WO2005067363A2 - Use of pyrimidine nucleotides for increasing muscle power - Google Patents

Abstract

The invention concerns compositions containing at least one pyrimidine nucleotide, and to the use of these compositions or of at least one pyrimidine nucleotide for restoring, maintaining and/or building up physical and/or mental capacity, for increasing muscle power, improving energy metabolism, treating a decline in performance and disruptions in performance, and for the treatment and/or prophylaxis of disorders and troubles responding to an increase in the supply of glucose in the muscle cells.

Description

 Use of pyrimidine nucleotides to increase muscle performance

description

The invention relates to at least one pyrimidine nucleotide-containing compositions and the use of these compositions or the use of at least one pyrimidine nucleotide to restore, maintain and / or to build physical and / or mental performance, to increase muscle performance, to improve energy metabolism, to treat Decline in performance and performance disorders as well as glycogenoses.

The term glycogenoses is understood to mean disorders of the glycogen metabolism. Such disturbances mostly arise from increased ones

Deposits of glycogen inside cells. Liver cells, kidney cells, muscle cells and nerve cells are particularly affected. The increased glycogen deposition is mostly caused by enzyme defects.

The object of the present invention is to provide physiologically well-tolerated substances which can be used to restore, maintain and / or to build up physical and / or mental performance, to increase muscular performance, to improve energy metabolism and to treat performance loss and performance disorders ,

This problem is solved by the technical teaching of independent claim 1. Further advantageous refinements, aspects and details of the invention result from the dependent claims, the description, the examples and the figures.

Surprisingly, it was found that pyrimidine nucleotides can be used to restore, maintain and / or to build up physical and mental performance, to increase muscle performance, to improve energy metabolism and to treat loss of performance and performance disorders.

TRD-PO 1102WO05 Registration.doc It has been found that administration of a pyrimidine nucleotide, preferably uridine 5'-monophosphate (UMP), cyclo-UMP, uridine 5'-diphosphate (UDP), uridine 5'-thphosphate (UTP), cytidine 5'- monophosphate (CMP), cytidine 5'-diphosphate (CDP) and / or cytidine 5'-triphosphate (CTP) and particularly preferably UMP or CMP or UMP and CMP have a positive effect on the drop in performance and / or performance disorders, have a performance-enhancing effect, homeostasis and promotes muscle regeneration and muscle building. It has also been found that in particular uridine 5'-monophosphate, uridine 5'-diphosphate, uridine 5'-triphosphate, cytidine 5'-monophosphate, cytidine 5'-diphosphate and / or cytidine 5'-triphosphate Build up and regenerate muscle cells, especially the skeletal muscle cells, which do the main work of the body.

The drop in performance is understood to mean the general drop in physical performance and the drop in physical performance in the case of endurance performance and / or continuous physical exertion. Here are both pathological

Understanding performance disorders, as well as increasing endurance performance in long-term activities and in athletes. For high-performance athletes

Increase in physical endurance, i.e. the increase in endurance performance in the foreground. When pathologically changed

Efficiency is the restoration of normal performance,

Compensation for poor performance and loss of power or the improved

Ability to regenerate, reduced convalescence (recovery phase from the acute onset of an illness to the complete recovery of the patient) are of particular importance.

The term "physical performance" can be defined as follows. Physical performance is understood to mean the totality of the individually necessary actions that are to be carried out under specific conditions at will. The respective physical performance is determined qualitatively by the use of main forms of motor stress and quantitatively by the intensity, duration and frequency.

In connection with physical performance, terms such as "automated performance", "physiological motivation" and "performance reserves" should also be mentioned. Here, the automated performance represents the basic energy requirement of the body, while the physiological willingness to perform represents the energy of the body that is deliberately to be tapped

TRD-PO 1102VVO05Registration.doc represents. The power reserves represent the body's autonomously protected energy reserves. The administration of at least one pyrimidine nucleotide, in particular UMP and / or CMP, in particular increases the physiological performance and willingness to perform.

General physical performance can be defined as the sum of the capacities of the aerobic and anaerobic systems, which is the total muscular performance that can be provided to perform mechanical work as long as possible.

The body needs energy for physical or athletic performance. This can be obtained from multiple sugars (carbohydrates), proteins (proteins) and fats. Carbohydrates and fats are primarily used to generate energy. A racing cyclist consumes about 500 kcal per hour.

In order to be able to use the energy stored in the carbohydrates and fatty acids, the body must metabolize it and thereby produce adenosine triphosphate (ATP). ATP is the universal energy source of the organism. The actual energy for the muscle is then created by splitting ATP into adenosine diphosphate (ADP) and phosphate. The body now has three options for recovering ATP from ADP: 1. Without oxygen consumption and without lactic acid production (anaerobic-alactacid metabolism), 2. Without oxygen consumption while producing lactic acid (anaerobic-lactic acid metabolism), 3. Under oxygen consumption (aerobic Metabolism).

The energy of the anaerobic-alactacid metabolism is only sufficient for approx. 6-8 seconds and therefore cannot supply the muscles with energy during long-term exertion.

In anaerobic-lactic metabolism, energy is produced from glucose without the consumption of oxygen. Lactic acid (lactate) is created as a breakdown product. This lactate is transported to the liver, heart, kidneys and less stressed muscles, where it is metabolized and eliminated. If the production rate of the lactate is higher than the elimination rate, the

TRD-PO 1102WO05AnmcIdung.doc Muscles "sour". The body uses this pathway at almost maximum loads, which it can then hold out for 40-50 seconds. Then the lactate levels rose so much that the further maximum performance is limited. The administration of a pyrimidine nucleotide, in particular UMP and / or CMP, extends this period, so that top performances using anaerobic-lactic metabolism are also possible for longer than 40-50 seconds.

For an athlete's permanent load, however, only the aerobic metabolic pathway remains, which can provide the body with the energy for the endurance load. Here, carbohydrates and fatty acids are completely broken down into water and carbon dioxide using oxygen. Since the body's fat deposits are quite large (even for those with normal weight), energies are available here at low to medium exercise intensity that enable endurance performance over several hours without noticeable loss of performance. But not only fatty acids are burned here. Some of the carbohydrates are always metabolized, because the fatty acids can be better converted together with carbohydrates.

Basically, there is an intensive relationship between the intensity of exercise and the lactate concentration in the blood. The more intensely the athlete exerts himself, the higher the lactate concentrations in the blood. Therefore, the lactate values are used to assess a person's level of training and performance.

In general, aerobic is the name given to training loads in which the lactate concentration does not rise above 2 mmol / l. In the mixed area between aerobic and anaerobic exposure, the lactate concentrations are 2 to 4 mmol / l; values over 4 mmol / l are referred to as anaerobic exposure. Highly anaerobic loads can cause lactate levels to rise to over 10 mmol / l.

The administration of at least one pyrimidine nucleotide, preferably UMP and / or CMP, extends the phase of long-term resilience and has a favorable effect on the aerobic metabolism, so that the lactate concentrations only increase at a later point in time. Thus, pyrimidine nucleotides and the compositions described herein extend the long-term resilience until the first symptoms of exhaustion become noticeable, for example by

TRD P01102WO05Anmeldung.doc the increase in lactate levels can be demonstrated. In addition, administration of a pyrimidine nucleotide improves muscle coordination, muscle fiber profile and capillarization, increases muscular aerobic performance and shortens the reconstitution time, ie shortens the recovery time of the muscle after high muscular loads. In addition, the administration of a pyrimidine nucleotide, in particular UMP and / or CMP, leads to an increase in the proportion of oxidative energy production, which limits the negative effects of the otherwise strongly increasing lactate concentrations, particularly in the final stages of athletic competitions, and decoupling aerobic energy production from excessive energy Lactate concentrations are counteracted.

The metabolic economy can also be characterized by the percentage utilization of the maximum oxygen uptake (VO2max). The more powerful an athlete is, the higher the percentage of VO2max he absorbs in the aerobic metabolic state. A highly trained athlete still consumes 85% of his already high VO2max with 2 mmol / l lactate. On the other hand, a less well-trained person with 2 mmol / l lactate only needs 65% of his VO2max and has to compensate with increased lactate formation as the load increases. The administration of a pyrimidine nucleotide, in particular UMP and / or CMP, according to the invention does not generally increase the VO2max value under continuous exposure, but leads to a later decrease in VO2max. That With the pyrimidine nucleotide, the continuous exercise phase can be extended while the VO2max remains the same, and the VO2max value drops and the lactate concentration increases only at a later point in time.

Fatigue can be divided into muscular fatigue and central fatigue. Central fatigue is the fatigue of the sensory organs and the central nervous system (CNS). Muscular fatigue often occurs after heavy stress on the skeletal and cardiac muscles. The loads lead to the muscular faster

Fatigue when the continuous output limit has been exceeded. The

Continuous output limit is the limit below which the used energy-rich connections are supplemented again on aerobic routes.

According to the invention, the pyrimidine nucleotides and the pyrimidine nucleotide-containing compositions for increasing the resilience of muscles,

TRD P01102WO05Anmeldurtg.doc used in particular the skeletal muscles or for the regeneration of muscles, in particular the skeletal muscles. The are also suitable

Pyrimidine nucleotides and the compositions disclosed herein according to the invention to counteract the muscular fatigue and can be used for the treatment and / or prophylaxis of muscle soreness, muscle strains and muscle cramps. Furthermore, the compositions or the pyrimidine nucleotides and in particular UMP, cyclo-UMP and / or CMP increase the glucose uptake in the muscle cells and can thus be used for the treatment of diseases which are caused by glucose deficiency in muscle cells.

According to the invention, the pyrimidine nucleotides can also counteract or compensate for degradation processes in old age or the age-related decrease in physical performance, irrespective of whether these degradation processes or the decrease in performance were naturally caused or caused by an illness. This counteraction is also based on building up and regenerating muscles, in particular skeletal and cardiac muscles, and increasing endurance performance.

In particular, uridine 5'-monophosphate and / or cytidine 5'-monophosphate and again preferably uridine 5'-monophosphate are suitable for the uses according to the invention. Furthermore, a combination of uridine 5'-monophosphate and cytidine 5'-monophosphate is particularly preferred.

Particularly advantageous embodiments of the present invention are compositions or combinations of pyrimidine nucleotides, preferably UMP or CMP or UMP and CMP with fatty acids and / or amino acids.

A combination of a pyrimidine nucleotide with a fatty acid, in particular with fatty acids which contain 8 to 12 carbon atoms, is therefore preferred. Substances containing such fatty acids, such as di- or triglycerides, can also be used instead of the fatty acids.

The fatty acids can be saturated as well as mono-, di- or polyunsaturated.

Such fatty acids are resorbed from the intestinal wall in an uncleaved form and serve to supply the body with energy.

TRD P01102WO05Anmeldung.doc Compositions of a pyrimidine nucleotide with at least one amino acid, in particular with alanine, lysine, phenylalanine, glutamic acid, methionine, serine, glycine, ornithine and / or taurine, are also preferred.

Combinations of a pyrimidine nucleotide with carbohydrates, in particular with maltodextrin, are also preferred.

In addition to the two-component combinations of pyrimidine nucleotide and fatty acid or amino acid or carbohydrate, multi-component combinations are preferred which contain at least one pyrimidine nucleotide, at least one fatty acid or a fatty acid-containing substance and at least one amino acid or at least one carbohydrate. It is also preferred if an amino acid-containing combination further includes a carbohydrate. It is also preferred if zinc ions in the form of zinc salts (zinc sulfate, zinc chloride, zinc acetate, etc.) are contained in the combination according to the invention.

The following combinations are thus preferred, for example: UMP + lysine UMP + lauric acid UMP + lysine + lauric acid UMP + CMP + alanine + caprylic acid UMP + glycine + capric acid + maltodextrin UMP + glycine + methionine + ornithine

The combinations described above and the pyrimidine nucleotides themselves not only have a performance-enhancing effect, in particular on muscle performance, but also have a positive effect on the body's energy metabolism, counteract signs of fatigue, improve the immune system and the associated proliferation of cytokines and prostaglandins and increase the protective function of the body Body, for example, with an ammonia detoxification.

Such combinations as well as the pyrimidine nucleotides themselves are particularly suitable for increasing the cardiac, i.e. performance related to the heart as well as the performance of the skeletal muscles.

TRD P01102WO05Anmcldung.doc The relationships between nutrition, ie energy intake, glycogen availability and endurance performance at a high level are still largely unclear. It is known, however, that the body's own fat reserves cannot be used directly for energy and that carbohydrates and fats consumed through food also first have to be converted in the body. This creates a so-called insulin hole in the case of heavy physical exertion, especially with heavy continuous exertion. Due to the inadequate supply of energy to the muscles, this can lead to a so-called "hunger branch" and even to the point of insulin coma.

The use according to the invention of the pyrimidine nucleotides, in particular of UMP or CMP and a combination of UMP and CMP ensures an adequate energy supply for the muscles, i.e. of the muscle cells and thus prevents the formation of an insulin hole. The aforementioned pyrimidine nucleotides can thus be used for the prophylaxis and / or treatment of the so-called "starvation branch" and insulin coma.

In the case of continuous physical stress, which occurs, for example, in a marathon runner, the pyrimidine nucleotides bridge the period of energy deficiency in the muscle cells. Since the body's own energy reserves cannot be implemented spontaneously and carbohydrates and fats taken in through food also have to be converted in the body, the muscle cells consume more energy than the body can provide from food or its own reserves in the case of such physical continuous loads. This results in an undersupply of the muscle cells, which the body tries to compensate for by reducing its own fat reserves, which is sometimes not possible with casual athletes and only after a certain time delay with competitive athletes. The pyrimidine nucleotides, in particular UMP and / or CMP, bridge this period of undersupply.

The combinations according to the invention and the administration of a pyrimidine nucleotide, in particular UMP, increase the performance of muscles, i.e. the performance of athletes, especially in endurance disciplines (e.g. marathon) or when there is a high level of stress over a longer period (e.g. at competitions or the Olympic Games).

TRD-P01102WO05Anrne lung.doc It is also known that prolonged physical or athletic exertion leads to glycogen depletion with the decline in the provision of quickly effective energy reserves. Such glycogen depletion has a negative impact on renewed increases in stress during an ongoing stress phase. Such increases in stress during a

Stress periods are, for example, the final sprint in bicycle races or sprints in football, especially at the end of a game or during an overtime. If an increase in performance is undertaken during an exercise phase or an attempt is made to achieve a new short-term peak performance during a prolonged continuous exercise or during glycogen depletion, this can lead to disturbances in concentration and coordination, in particular motor coordination, reduced attention, a reduction in the situational complex ability to act and Creativity, affect incontinence and loss of aggressiveness control. The administration of at least one pyrimidine nucleotide or one of the combination preparations described herein reduces or prevents the phenomena described above, so that these combinations and the pyrimidine nucleotides themselves for the purpose of correcting disorders of concentration and coordination, in particular motor coordination, for increasing attention and the complex situation and the ability to act Creativity, as well as for the treatment of affect incontinence and for attaining or regaining the aggressiveness control.

Furthermore, administration of at least one pyrimidine nucleotide or one of the compositions disclosed herein helps optimize fat oxidation.

The administration of at least one pyrimidine nucleotide or at least one of the combinations described herein supports the development and rehabilitation of the muscles and is therefore suitable for the treatment of patients who have been in bed for a long time and whose muscles have regressed and must be rebuilt.

The administration of at least one pyrimidine nucleotide or a composition containing at least one pyrimidine nucleotide according to the invention increases physical performance and physical endurance, delays the drop in performance during a continuous exercise phase and promotes the maintenance of homeostasis, particularly during a continuous exercise phase, over a prolonged period.

TRD-P01102WO05 notification doc The term stress encompasses demands on the organism of an individual that are caused by the environment and / or the organism itself. The individual reacts to maintain homeostasis, thereby performing.

The term homeostasis is derived from the Greek word for "similar, similar" and denotes the constant endeavor of the organism to harmonize different physiological functions (such as body temperature, pulse rate, blood sugar level, etc.) and to keep this state as constant as possible. This optimizes the adaptation to the environment and minimizes the effort required to sustain life.

In this context, the work performed by the individual cannot be seen in the physical sense (work / unit of time (watts)). The term performance is intended to encompass the physiological meaning, i.e. a goal-oriented activity, which in the organism reactions to provide energy for e.g. which causes muscle work.

Stress is understood to mean external and internal predetermined demands on the organism. Based on this definition, each body function represents a requirement. If the organism fulfills these requirements, it performs as already mentioned, whereby depending on the performance and the efficiency, a greater or lesser strain results.

These demands placed on the organism can be unplanned (e.g. due to the environment, such as special events, climate, pathogens, new sensory stimuli), or planned (e.g. work, leisure, sport, etc.). However, the intensity or scope of the request is only determined by the volume of these events. The type of stress can be divided into two characters, a physical character (e.g. a sports stress) and a psychological character (e.g. change of location, isolation). The psychological stress can often only be described verbally and should not be the subject of further elaboration here. The implementation of the burden with the already mentioned goal of maintaining homeostasis through adaptation also takes place here, among other things. by means of the endocrine systems as well as through the autonomic nervous system. The consequences can vary

TRD P01102WO05Anmeldung.doc manifest. If the requirements for intensity and volume do not represent an actual burden, ie the organism is under-challenged from the start, adaptation is not necessary. In contrast, an adequate burden results in an adaptation and maintenance of homeostasis. However, these regulatory mechanisms can be permanently disturbed if there are damaging influences, such as the effects of certain stimuli that go beyond a physiological level or a noxious substance (eg excessive demands). The result is a change in the homeostatic balance of the organism. No adaptation takes place, while maintaining homeostasis cannot be achieved. Persistent noxae without corresponding phases of recovery lead to fatigue, ie to a decrease in performance. The permanent state of fatigue ultimately leads to the consumption of all energy reserves, to so-called exhaustion, which results in physical damage or illnesses.

The so-called overtraining also presents itself with these symptoms. The term overtraining describes a chronic condition of the imbalance between training and recovery phases, which is expressed in fatigue. The

Recovery phases are not sufficient for the training status, further adaptation of the organism to the training cannot take place. The consequences are reduced performance, weight loss, behavior change, etc., and even physical damage or illness. After an adequate recovery phase, however, the original performance potential can be regained.

However, the achievement of a certain service also depends on the performance. Efficiency is made up of several factors. These include genetic predisposition (race, gender, predisposition), functional requirements (musculoskeletal system, cardiovascular system, breathing), as well as health, psyche and training or exercise.

Exercise can also increase physical performance. The term exercise refers to the activity that achieves the increase in performance without organic changes. Training is the opposite. The term training describes the effort to maintain and / or improve performance over a longer period of time through targeted physical activity.

TRD-P01 102WO05Anmcldung.doc Stress therefore places various demands on the organism while it tries to achieve homeostasis through adaptation.

The administration of at least one pyrimidine nucleotide or a composition containing at least one pyrimidine nucleotide according to the invention increases the physical performance and keeps the performance constant over a longer period of time before a drop in performance or signs of fatigue occur. Thus, symptoms of one occur

Overtraining only occurs later when a pyrimidine nucleotide, in particular UMP or CMP or UMP and CMP, is administered. Furthermore, homeostasis is maintained longer by the administration, i.e. the aforementioned physiological functions remain in balance for a longer time by the administration of a pyrimidine nucleotide.

The pyrimidine nucleotides can also be used for the treatment of metabolic disorders and organ disorders, in particular disorders of the glucose metabolism or carbohydrate metabolism, as well as organ disorders due to impaired glucose metabolism or carbohydrate metabolism. The following describes the glucose metabolism, the disruption of which can be treated according to the invention by pyrimidine nucleotides, in particular due to malfunctions of the enzymes and hormones involved.

Metabolism of carbohydrates and glucose metabolism The metabolism of carbohydrates can be divided into the following steps: 1) digestion / absorption (absorption) in the intestine from food, 2) conversion and breakdown of carbohydrates / formation of new carbohydrates and 3) storage of carbohydrates.

The control of these complex metabolic pathways is subject to the supply and demand for carbohydrates, the enzymes involved in these metabolic pathways and the hormones which regulate the level of glucose in the blood, in particular insulin, glucagon, cortisol, adrenaline and others.

The disorders of the carbohydrate metabolism are divided into hyperglycaemia, hypoglycaemia and the innate disorders of the carbohydrate metabolism.

(TRD P01102WO05Anmcldung.! Oc The digestion of carbohydrates begins in the mouth when they are exposed to the amylase released by the salivary glands. The amylase cleaves α-1,4-glycosidic bonds at random. The result is carbohydrate fragments of different chain lengths (dextrins) and maltose. The acidic gastric juice inactivates the amylase from the salivary glands. In the intestine, pancreatic amylase causes starch and glycogen to split into maltose. The intestinal disaccharidases split both maltose and lactose and sucrose, so that the carbohydrates as the monosaccharides glucose, galactose and fructose are absorbed by the intestinal cells and transferred to the blood, where they first reach the liver via the portal circuit.

Because only the glucose of the organism can be used to generate energy from the carbohydrates, the galactose and fructose in the liver are converted into glucose.

In a first step, a phosphate group is then transferred from the ATP to the C6 atom of the glucose molecule. This reaction is catalyzed by glucokinase in the liver cells and by hexokinase in the other cells. The magnesium ion is an activator of hexokinase (see Fig. 4: Generation of α-D-glucose-6-phosphate).

Glucose-6-phosphate is the starting molecule for three different metabolic pathways: 1 Degradation of glucose in glycolysis 2) Degradation of glucose in the hexose monophosphate shunt (pentose phosphate pathway). The end products are fructose-6-phosphate and glyceraldehyde-3-phosphate. 3) Storage of the glucose as glycogen.

Fig. 3 shows the central position of glucose-6-phosphate in the glucose metabolism (UDP: uridine diphosphate).

The breakdown of glucose to pyruvate / lactate is called glycolysis. The special thing about it is that energy can be obtained anaerobically (i.e. without the use of oxygen). The enzymes for glycolysis are in the cytosol of the cells.

TRD-PO 1102WO05 Registration.doc 5 shows the glycolysis and the necessary enzymes: 1 = hexokinase, glucokinase 2 = phosphohexose isomerase, 3 = phosphofructokinase, 4 = aldolase, 5 = triosephosphate isomerase, 6 = phosphoglyceraldehyde dehydrogenase, 7 = phosphoglycerate kinase, 8 = phosphoglycerolase , 10 = pyruvate kinase, 11 = lactate dehydrogenase (LDH).

As is clear from FIG. 5, glycolysis can be divided into two phases. The first phase serves to convert the molecule so that the two similar fragments of glyceraldehyde-3-phosphate (glyceral-3-phosphate) from one molecule of glucose. and dihydroxyacetone phosphate

(Glyceron phosphate) arise. The two trios can also be converted into each other (see Fig. 6). The two energy-supplying reactions take place in the second phase.

Under anaerobic conditions pyruvate is converted to lactate to NAD ⁺ to gain from NADH + H ⁺ again. Glycolysis is the only way to build the high-energy ATP. Under aerobic conditions, pyruvate can be broken down into CO ₂ and water in the citrate cycle and the respiratory chain with further energy gain.

In glycolysis, 1 molecule of glucose is broken down into 2 molecules of pyruvate. In addition, 2 molecules of ATP and 2 molecules of NADH + H ^{+ are formed,} as can be seen from FIG. 7.

Under anaerobic conditions, pyruvate is converted to lactate, NAD ^{+ is} regenerated (see FIG. 8: conversion of pyruvate to lactate by the lactate dehydrogenase (LDH))

The glucose is stored in the form of the glycogen. Glycogen is the intracellular carbohydrate reserve in humans. The liver and muscles in particular are extremely rich in glycogen. However, the glycogen content of the liver is heavily dependent on the nutritional status and drops to a minimum value even after a shorter fast. Only erythrocytes contain no glycogen.

The strong branching of the glycogen molecules enables the enzymatic degradation to be used simultaneously at different locations if required. Glycogen is made up of up to 100,000 glucose molecules (see Fig. 9).

TRD P01102WO05Anmcldung.doc 9 shows the schematic representation of a glycogen molecule. Linear chains are formed by α-1,4-glycosidic bonds, and α-1,6-glycosidic bonds lead to branching.

Glycogen is branched after every 8th to 12th glucose molecule. Because only the number of particles is important for the osmotic pressure, the combination of many individual glucose molecules to form glycogen molecules can avoid large water retention in the cell.

The formation of new glucose is called gluconeogenesis. Lactate can be reconstructed into glucose in the liver via pyruvate, whereby 3 molecules of ATP are required. The enzymes for the are missing in the muscles

Gluconeogenesis (glucose-6-phosphatase). The muscle cells therefore release the lactate to the blood, which means that it reaches the liver for further use. This interplay between muscles and liver is called the Cori cycle. Amino acids that are degradable to pyruvate can also be used for new glucose formation.

10 shows a small and greatly simplified section of the metabolism of glucose. The glucose absorbed in the intestine is transported to the brain, liver and muscles, among other things. In the muscle cells, glucose is broken down into lactate with energy gain. Lactate is transported by blood from the muscle cells to the liver. The liver can rebuild lactate into glucose. However, energy is consumed in the process. The liver can store the glucose as glycogen or make it available to other organs. In the brain, glucose is broken down into CO ₂ and H ₂ O with energy gain.

At low insulin levels, the muscle cell is actually not permeable to glucose molecules (in contrast to the liver). It then covers its energy requirements exclusively through fatty acids. However, there is an exception. If the insulin level rises sharply after a very high carbohydrate intake, then the muscle cell is also permeable to glucose.

Under the influence of high insulin levels (after eating), the muscles can also produce and store glycogen. During extreme loads (e.g. sports), the muscles then make use of it. From the glycogen arises

TRD P01102WO05Anmeldung.doc Glucose, which cannot leave the muscle cell. The cell membrane of heavily used muscles can also absorb glucose independently of insulin (e.g. in competitive athletes).

The nerve cells cover their not inconsiderable energy requirements almost exclusively with glucose. This fact also explains why dropping blood glucose levels below certain levels can lead to "hypoglycemic shock" with decreased consciousness or even coma. The administration of at least one pyrimidine nucleotide according to the invention can counteract this.

According to the invention, the pyrimidine nucleotides, especially UMP and / or CMP and the compositions containing pyrimidine nucleotides, can also be used for the treatment of hypoglycaemia, hyperglycaemia, congenital carbohydrate metabolism disorders, fatigue, Cushing's disease, metabolic disorders such as a corticosteroid deficiency, hypothyroidism, disorders in sugar metabolism, muscle weakness , and / or glycogenoses are used.

In hyperglycaemia, the blood glucose level rises above normal (fasted over approx. 110 mg / dl or over 2 hours after eating over approx. 140 mg / dl). One speaks of an excess sugar (hyperglycemia). Typical symptoms of hyperglycaemia are: increased urge to urinate (polyuria), strong thirst (polydipsia), itchy skin (pruritus), fatigue, chronic infections, weight loss, visual disturbances and loss of consciousness (coma diabeticum) (from blood sugar levels above approx. 400 mg / dl).

Hyperglycaemia can have various causes, such as eating too much or incorrectly, exercising too little (e.g. during hospitalization), injecting too little insulin, taking too short a time between injection and eating, forgetting tablets, excitement (here the hormone adrenaline is released, which is an opponent of insulin), surgery, inflammation, pregnancy, fever and taking certain medications (e.g. cortisol).

With hypoglycemia, the blood glucose level drops below a certain value (below approx. 60 mg / dl). Now one speaks of a hypoglycemia. This leads to different symptoms, which are mainly due to the fact that the brain is no longer adequately supplied with glucose. Typical symptoms of

TRD-PO 1102 WO05Anincldung.doc Hypoglycemia includes: tremors, cramps, cravings, sweating, restlessness, aggressiveness, confusion, palpitations and, in severe cases, loss of consciousness.

Hypoglycemia can have various causes, such as not eating enough carbohydrates, skipping meals, forgetting snacks, unusual physical exertion (sports etc.), injecting too much insulin, too long a gap between injection and food intake, drinking alcohol and insulin-releasing medications (e.g. sulfonylureas) ) taken.

Prolonged hypoglycemia can damage the cerebral cortex, reduce intelligence, and reduce learning ability.

Fatigue refers to chronic fatigue, which mostly occurs in cancer patients due to chemotherapy.

The cause of Cushing's disease is an overproduction of cortisol. Cortisol is the main representative of glucocorticoids (adrenal cortex hormones: cortisol, cortisone, corticosterone and structurally related synthetic compounds such as dexamethasone, triamcinolone), which disrupt the intermediate metabolism, especially the sugar metabolism. Cortisol is an insulin antagonist in terms of its effect on intermediate metabolism. While insulin inhibits hepatic gluconeogenesis, cortisol stimulates it. Insulin lowers blood sugar while cortisol increases it. Insulin stimulates the build-up of proteins from amino acids, while cortisol promotes protein breakdown to amino acids (proteolysis). Insulin inhibits fat loss (lipolysis) while cortisol stimulates it. Symptoms of Cushing's disease include muscle weakness. This muscle weakness is the result of the protein breakdown mentioned earlier, which is promoted by cortisol.

Glycogenoses as metabolic disorders cause various complaints and diseases, which are described in more detail below.

A certain group of metabolic disorders are glycogenoses, especially type I to XII glycogenoses. Glycogenoses are caused by an enzyme defect, have various symptoms and can affect various organs.

TRD P01102WO05Anmeldung.doc The following Table 1 gives an overview of the glycogenoses known to date, the organs affected, the enzyme defect and the symptoms.

Table 1: Glycogenoses

TRD P0U02WO05Anmeldung.doc

The table was taken from the following website: http://www.morbus-pompe.de/index.html? home = glykogenosen_uebersicht.html

The glycogenoses can be roughly divided into two classes, firstly the liver glycogenoses (e.g. types I, III, IV, VI) and secondly the muscle glycogenoses (e.g. types II, V, VII, X).

Von Gierke's disease represents the autosomal recessive inheritance - hepatorenal - type 1 of glycogenosis.

As a result of a lack of glucose-6-phosphatase, this type of glycogenosis mainly leads to fasting hypoglycaemia, hemorrhagic diathesis, due to thrombocytopathy due to glycogen accumulation, liver insufficiency and can later even lead to kidney enlargement (nephromegaly), infantilism (adiposogenital type) and type diuretic dystrophy (type skin dysentery) Meesmann) lead.

TRD-P01102WO05Λnmcldung doc Forbes syndrome is a type of glycogenosis that is based on the autosomal recessive hereditary deficiency of amylo-1, 6-glucosidase and is associated with glycogen deposition in the liver, muscles and heart, whereas the F.-Hers glycogenosis leads to glycogen deposits only in the liver.

The person skilled in the art understands amylopectinosis as cirrhotic type IV of glycogenosis with a deposition of an amylopectin-like substance in the reticulo-endothelial system.

McArdle (-Schmid-Pearson) syndrome is an autosomal recessive inherited glycogenosis. This glycogenosis is characterized by an enzyme defect or the absence of α-glucan phosphorylase. Myopathies develop as a result of glycogen accumulations in the skeletal muscle and the lack of ability to produce lactic acid. Weakness, stiffness, cramps and pain in the muscles are typical symptoms.

Hers disease is a Cori 6a or 6b glycogenosis. As a result of an autosomal recessive hereditary deficiency of α-glucan phosphorylase, glycogen deposits occur in the liver, which can also be enlarged due to the disease. Typical symptoms are obesity and short stature. Hers disease is usually accompanied by crisis-like acidosis, adrenaline-resistant hypoglycemia and / or hyperlipemia. Hyperlipemia is mostly caused by a lack of phosphorylase and is similar to Mc Ardle syndrome.

The pyrimidine nucleotide is used according to the invention in a daily dose of 1-500 mg, preferably 40-400 mg and particularly preferably 50 to 300 mg.

A further use of a pyrimidine nucleotide and one of the combinations described herein containing a pyrimidine nucleotide consists in the production of a pharmaceutical composition which is used to restore, maintain, increase and / or to build physical and / or mental performance, to increase muscle performance, to increase muscle performance physiological performance, to improve the energy metabolism as well as for the treatment of performance decline and performance disorders as well as for the treatment of metabolic disorders, organ dysfunction, general performance decline, decrease in

TRD P01102WO05Anmeldung.doc Endurance performance, deteriorated regeneration ability, poor performance, reduced physical stamina, reduced convalescence, degradation processes in old age, loss of strength, hypoglycemia, hyperglycemia, type 2 diabetes mellitus, fatigue, Cushing's disease, muscle weakness, and / or glycogenosis can be used.

In addition to the pyrimidine nucleotide or the pyrimidine nucleotide mixture, such pharmaceutical compositions can contain the customary solid or liquid carriers, diluents or solvents or the customarily used auxiliaries. These compositions are used in accordance with the desired type of application, preferably with an active substance concentration of pyrimidine nucleotide of 1 to 500 mg, preferably 10 to 100 mg and particularly preferably 50 to 100 mg, and are prepared in a known manner.

The pyrimidine nucleotides which can be used according to the invention and the compositions which can be used according to the invention are suitable for intravenous, intraperitoneal, intramuscular, subcutaneous, rectal, vaginal, transdermal, topical, intradermal, intestinal, oral, intragastric, intracutaneous, intranasal, intrabuccal, percutaneous or any other, sublingual Application.

The preferred compositions are in a dosage form which is suitable for oral administration. Dosage forms of this type are, for example, tablets, mini-tablets, micro-tablets, effervescent tablets, film-coated tablets, capsules, pills, powders, solutions, dispersions, suspensions or inhalation solutions.

Corresponding tablets can be prepared, for example, by mixing a pyrimidine nucleotide with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, glycerides of fatty acids, microcrystalline cellulose, cellulose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, polyvinylpyrrolidone, lubricants such as magnesium stearate or talc and / or agents for achieving a depot effect such as carboxypolymethylene, carboxymethyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several

TRD P01102WO05Anmcldung.doc Layers exist. Silicon dioxide / talc can be added to improve the flow properties.

Coated tablets, film-coated tablets can accordingly be prepared by coating cores which are produced analogously to the tablets with usually in

Dragee coatings / film coatings are used, for example hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet / film cover can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used. A suitable dye can be added to the film / coated tablet coating or tablet core.

Solutions or suspensions with the active ingredient which can be used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar as well as flavoring agents such as vanillin or flavoring extracts e.g. Orange extract included. You can also use suspension aids such as

Contain sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoate sorbic acid / K ⁺ sorbate. Vesicle-forming substances (eg PC) can also be used.

Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol, cellulose, microcrystalline cellulose and encapsulating them in capsules (gelatin, hydroxypropylmethyl cellulose). Capsules containing the active ingredient can also be obtained by encapsulating mini tablets of the above composition.

Of course, parenteral preparations, such as injection or infusion solutions, can also be used. Injection solutions of a pyrimidine nucleotide or pyrimidine nucleotide mixture in physiological saline are particularly suitable for parenteral administration.

Methods for producing various formulations and the various application methods are known to the person skilled in the art and are described in detail, for example, in "Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton PA".

TRD P01102WO05Anmeldung.doc Examples

Example 1: Increasing endurance performance

A study in rats showed that administration of UMP or CMP or a mixture of UMP and CMP increases endurance performance in rats.

A test group of test animals was given 5 mg / kg UMP or 6 mg / kg CMP or 3 mg / kg UMP and 2.5 mg / kg CMP dissolved in 0.9% saline daily for a period of 10 days. A control group, on the other hand, only received the 0.9% NaCl solution without pyrimidine nucleotide.

The endurance performance of the rats was tested in an impeller 30 minutes after the injection. The impeller was designed to be driven by a motor to force the rats to run in the impeller. If a rat slowed or interrupted its running, it fell on its back due to the movement of the impeller and touched a wire through which a small current flowed. The electric shock caused the rat to keep moving on the impeller until the muscle slack became so strong that the rat finally stopped walking.

In the test group as well as in the control group, the time was measured during which the rats in the exercise bike moved until they gave up their running activity due to muscle relaxation.

Figure 1 clearly shows that from the 6th day of the test, the rats in the test group were clearly superior to the animals in the control group in terms of endurance performance.

This shows that individual as well as mixtures of pyrimidine nucleotides, especially UMP and / or CMP, can significantly increase physical endurance performance.

TRD P01102WO05Λnmeldung.doc Example 2: Provision of short-term peak loads

A study in rats showed that the administration of UMP or CMP or a mixture of UMP and CMP made it possible to achieve short-term peak performance.

A test group of test animals was given 5 mg / kg UMP or 6 mg / kg CMP or 3 mg / kg UMP and 2.5 mg / kg CMP dissolved in 0.9% saline daily for a period of 10 days. A control group, on the other hand, only received the 0.9% NaCl solution without pyrimidine nucleotide.

In half of the test animals in each group, the glucose level in muscle cells was determined without prior physical exertion.

The other half of the test animals in each group were subjected to a five-minute exercise at high running speed on the impeller, and immediately afterwards the glucose content in muscle cells of the test animals was determined.

FIG. 2 shows that the rats in the test group have a significantly higher glucose level in the muscle cells both without and with physical exertion.

If the glucose level is taken as a measure of the possibility of performing physical work, the rats treated with UMP or CMP or UMP and CMP appeared to have significantly larger energy reserves than the test animals of the control group even after a short period of heavy exposure.

The administration of the pyrimidine nucleotides thus enables short-term peak performances to be achieved without showing any significant state of exhaustion.

TRD-PO 1102WO05 Registration.doc

Claims

claims

1. A composition comprising at least one pyrimidine nucleotide and at least one fatty acid or at least one fatty acid-containing substance and at least one amino acid.

2. The composition of claim 1, wherein the fatty acid-containing substance is a di- or triglyceride and the at least one fatty acid is selected from the group consisting of saturated, monounsaturated, di-unsaturated and polyunsaturated fatty acids having 8 to 12 carbon atoms.

3. The composition of claim 1 or 2, wherein the at least one amino acid is selected from the group comprising: alanine, lysine, phenylalanine, glutamic acid, methionine, serine, glycine, ornithine and taurine.

4. Use of a composition according to claim 1, 2 or 3 or at least one pyrimidine nucleotide to restore, maintain, increase and / or to build physical and / or mental performance, to increase muscle performance, to increase physiological performance, to improve energy metabolism as well as for the treatment of drop in performance and performance disorders.

5. Use according to claim 4, characterized in that the pyrimidine nucleotide is uridine 5'-monophosphate, cyclo-UMP, uridine 5'-diphosphate, uridine 5 ^* -triphosphate, cytidine 5'-monophosphate, cytidine -5'- diphosphate or cytidine 5'-triphosphate.

6. Use according to claim 5, characterized in that the pyrimidine nucleotide is uridine 5'-monophosphate or cytidine 5'-monophosphate.

7. Use according to any one of claims 4-6, characterized in that it is in the restoration, maintenance and / or to build physical and / or mental performance, increase in muscle performance, improvement of energy metabolism and the treatment of performance decline and Performance disorders around metabolic disorders, organ dysfunction, general

TRD-PO 1102WO05 Registration.doc Decline in performance, decrease in endurance performance, impaired regenerative ability, poor performance, reduced physical stamina, reduced convalescence, aging processes, loss of strength, hypoglycemia, hyperglycemia, type 2 diabetes, fatigue, Cushing's disease, muscle weakness, and / or glycogenosis.

8. Use according to claim 5, characterized in that the glycogenoses are type I - XII glycogenoses, hepatorenal glycogenosis type I, v. Gierke disease, generalized malignant glycogenosis type II, Pompe disease, hepatomuscular benign glycogenosis type III, Cori disease, Forbes syndrome, liver cirrhotic reticuloendothelial glycogenosis type IV, Andersen disease, amylopectinosis, muscular glycogenosis type V, McArdle's disease, hepatic glycosis, hepatic glycosis, hepatic glycosis, hepatic glycosis, hepatic glycogenosis, hepatic glycosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, hepatic glycogenosis, type VI, McArdle disease, hepatic glycogenosis, hepatic glycogenosis , muscular glycogenosis type VII, Tarui disease and / or hepatic glycogenosis type VIII.

9. Use according to any one of claims 4-8, characterized in that the pyrimidine nucleotide is used in a daily dose of 1-500 mg, preferably 10-100 mg and particularly preferably 50-100 mg.

10. Use of a pyrimidine nucleotide for the preparation of a composition which is suitable for oral administration or for injection.

TRD-PO 1102WO05 Registration.doc