The method of treatment of pathological abnormalities in diabetes type ii

 

(57) Abstract:

The way long term modification and regulation of lipid and carbohydrate metabolism, to reduce obesity, insulin resistance and hyperinsulinemia and hyperglycemia, or both (the hallmark symptoms of insulin dependent or type II diabetes), through the introduction of oral, sublingual or parenteral) vertebrate, a person or animal of a dopamine agonist, such as bromocriptine. The introduction of bromocriptine produced at certain limited times of the day, depending on the normal circadian rhythm of insulin resistant and insulinsensitizing representatives of similar species. The insulin resistance, hyperinsulinemia and hyperglycemia, or both, you can control a person on a long term basis with the help of this treatment, due to the fact that short-term daily administration of the drug correct hormonal "schedule" in the nerve centers of the brain that produces a long lasting effect. 4 C. and 16 h. p. F.-ly. table 4.

Diabetes is one of the most common diseases, the onset of which occurs without obvious symptoms may occur suddenly or remain undiagnosed for years, by blindness, heart disease, stroke, kidney disease, loss and hearing loss, gangrene and impotence. One third of all visits to doctors caused by this disease and its complications are the leading cause of death in this country.

Diabetes affects how the body uses sugar and starch, which are in the process of digestion into glucose. Insulin, a pancreatic hormone, makes glucose available to the body cells, which use it for energy. In muscle, adipose and connective tissue insulin facilitates entry of glucose into cells by altering the cell membrane. Penetrated into the cells, the glucose in normal turns in a liver in CO2and H2O (50%), glycogen (5%) and fat (30-40%), which is stored in fat depots. Fatty acids circulating in the blood are returned to the liver and converted into ketone body utilization in the tissues. Fatty acids are metabolized and also in other organs, in which the formation of fat is the main road through the utilization of carbohydrates. The effect of insulin is that it facilitates the storage and utilization of carbohydrates, protein and fat. Insulin deficiency is a common and serious is not producing it at all and insulin must be administered to the diabetic daily for survival. When type II diabetes the pancreas produces insulin but not enough, or it is not fully active due to the resistance of the cells, or both. In both forms there are many variances in the body, but the fundamental defects that can cause these deviations are reduced entry of glucose into various peripheral tissues and increased release of glucose from the liver into the circulating blood (increased liver glycogens). Thus, there is an excess of extracellular glucose and lack of intracellular glucose that can be called "hunger amidst plenty". There is also a decrease of the penetration of amino acids in muscle tissue and increased lipolysis. So, all this leads, as a consequence of the diabetic process, to increase the level of glucose in the blood and to the prolongation of high blood sugar, which is indicative for the condition, causing damage to blood vessels and nerves. Obesity or excess fat is often associated with increased resistance of cells to insulin, which precedes the beginning of the apparent diabetes. Before diabetes pancreas suffering Aire the TKA insulin drops and develop diabetes.

Decrease fat reserves of domestic animals on a regular basis is beneficial for humans because animals supply a large part of the human diet, and the fat of animals in the future will be fat reserves of the man himself. Decrease fat reserves in the human body also has a significant advantage, both cosmetic and physiological. In fact, obesity and resistance to insulin, which is accompanied by hyperinsulinemia and hyperglycemia, or both, are hallmarks of type II diabetes. Limited nutrition and exercise can only produce limited results in reducing the fat reserves of the body. Unfortunately, until now there were no effective treatment for controlling hyperinsulinemia, and insulin resistance. Hyperinsulinemia is the high content of insulin in the blood. Insulin resistance can be defined as a condition in which normal amounts of insulin causes subnormal biological response. It is believed that diabetics who are treated with insulin, there is insulin resistance, in all cases, when a therapeutic dose of insulin than sector is Sulina in the blood, i.e., hyperinsulinemia, in the presence of normal or elevated levels of glucose in the blood. Despite decades of research on this serious problem, the etiology of obesity and insulin resistance remains unknown. The fundamental mechanisms of biological measurement time, circadian or diurnal rhythm, are present at all levels of the organization. It was reported about the daily rhythms of many hormones, including the adrenal steroids, such as corticosteroids, namely cortisol and prolactin, a hormone secretory pituitary. In a long article discussing the state of the question at that time, wrote: "Despite the fact that there is a correlation between hormonal rhythms and other rhythms, there is little evidence that the day of the presence or peak hormone levels has important physiological significance". (Temporal Synergism of Controls and Adrenal Steroids, the authors Albert H. Meier, General and Comparative Endocrinology, Supplement 3, 1972 Copyright 1972 by Academic Press, Inc.) The article then describes the physiological response of birds to the injection of prolactin, which is produced from day intervals. This reaction included the increase and decrease fat reserves in the body depending on the time of day, when it was made injection, and the time of year, and time is Thus it was found that prolactin stimulates obesity only when entered at a certain time of day, and the reaction time varied from lean animals and backward animals. In an article entitled "Circadian and seasonal variations of plasma concentrations of insulin and cortisol levels in Syrian hamsters," written by Christopher J. de Souza and Albert H. Meier, Chronobiology International, vol. 4, No. 2, pp. 141-151, 1987, reported on the study of circadian oscillations of plasma insulin and cortisol levels in scoresenting and squarefactory Syrian hamsters, which are contained in the conditions of shortened and elongated light of day, to determine possible seasonal fluctuations in their daily rhythms. The main concentration of insulin was higher in females (compared with males) scoresenting hamsters in terms of short day length. This difference can be attributed to the higher fat stock females compared to low stock males scoresenting hamsters contained in the conditions of short day length. Plasma concentrations of both insulin and cortisol varied during the day for groups of animals, but were unequal. Circadian fluctuations of cortisol were similar, regardless of gender, season, and prodoljitelnoe food neither the glucose concentration was not varied significantly depending on the season or the length of a day. Reported that neither time of day nor the season did not affect the concentration of glucose or cortisol levels. Were made without evidence that diurnal rhythms of cortisol and insulin are regulated by different neural peacemakerdie systems and that changes the proportions of the phases in circadian systems occur in part due to seasonal changes in fat reserves in the body. Circadian rhythms of prolactin and glucocorticoid hormones, such as cortisol, have been apprehended so far as having no clear role in the regulation of circadian and seasonal fluctuations in the fat reserves of the body and in the organization and integration of the General metabolism of the animals. (See"Circadi an Hormone Rhythms in Lipid Regulation, Albert H. Meier and John T. Burns, Amer.Zool. 16:649-659 (1976).

Insulin is a hormone with multiple biological actions; many of its tissue-specific effects. For example, insulin can increase the secretion of the mammary glands, stimulate the synthesis of fat in the liver, speed up the transport of glucose into muscle tissue, to stimulate the growth of connective tissue, and so on, the impact of the molecules of insulin in one fabric is not necessarily related to what passed at the molecular level. In contrast to the previously shown data Meier and Cincotta that dopamine agonists (for example, bromocriptine) inhibit lipogenic (or lipoliticeski) response of liver cells to insulin, a new method is described and demonstrated in this paper suggests that daily in due time, the introduction of a dopamine agonist (e.g., bromocriptine) has a new and unique drug's ability to stimulate hypoglycemic (or redistribution in relation to glucose) answer all body tissues (primarily muscle) insulin. This is the opening of a new medical use of dopamine agonists (such as bromocriptine) is completely the opposite effect on a totally different biological activity of the insulin molecule and a different tissue of the body, unlike the previous one, shown in the work of Meier and Cincotta.

The main aim of the present invention is to provide a process or method of regulation and repair insulinsensitizing level of plasma glucose and insulin levels in the blood of vertebrates, i.e. animals, including humans.

In particular, the goal is to create a way to fix circadian nerve centers animals, the reality of the cellular response to insulin and overcoming hyperinsulinemia and/or hyperglycemia, which is usually accompanied by insulin resistance.

A more specific goal is to create a way to fix Stadnyk nerve centers animals, including humans, to reduce obesity and maintain fat reserves in lean humans and animals at a more normal level and long-term basis.

An additional and equally specific goal is to create a method, normalizing on a long term basis circadian nerve centers, particularly in humans, to improve and enhance the sensitivity and ability to respond to insulin cells and suppression of hyperinsulinemia and hyperglycemia, or both.

These and other objectives are achieved in accordance with the present invention and are characterized as a way or method of regulation of lipid metabolism and glucose to achieve continuous, long term and permanent effects by introducing daily at certain times of the doses of the dopamine agonist, or prolactin inhibitor, such as L-DOPA and various related LPV connection, vertebrate animals or man. The introduction of these drugs on a daily basis continues for a period of time sufficient to normalize the phase Konya fluctuations of the nerve centers of prolactin and corticosteroids, respectively. The ratio of the phases of oscillations of prolactin and, preferably, both of the nerve centers are modified and improved, so that at the termination of the daily administration of dopamine agonist, or prolactin inhibitor fat metabolism of the animal or human remains for a long period of time (at least one month), if not forever, altered metabolic level.

The dopamine agonist, or prolactin inhibitor is administered preferably orally, sublingually, or by subcutaneous or intramuscular injection. Thus, prolactin inhibitory compound, preferably a preparation of ergot, is administered to a patient having one or more symptoms that need to change, for example, obesity, insulin resistance, and hyperinsulinemia or hyperglycemia. Examples prolactinemia compounds, preparations of ergot, are: 2 - bromo-alpha-ergocryptine; 6-methyl-8-beta-carbobenzoxy-aminomethyl-10 - alpha-Ergoline; 1,6-dimethyl-8-beta-carbobenzoxy-aminomethyl-10 - alpha-Ergoline; 8-acylaminoalkyl, such as 6-methyl-8-alpha-(N-acyl)-amino-9-Argolis and 6-methyl-8 - alpha- (N-phenylacetyl)amino-9-Argolis; ergocornine; 9, 10-dihydroergocornine and D-2-halo-6-izobreteniya also useful non-toxic salts of the prolactin-inhibiting compounds LPV, formed with pharmaceutically acceptable acids. It was found that in the practice of the present invention is particularly useful bromkriptin or 2-bromo-alpha-ergocryptine.

When treating an animal or human fat reserves of the body can be reduced or increased, and the effect lasts as long as the fat stores of the body is not stabilized at the optimum or close to optimum, depending on the desired level of fat reserves for a specific object of treatment during the period of time sufficient to ensure that after the end of treatment, the rhythm of prolactin, and preferably, the rhythm of prolactin, and the rhythm of glucocorticoids has been fixed so that for a long time to maintain reduced or increased levels of body weight. For a person with almost no options, the goal is usually to decrease fat reserves in the body and obesity. It was found that there is a relationship between obesity and insulin resistance and that obesity can lead to increased insulin resistance. Similarly, it was found that circadian rhythms in plasma concentrations of prolactin and glucocorticoids, respectively, cause important PI glucocorticosteroids, accordingly, the difference between the thin and thick animals. Thick animal prolactin peak level on the hour through 24 hours (people usually around noon), and prolactin levels in lean animals in a different time of day (people usually during sleep). Slim level of glucocorticoids, such as cortisol, reaches a peak within 24 hours from the hour (usually during different prolactin); people usually several hours after awakening. Thus, the phase relationship of the rhythms of cortisol and prolactin differ in lean and backward animals. Peak production of prolactin and glucocorticoids, respectively, can to some extent be different in males and females separate. It was found that a daily dose of dopamine agonist, or prolactin inhibitor, given backward object of treatment immediately after time of day, which normally gives the peak prolactin slim objects of the same species and sex, lead to weight reduction greasy animal (or person). Such treatment, if there is continued for sufficient time, and normalizes for long-term or permanent basis phase navalnyj oscillation rhythms as prolactin and glucocorticosteroid nistam dopamine or inhibitor of prolactin is to lose weight, and its fat stores, if you continue treatment on a daily basis, will be reduced and stabilized at the level existing at the thin representatives of the same species. At the termination of the daily treatment of the rise and fall of the levels of prolactin and glucocorticoids in the blood of the patient will correspond to those of the thin representatives of the same species and enough to last a long time. The effect of such an adjustment of rhythms of prolactin or prolactin and corticosteroids, is also reflected in the increased sensitivity of cells to insulin, reduces hyperinsulinemia or hyperglycemia, or both of these options and, thus, modifies the pathological parameters inherent in the early development of type II diabetes, in the long term.

When treating vertebrates, in General, the dose of dopamine agonist, or prolactin inhibitor given daily once a day, usually from 10 to 150 days, in amounts ranging from about 3 to 100 micrograms per pound of body weight (1 pound 0,454 kg) to normalize the circadian rhythm of plasma prolactin. In the treatment of a person, a dopamine agonist, or prolactin inhibitor given daily, preferably with dose levels, varying priblizitel lasts approximately from 10 to 150 days, preferably from 30 to 120 days, more preferably from 30 to 90 days, most preferably from 30 to 60 days, get greasy patient a short period of time after is usually from 1 to 8 h, preferably from 4 to 8 h after the onset of the peak prolactin concentrations in lean people, modifies and improves lipid metabolism greasy patient to settings, existing thin representatives of the same species. Prolactin peaks have thin, sensitive to insulin patients during sleep, usually around its middle, and, therefore, it is time for the introduction of a dopamine agonist to reduce fat from greasy patients to improve the patient's sensitivity to insulin, suppression of hyperinsulinemia or hyperglycemia, or the reduction of both, and varies from about 1 to 10 hours from the middle of the sleep period, preferably from 1 to 8 h, more preferably from 1 to 4 h after the middle of the sleep period. Reserves of body fat greasy patient, including the fat of the arterial wall, plasma and adipose tissue will decrease after treatment be maintained at the level existing at thin people over an extended period of time. Thin or greasy patients manifesting the tee to insulin, and hyperinsulinemia and/or hyperglycemia, which treat a dopamine agonist, or prolactin inhibitor, become more sensitive to insulin (i.e., reduce insulin resistance), and the effects of hyperinsulinemia and/or hyperglycemia reduced for the long term. Thus, injections of the dopamine agonist, or prolactin inhibitor corrects the phase relations of the two neural oscillations and their numerous circadian manifestations, changing metabolism for a long time, if not forever. In other words, the result is confined to a specific time of day daily doses of the dopamine agonist, or prolactin inhibitor becomes long-term elimination of the basic pathological changes associated with the development of type II diabetes. Inventory levels of body fat, the concentration of insulin in plasma and insulin resistance, hyperglycemia or all of these pathological changes can be minimized for a long time with such a treatment, high levels frequently observed in obese patients with hyperinsulinemia, to a lower and more desirable levels inherent to thin and sensitive to insulin people.

If we are talking about a person, "Aire is illiams, In Textbook of Endocrinology, 1974, pp. 904-916). The time of day at which the levels of prolactin and glucocorticoids, respectively, reach their peak in the blood of people during the day varies from thin and greasy subjects, and the peak of each type of subjects you can easily determine. Other species can also easily determine what is evil and backward members of the species, by correlating samples of body weight with levels of prolactin and glucocorticoids in plasma, respectively, thin and greasy species. These levels differ among members of different species, but among members of the same species there is a close relationship between levels of prolactin and glucocorticoids, respectively, at a certain time of day, depending on obesity or thinness of this representative.

These and other features of the present invention can be better understood from the data of the experimental work with animals and people. In the examples, the designation ARTICLE refers to the light / dark cycle; the first number following ARTICLE, refers to the number of hours with the light; the second is the number of hours in the dark in the loop. Thus, ARTICLE 14:10 refers to the cycle in which 14 h light and 10 h of darkness, and the period of the day is expressed on the basis of 2400 hours of Microgramma.

Example 1. Six adult female pigs produced implantation with bromocriptine(10 mg per animal per day) over a period of time during which varied periods of daylight and darkness (12:12). It was expected that bromkriptin of the implant will penetrate into the bloodstream in large quantities closer to the beginning of the daily activity of animals. A control group of six pigs in a similar manner were subjected to periods of changing daylight and darkness, but did not enter bromkriptin. The dark period lasted from 18.00 to 06.00, and the period of daylight from 06.00 to 18.00. Daily animals took the blood at intervals of four hours within 14 days in order to determine the level of cortisol in plasma (g/DL) and the level of prolactin in plasma (g/ml). The average values in each series of tests for each group were as follows (see tab. 1 and 2).

Effects of implants bromocriptinum on fat reserves and plasma concentrations of triglycerides, glucose and insulin are shown in table.3.

Plasma was investigated at 16.00, 20.00 and 24.00 two weeks after treatment. Samples were taken from all the animals of the experimental and control groups.

These data clearly show that implants with bromocriptinum changed the Oia, favorable for diabetics. These data indicate that closer to the sunset, when the lipogenesis pigs in norm greatest, bromkriptin reduced concentration of triglyceride in plasma by 48%. Because lipid is produced in the liver and transported by the blood into the fat, lower triglycerides is more evidence that bromkriptin has an inhibitory effect on the synthesis and deposition of fat. In addition, although the decrease in the concentration of insulin in plasma and was not statistically significant, bromkriptin reduced the levels of glucose in plasma by 13% during the early period of darkness (2000-2400). The decline in blood glucose without increasing insulin levels can be explained by the reduction of insulin resistance (increased hypoglycemic response to insulin). Bromkriptin reduced fat reserves by 14% after 28 days of treatment.

Further studies were performed on the people, and they showed that the symptoms of insulin-independent diabetes (type II), can be reduced by treatment with bromocriptine. Below examples.

Example 2. 50-year-old woman with symptoms of diabetes daily was given pills bromocriptine (1,25-2,50 mg / day) immediately after waking up. In the beginning Leche is In the weeks subsequent treatment glucose levels in the blood of the patient fell to 180 mg/DL, 155 mg/DL 135 mg/DL, 97 mg/DL and 101 mg/DL. Levels below 120 mg/DL fasting is considered normal. The body weight and metrics fat reserves also decreased by 12% during treatment.

Example 3. 45-year-old woman was treated with hypoglycemic drugs (diabinese), which reduced the level of blood glucose of 250 mg/DL to about 180 mg/DL during the year of treatment. After daily oral administration of bromocriptine (parlodel, 1,25-2,5 mg per day) for about an hour after waking up, the level of glucose in the blood dropped to 80 mg/DL for 2 weeks. Cancel hypoglycemic drugs has allowed the glucose level several to rise and stay about 100 mg/DL (normal level) in the next two months. In the treatment bromocriptinum body weight and fat reserves declined by approximately 10%.

Example 4. 55-year-old man who suffered from diabetes and weighed about 300 pounds, did not respond to previous treatment efforts. At the beginning of the oral administration of bromocriptine (parlodel, 2.5 mg per day), which was given between two and three hours after waking up, the concentration of glucose in plasma averaged about 350 mg/DL. Within 2.5 months of treatment bromocriptinum body weight and the concentration of glucose in plasma gradually, but posleduushie examples demonstrate the effect of bromocriptine in the treatment group patients men and women diagnosed with insulin-independent type II diabetes. Separate entities referred to in examples 2, 3 and 4, included in the population table. 4.

Example 5. Fifteen people suffering from insulin-independent (type II) diabetes, treated with bromocriptine to establish the effects of treatment on their fat reserves and hyperglycemia. Seven patients (2 men and 5 women) were treated with oral introduction stimulators of endogenous secretion of insulin (hypoglycemic drugs: diabenese and Micronase), and seven patients (2 men and 5 women) received daily injections (morning and evening) of insulin. Only those patients who showed high hyperglycemia (i.e., hungry glucose levels greater than 160 mg/DL) in the morning before the introduction of insulin, or taking other medications were taken for this study. One male patient with obesity, which abandoned the traditional method of treatment of diabetes, was allowed to participate in the study bromocriptinum, and he was included in the group receiving hypoglycemic drugs.

Bromkriptin was taken orally every day during the day, designed to correct circadian hormonal rhythms, with the purpose of get the 5 h after awakening. Nausea is usually avoided, since lower doses (1.25 mg) in 2-3 days, and then increasing the dose levels up to 2.5 mg daily In 10% of patients showed slight nausea that quickly passed, only lasted the first few days. Patients were instructed to ensure that they did not change their usual daily activity and food during treatment. Patients disciplined complied with all conditions of the experiment, it was confirmed weekly surveys of patients who monitored the number of accepted food, and transient effects of anorexia, sometimes called high doses of bromocriptine, this study was not observed.

The thickness of the skin fold was measured on the left side of the body specialist anthropometry in four areas: biceps, triceps, over the shoulder and over Powszechny bone, according to the recommendations of the International biological program. Percentage body fat was determined from the common logarithm of the sum of four skin folds, using the equations of Durnin and Rahman and Siri. Recent studies have shown quite an exact match data on body fat, obtained by the methods of hydrodensitometry and methods of measurement of thickness of skin folds. Measurement of skin folds production is Omak levels of plasma glucose in the morning were measured in patients with diabetic group in the morning and at the beginning of treatment and after 4-8 weeks. The results are presented in table.4.

Each patient with diabetes after 4-8 weeks of treatment with bromocriptine decreased as the concentration of glucose in the blood, and the thickness of skin folds, as can be seen from the table. 4. The initial concentration of glucose in blood on an empty stomach in the morning before taking diabetic medication was 28314 Skibo mg/DL and 23119 mg/DL for patients treated with insulin and hypoglycemic drugs, respectively. After 4-8 weeks, the average glucose concentration decreased (p <0.05 table Student) to 184 22 mg/DL (insulin) and to 16619 mg/DL (hypoglycemic agents). During treatment bromocriptinum three patients completely abolished oral hypoglycemic drugs, and the level of glucose in the blood remained within the normal range (<120 mg/DL) for at least two months after cessation of treatment bromocriptinum, three other patients during treatment with bromocriptine were reduced dose of hypoglycemic drugs and insulin.

Body fat decreased significantly in the treatment bromocriptine patients with insulin-independent diabetes, taking hypoglycemic drugs, as evidenced by the average decrease of 21% of the thickness of skin folds in four NTA and reducing overall body fat by 10.7% during 4-8 weeks. Patients receiving insulin, these values decreased to a lesser extent: skin fold 16%, fat - 3.1 lbs % body fat is 5.1. Body weight was slightly reduced (2.4 lbs each, not statistically significant) in patients taking hypoglycemic drugs, and not decreased in patients taking insulin.

These results show that treatment with bromocriptine can radically reduce fat stores in humans. Treatment bromocriptinum also significantly reduced hyperglycemia in two months in patients with insulin-independent (type II) diabetes. These results were achieved without changing individual habitual diets and exercise.

Surprisingly, reduction of fat reserves in the body (4.4% of body weight) achieved in the present study, after 6 weeks without any restrictions in diet, are equivalent to the reductions achieved by a low calorie diet (420 kcal / day) for the same period of time. On the contrary. Amatruda and co-authors reported an 8% decrease in body weight in obese patients suffering from insulin-independent diabetes, of which less than 50% can be attributed to fat loss. In addition, Kanders, etc. soo is the same very low-calorie diet. This quantity is expressed in the loss of approximately one pound of fat per week under these conditions, low-calorie diet, which is 1.4 pounds a week less than the average achieved in the treatment of bromocriptinum in this study.

The reduction of body fat obtained in the treatment of bromocriptinum, differs significantly from the reduction obtained by restriction of calories consumed. With very low calorie diets only about 45% of the weight lost comes on fat: the rest is protein, carbohydrates and water.

These data show that the metabolic status of the at least partially regulated by the interaction of circadian neuroendocrine rhythms. This hypothesis suggests that the circadian rhythms of cortisol and prolactin are individual reflections of the two separate circadian systems and that daily injections of these hormones can coordinate the phase relationship of these two systems. Thus, on the model of hamsters was found that the 0-hour ratio coordinates circadian oscillations to the sample, the existing thin and sensitive to animal insulin, and 12-hour ratio ensures the preservation of the sample, the existing backward and timerunner injection of dopamine receptor agonist, or prolactin-inhibitory drug is a long time. Once adjusted, the phase relation of two circadian oscillations tends to remain at a modified level.

A change in the phase relationship of the two circadian neuroendocrine fluctuations are confirmed by changes in the phase relations of their circadian manifestations. These expectations were fully justified in terms of the rhythms of plasma corticosteroids and prolactin. In some species the phase relationship of these two hormonal rhythms vary from thin and greasy animals.

It is shown that the phase relationship between the circadian rhythm of the concentration of insulin in plasma and rhythm lipogenic response to insulin varies from thin and greasy animals. Despite the fact that day intervals ability to lipogennaya response remain near the beginning of the day phase insulin rhythm vary markedly. Peak concentrations of insulin, for example, occurs near the beginning of the light period, greasy female hamsters contained in the conditions of short day length. That is, the fluorescent peaks lipogenic stimulator (i.e., insulin) and lipogenic response to insulin coincide with greasy animals and do not coincide with lean animals.

Phase relations prolactinomas and insulinomas these rhythms, thus, must be coordinated phase for the regulation of lipogenesis. Phase coordination of these and possibly other rhythms may also be responsible for insulin resistance.

It is obvious that there may be various modifications and changes without derogating from the idea and scope of the present invention.

1. The method of therapeutic modification and regulation of lipid metabolism and glucose in animals and humans, comprising the administration to a subject, insensitive to insulin, or suffering from diabetes, or both, every day at a certain time of the dopamine agonist in a dosage and over a period of time sufficient to enhance the sensitivity of the subject to insulin, suppression of hyperinsulinemia or reducing hyperglycemia, or as to suppress hyperinsulinemia, and to reduce hyperglycemia.

2. The method according to p. 1, characterized in that after the discontinuation of treatment with dopamine agonist effect of the treatment lasts at least one month.

3. The method according to p. 1, wherein the dopamine agonist, entered daily at the specified time a specified subject, is sufficient to modify and coordination of neural phase fluctuations as about the e dose of the dopamine agonist is administered daily, once a day, during the time period from 10 to 150 days, in the amount of about 3 to 100 mg per 1 lb of body weight.

5. The method according to p. 1, characterized in that timesofindia daily dose of the agonist is administered daily in an amount of 3 to 40 mg per 1 lb of body weight within 10 150 days, in the treatment of the person.

6. The method according to p. 5, wherein the dose is administered in amounts ranging approximately 3 to 20 mg per 1 lb of body weight within 30 to 120 days.

7. The method according to p. 5, wherein the dopamine agonist is administered resistant to insulin or resistance to insulin and suffering from diabetes face every day while varying approximately 1 to 8 hours after the time at which the peak occurs in the concentration of prolactin in thin, sensitive to insulin parties to modify or correct the metabolism of the patient to the level and characteristics of thin people.

8. The method according to p. 1, wherein the dopamine agonist is chosen from 6-methyl-8-beta-carbobenzoxy-amino-ethyl-10-alpha-Ergoline; 1,6-dimethyl-8-beta-carbobenzoxy-aminomethyl-10-alpha-Ergoline; 8-acylaminoalkyl; ergocornine; 9,10 dihydroergocornine; bromine-cription; D-2-halo-6-alkyl-8-substituted Ergoline.

9. The way terapevtichne in the bloodstream of a person, characterized in that it includes an introduction to the man, insensitive to insulin or diabetic, or located in both the state of the dopamine agonist daily hours, in the amount and for a time sufficient to increase the effects of redistribution of glucose caused by insulin, and lower hyperglycemia.

10. The method according to p. 9, wherein the dopamine agonist is administered to a person to reduce hyperinsulinemia.

11. therapeutic method of the modification and adjustment of neural phase fluctuations in the rhythm of prolactin or a rhythm of prolactin and rhythm of glucocorticosteroids have insensitive to insulin or diabetic animals or humans, characterized in that it includes an introduction to the subject, insensitive to insulin or suffering from diabetes, the dopamine agonist daily at this time of day, when the levels of prolactin and cortisol in the blood reaches its peak at the time, similar to that which exists in a thin, sensitive to insulin entities in the amount of 3 to 40 mg per 1 lb of body weight, and continue treatment for 10 to 150 days and sufficient to improve the sensitivity of the subject to insulin, suppression of hyperinsulinemia or reduce hypergene neural phase fluctuation of prolactin in the body of the subject, being treated, will be largely correspond to that of a thin, sensitive to insulin of the subject, and this effect will continue for a long time.

12. The method according to p. 11, wherein the dose of the dopamine agonist is administered within 30 to 120 days.

13. The method according to p. 11, wherein the dopamine agonist is administered to the subject daily at this time of day that corresponds to that evokes the rhythm of prolactin in the plasma or the rhythm of prolactin and rhythm of cortisol, reaching a peak as the greasy subject of the same species, to increase reserves in the thin body of the subject.

14. The method according to p. 11, wherein the dopamine agonist is administered to the subject daily to increase the sensitivity of cells to the effects of redistribution of glucose caused by insulin.

15. The method according to p. 11, wherein the dopamine agonist is administered to the subject daily to reduce hyperinsulinemia.

16. The method according to p. 11, wherein the dopamine agonist is administered to the subject daily to reduce hyperglycemia.

17. The method according to p. 11, wherein the dopamine agonist selected from: 6-methyl-8-betacarbolines-amino-ethyl-10-alpha-Ergoline; 1,6-Dima is bromkriptin and D-2-halo-6-alkyl-8-substituted Ergoline.

18. The method of inoculation and the regulation of glucose metabolism and lipids in insensitive to insulin, suffering from hyperinsulinemia or diabetes person, characterized in that it includes an introduction to the subject, demonstrating one of these or all of these pathological conditions, characteristic of type II diabetes, during the period of time from 30 to 120 days, number 3

40 mg per 1 lb of body weight, daily doses of dopamine agonist 1 10 h after the normal time of day that the prolactin level reaches its peak in lean subject of the same species and sex, not having any of these diseases to cause changes in the neuroendocrine system being treated person, imitate them slim entity, resulting in sensitivity to insulin subjected to treatment of the subject is improving, hyperinsulinemia suppressed or reduced hyperglycemia or hyperinsulinemia suppressed and reduced hyperglycemia, and all these parameters, which are characteristic for the development of diabetes type II, modified for a long time.

19. The method according to p. 18, wherein the dopamine agonist is administered daily at a certain time, sufficient for the human subject.

20. The method according to p. 18, wherein the dopamine agonist is chosen from 6-methyl-8-beta-carbobenzoxy-amino-ethyl-10-alpha-Ergoline, 1,6-dimethyl-8-beta-carbobenzoxy-aminomethyl-10-alpha-Ergoline, 8-acylaminoalkyl, ergokornina, 9,10-dihydroergocornine, bromine-criptine and D-2-halo-6-alkyl-8-substituted of ergolines.

 

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in which Y is C= O or CHOH; R1is hydrogen or lower alkyl; R2is hydrogen, lower alkyl or phenyl-lower alkyl; R3is hydrogen, OR4in which R4is hydrogen, COR5in which R5is lower alkyl, X is hydrogen, lower alkyl, halogen, lower alkoxy-, hydroxy-group or trifluoromethyl, their geometric or optical isomers, N-oxides, or their pharmaceutically acceptable salts and accessions acids (acid additive salts), which are useful in reducing dysfunction in memory and are thus indicative for the treatment of disease Allgamer

The invention relates to a new monohydrate 5- (2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinil)ethyl)-6-chloro-1,3 - dihydro-2H-indol-2-he hydrochloride, containing pharmaceutical compositions, and method of neuroleptic treatment of diseases with the use of the specified monohydrate

The invention relates to medicine, namely to psychiatry and neurology
The invention relates to medicine and can be used for treatment of addiction, including alcohol and tobacco
The invention relates to medicine and can be used to restore physiological homeostasis
The invention relates to medicine, namely to the sexologist, and can be used in the treatment of impotence
The invention relates to medicine, namely to addiction

The invention relates to medicine, namely to addiction

Drug for analgesia // 2083202
The invention relates to the field of pharmacology of narcotic substances, in particular to the issue of reducing the formation of morphine dependence and enhance its analgesic potency when it is used as a tool in blood

Drug for analgesia // 2077326
The invention relates to the field of pharmacology, drug substances

The invention relates to medicine, in particular, to dentistry and concerns the development of tools for the prevention and treatment of hypoxic conditions of the periodontium

The invention relates to medicine, specifically, Hematology, and can be used for pharmacological correction of violations that occur in blood system with the introduction of cytotoxic drugs

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

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