
Average + STDControl DC 15DC 22,5DC 30
Glucose on an empty stomach4,15±0,184,05±0,233,94±0,273,95±0,17
P0,350,0820,037
Insulin on an empty stomach49,62±3,2748,82±3,2748,39±2,3851,32±2,94
P0,550,270,2

The results obtained for the DC 30 (Group 4)compared with the control group (Group 1) were statistically different (p=0,037). Though the DC 22,5 (Group 3) were found to have lower levels of glucose in the blood, the results were not statistically significant compared with the control group (p=0,082).

According to the results it is assumed that the group probably facilitates hydrochloride provides dose-dependent effect on lowering levels of blood glucose in the normal Wistar rats on an empty stomach. Group probably facilitates hydrochloride does not affect the levels of insulin in the blood in normal Wistar rats on an empty stomach.

Example 3

The effects one is belt the introduction of Metformin (at a dose higher than in Example 1) and cysteamine connection diabetic rats

Thirty-six rats Goto-Kakizaki Wistar rats (GK rats) (acquired in Central Shanghai laboratory animal Slaccas Laboratory Animal Center) at the age of about 13 weeks and body weight 321-323 g gave to adapt to the conditions of detention for two weeks in individual cages. Feed and water were provided ad libitum.

36 GK rats were divided into 4 groups according to body weight (W) and the level of glucose in plasma. Group 1 (control, n=10) were injected with saline via a stomach tube (2 ml/rat); Group 2 (group probably facilitates hydrochloride DC, n=6) were injected group probably facilitates hydrochloride via a stomach tube (22,5 mg/kg body weight (W) in 2 ml tap water); Group 3 (Metformin, Met, n=10) took Metformin via a stomach tube (34 mg/kg BW in 2 ml tap water); Group 4 (Met+DC, n=10) was administered Metformin in the dose of 34 mg/kg BW in 2 ml of tap water during the first 10 days and then were injected together group probably facilitates hydrochloride of 22.5 mg/kg BW plus Metformin at a dose of 34 mg/kg BW in 2 ml of tap water in the next 10 days. All animals were treated with the indicated doses at 10:00 for 20 days.

Four groups of animals were kept in a room (temperature 23±3°C and relative humidity 65±1%) in different cells from the bottom of the wire mesh to reduce coprophagia during the experiment. Rats were subjected to starvation is the Oia during the night from 22:00 to 9:30 the next day before how to test for glucose tolerance. Rats were injected glucose in a dose of 2 g/kg BW in 2 ml of tap water at 9:30 for the test on glucose tolerance and the blood was collected from the tail vein after 0.5 hours, 1 hour, 2 hours and 3 hours after administration of glucose. The concentration of glucose in plasma were determined using equipment Glucotrendr2 (Roche Diagnostics, Basel, Switzerland). The concentration of insulin in plasma were determined by radioimmunoassay analysis (Insulin RIA Kit, NO:0410 purchased at a Research Institute in Shanghai Radioimmunoassay). Effects on glucose levels in plasma are shown in Table 5 and the effects on insulin levels in plasma are shown in Table 6.

td align="center"> to 11.52±1,45
Table 5
Test for glucose tolerance for group probably facilitates hydrochloride (DC)input only, and plus Metformin in diabetic GK rats (mean+STD, mol/l)
NOn an empty stomach0.5 hours1 hour2 hours3 hours
Control105,56±0,2215,78±1,9615,32±1,58cent to 8.85±0,8
DC65,80±0,3616,68±1,115,68±0,811,00±0,88,33±0,64
Metformin10of 5.53±0,5315,24±1,3413,98±0,95*9,62±0,83*7,71±1,37*
Metformin + DC105,46±0,4614,07±1,84+to 12.44±0,96*7,71±0,83*6,35±0,73*

The group, which was administered with Metformin, the results obtained after 1 hour, 2 hours and 3 hours, statistically differed (p<0,05, table denoted by *) from the control group. Where group probably facilitates hydrochloride was administered simultaneously with Metformin, the results obtained after 1 hour, 2 hours and 3 hours, statistically differed (p<0,05, table marked with*), which was introduced only Metformin. The results obtained after 0.5 hours while introduction of Metformin and group probably facilitates hydrochloride, reduced compared with the control group (p=0,059, in the table on the right +).

Table 6
The effects of group probably facilitates hydrochloride (DC) on the level of insulin (units/l) adiponectin (ng/ml) in diabetic GK rats (mean+STD)
ControlDCMetforminMetformin+DC
The level of insulin on an empty stomach20,69±1,6722,46±2,65of 18.75±3,9821,08±4,37
P0,1320,230,82
Adiponectin3922±5284318±5903917±4163743±366
P0,0340,9710,206

The results from Table 6 are related to glucose levels in the group, which was introduced only Metformin after 1 hour, 2 hours and at the point of time 3 hours after administration of glucose, statistically significant ex is cialis from the respective control groups. Group probably facilitates hydrochloride, input only, had no effect on glucose levels and insulin levels in diabetic GK rats. The introduction of Metformin resulted in lower, but statistically insignificant, levels of insulin. However, when Metformin was administered simultaneously with group probably facilitates hydrochloride, strengthening lowering levels of glucose (especially compared to therapeutic effect of Metformin when his only introduction) was observed at all time points, except at the point of time on an empty stomach.

It was also revealed that the level of adiponectin was significantly increased with the introduction of group probably facilitates, but not Metformin only. It is assumed that the introduction of only one cysteamine connections can be useful to prevent early as diabetes and hypercholesterolemia in patients at risk, as adiponectin plays an important role in the development of both biological state.

Table 7
The effects of group probably facilitates hydrochloride (DC) and Metformin or their combination on the expression of glut4 in various tissues of diabetic GK rats (mean + STD), expressed in multiples of the changes compared to the control level
DCMetforminMetformin + DC
liverof 3.77±3,152,43±1,852,8±1,0
P0,0020,310,04
muscles1,5±0,741,38±0,671,31±0,75
P0,0010,1520,633
adipocyte2,7±1,162,14±1,393,49±2,37
P0,0050,0950,095

As shown in Tables 5-7, cysteamine connection (such as a group probably facilitates hydrochloride) can significantly increase the expression of total glut4 in the liver, muscle, and adipocytes in GK rats. This increase much more going on in the liver and adipocytes compared with muscles. In this activity assumes that cysteamine the connection can be not only useful to prevent biological conditions associated with expre the Sion of glut4, but also for the treatment of biological conditions associated with low expression of glut4. For example, on the basis of these results cysteamine compounds may be useful for treatment of complications, conditions or diseases associated with low expression of glut4.

Metformin when only the introduction also increases, but not significantly, the levels of expression of total glut4 in all measured tissues. However, the levels of expression of a common carrier of glucose (glut4) in addition rose, when Metformin was administered simultaneously with cysteamine connection.

Example 4

The effect of introducing cysteamine connections to people with diabetes

A small open randomized study conducted at the National reference center for diabetes in China. Were attracted sixty patients of both sexes (aged 30 to 75 years) with diagnosed type 2 diabetes. All subjects were informed and gave their consent to participate. Diabetes was diagnosed on the basis of who criteria established in 1999. In addition, selected patients had to meet the following criteria: (1) history of diabetes less than 5 years; (2) the level of plasma glucose on an empty stomach in the range 7-14 mmol/l; (3) the level of triglycerides in serum was 2.5 mmol/l or higher; (4) the excretion of protein in the urine is 30 mg/day or higher, and (5) lack of reception proteolipid the x drugs and ACE inhibitors in the past month. From the study were excluded patients with the following conditions: (1) dysfunction of the heart, liver and/or kidney; (2) acute diabetic complications and/or any acute cardiovascular complications or other chronic diseases in the last three months, and (3) pregnancy or breast-feeding.

Patients were randomly divided into four groups of 15 patients each. The subjects of the control group did not use anti-inflammatory drugs. The group, which was introduced only group probably facilitates (DC), obtained 540 mg/day group probably facilitates hydrochloride. Group introduction only of Metformin (Met), the dose of Metformin remains constant during this two-month period. In the group DC+Met patients were administered the same dose of Metformin, which they received initially, include an additional 100 mg/day group probably facilitates hydrochloride. All patients were subjected to treatment within two months and samples were taken for analysis and measured after one month and two months after the study. The following results are obtained from samples taken and measured at the beginning of the first month after the study.

Table 8
The effects of group probably facilitates hydrochloride is and the level of lipids and insulin in diabetic patients
Before the introduction ofnAfter introductionnThe difference in vapor95% CIp
Insulin-like growth factor (IGF)49,36±5,751044,37±7,28104,99±5,121,33~8,650,013
The fasting insulin (FINS)35,39±14,43613,25±6,36622,14±19,391,79~42,50,038
C-shock protein (FCP)739±1837557±1197182±16430,1~333,90,026
Sugar fasting (FBS)7,52±1,57118,21±2,4311-0,69±2,11 -2,11~0,720,301
Evaluation model of homeostasis (NOMA)11,94±4,6265,43±3,1966,51±4,941,32~11,70,023
Uric acid in the blood (UA)389±50,9811359±60,161129,5±37,874,07~54,950,027
24 hour microalbuminuria42,73±31,33830,97±25,12811,77±by 40.73-22,28~45,820,441

Table 9
Effects of Metformin on lipid levels and insulin in diabetic patients
Before the introduction ofnAfter introductionnThe difference between the pairs 95% CIp
Insulin-like growth factor (IGF)52,81±10,041047,32±9,12105,49±7.23 percent0,32~10,660,04
The fasting insulin (FINS)19,35±10,025of 12.33±6,057,01±10,23-5,69~19,710,02
C-shock protein (FCP)579±2125693±2205-114±295-480~2530,437
Sugar fasting (FBS)of 8.92±2,712of 8.37±2,03120,54±2,78-1,22~2,30,512
Evaluation model of homeostasis (NOMA)7,33±3,355,35±3,91 51,98±4,47-3,57~7,530,378
Uric acid in the blood (UA)320±6710324±5310-4,41±48,7-39,22~30,40,781
24 hour microalbuminuria27,5±23,69832,86±21,938-5,38±14,36-17,39~6,60,324

Table 10
Effects of Metformin on lipid levels and insulin in diabetic patients
Before the introduction ofnAfter introductionnThe difference in vapor95% CIp
Insulin-like growth factor (IGF)55,59±10,4814 148,83±to 8.413,97~13,690,002
The fasting insulin (FINS)22,33±16,59816,67±at 9.538to 5.66±12,07-4,43~of 15.750,226
C-shock protein (FCP)752±2878699±388854±232-140~2470,535
Sugar fasting (FBS)8,71±1,88138,9±1,3513-0,19±2,14-1,48~1,10,752
Evaluation model of homeostasis (NOMA)9,2±6,998of 6.73±4,0782,46±4,87-1,61~6,530,196
Uric acid in the blood (UA)309±73,7 13313±8113-4,69±46,93-33,05~23,660,725
24 hour microalbuminuria23,37±21,02922,11±30,3591,25±17,98-12,56~15,080,839

As shown in Tables 8-10, the introduction of group probably facilitates hydrochloride significantly reduces the levels of fasting insulin (FINS), NOMA (evaluation model of homeostasis) and uric acid in the blood (UA). On the contrary, with the introduction of a single Metformin decreased only IGF-1. Such results it is assumed that cysteamine connection, you can enter the patient for improvement of insulin resistance. Additionally, the results indicate that the introduction of patient group probably facilitates hydrochloride significantly reduces the levels of insulin-like growth factor 1 (IPF), C-peptide (CP) and microalbuminuria (reliably, but statistically not significant), suggesting that cysteamine connection can be used solely, or in combination with additional therapeutic means to treat or prevent complications associated with diabetes and syndrome resistant the STI to insulin. Abbreviation FBS means blood sugar on an empty stomach.

Example 5

The effect of group probably facilitates hydrochloride in rats with obesity

Table 11
The effects of group probably facilitates hydrochloride in rats with obesity (mean±STD)
ControlDC 11,25DC 22,5
Triglycerides TG (mmol/l)1,22±0,131,15±0,121,1±0,08
P0,2360,024
Cholesterol CH (mmol/l)1,88±0,351,6±0,311,55±0,27
P0,0710,029
HDL (mmol/l)0,99±0,131,11±0,161,04±0,09
P0,083in 0.288
LDL (m is ol/l) 0,65±0,170,61±0,180,63±0,18
P0,60,759
Free fatty acids FFA(mmol/l)1216±236842±2561087±181
P0,0030,189
Uric acid UA (mmol/l)be 18.49±2,8717,41±1,9916,12±1,04
P0,3420,024

As shown in Table 11, the group probably facilitates the dose of 11.25 mg/kg and 22.5 mg/kg can reduce levels of triglycerides and cholesterol levels in rats with obesity. There is a tendency that in rats with obesity group probably facilitates can raise HDL levels and lower LDL levels, but not significantly. Additionally, the group probably facilitates in the indicated doses significantly reduces the levels of uric acid, and free fatty acids. From these results it is assumed that the introduction of the group probably facilitates the patient risk group for the development of hypercholesterolemia (that is, PA is ient with asymptomatic violation of lipid metabolism) may be useful. In addition, from these results it is assumed that the introduction of cysteamine connection to a patient diagnosed with hypercholesterolemia (or with violation of lipid metabolism) may, if not eliminated by this treatment, but to facilitate his/her symptoms related to biological condition. In addition, it can be proven that the introduction of cysteamine compound is therapeutically effective to slow or even prevent any complications, conditions or diseases associated with disturbance of lipid metabolism or hypercholesterolemia.

Example 6

Compositions of the present invention contain from about 1 to 95% by weight cysteamine compounds and from about 1 to 80% by weight of the carrier, such as starting materials compounds of inclusion. In specific embodiments, the implementation of the compositions of the present invention optionally at a dose contain an additional therapeutic agent to provide therapeutic results with the simultaneous introduction of cysteamine connection.

In this example, the source material compounds include mainly contain cyclodextrin and/or its derivatives, which are selected from the group comprising methyl-β-cyclodextrin (M-β-CD), hydrodiuril-β-cyclodextrin (HP-β-CD), hydroethyl-β-cyclodextrin (β-CD), policyclic the trine, ethyl-β-cyclodextrin (E-β-CD) and branched cyclodextrin. While working the contents of the source materials of the compounds included in testamentaria composition varies from 1 to 80% by weight, preferably operating range is from 1 to 60% by weight, and you can also use the preferred operating range of 10 to 40% by weight of the original material connection enable. The actual number used in the preparation of testamentaria composition of starting materials compounds include will depend on the actual content cysteamine connection and additional therapeutic agent (funds), if present.

In specific embodiments, the implementation of the compositions prepared according to the present invention are in the form of small pellets, each of which has a preferred diameter being from 0.28 to 0.90 mm, These pellets are manufactured with the application of the method microencapsulation. The method encompasses the use of macromolecular substances with properties of the inclusion. One substance that can be used, represents the above-described starting materials compounds of inclusion (which contain mainly cyclodextrin). Starting materials compounds include are macromolecular substance that is actuat as molecular capsule for coverage molecule group probably facilitates and/or additional therapeutic agent (medium), whereby cysteamine connection and/or therapeutic agent in the composition is protected and isolated from the world, the rise of temperature, air and humidity environment. Thus, it remains stable cysteamine connection. Starting materials compounds include, used for a method of microencapsulation, preferred are combinations of cyclic polysaccharide having from 6 to 12 glucose molecules, which is obtained by reaction of cyclodextrin glycosyltransferase and starch in the presence of bacteria. In various studies using acute, subacute and chronic toxicity tests have shown that macromolecular substance can reduce toxic levels in the patient. After phase microencapsulation each granule may be coated with at least one and preferably multiple layers of the above materials to cover.

Below is an example of how to prepare the above recipe cysteamine connection. In jacketed reactors, associated with polytetrafluoroethylene and equipped with a stirrer, a polytetrafluoroethylene-coated, with an atmosphere mainly consisting of nitrogen, add 4080 g (75% weight solution group probably facilitates hydrochloride in ethanol. Purity, melting point and burning the rest ispolzuemogo the group probably facilitates preferably be 98% or higher, from 66°C to 70°C and 0.05% or below, respectively. 1200 g of β-cyclodextrin is then added to the reactor like when the protection of nitrogen gas. (As β-cyclodextrin meets the requirements for food additives. In particular, the purity in terms of dry weight is more than 98%; the weight loss at drying is less than 10.0 percent; burning the balance is less than 0.2%; the content of heavy metals is less than 10 ppm; the arsenic content is less than 2 ppm). Then the mixture is then heated for 3 hours at 40°C. Then heating stopped and continue stirring for further two hours received after this the product is crushed and sieved (e.g., cell 40), filtered after vacuum drying of the product, dried at 40-50°C. All parts of the equipment that may come into contact with components of the composition, preferably should be made of stainless steel.

In the mixer tank types protected under dry environment add 4200 g (in terms of dry weight) cysteamine connection, which has been described above, the step of incorporating, 2600 g of fillers and 1200 g agents of disintegration and 1700 binding agents. These components are then thoroughly mixed, you can add a suitable amount of anhydrous ethanol and then mixed with the latter. Get the I mixture is a soft material with moderate strength, so that you can form into a ball, lightly holding hands. Spherical the resulting mixture can then be broken a light touch. After granulating the mixture in the granulator under the protection of nitrogen, the resulting small granules are immediately placed in the dryer on a liquid basis, and then dried at a temperature of 40-50°C essentially in a vacuum environment.

Materials for Intercollege coverage prepare then the method with the following recipe: phthalate cellulose acetate 8.0 g, polyethylene terephthalate 2.4 ml, ethyl acetate 33,0 ml) and isopropyl acetate to 33.6 ml of the Above obtained granules uniformly cover under the protection of nitrogen, at least one layer, but preferably multiple layers of materials Intercollege coating described above. Materials Intercollege coating dissolves only in an alkaline environment. This can protect cysteamine connection from premature extinction of the composition, while it is still in the stomach of the patient. As previously noted, cysteamine connection can adversely irritate the mucous membrane of the stomach of the patient.

The resulting granules testamentaria song and then completely dried in essentially a vacuum dryer at a temperature of from 40 to 50°C. the ZAT is remove all the solvents. Allow cooling of the obtained pellets to room temperature, the microcapsules are mixed with a suitable quantity of flavors and fragrances in the mixer with the double helix on the bracket. Testamentaria composition is a microcapsule with a group probably facilitates hydrochloride and cyclodextrin inside and the outer shell, covered intersolubility materials for cover.

The resulting composition will have melkonarublennoy (or microcapsular) shape having a smooth surface, good flowing properties, and is easily mixed with various animal feed. The diameter of each pellet of the composition is preferably from 0.28 to 0.90 mm Compositions also have excellent stability. It was found that after the composition is Packed in a sealed plastic bag and store in the course of one year in a cool, dark and dry place, their properties remain unchanged.

The composition having the above specific structure, has many functional advantages over isolated cysteamine connection. First, the activity cysteamine connection and additional therapeutic agent (funds), if any, contained in the composition is retained after cooking. Secondly, the composition should not cause nor is such a significant adverse effect on the stomach of the patient. Thirdly, the activity of the composition is maintained not only during the period of storage, but more importantly, when passing through the gastrointestinal tract, until then, until it reaches the intestines of the patient.

All patents, patent applications and publications referred to or cited in the present invention, incorporated in it by reference in their entirety, including all figures and tables, to the extent they do not conflict with the explicit teachings of this specification.

You must understand that the examples and embodiments of described in this invention, are intended for illustrative purposes only and that various modifications or light changes proposed by the specialists in this field must be within the essence and scope of this application.

1. A method of modulating at least one biological factor for the treatment of a biological condition associated with the specified biological factor, where the condition is selected from the group consisting of hypercholesterolemia, hyperlipidemia, hyperinsulinemia, high levels of triglycerides, high levels of uric acid, obesity and low levels of high density lipoprotein, and biological factor represents at least one factor selected from the group consisting of levels of C-peptide, ur the init of uric acid in the blood, levels of microalbumin and levels of adiponectin, where the method includes the administration to a patient who has been diagnosed with a specified biological condition, the effective number of group probably facilitates or its salts.

2. The method according to claim 1, where the biological state is a hypercholesterolemia or hyperlipidemia, and an effective amount of group probably facilitates or its salts is from about 1.0 mg to about 300 mg per kilogram of body weight daily, or an equivalent molar amount.

3. The method according to claim 2, where the effective amount of the group probably facilitates or its salts is from about 5.0 mg to 150 mg per kilogram of body weight daily, or an equivalent molar amount.

4. The method according to claim 3, where the group probably facilitates or its salt is a group probably facilitates hydrochloride, and the effective amount is from about 10 mg to 100 mg per kilogram of body weight daily, or an equivalent molar amount.

5. The method according to claim 2, additionally comprising the step of simultaneously applying the group probably facilitates or its salts with other well-known cholesterol-tool.

6. The method according to claim 5, where other known means selected from the group consisting of lovastatin; pravastatin; simvastatin, fluvastatin, atorvastatin; resins bile acid; nicotinic acid; Niacin and fibrates.

7. The method according to claim 2, the additional includes the step of simultaneously applying the group probably facilitates or its salts with other known materials, used to treat complications associated with hypercholesterolemia or hyperlipidemia.

8. The method according to claim 7, in which other known materials selected from the group consisting of beta-blockers; benazepril; ramipril; torsemide; alpha-adrenergic blockers, aspirin, ACE inhibitors; protivodiabeticakih means; anticoagulant funds; hypertensive means; antibiotics; blockers H2-receptor and insulin.

9. The method according to claim 1 where the effective amount of the group probably facilitates or its salt is from about 0.1 mg to 1000 mg per kilogram of body weight daily, or an equivalent molar amount.

10. The method according to claim 9, where the effective amount of the group probably facilitates or its salt is less than about 30 mg per kilogram of body weight daily, or an equivalent molar amount.

11. The method according to claim 1, further comprising a stage of encapsulating the group probably facilitates or its salts in the source material connection enable to ensure a solid form group probably facilitates or its salts for injection.

12. The method according to claim 11, where the source materials connections enable selected from the group consisting of proteins; crown ethers; polyoxyalkylene; polysiloxanes; zeolites; cholestyramine; colestipol; colesevelam; colestimide; sevelamer; cellulose derivatives; derivatives of dextran, starch; producing the different starch and their pharmaceutically acceptable salts.

13. The method according to item 12, where the source material compounds include contains the cyclodextrin to form small granules group probably facilitates or its salts.

14. The method according to item 13, where the size of the granules have a diameter of approximately from 0.28 to 0.90 mm

15. The method according to item 13, where the cyclodextrin is tsiklodekstringlyukanotransferazy; the method further includes the step of the reaction tsiklodekstringlyukanotransferazy with glucose molecules in the presence of bacteria.

16. The method according to item 13, further comprising the stage of adding the group probably facilitates or its salt in a mixer; adding the source material compounds included in the mixer; heating the mixture for the formation of a solid product, and vacuum drying the solid product.

17. The method according to item 16, further comprising a stage Intercollege coating solid product.



 

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3 cl, 4 dwg, 9 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns a new glucitol derivative of formula (I): wherein m represents an integer chosen from 1-3; each R1, R2, R3 and R4 are independently choose from hydrogen atom and benzyl groups; Ar1 represents a naphthyl group which can be substituted by one or more substitutes chosen from the group, consisting of C1-C6alkyl group or halogen atom; A represents 5-7-members aromatic heterocyclic group containing one or more heteroatoms independently chosen from oxygen atom and sulphur atom which can form a condensed cycle with an aromatic carbocycle or an aromatic heterocycle where A can be substituted by one or more Rb provided when A is a benzocondensed cycle containing two or more rings, the group -(CH2)m- is connected with a heterocycle in A; Each Rb is independently chosen from C1-C6alkyl group, halogen atom and C1-C6-alkoxy group; or to their pharmaceutically acceptable salts. These compounds are used as a Na+ cotransport inhibitor and exhibits ability to reduce blood sugar level.

EFFECT: invention covers a pharmaceutical composition based on these compounds and to the method for treatment and prevention of such diseases associated with hyperglycemia, as diabetes, diabetes complications and obesity.

12 cl, 4 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: described are novel thiophene derivatives of formula (1) and pharmaceutically acceptable salts thereof, where A is -CH2CH2-, -NH-CH2-, -CH2-O or -CH2NH-, R1 is hydrogen or alkyl, when X is C-R4, R1 additionally represents halogen, and when A is -CH2-CH2- or -CH2NH, R1 additionally represents alkoxy, R2 is hydrogen, alkoxy, fluoralkoxy, hydroxyalkoxy, hydroxyalkyl, di-(hydroxy)alkoxy, pyridinyl-3-methoxy, pyridinyl-4-methoxy, R3 is hydrogen, alkyl, trifluoromethyl, and when X is C-R4, R3 additionally represents halogen, and when A is -CH2-CH2-, R3 additionally represents alkoxy, X is N or C-R4, R4 is hydrogen, alkyl, alkoxy or halogen, R5 is methyl or ethyl. Also described are isomers of the said compounds, an initial compound for synthesis of formula (1) compound, which has agonistic effect on S1P1/EDG1 receptors, as well as a pharmaceutical composition based on formula (1) compound and use of formula (1) compound.

EFFECT: obtaining a pharmaceutical composition for preventing or treating diseases or disorders associated with activated immune system.

19 cl, 2 tbl, 167 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R is hydrogen or (lower)alkyl; R1 is a (lower)alkyl or (C3-C7)cycloalkyl; X is nitrogen while Y is carbon or Y is nitrogen while X is carbon; m equals 0 or 1; Z is C(O) or SO2; R2 is selected from a group consisting of (lower)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl substituted with (lower)alkyl, (lower)phenylalkyl, where the phenyl ring is not substituted or is mono- or disubstituted with (lower)alkoxy or halide, pyridyl which is mono- or disubstituted with a halide, and NR3R4 or when Z is C(O), R2 can also be a (lower)alkoxy; R3 is hydrogen or (lower)alkyl; R4 is selected from a group consisting of (lower)alkyl, (lower)alkoxyalkyl, (C3-C7)cycloalkyl, unsubstituted phenyl or phenyl which is mono-substituted with (lower)alkoxy, or (lower)phenylalkyl, where phenyl is not substituted or is mono- or disubstituted with a halide; or R3 and R4 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-member heterocyclic ring which optionally contains an additional heteroatom selected from oxygen, the said heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from (lower)alkyl, halide and alkyl halide, or is condensed with a phenyl or cyclohexyl ring, and to their pharmaceutically acceptable salts, as well as to pharmaceutical compositions containing these compounds.

EFFECT: obtaining novel compounds and pharmaceutical compositions based on the said compounds, which are suitable for treating and/or preventing diseases which are associated with modulation of H3 receptors.

25 cl, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and biotechnology and concerns an anticancer drug based on nanoparticles bearing recombinant human tumour necrosis factor alpha. Substance of the invention includes the anticancer drug representing nanoparticles each of which contains a nucleus consisting of polynucleotide complex representing double-helical RNA (dhRNA) - an interferonogenesis inducer, and coated with a layer of spermidine conjugate with polyglucin held by ionic interaction between negative polynucleotide complex and positive spermidine, while recombinant human tumour necrosis factor alpha is covalently bound with activated polyglucin. As double-helical RNA, the anticancer drug contains double-helical RNA of Saccharomyces cerevisiae yeast. Nanoparticles are ball shaped and sized about 50-70 nm; 60-80 molecules of recombinant human TNF-α of cytolytic activity 106 ME/mg of protein and higher, 60-80 molecules of polyglucin and 1000-1300 molecules of spermidine are necessary for one molecule of double-helical RNA of Saccharomyces cerevisiae yeast.

EFFECT: reduced dose of TNF-α and lower toxicity.

5 cl, 5 ex, 4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to preparation of a plant drug for treating stomach cancer. The drug for treating stomach cancer contains cod-liver oil, badger fat, plant seed blood chosen from the group: pomegranate, hot pepper, fennel and activated coal in the following ratio, wt %: cod-liver oil 28; badger fat 28; seed blood 42; activated coal the rest.

EFFECT: treatment with the declared drug involves activating body defences, resistance ensured by improved functioning of an individual's organs and systems, and targeting the lesion focus.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, particularly to the technology of producing selenoxanthenes and can be used in producing food additives, medicinal agents and cosmetic agents, which exhibit broad biological activity. An agent is described, which is an α-crystalline form of 9-phenyl-sym-octahydroselenoxanthene, which has antixodant, detoxication, immunomodulating, antiatherogenic, antisclerotic, anabolic, hypolipid action, and the corresponding structural formula with powder X-ray pattern obtained on Cu-K radiation sources with characteristic reflection indices expressed in degrees of the diffraction angle 2θ: 6.0 12.0 15.0 17.0 19.0 20.0 21.5, 21.7, 20.9 25.0 27.0 28.0 29.0 37.0 and melting temperature 96.8°C, as well as to a method of producing said agent, involving crystallisation of the corresponding 9-R-sym-hydroselenoxanthene from low-polar or non-polar solvent, preferably hexane, chloroform or isopropyl alcohol.

EFFECT: design of an efficient method of producing selenoxanthenes.

3 cl, 1 dwg, 1 tbl

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