WO2012136204A2

WO2012136204A2 - Preparation or dietary supplement

Info

Publication number: WO2012136204A2
Application number: PCT/DE2012/100090
Authority: WO
Inventors: Gunnar Frank
Original assignee: Gunnar Frank
Priority date: 2011-04-04
Filing date: 2012-04-03
Publication date: 2012-10-11
Also published as: WO2012136204A3; DE102011001768A1

Abstract

The invention relates to a pharmaceutical preparation or dietary supplement as a preparation or dietary supplement for improving the alcohol metabolism. To achieve a particularly efficient acetaldehyde degradation, the preparation comprises, as an essential component, glutathione and/or substances from which the body synthesizes glutathione. This considerably accelerates and/or catalyses the enzymatic conversion without a direct chemical reaction of glutathione with the acetaldehyde taking place. It has emerged that the acetaldehyde degradation rate can be increased considerably in this manner, so that the undesired side-effects are noticeably reduced or disappear even after a short period of time.

Description

Preparation or dietary supplement

The invention relates to a pharmaceutical preparation or dietary supplement for improving the metabolism of alcohol, in particular ethanol.

Such a preparation or dietary supplement is suitable to increase the alcohol metabolism, so as to avoid or reduce the adverse effects of alcohol consumption.

It is known that 2-10% of the ethanol consumed by a human is given off unchanged via urine, sweat and respiratory air, while the remainder is released by the enzymes:

^■ alcohol dehydrogenase (ADH)

■ Catalase

^■ cytochrome P450 2E1

to acetaldehyde (AcA) in the cells of the alcohol degrading tissue, mainly in the liver. This reaction (Figure 1) occurs in the cytoplasm of liver cells and is mainly catalyzed by the local enzyme alcohol dehydrogenase (ADH). The reaction uses one molecule of the coenzyme nicotinamide adenine dinucleotide (NAD +) per alcohol molecule: NAD + NADH

Alcohol -► AcA

ADH

Fig. 1

During the reaction, NAD + and ADH form an enzyme-coenzyme complex (ADH-NAD + complex), while NAD + is simultaneously reduced to NADH. The NADH is then released and the ADH is ready to repeat the reaction by incorporating a new NAD + molecule. The cell has a limited capacity to oxidize NADH back to NAD +, which determines the maximum rate of the reaction. There is a surplus of ADH enzymes for the reaction. The alcohol-reacted acetaldehyde molecules migrate into cytoplasmic organelles, known as mitochondria, where they are oxidized to acetic acid in a reaction catalyzed by the enzyme aldehyde dehydrogenase (ALDH) (Figure 2)

igsäure

ALDH

Fig. 2 In this reaction, too, one molecule of the coenzyme NAD + is reduced to NADH. Both the latter and the previously cytoplasmic NADH are reoxidized in the mitochondrial respiratory chain with the maximum capacity of the system to NAD +. The maximum capacity of the mitochondrial respiratory chain depends on the overall level of metabolism of the body.

The process of alcohol metabolism described above is summarized in FIG. 3.

Fig. 3

The metabolic harmless acetic acid derived from alcohol by acetaldehyde is oxidized to carbon dioxide and water mainly in extrahepatic tissues.

The capacity of the cells to oxidize NADH back to NAD + is exceeded during the degradation of the alcohol as shown in Fig. 1 and 2. As a consequence, the cells accumulate an excess of NADH over NAD +. This change in the cellular oxidation-reduction equilibrium, which always occurs in conjunction with alcohol metabolism, causes an inhibition of the NAD + -mediated enzyme reactions.

There are two differentiable redox coenzyme systems in the human body. This provides a high redox potential for biological oxidation and a low redox potential for biological reductions.

As an oxidizing agent, the organism NAD +, as a reducing agent is mainly reduced nicotinamide adenine dinucleotide phosphate (NADPH) is used. In order to achieve a correspondingly positive redox potential, the ratio NADH / NAD + is small (<1), whereas in order to obtain a negative redox potential, the ratio

NADPH / NADP + large (> 1).

To maintain the balance between the two coenzyme systems u.a. the enzyme NAD (P) + transhydrogenase. From reduced NADH and oxidized NADP +, it catalyzes oxidized NAD + and reduced NADPH. This reaction can be according to the formula

NADH + NADP + NAD + + NADPH

expire in both directions. The metabolism of ethanol occurs mainly in the liver. However, the resulting acetaldehyde is much more toxic than ethanol. Acetaldehyde is a cytotoxin that binds to various proteins of the liver and also to DNA and damages the mitochondria as well as the microtubular system.

Acetaldehyde is the first degradation product of ethanol, which is degraded in a further step to acetic acid. Acetaldehyde is held responsible for a number of alcohol-related organ damage.

An accumulation of acetaldehyde by inhibiting the acetaldehyde degradation leads to headache, accelerated pulse rate, palpitations, nausea and vomiting and occurs in genetically induced alcohol intolerance after alcohol consumption on a regular basis. Much of the cat symptoms are attributed to the toxic effects of acetaldehyde.

In a normal liver, 99% of the alcohol introduced by the blood circulation is degraded to acetic acid. The remaining percent is released as acetaldehyde in the cycle. Therefore, the capacity of the alcohol-degrading tissue is not sufficient to oxidize all the acetaldehyde (Fig. 1) in acetic acid as shown in Fig. 2. Acetaldehyde enters the bloodstream at a rate of approximately 1 mg / min (60 mg / h).

In the case of impaired ALDH activity, even greater amounts of acetaldehyde than those mentioned above are released into the bloodstream. As small as 10% in the capacity of hepatic ALDH triples the amount of acetaldehyde released into the circulation.

In view of the above facts, acetaldehyde binding compounds have been developed to reduce the amount of acetaldehyde released into the large blood circulation and to reduce the consequences of such release. These compounds include the sulfur-containing amino acids cysteine and methionine. Oral administration of methionine to subjects while drinking alcohol has resulted in a 20% reduction in blood acetaldehyde concentrations. However, it should be noted that methionine-bound acetaldehyde can later liberate and thus extinguish the small advantage achieved. In addition, methionine and other similar substances do not affect the rate of alcohol metabolism or the

NADH / NAD + ratio. It is also known that D-glyceraldehyde (D-GA), a metabolite of fructose, may have an accelerating effect on alcohol metabolism. No. 4,450,153 A proposes a solution to the problem in which the blood alcohol concentration can be lowered rapidly when an alcohol oxidase enzyme isolated from certain types of yeast is used. The said enzyme breaks down alcohol in the extracellular space to acetaldehyde. As a result, large amounts of acetaldehyde enter the bloodstream and consequently pose the risk of acetaldehyde poisoning.

EP 1 562 576 B1 describes the use of D-glyceric acid, its salts or its ester for the preparation of a pharmaceutical preparation for the improvement of alcohol metabolism. For this purpose, D-glyceric acid, d. H. the dextrorotatory optical isomer of glyceric acid. Because D-glyceric acid is administered in greater than physiological amounts, it undergoes a conversion to D-GA. This reaction uses the coenzyme NADH, which is oxidized to NAD +. Thus, the enzymatic capacity of ALDH increases with respect to acetaldehyde. Thus, when the rate of alcohol elimination from the body is increased by administering D-glyceric acid according to DE 603 06 410 T2, the acceleration of the alcohol oxidation proceeds in parallel with the improvement of the oxidation of the acetaldehyde to acetic acid, so that the alcohol metabolism improves becomes.

Furthermore, methods have been proposed which reduce the adverse health effects of alcohol with agents that alter the rate of alcohol metabolism. Both the amount of acetaldehyde released by the liver and the NADH / NAD + ratio can be reduced by 4-methylpyrazole (4-MP). As a result, the production of acetaldehyde is reduced and allows a more extensive conversion of acetaldehyde to acetic acid. 4-MP is useful in special circumstances requiring slowing of alcohol metabolism, such as methanol intoxication. In conjunction with conventional alcohol consumption, there is a risk of alcohol intoxication.

Furthermore, the accelerating effect of fructose on the rate of alcohol elimination is also known. The clearance rate can be improved up to 20%, but this requires that large doses (1 -5 g / kg) be taken with the alcohol. Attempts have been made to prevent "hangover symptoms" by fructose without being able to determine any specific benefit. It has turned out that a accelerated alcohol metabolism by fructose, especially by alcohol dehydrogenase. This process results in the formation of an appropriate amount of acetaldehyde which does not degrade the cell to acetic acid. This is reflected as a corresponding increase in the concentration of acetaldehyde in the blood.

Due to its antioxidant effect glutathione is sold as a dietary supplement. However, the therapeutic benefit of dietary glutathione is highly questionable because the orally taken tripeptide can neither be resorbed nor absorbed into the cells due to its size. It is decomposed into its amino acid constituents before absorption and resynthesized in the cell interior. In addition, every body cell has the ability to produce glutathione.

Furthermore, WO 2006/103316 A1 and WO 2007/135241 A2 propose a combination of cysteine with various other substances, which is intended to achieve a uniform release of the cysteine in the gastrointestinal tract and a prevention of absorption. In particular, the cysteine should enter into a chemical bond with the acetaldehyde. This is intended to reduce or eliminate the acetaldehyde from the cysteine in the gastrointestinal tract. Another reaction, such as a glutathione synthesis, can not occur in the intestine due to lack of enzymes.

However, in practice, the low efficiency of the cysteine, which may be due to a reaction of the cysteine with other reactants, has proven to be disadvantageous. In particular, it can be assumed that the release of the cysteine in the gastrointestinal tract the amount of substance available for binding the acetaldehyde is comparatively low.

EP 0 397 646 A1 relates to a pharmaceutical preparation for the treatment of liver diseases. The liver protection preparation can be used for the treatment of metabolic and toxic liver diseases in human and veterinary medicine. Glutamic acid and cysteine play an important role in the formation of glutathione, which is important in the detoxification processes of the liver.

WO 2007/017139 A1 describes a composition for controlling the metabolism of alcohol and for reducing the risk of alcohol-related diseases, wherein the composition may, inter alia, also contain glutamine. To avoid catworm symptoms, US 2003/021 1 172 A1 proposes a composition containing glycine and glutathione.

DE 10 201 1 008 478 A1 shows a holistic dietary supplement which consists of mixtures of various dried vegetable and fruit powders. Due to the large number of active substances contained therein, the new dietary supplements are generally used for the prevention of malnutrition and diseases, which also glutathione, coenzyme Q10 and / or L-carnitine may be added. EP 1 982 604 A1 relates to a food supplement which comprises a vegetable constituent, a grass constituent, a fruit constituent, a vitamin and preferably an amino acid which may also contain L-glutamine or L-cysteine.

The object of the present invention is to propose a preparation or food supplement for improving the metabolism of alcohol, in particular ethanol, which ensures efficient degradation of the acetaldehyde.

The object is achieved by a preparation or dietary supplement for improving the metabolism of alcohol, which contains as an essential component glutathione and / or substances from which the body synthesizes the glutathione. The invention is based on the finding that in glutathione reductase from a GSSG dimer with consumption of NADPH, the production of the required for the degradation of acetaldehyde by acetaldehyde dehydrogenase to acetate coenzyme NAD + can be increased, the essential idea of the invention is that not as in the prior art teaching, the acetaldehyde is removed from the gastrointestinal tract by a chemical bond, but rather is formed by the glutathione NAD + which, as a limiting ingredient, accelerates ADH and ALDH. In contrast to the prior art, therefore, the enzymatic conversion is substantially accelerated or catalyzed without a direct chemical reaction of the glutathione with the acetaldehyde. It has been shown that the rate of degradation of acetaldehyde can be significantly increased in this way, so that after a short time, the undesirable side effects are significantly reduced or disappear.

A particularly promising embodiment of the invention is also achieved in that the substances used comprise at least cysteine and also glycine and / or glutamic acid. The supply of cysteine as well as glycine and / or glutamic acid increases the production of glutathione in the body. The glutathione transfers electrons free radicals to neutralize them, whereby the glutathione is oxidized. This is converted by glutathione disulfide reductase into doubly reduced glutathione. This NADPH is oxidized to NADP +, which is subsequently converted to NAD +. The NAD + is thus directly available for the degradation of alcohol as well as the acetaldehyde degradation.

Surprisingly, it has been found that not only the administration of cysteine, but the combination with glycine or glutamic acid causes that unlike the prior art, the cysteine is not consumed by further reactions, but remains available for the production of glutathione.

This effect, based on current knowledge, is attributable to the fact that the glutathione synthesis is stimulated by the presence of at least two of the required building blocks. Suffice a small amount of additional substrate to initiate the reaction. Once the synthesis is activated, the missing amino acids from the body's own stores, v.a. Proteins, won to continue the reactions. It makes sense to give priority to cysteine, which accounts for 2.8% of the lowest proportion of the average amount of amino acids present in proteins in the human body. The presence of glycine (7.5%) and glutamic acid (6.2%) is significantly higher. The rate of synthesis decreases again when no substrate is in excess.

In contrast, the sole administration of cysteine leads to the formation of glutathione, but due to the lack of stimulation by another building block and by the reaction with other reactants, the rate of synthesis will be lower. For initial stimulation, a substrate amount of 10% to 20% of the cysteine used suffices.

A particularly effective modification is achieved by administration as a powder, granules, capsule, tablet or in a solution. This achieves a simple dosage for the user and at the same time creates the conditions for a release of the constituents in the desired proportions.

In particular, it is advantageous if, according to one embodiment of the invention, the release of the cysteine and of the glycine and / or the glutamic acid is delayed in time by a corresponding galenics.

If, according to another promising modification, the ratio between glutamic acid, cysteine and glycine is 1: 2: 1 or, for cysteine, glutamine and glycine, between In addition, a one-sided excess, which in practice leads to an undesirable shift in the reaction equilibrium, can be avoided. Preferably, the preparation or dietary supplement contains essentially only two of the components cysteine, glutamine and glycine, these being present in an amount ratio of 1-20: 1-20. In practice, this corresponds to a daily dose in an amount between 100 mg and 13.4 g of the respective component cysteine, glutamine or glycine.

Particularly advantageous synergistic effects and effects are also achieved, in particular, when the preparation or food supplement contains nicotinamide in addition to the components cysteine and glutamine. A similar advantage can be achieved for the main constituents glycine and cysteine by a substantial proportion of magnesium.

Significant improved absorption is also achieved by the preparation or dietary supplement containing pantothenic acid and zinc. Furthermore, it has already proven to be particularly practical if the preparation or dietary supplement additionally contains vitamins and minerals, which improve the effectiveness.

Claims

PAT EN TAN SPRU

1 . A preparation or dietary supplement for improving the metabolism of alcohol, which contains as an essential component glutathione and / or substances from which the body synthesizes the glutathione.

2. A preparation or dietary supplement according to claim 1, characterized in that the substances comprise at least cysteine and glycine and / or glutamic acid.

3. preparation or dietary supplement according to claim 1, characterized by the dosage form as a powder, granules, capsule, tablet or in a solution.

4. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the release of the cysteine and glycine and / or glutamic acid is delayed in time by incorporation into a structure.

5. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the quantitative ratio between glutamic acid, cysteine and glycine (1: 2: 1) corresponds.

6. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the components cysteine, glutamine and glycine in a ratio of 1 -20: 1 -20: 1 -20 are included.

7. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the preparation or dietary supplement of the components cysteine, glutamine and glycine contains exactly two components in an amount ratio of 1 -20: 1-20.

8. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that in the preparation or dietary supplement based on a daily dose amount of the components cysteine, glutamine or glycine in each case between 100 mg and 13.4 g, preferably less than 2 g , is.

9. Preparation or dietary supplement according to at least one of the preceding claims, characterized in that the amount contained in the preparation or dietary supplement based on a daily dose in a combination of exactly two of the components cysteine, glutamine or glycine in each case between 100 mg and 13.4 g , preferably less than 2 g.

10. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the preparation or dietary supplement cysteine, glutamine and nicotinamide.

1 1. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the preparation or dietary supplement contains glycine, cysteine, and magnesium.

12. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the preparation or dietary supplement contains pantothenic acid and zinc.

13. A preparation or dietary supplement according to at least one of the preceding claims, characterized in that the preparation or dietary supplement additionally contains vitamins and minerals to improve the effectiveness.

14. A preparation or dietary supplement, characterized in that the preparation or dietary supplement contains glutamic acid, cysteine and / or glycine or a combination of these substances.