EP0455770A1 - Use of guanidinoacetic acid to induce an increase of the creatine contents in muscles - Google Patents

Abstract

Guanidinoacetic acid, or one of its salts, alone or in combination with methionine or with sulfo-adenosil-methionine (SAMe) is used in conditions and physical states which require an increase in muscle content intercellular to creatine.

Description

USE OF GUANIDINOACETIC ACID TO INDUCE AN INCREASE OF THE CREATINE CONTENTS IN MUSCLES Prior Art

It is known that in the muscular tissue exist different biological compounds of an energetic content of which the principal one is adenosine triphosphate (ATP) .

Among these substances a very important one is creatine phosphate, which is in relationship with ATP in the sense that between the two compounds there is an exchange of phospate groups. The importance of creatine is demonstrated by the fact that in conditions of myocardial ischemia there is an arrest of the contractile function of the heart at the moment of the depletion of the creatine itself while 30% of the ATP is still present. This is due to the fact that the ATP available to give immediate energy for the contraction is only a small part of the ATP present, which functions as a reserve. The duty of creatine is to recharge the ATP until it can give energy for the contraction. From these considerations an important problem clearly emerges, that is, the problem of increasing, when necessary, the amount of creatine in the muscle. .This would allow a prolonged efficiency and more potency of both the cardiac and skeleton muscle. In fact, while the reserve of ATP is easily refurnished both in aerobiosis and in anaerobiosis, the contractile performance peculiarly in anaerobiosis, is a function of the quantity of creatine present. Therefore, said substance is of great interest both in the medical and sports field: one only has to think, for example, of how many lives could be saved in case of myocardial infarct if it would be possible to make the cardial contractions continue in conditions of ischemia until a correct oxigenation of the infarcted tissue is restored or, in the case of sports activity, how well an athlete could perform in a sport with such an explosive type of effort, as in the 100 meter race, where the athlete carries out his performance in apnea. On the other hand, it should be kept in mind that creatine is sinthesized principally in the kidneys and in the liver and therefore, there will be a deficiency of it in the course of all the nephropathies and hepatopathies with a parenchymal derangement. Unfortunately, the administration of exogenous creatine does not bring any positive result, because exogenous creatine inhibits the sinthesis of endogenous creatine for a quantity equal to the quantity of creatine administered. Summary We have now found that the prior art difficulties can be overcome through the administration of guanidinoacetic acid or of one of its salts, alone or in association with methionine or with sulpho- adenosyl-methionine (SAMe) .

Such an administration brings an increase of the intercellular muscular content of creatine and therefore ^• increases the availibility of energy for both the skeletal and cardiacal muscular cells.

Detailed description of the invention

The effects and the advantages of the administration of guanidinoacetic acid (GAA) alone or in association with methionine or sulpho-adenosyl-methionine (SAMe) in the aim of increasing the intercellular muscular content of creatine will be further illustrated in the course of the following detailed description.

In an experiment conducted with rats GAA was administered as a supplement to a standard diet. To determine the increase of the intercellular muscular content of creatine, the urine excreted by them during 24 hours was collected and the concentration of creatinine was measured. The dosage provides a reliable measure of the intercellular content of creatine in that, as known, the renal elimination of creatinine is a mathematical function of the intercellular concentration of creatine and does not depend on any other parameter as, for example, muscular exercise or calorie intake.

The experimentation with GAA was realized in two stages each of a week's duration, and intervalled by a period of three days between the first and second stage. In the week preceeding the experimentation with GAA the creatininuria was monitored in the rats fed with a diet which contained methionine in an amount equal to the one needed by the rat plus an amount of methionine of 1.7 mg/kg of body weight, which corresponds to the one necessary to activate the GAA which will be added in the successive weeks. In the first stage of the experiment with GAA the rats were fed with the diet of the preceding week supplemented with GAA in quantity of 1.7 mg/kg of body weight.

After a week, the integration of the diet with GAA was suspended for three days. After this suspension the rats were fed with a diet supplemented with GAA again for one week (second stage) . The results obtained are reported in Table 1.

TABLE 1: Creatininuria (mg/24 h) in rats fed with a diet supplemented with GAA (average values of a week ± standard deviation)

Before the After treatment After treatment treatment 1st stage 2nd stage

5.2 ± 0.1 7-8 ± 0.5 9-2 ± 0.3

It should be observed that in the synthesis process of creatine starting from GAA there is the danger of subtracting methionine from other metabolic processes. For this reason the present invention also forsees the association of methionine or SAMe to GAA with a molar ratio between methionine or SAMe and GAA of between 0.5:1 and 3:1. The administration of GAA and of the association GAA-methionine or GAA-SAMe therefore finds a very important indication in all the conditions in which it is necessary or opportune to increase the intramuscular concentration of creatine and particularly in the nephropathies and hepatopathies with parenchymal damage, in older people, in conditions of hyponutrition and chronic and acute myocardial muscle ischemia.

Such substances are also usefully administered to athletes who practice sports which require explosive efforts. The adminsitration of GAA and of the GAA-methionine or GAA-SAMe association can be 5 made orally or parenterally employing said substances in a pure state or in the form of compositions comprising diluents and pharmacologically acceptable excipients. GAA can be used as such or in the form of salt with a pharmacologically acceptable cation. The daily dose of GAA to be administered is comprised between 10 0.0001 to 5 mg/kg of body weight in several daily doses.

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Claims

CLAIMS 1. Use of guanidinoacetic acid or of one of its salts for administration in affections and physical conditions which require an increase of the intracellular muscular contents of creatine. 2. Use according to claim 1, characterized in that the guanidinoacetic acid or one of its salts is in association with methionine or with SAMe in a molar ratio between methionine or SAMe and guanidinoacetic acid comprised between 0. :1 and 3:1- 3- Use of guanidinoacetic acid or one of its salts for the preparation of pharmaceutical compositions comprising diluents and pharmacologically acceptable excipients suitable for the treatment of affections and physical conditions which require an increment of the intracellular muscular contents of creatine. 4. The use according to claim 3_t characterized in that the guanidinoacetic acid or one of its salts is in association with methionine or with SAMe in a molar ratio between methionine or SAMe and guanidinoacetic acid comprised between 0.5/1 and 3:1- 5- The use according to claims 1 to 4, characterized in that the daily quantity of guanidinoacetic acid to be administered is comprised between 0.0001 and 5 mg/kg of body weight in several daily administrations.