CZ155494A3 - The use of dopamine and prolactin stimulator antagonist for preparing a pharmaceutical preparation and the pharmaceutical preparation itself - Google Patents

Abstract

A process for the long term modification and regulation of lipid and carbohydrate metabolism - generally to reduce obesity, insulin resistance, and hyperinsulinemia and hyperglycemia, or both (these are the hallmarks of noninsulin dependent, or Type II diabetes) - by administration (i.e., by oral, sublingual or parenteral administration) to a vertebrate, animal or human, of a dopamine agonist, e.g., bromocriptine. Administration of the bromocriptine is made over a limited period at a time of day dependent on the normal circadian rhythm of insulin resistant and insulin sensitive members of a similar species. Insulin resistance, and hyperinsulinemia and hyperglycemia, or both, can be controlled in humans on a long term basis by such treatment inasmuch as the short term daily administration resets hormonal timing in the neural centers of the brain to produce long term effects.

Description

Diabetes, January of non-insecticide serious diseases, can strike suddenly or remain undiaanosticated for years, attacking blood vessels and nerves. Diabetics as a group suffer from blindness, heart disease, stroke, kidney disease, hearing loss, qangrene and impotence more often. This disease is caused by a third of medical visits in January and by complications is the leading cause of death in the United States.

Diabetes adversely affects the way in which the body uses sugars and starches, which are converted to aucose during digestion. Insulin, a hormone produced by the pancreas, makes glucose available as a source of energy for body cells. In muscle, beech tissue and edible tissue, insulin facilitates the entry of glucose into cells by acting on cellular neo-gates. The injection of glucose is normally metabolized in the liver to CO? and H 2 O <50. glycogen (5 and fat <30-40) stored in beech stores. Fatty acids circulating. Returned to liver and metabolized to ketones, which are used in tissues. Fatty acids are also metabolized by other organs, the main route of use The net effect of insulin is to promote the storage and utilization of carbohydrates, proteins and fat Insulin deficiency is a common and serious pathological condition in humans In both diabetes and pancreas, insulin is not produced at all or only a little, and insulin is required daily to survive In type II diabetes, the pancreas produces insulin, but the amount of insulin is insufficient or not completely effective due to cell resistance or resistance, both forms of which are widespread abnormalities, but the underlying deficiencies can be traced. 1. decreased entry of itukosv into the peripheral peripheral tissues; increased hepatic excretion of the liver (increased hepatic qluconenesis). Thus, there is a intracellular excess of glucose and an intracellular glucose deficiency, which has been called starvation in the middle of the excess. There is also a decrease in the entry of amino acids into the muscle and an increase in limolysis. Thus, the diabetic state results in elevated blood glucose levels and long-term high blood sugar levels, which indicate an indicated condition leading to vascular damage and nerve disorders. Obesity or excessive fat stores are often associated with increasing cellular insulin resistance that precedes the onset of clinically recognized diabetes. Prior to the onset of diabetes, the pancreas of obese individuals were burdened with the production of additional insufficiency, but eventually, legally, after several years, insulin production declined and diabetes developed.

Long-term or permanent reduction of fat deposits ^; ib orcanisr u in domestic animals would probably bring considerable economic benefits to humans, especially orot.o that animals supply a major proportion of human nutrition and animal fat can ultimately transform. for a new human fat supply. Similarly, the reduction in the body's fat stores in humans bv had a significant cosmetic and physiological benefit. Indeed, obesity and insulin resistance, which is usually accompanied by hyperinsulinemia and hyperglycemia, or both, are a hallmark of type II abortion. A controlled diet and exercise can be achieved. moderate results in reducing body fat stores. Unfortunately, however, no effective treatment has been found to reduce either hyperinsulin inemia or insulin resistance. Hyperinsulinemia is higher than normal blood insulin levels. Insulin braking can be defined as st.av. when a normal amount of insulin elicits an above-normal biological response.

In diabetic patients. For example, when treated with insulinene, insulin resistance is considered to be present whenever the therapeutic dose of insulin exceeds the secreted amount of insulin in normal subjects. Insulin resistance also occurs in a situation defined by a higher than normal level of insulin, i. in hyperinsulinemia, where the blood glucose level is normal or elevated. Despite decades of research into these serious health problems, the etiology of obesity and insulin resistance is unknown.

Basic unit of biological time measurement, daily rhythm. is present at all levels of the organization. Daily rhythm has been reported for many hormones, including adrenal steroids. for example glucocorticosteroids, especially cortisol. and nrolactin, a hormone secreted by the pituitary gland. In an earlier article discussing the prior art, it is stated that although a correlation has been established between hormonal rhythms and also rhythm. we, there is little direct evidence that the time of daily presence or peak hormone levels has significant iyziolcoirkru re levanci ”, see T & nporal Synerctisn of Prol & otin # -? d Measured! Steroids, Albert H. Meier. General and Conparative Endorrinn logos. Supplement 3, 1972, copyright 1972 Academie Press. lne. The article then describes an avian physiological response to proactin injections administered at daily intervals. These responses include increasing and decreasing body fat stores depending on the daily time of injection and the season, the season being determined by the normal body weight and the resulting fat stores in the animal. Thus, it has been found that prolactin only stimulates fat on. injection at a certain time of day and that the response time varies between lean and fatty animals.

In an article titled Circadian <% nd Seesonel Variation of Plasma Insulin .and Cortisol Concentrations in the Syrian Hanster, Hesocricetus Huratus by Christopher J. de Souza and Albert H. lle i era. Chronobiolomy International, Vol. 4, No. 2. pp. 141-151. 1987, a study of daily changes in plasma insulin and cortisol concentrations in scotosensitive and scotorefractive Syrian hamsters bred in short and long daylight conditions to determine foot changes in their daily rhythms is described. Baseline insulin concentrations were found to be greater in females than in male scotosensitive hamsters in short daylight. Presented. that the observed difference may be due to the observed strong fat stores in ambulances and weak fat stores in male scotosensitive hamsters under short daylight conditions. Plasma concentrations of cortisol and insulin varied throughout the day in the groups of test animals. but they were not equivalent. The daily variations of cortisol were similar regardless of gender, seasonal condition and daylight. In contrast, the daily changes in insulin varied significantly. Neither the daily feeding pattern nor the glucose concentration changed significantly with seasonal or daylight conditions. It is reported that time of day or season does not appear to affect glucose concentration or cortisol levels. It is concluded that the daily rhythm of cortisol and insulin are regulated by various neural cardiovascular systems and that changes in the phase relation of the daily systems are partly due to seasonal changes in body fat stores. Thus, the daily rhythms of prolactin and glucocorticosteroid hormones, such as cortisol, have been found to play a significant but far from fully understood role in regulating daily and seasonal changes in body fat stores and in organizing and integrating overall animal metabolism; See Circon Hornone Rhythns in Lipid Regulation, Albert H. Meier and John T. Burris, Amer. Zool. 16 = 649-659 (1976).

Tnsulin le hormone with many biological activities, many of which are tissue specific. For example, it can increase milk production in the mammary gland, stimulate the synthesis of fat in the liver, prociotcivat transport α 1 bevels into muscle tissue, stimulate growth. connective tissues and the like. The effects of an insulin molecule on one tissue are not necessarily dependent upon other effects on other tissues. Ie. that these insulin activities can be and are molecularly separated from each other. In contrast to the prior art of Meier and Cincotta, which states that dopamine agonists (e.g. bromocriptine) inhibit the ability of a lipogenic (fat synthesizing) hepatic cell response to insulin, it is described and demonstrated in the present invention that a suitably timed daily administration of dopamine agonist ( Bromocriptine, for example, has another new and distinctly unique beneficial therapeutic ability that consists in stimulating the ability of the whole body's hypoglycemic (glucose secreting) response (primarily muscle) to insulin. This new outfit of this new therapeutic property of dopamine anonists (e.g. bromocriptine) represents a completely opposite effect on a completely different biological activity of the insulin molecule and on a completely different body tissue from previous work on dopamine acronides from Meier and Cinc.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method or method for regulating and adjusting insulin sensitivity and plasma glucose and insulin levels in vertebrates, i.e., animals, including humans.

In particular, it is an object of the present invention to provide a method for treating the daily neural centers of animals, including humans, to induce long-term changes in the size of body fat stores. the sensitivity of the cellular response to the type of insulin and overcoming hyperinsulinenia and / or hyperglycenia which usually accompanies insulin resistance.

Specifically, to find a process for treating daily non-urinary animal centers, including humans, to reduce obesity and maintain long-term lean body fat lean and non-human body fat stores.

Another and more specific object of the present invention is to provide a method of modifying long-term daily neural centers, particularly in humans, to increase and improve the sensitivity and ability of cells to respond to insulin and to suppress hyperinsulinemia and hyperglycemia or both.

The present invention provides a method for controlling lipid and glucose metabolism to produce long-lasting, sustained and sustained effects by administering timed daily doses of a dopamine agonist or prolactin inhibitor such as L-dopa and various ergot-related compounds to a vertebrate. Doses are administered daily for a period of time sufficient to adjust phase oscillation for 1 acti of rhythm or oscillations of both prolactin and glucocorticosteroid rhythm to represent both act and new. respectively. <? 1cortocortis of skeletal neural oscillations. The phase relationship of the spring new oscillation, preferably of both neural oscillations, is modified and modified so that, after omitting daily doses of the dopamine aconist or prolactin inhibitor, the metabolism of the animal or human continues, if at all, for at least one month. point or points.

The dopamine agonist or prolactin inhibiting compound is administered to a vertebrate, preferably orally, sublingually, or by subcutaneous or intramuscular injection into the bloodstream.

For 1 act-i n inhibiting compound, preferably a prolactin inhibiting ergot-related compound, is administered to a subject exhibiting any one or more of the symptoms desired to be altered.

such as obesity, insulin resistance, hyperinsulinemia, or hyperglycemia. Examples of ergot-related prolactin-inhibiting compounds are 2-bromo-α-ergocryptine, 6-methyl-8β-carbobenzyloxymethyl-1α-ergolinyl. 1,6-Dimethyl-8 (3-carbobenzyloxyaminomethyl-10a-ergoline, 8-acylaminobioergenes such as 6-methyl-8a-CN-acyl) amino-9-ergolene and 6-methyl-8a-erga. N-phenylacetyl) anino-9-ergolene, ergocornine, 9,10-dihydroeruocornine and D-2-halo-6-alkyl-8-substituted ergolines, for example D-2-bromo-6-methyl-8-cyanomethylergoline. In addition, nontoxic ergot salts of related prolactin-innovating compounds formed from pharmaceutically acceptable acids are suitable for practicing the invention. Bromocriptine or 2-bromo-α-eroacryptine has proven to be particularly suitable for carrying out the invention.

In the treatment of an animal or human subject, body fat stores may be depleted or increased and treatment continues to stabilize body fat stores at an optimal or near optimal level, depending on the desired level of body fat deposits in the subject, for a sufficient period of time such that For treatment, the proactivity is a new rhythm, and preferably both the proactivity and the glucocorticosteroid rhythm are adjusted to maintain decreased or increased body weight stores over the long term. In humans, almost without exception, the purpose is to reduce body fat and obesity. It has been found that there is a correlation between obesity and insulin resistance and that obesity can lead to increased insulin resistance. Similarly, it was found that the daily rhythm of plasma prolactin concentration, respectively. glucocorticosteroid, has significant implications for regulating body fat stores and that the phase relationship between the prolactin level, resp. glucocorticosteroids are different in lean and fatty? In a fat animal, prolactin will reach peak levels at a given hour of a 24 hour interval (in humans usually near noon) and in a lean animal daytime (in humans usually during sleep). The lean animal will be glucocorticosteroids. cortisol. culminating at a 24 hour interval at a certain hour (usually other than prolactin); in humans usually several hours after awakening, the cortisol phase relations and for 1 act of rhythm are different in lean and fatty animals. The peak period of prolactin and glucocorticosteroid production may vary slightly between males and females for a given species. In this context, daily doses of a dopamine agonist or prolactin inhibitor administered to an obese subject shortly after the time of day when normally prolactin peaks in a lean subject of the same species and sex have been shown to induce weight loss in that subject. Such treatment, when performed for a sufficient period of time, adjusts the phase of neutral oscillations for a single act or a new corticosteroid rhythm in an obese subject in the long term or permanently as in a lean subject. The losing subject will lose body fat stores upon initiation of dopamine agonist treatment, and on continued daily treatment, body fat stores will decrease in the obese subject and stabilize at a value for a lean subject of the same species. Upon discontinuation of daily treatment, the rise and attempt of prolactin or prolactin levels, together with g1 cocortis and bone steroids, in the blood of the treated patient will correspond to the values of the lean subject of the same species over the long term. The effect of such a rhythm adjustment of the prolactin or prolactin and the glucocorticosteroid also increases the subject's insulin sensitivity, decreases hyperinsulinemia or hyperglycemia, or both. thus, it affects the long-term pathological conditions that are characteristic of the onset of type II diabetes.

In the treatment of vertebrates, generally, doses of the dopamine agonist or prolactin agonist to adjust the daily rhythm of plasma prolactin are administered once daily each day, usually for about 10 to 10 hours.

150 days, in a size of about 3 µg to about 100 µg per pound of body weight: In the treatment of humans, a dopamine agonist or prolactin inhibitor is administered daily, preferably at a dose of about 3 to about 40 µg, preferably 3 to about 20 µg per day. pound of body weight. The treatment for about 10 to about 150 days, preferably about 30 to about 120 days. preferably about 30 to about 90 days, most preferably about 30 to about 60 days. applied to an obese person daily briefly - generally about 1 to about 8 hours, preferably about 4 to about 8 hours - after peak concentration of the prolactin for the lean person will result in alteration and adjustment of the obese person's lipid metabolism to the lean person values. Prolactin culminates in a insulin-sensitive lean person during sleep time, usually about midway through sleep time; therefore, the period of administration of the dopamine agonist to reduce the fat stores of the obese subject, improve the subject's insulin sensitivity, suppress hyperinsulinemia or hyperglycemia, or both, or suppress hyperinsulinemia and reduce hyperglyceria, ranges from about 1 to about 10 h - preferably from about 1 to about 8h, preferably from about 1 to about 4 hours - after half the sleep time. Body fat stores, including adipose tissue, arterial walls, and plasma fat, in an obese person will decrease and cope with lean values and remain on them for a long time after discontinuation of treatment. A bowel or obese person showing the effects of insulin resistance or hyperinsulinemia and / or hyperglyceria or concurrent insulin resistance and hyperinsulinemia and / or hyperglycaemia, treated with a dopamine agonist or prolactin inhibitor, will become more sensitive to insulin (ie will have lower insulin resistance) and the effects of hyperinsulinemia and / or hyperglyceria are reduced in the long term. Thus, injection of a dopamine agonist or a prolactin inhibitor alters the phase relationship of both neural oscillations and their multiple daily expression for long-term, if not permanent, metabolic changes. In other words, timed daily doses of a dopamine agonist or a prolactin inhibitor will result in a long-term reversal of the major pathologies usually associated with the development of type II diabetes. The level of body fat stores, plasma insulin concentration and insulin resistance and hyperglycenia, or all three of these pathological conditions, can be reduced in the long term from the high levels often found in obese hyper-insufficient persons to much lower and much more desirable levels than occur in lean, insensitive people.

For the human subject, "obesity can be defined as a body weight more than 20% above the ideal body weight for a given population" (R. H. Villiams, Textbook of Endocrinology, 1974, pp. 904-916). Day time. in which the level of prolactin, resp. glucocorticosteroid varies in obese and lean subjects, and the peak for each type of subject can be readily determined by measuring defined bold and lean specimens. Other animal species can be easily distinguished by obese and lean members of the species by body weight formulas correlated with prolactin levels. respectively. glucocorticosteroids, in lean plasma. respectively. obese members. Levels vary between members of different species, but there is a close correlation between members of the same species between prolactin levels, respectively. glucocorticosterone. at a certain time of day, depending on the obesity or thinness of the specimen.

DETAILED DESCRIPTION OF THE INVENTION

The invention is explained in more detail in connection with the following information and data from animal and human experiments. The term “LD” in the examples refers to the light / dark cycle, where the first number after LD stands for light hours and kind. hours of darkness during the cycle. Thus, LD 14 = 10 indicates a cycle in which 14 hours of light and 10 hours of darkness and a one day period is set to 2400 hours. The letter n indicates the number of animals in the group. BW refers to body weight.

The following example shows data showing the altered phase relationship of the daily rhythms of plasma corticosteroid concentrations and proactivity in pigs; the changes are favorable for the treatment of diabetics.

Example 1

Six adult female pigs were given bromocryptine implants (10mg / pig / day) and exposed to daily light and dark cycles (12-12) for the duration of application. Bromocriptine from the implants can be expected to enter the circulation in larger amounts around the onset of daily activity. A control group of six pigs were subjected to the same cycles of light and dark. but without bromocryptine. Dark time was from 1800 to 0600 and light time from 0600 to 1800. Daily blood tests for 14 days were carried out after 4 hours for swine blood tests to determine cortisol plasma levels (Cug / dl) and plasma prolactin levels (pq / nl). in both groups. The averages for each series of tests performed for each group are shown in the table:

cortisol plasma levels (Cuc / dl)

time treated pigs control 0800 1.9 4.8 1200 1.5 3.4 1600 3.2 1.6 2000 2.8 1.9 2400 3.5 2.7 0400 3.2 5.5

plasma proiactin level (ii ^f / d1)

time treated pigs con 0800 1.8 0.5 1200 2.3 3.3 1600 2.8 1.3 2000 2.4 1,2 2400 2.3 1.7 0400 1.5 0.1

The effect of bromocriptine implants on fat stores and plasma triglyceride, glucose and insulin concentrations is shown in the table below:

dorsal fat triglyceride glucose insulin treatment 100% control____naZd 1 _ma / d 1___uaZm 1 control 100 52 + 8 99 +5 10.8 + 1.8 bromocript in 86 ³ 27 + 3 ³ 86 - + 3 ³ 8.8 ± 0.3 ~ 10 ng / day / pig

NB: Dorsal fat was used as an index when determining fat stores. These data were obtained 28 days after treatment of the animals.

Samples 1600, 2000 and 2400 were taken from the plasma after two weeks of treatment. Samples were taken from each pig in both the treated and control groups.

These data clearly show that bromocriptine implants have altered the phase relationship of the daily rhythms of plasma corticosteroid and proiactin concentrations and induced changes favorable to diabetics. Data suggests that near sunset, when lipogenesis is normally greatest in pigs, bromocriptine reduces plasma triglyceride concentration by 48 Because lipid is produced in the liver and transported by blood to adipose tissue.

the lowering of triglyceride is further evidence that bronctriptine has an inhibitory effect on fat synthesis and storage. Addition. although the decrease in plasma insulin concentration was not statistically significant, bromocriptine reduced glucose levels by 13% in the first dark period (2000 to 2400). Decreasing the level of olucose without increasing the insulin concentration in the blood can be explained as a decrease in insulin resistance (greater ability of a hypoglycaemic response to insulin). During the 28-day treatment, bromocriptine reduced body fat stores by 14%.

Further human studies have been conducted to show that treatment with bromocriptine is useful in reducing the symptoms of type II diabetes. independent of insulin. Examples are given below.

Example 2

A 501-year-old woman showing symptoms of diabetes was given oral bromocript tablets daily after waking up. (1.25 to 2.50 nq / day). At the start of treatment, a blood glucose concentration close to 250 mg / dl was found by routine testing. In the weeks after the initial treatment, the patient's glucose level dropped to 130 mg / dl. 155 mg / dl, 135 mg / dl, 97 mg / dl and 101 mg / dl. Slimming levels below 120 mg / dl are considered normal. Body weight and body fat indexes also decreased by about 12% by treatment.

Example 3

A 45 year old woman was treated with a hypoglycaemic agent (diabenase), which reduced the patient's blood glucose from 250 mg / dl to about 130 mg / dl during 1 year of treatment. After daily oral administration of bromocriptine (pariodel, 1.25 to 2.5 mg / day) about 1 h after waking, blood glucose levels dropped dramatically to 80 mg / dl in 2 weeks. By removing the hypoglycaemic agent, the glucose level increased and remained close to 100 mg / dl (normal) over the next two months. Body weight and fat were reduced by about 10% with bromocriptine therapy.

Example 4

A 55-year-old woman, weighing nearly 300 pounds, was known to be diabetic, but she had resisted all medical warnings. At the start of bromocriptine oral therapy (parlodel, 2.5 ng / day), administered two to three hours after waking, its mean plasma glucose concentration was nearly 350 mg / dl. During the 2.5 months of bromocriptine treatment, body weight and plasma glucose concentration decreased gradually but steadily. Body weight decreased by 22 pounds and glucose level to 160 mg / dl.

The following example demonstrates the effect of bromocriptine treatment on a group of people. male women diagnosed with type II insulin. independent of insulin. Individual subjects described with reference to Examples 2, 3 and 4 are also included in the table.

Example 5 persons diagnosed with non-insulin-dependent diabetes (type II) were treated with bromocriptine to determine the effects of treatment on body fat and hyperglycemia. Seven diabetic patients (2 males and 5 females) received oral stimulants of endogenous insulin secretion (hypoglycene drugs diabenase and micronase) and 7 diabetic patients received daily insulin (morning and evening) injections. Only subjects who were found to be very hyperglycemic (i.e., plasma glucose > 160 mg / dl) in the morning after an overnight night and before insulin injection or other treatment were administered were enrolled.

In this bromokr i pt. In a new trial, an obese15 man with severe hypermlycemia who was refusing conventional diabetes treatment was allowed to participate: he was included in the hypoglycaemic group.

Bronocriptine was used daily at times calculated to adjust the daily hormonal rhythms to phase relationships that cause body fat loss. Usually, bronocriptine was administered in the morning up to 5 hours after waking up. Nausea was usually prevented by the original lower doses (¢ 1.25 mu) for 2 to 3 days and then the dose was increased to 2.5 mg daily. Only mild nausea was observed in less than 10% of the participants, which was transient and lasted only the first few days. The participants were thoroughly instructed not to change their daily activity or eating habits during the experiment. Patients also cooperated very well, as shown in the weekly reports of subjects who controlled their food intake, and there were no transient anorexia induced by higher doses of bromocriptine during this experiment.

Skin fold thickness was measured by a trained anthropomorphic expert according to the recommendations of the International Biological Program in four areas on the left side of the body = biceps, triceps, under the shoulder blade and above the hip. Because of frequent use, body fat percentage was estimated from the normal logarithm of the sum of these four skin folds using the equations of Durnin and Rahman and Siri. In a recent study, a very similar estimate of body fat is described by hydrodensitometry and skin fold thickness measurements. Skin fold thickness measurements were always taken by the same person at the beginning and then at weekly intervals. At the same time, blood pressure was measured. The fasting plasma glucose level in the morning was measured at baseline in the diabetic group and then after 4 to 8 weeks.

Tabu 1ka

Reduction of plasma and body fat concentrations in type II diabetes after 4 to 8 weeks of timed administration of bronocriptine by subjects to hypoglycemic subjects. drugs (8) insulin (7) measured parameter initial.

vočá t.kon.

glucose in plasma

(Mg / dl) 231 + 19 plasma glucose (% of baseline) total body weight (bb) 255 + 21 body weight loss skin fold measurement (¾ of baseline) ² body fat C% of body.

weight i) 36.5 + 2, body fat loss

Ob)

166Í19 ¹

72 + 6 ¹

253 + 20

-2.4 + 2.0

79 ¹

283 + 14 .182 + 9

184 + 22 ^a

65 + 3 ¹

132 + 10

-0.4 + 2.0

84 ¹

32.9 + 2.0 ¹ 33.4 + 2.2 31.7Ϊ1 ,? ¹

-10.0 + 2.2 ^L -3.1 + 0.9 ^{L L of} each individual in the nypoglycemic drug group (8 subjects) or insulin C7 subjects) showed a decrease in plasma glucose, skin fold thickness, and total body fat. Decreases were significant (p <0.05).

² Initial values (nm) of the skin fold in the area under the scapula, triceps, biceps and over the hip were 26 ± 3, 14 ± 2, 9 ± 0 and 19 ± 2 in the hypoglycemic group and 26 ± 2, 15 ± in the insulin group 2. 12 + 2 and 19 + 1.

After 4-8 weeks of treatment with bromocriptine, the blood glucose concentration decreased in each diabetic subject.

so the size of the skin fold. As shown in the table, the fractionate blood glucose concentration on lachrio prior to morning diabetes medication was 283 + 14 mg / dl for the insulin group and 231 ± 1.9 mg / dl for the hypoglycemic group.

After 4 to 8 weeks, mean glucose concentrations decreased <p <0.05 in the student's test) to 184 + 22 mg / dl (insulin) and 166 + 19 mg / dl (hypoglycaemic drugs). During administration of bromocriptine, oral hypoglycaemic therapy was completely discontinued in three subjects and blood glucose levels remained almost normal (at least two months after bromocriptine treatment was discontinued (120 mg / dl)). Doses of hypoglycaemic drugs and insulin were reduced in three other subjects during bromocriptine administration.

Body fat stores were significantly reduced in NIDDM subjects receiving hypoglycaemic drugs with timed bromocriptine treatment, as evidenced by an average reduction in skin fold thickness of 21% in the four areas measured. This reduction achieves an average loss of 10 pounds for each individual and a reduction in total body fat of 10.7% over 4 to 8 weeks. Decreases in skin fold thickness <16%), body fat <3.1 lb) and body fat percentage <5.1) were less in subjects taking insulin. Body weight was perhaps slightly reduced (<2.4 lb per subject, not statistically significant) in subjects receiving hypoglycaemic drugs and did not decrease at all in subjects receiving insulin.

These results indicate that bromocriptine treatment can dramatically reduce body fat stores in human subjects. Bromocriptine treatment also significantly reduced hyperglykeini in insulin-independent diabetics (type II) in two months. These results were achieved without altering existing individual diets and exercise regimens.

It is unbelievable that the body fat reduction (4.4% body weight) achieved in this experiment after 6 weeks without food restriction is equivalent to that achieved over a similar period using a very low calorie diet (420 kcal / day). Amatruda and coworkers, on the other hand, report an 8% weight loss in obese NIDDM subjects, which can be considered bold, under these conditions less than 50%. Kanders et al. report an average weight loss of 2.8 lbs per week in non-diabetic female subjects subjected to similar very low calorie diets. It also achieves a reduction of about 1 lb of fat per week under these challenged caloric conditions, which is less than the 1.4 lb of fat loss on average achieved by the bromocriptine treatment of this study.

The body fat reduction achieved with bromocriptine treatment differs significantly from the fat reduction achieved by calorie reduction. In very low calorie diets, fat only forms

And about 45% weight loss; the rest includes proteins, carbohydrates and water.

These data suggest that metabolic conditions are at least partially regulated by the interaction of daily neuroendocrine rhythms. According to this hypothesis, the daily rhythms of cortisol and prolactin are the individual expressions of two separate cyclic systems, and daily injections of these hormones can modify the phase relationship of the two systems. Thus, in a model hamster experiment, it was found that a zero hour shift adjusts the daily oscillations to a pattern that maintains an insulin-lean state of leanness, and a 12h shift allows to maintain a pattern that maintains an insulin-resistant obese state. Another significant contribution of this study is that the effects of timed injections of a dopamine agonist or a prolactin inhibitor compound are sustained. It seems that after adjusting the phase state, both daily oscillations are trying to maintain, the altered scheme.

Evidence of changes in the phase relationships of two daily neuroendocrial oscillations changes the phase relationship of their daily expression. This assumption is met with respect to plasma glucocorticosteroid and prolactin rhythms. In several of the twisted species, the phase relationship of the rhythms of both hormones differs in lean and fatty animals.

The phase relationship between the daily rhythm of plasma insulin concentration and the rhythm of lipogenic response to insulin has been shown to differ in lean and fatty animals. While the daily lipogenic response capability remains close to the onset of daylight, the phase of insulin rhythm changes significantly. For example, the maximum insulin concentration occurs in obese female hamsters reared under short day conditions. near the onset of light. That is, the daily peaks of lipogenic stinulum (i.e., insulin) and lipogenic responses to insulin in fatty animals, shoreline, and skinny sun.

Phase relationships between prolactin and insulin rhythms as well as tissue hormone response rhythms. are important elements of lipogenesis regulation. Thus, all these rhythms are phase adjusted to regulate lipogenesis. The phase adjustment of these and possibly other rhythms may also be responsible for both insulin resistance and insulin.

The invention can be modified and varied in various ways without exceeding its scope.

Claims (10)

PATENTOVÉ Claims Use of a dopamine agonist and a prolactin stimulator for the preparation of a medicament for regulating lipid and glucose metabolism. Use according to claim 1 for reducing insulin resistance. fat stores, hyperinsulinemia and / or hyperglycemia. Use according to claim 1 for modifying and restoring natural phase oscillation of prolactin and glucocorticosteroids. Use according to claim 1 for the treatment of an obese person for the purpose of modifying and adjusting lipid metabolism to values for a lean person. The use according to claim 1, wherein the dopamine agonist is selected from the group consisting of 6-methyl-8 (3-carbobenzyloxyaminoethyl 1 -10-ergolinol), 1,6-dimethyl-8 (3-carbobenzyloxyaminomethyl-10α-). ergoline, 8-acylaminoergolenes, ergocornine, 9,10-dihydroergocornine, bromocriptine and D-2-halo-6-alkyl-8-substituted ergolines. The use of claim 1, wherein the prolactin stimulator is selected from the group consisting of metoclopramide, haloperidol, pimozide, phenothiazine, sulpiride, chlorpromazine and serotonin agonists. Use according to claim 1, wherein the further compound is a thyroid hormone. The use of claim 1 for modifying and modifying neuronal phase brain oscillations to regulate the level of prolactin in the bloodstream of a human subject. Use according to claim 8 for reducing hyperinsulinenia. Use according to claim 8 for modifying and correcting neural phase oscillations of prolactin and glucocorticosteroid rhythms in an obese insulin resistant human. Use according to claim 11 fat in a thin person. 10 ke increase body content 12. Use according to those man to insulin ». claim 10 ke increase cellular c 11 ivos 13. Use according to claim 10 ke reduction hyperinsulinemia 14. Use according to claim 10 ke reduction hyperglycemia. 15. Use according to claim 10, wherein the dopamine agonist is selected from the group consisting of 6-methyl-.beta.-carbobenzyloxyaminoethyl-.alpha.-ergoline, 8-acylaminoergolenes, bromocriptine and D-2-halo-6-alkyl1-8-substituted ergolines. Use according to claim 1, wherein bromocriptine and metoclopramide are used. 17. A pharmaceutical composition comprising a dopamine agonist and a prolactin stimulator. 18. The pharmaceutical composition of claim 17, wherein the dopamine agonist is bromocriptine and the prolactin stimulator is methoclopramide.