MXPA00012598A - Composition comprising a carnitine and glutathione, useful to increase the absorption of glutathione and synergize itseffects - Google Patents

Abstract

A composition is disclosed useful to increase the absorption of glutathione and synergize its effects, that, depending on user's conditions, may take the form of a dietary supplement, dietetic support or of an actual medicine, which comprises as characterizing active ingredients:(a) propionyl L-carnitine or a pharmacologically acceptable salt thereof;(b) glutathione or a glutathione-containing yeast;(c) a glutathione-free yeast if the component (b) consists of glutathione.

Description

COMPOSITION COMPRISING CARNITINE AND GLUTATION, USEFUL TO INCREASE THE ABSORPTION OF GLUTATHION AND SYNERGIZE YOUR EFFECTS Description of the Invention The present invention relates to a composition for the prevention and / or treatment of alterations of those organs that carry out the most intense metabolic functions, such as the liver, kidneys, cardiovascular system and the brain. More particularly, this composition is useful for treating or preventing hepatosis, nephropathies and cardiovascular or cerebral damage such as damage caused by aging or due to an altered metabolism of these organs or that is caused by toxic substances.

Therefore, the composition can take the form and exercise the action of a dietary supplement or an existing medication, depending on the support or preventive action, or the strictly therapeutic action, which the composition is intended to effect in relation to the individuals in particular in which it is to be used. Ref: 125316 M? M? S? More particularly, the present invention relates to an oral, parenteral, rectal, or transdermally administrable composition comprising in combination: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with another "carnitine", wherein "carnitine" is intended to be L-carnitine or an alkanoyl L-carnitine selected from the group comprising acetyl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine or their pharmacologically acceptable salts; and (b) glutathione or yeast containing glutathione; (c) a glutathione-free yeast if component (b) consists of glutathione.

Glutathione (GSH), N- (N-L-L -? - glutamyl-cysteinyl) glycine, plays an essential role in the organic reactions of redox and toxification. Glutathione is synthesized in the body starting from the glutamic acid and cysteine which, in the presence of ATP, forms the? -glutamyl-cysteine, which, in turn in the presence of ATP, reacts with the glycine leading to the formation of glutathione Glutathione is found in all body parts. Its highest concentrations, however, have to be found in the liver, heart and brain, that is, in those organs where the metabolic, energetic and detoxification reactions are more important. These tissues also contain glutathione peroxidase and glutathione reductase, which regulate the redox system related to the glutathione cycle, and ensure the maintenance of sufficient amounts of reduced glutathione after the latter has been oxidized.

Although the biochemical and detoxification activities of glutathione have been known for some time, particularly against heavy metals (which are among the most important environmental pollutants) or against liver-damaging drugs such as paracetamol, only the most recent investigations have revealed the predominant role of glutathione among the various redox systems, as well as its specific pharmacological role. A direct involvement of glutathione to exert a protective effect against the formation of atheromatous plaques has been observed by directly quantifying the presence of the antioxidant / pro-oxidant system related to glutathione in these plaques. These investigations reveal low concentrations of glutathione and a rather poor activity of the redox system related to glutathione. There is a particularly marked reduction in the concentration of glutathione peroxidase and at the same time an increase in the concentration of the oxidant factors. However, these abnormalities are not evident in normal vascular tissue. Glutathione also plays a mainly protective role in liver diseases. Moreover, the hepatoprotective effects of many drugs are mediated by glutathione. It has also been reported that an increased level of glutathione can reduce the rejection of a liver transplant. At the neurocerebral level, also the role of glutathione differs from the other redox systems that are best known by conferring protection against tissue and cell damage that is detected during aging, Parkinson's disease, or in Alzheimer's disease. At the brain level, in fact, glutathione is able to play various roles, and particularly that of a possible neurotransmitter. A deficiency of glutathione can increase the levels of cytotoxic substances and trigger the apoptosis of different groups of neuronal cells. During aging there is an increase in the oxidative process and a reduction of natural antioxidant substances, including most notably glutathione, with the result that glutathione deficiency can be taken as one of the causes of aging. The favorable role of glutathione can also be observed at the intestinal level where its presence affects the formation of lipid hydroperoxides and peroxides, which play an important role in intestinal detoxification and prevent diseases associated with the liver and intestine. L-carnitine and its alkanoyl derivatives are well known for the important role they can play at the metabolic level, particularly with respect to the oxidation and utilization of fatty acids by β-oxidation.

In fact, L-carnitine, whether ingested in the diet or synthesized by the body, is concentrated by the blood in organs that are metabolically more active in the utilization of fatty acids, such as in the skeletal muscles and the body. heart. A deficiency of L-carnitine may be the cause of myopathy, while oral administration of L-carnitine improves the clinical status associated with these diseases. L-carnitine also plays an important role in the itochondrial oxidation of glucose in terms of energy production, with the result that adequate levels of L-carnitine are necessary for normal energy metabolism at cardiac and muscular levels. Its administration improves resistance to fatigue in subjects suffering from coronary insufficiency, as well as intensifying coronary flow, producing an improvement in the clinical effects of cardiac decompensation. Other biological properties of L-carnitine and its alkanoyl derivatives, particularly propionyl L-carnitine, are its ability to stabilize membranes ^^ & BS? ^^^^^^^^^^ k & ^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡and protect them against injuries induced by oxidative processes. It has been surprisingly discovered that a composition of a combination comprising as active ingredients: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; (b) glutathione or yeast containing glutathione; (c) a glutathione-free yeast if component (b) consists of glutathione; the prevention and / or treatment of the abnormalities of the metabolically more active organs such as the liver, kidneys, cardiovascular system and brain is extremely effective, both as a result of a powerful synergistic effect made with its components and as a result of its increased uptake in tissues, particularly glutathione. This composition is particularly useful for the prevention or treatment of liver disease, kidney disease and cardiovascular or cerebral damage, such as, for example, that which occurs due to aging, or due to a deteriorated metabolism of the organs previously. mentioned or due to toxic substances. It has also been found that, advantageously, component (a) can also comprise another * carnitine ", selected from the group comprising acetyl L-carnitine, valeryl L-carnitine and isovaleryl L-carnitine, or their pharmacologically salts acceptable ingredients or mixtures thereof When component (a) of the composition consists of a mixture of carnitines, a mixture of L-carnitine, acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof is preferred. component (b) consists of glutathione, component (c) then consists of a glutathione-free yeast selected from the group comprising Saccharomyces cerevisiae and Saccharomyces fragilis Other examples of these yeasts are well known to those skilled in the art. When component (b) consists of a yeast that does contain glutathione, the yeast preferably must contain from 7 to 10% glutathione by weight. to proper yeast that .. & contains glutathione is the YH - Extract Torula Yeast. { Candi da utili s) that is produced by Kohjin, in Japan. The weight to weight ratio (a): (b): (c) ranges from 100: 1: 100 to 1:10:10 and preferably from 10: 1: 10 to 1: 1: 1. It has also been proven that both the synergistic effect and the uptake of tissues are increased more when the composition also contains: (d) at least one of the precursors of glutathione biosynthesis, selected from the group consisting of glutamic acid , glycine, cysteine and magnesium. The optimum result is obtained when all the aforementioned precursors are present in the composition. The preferred ratio (a): (d) is from 1: 1 to 1: 0.5. The components constituting the combination according to the invention have an unexpected and surprising synergistic effect in protecting the body against toxic damage of both endogenous origin, such as metabolic damage due to aging, and of exogenous origin, such as damage caused by environmental pollutants or other harmful agents. In particular, the novel composition can be usefully employed in the prevention and treatment of all those abnormalities that occur in association with aging, whether of neurocerebral or cardiovascular origin, or in situations of parenchymal affliction of organs, such as, for example, example, of the liver, which as a result of its metabolic and detoxifying action is more exposed to lesions induced by external toxic agents or by toxic metabolites. The effectiveness of the new composition derives both from the aforementioned synergistic effect and from the increased concentrations of the active tissue of its components, particularly glutathione, as a result of its enhanced uptake. The composition according to the invention can be used both as a dietary supplement or as a dietary supplement with a preventatively preventive action and as a drug for the treatment of frank conditions of disease. The metabolic effects exerted both by carnitines or glutathione or yeast containing glutathione and by the amino acids present in the composition are well known, and a deficiency of these compounds in the body can cause diseases of even a serious nature. It is not, however, foreseeable that their combination can intensely intensify the effects and favor the processes of uptake, and therefore increase their tissue concentrations. In particular, various forms of hepatic and cerebral affliction, atherosclerotic abnormalities and intoxication due to heavy metals, chemotherapeutic agents or other drugs can benefit from the use of this composition. The surprising synergistic effect produced by the combination of the * carnitines "and glutathione in the presence of a yeast and glutathione amino acid precursors and their enhanced uptake have been demonstrated in various pharmacological analyzes (some of which are described here below) are selected because of their ability to provide highly predictable indications regarding the practical use of this composition both in the field ^ .. ^^ TC ^ ..-,., ^ .. - -K, ^. ~ TO. . - '- preventive / nutritional as in the strictly therapeutic field.

Toxicology Analysis Before the various pharmacological analyzes, the limits of toxicity and tolerability of the new composition are analyzed in animals. These toxicity analyzes are carried out in both rats and mice, by administering several different products in combination in a single high dose administration or by administering them to the same animals continuously for at least 60 days. In this way it is observed that one can administer an oral combination of up to 1 g / kg of propionyl L-carnitine and acetyl L-carnitine together with 500 mg / kg of glutathione or 2 g / kg of yeast containing 10% glutathione and also the same products together with glutamic acid (100 mg / kg), glycine (100 mg / kg), cysteine (100 mg / kg) and magnesium (10 mg / kg) without the appearance of any signs of intolerance or toxicity. The prolonged administration for 60 days of 0.5 g / kg of propionyl L-carnitine or acetyl L-carnitine together with 100 mg / kg of glutathione or with 1 g / kg of yeast extract containing 10% glutathione is also well tolerated. together with glutamic acid (50 mg / kg), glycine (50 mg / kg) and magnesium (5 mg / kg). After these tests, the examination of the blood samples does not reveal any abnormality of any kind in the animals subjected to treatment. At necropsy, also, the histological analyzes carried out in the main organs did not detect any change of pathological nature compared to the control animals.

Pharmacological Analysis To evaluate the hepatoprotective antitoxic and anti-aging effects of the new composition, various analyzes are selected from those that are not only more suitable for revealing pharmacological effects, but that are also reliably predictable for the purposes and their practical applications to both way of a nutritional composition as a pharmaceutical in the field of the prevention and treatment of hepatic diseases of toxic or metabolic origin and in diseases due to aging.

Analysis of Acetaminophen-Induced Toxicity (Paracetamol) Several groups of male mice receive oral administrations of 600 mg / kg of acetaminophen, which is a sufficient dose to cause death within 24 hours in 50% of the animals thus treated. At the same time as the administration of acetaminophen, a group of animals (group G) are administered glutathione (G) and a second group (group YG) are administered yeast containing 10% glutathione (YG); a third group (group) is administered propionyl L-carnitine (PC), a fourth group (group AA) is administered a combination of glutamic acid, cysteine, glycine and magnesium (AA), a fifth group (group CC) are administered a first combination according to the invention, called 'complete combination' (CC), consisting of PC + G + AA, while even a sixth group (CYC group) are administered a second combination according to the invention , called 'complete yeast combination' (CYC), which consists of PC + YG + AA Mortality 24 hours after treatment is observed in all groups undergoing treatment.The results of the analysis are given in Table 1. The results of these analyzes indicate that, while partial protection against acetaminophen-induced mortality is achieved with glutathione, this protection is not observed after propionyl L-carnitine or the combination of amino acids. It has glutathione shows a greater degree of protective activity than that conferred only by glutathione. When the complete yeast combination, CYC, is administered, the protection appears to be total, thus demonstrating an obvious synergism between glutathione, propionyl L-carnitine and the other components of the combination. These synergistic effects seem even more marked when the mice are given a dose of 900 mg / kg acetaminophen, which causes the deaths of 100% of the animals. In this case, only the administration of the complete combination of yeast, CYC, protects more than 50% of the animals that undergo treatment to avoid death (see Table 2). The protection against acetaminophen at a dose of 900 mg / kg provided by the new composition is even more marked when the animals are subjected to treatment for 7 consecutive days before the administration of acetaminophen with the various components of the combination ( see Table 3). The result is probably related to the increased concentration of glutathione and the other components due to the increased uptake by the tissues related to the presence of yeast, as well as to the increased synthesis of glutathione itself due to the greater presence of its precursors .

Table 1 Protection to avoid mortality induced by acetaminophen (600 mg / g /%) f.) Treatment / group mg / kg mortality of animals C 6/10 m ^^ PC 100 6/10 G 50 4/10 YG 500 3/10 AA 130 5/10 CC 280 2/10 CYC 780 0/10 C = Witnesses PC = Propionyl L-carnitine G = Glutathione YG = Yeast containing 10% glutathione AA = Combination of amino acids and magnesium (glutamic acid 30 mg, cysteine 25 mg, glycine 50 mg + magnesium 5 mg) CC = Complete combination = (PC + G + AA) CYC = Complete combination of yeast = (PC + YG + AA) Table 2 Protection to avoid mortality induced by acetaminophen (900 mg / kg /%) Treatment / groups mg / kg mortalid of animals ad C 10/10 PC 100 10/10 G 50 7/10 YG 500 6/10 AA 130 9/10 CC 280 5/10 CYC 780 3/10 Table 3 Protection to avoid mortality induced by acetaminophen (900 mg / kg /%) after prolonged administration of the composition or its components for 7 consecutive days Treatment mg / kg mortalid ad C 10/10 PC 100 9/10 G 50 5/10 YG 500 3/10 AA 130 9/10 CC 280 1/10 CYC 780 0/10 Intoxication Analysis by Carbon Tetrachloride (CC14) in Isolated Mouse Hepatic Cells In addition to acetaminophen intoxication, the protective and synergistic activity exerted by the various components of the composition according to the invention are also detected at the hepatic level in relation to intoxication by CC14. The cells used in these analyzes are liver cells isolated from mice after perfusion with collagenase according to the method described by Seglen (Seglen F. O., Method Cell, Biol. Chem. 264: 4747, 1989). Approximately 4-6 x 108 of viable liver cells are collected, which are calculated by the exclusion of non-viable cells by means of trypan blue. The cells thus isolated are suspended in 25 cm2 plastic receptacles in the presence of antibiotics and 10% inactivated fetal bovine serum. To the cell suspension thus obtained, CC14 (10 mmol.L "1) / glutathione (GSH 20 mg.L" 1), propionyl L-carnitine (100 mg L "1) or glutathione combined with propionyl are added. L-carnitine After an incubation period of 4 hours, the percentage of dead cells is estimated by the release of lactate dehydrogenase, as described by Casini et al. (Casini et al., J. Biol. Chem., 257: 6721, 1982) The examination of the protective effect against CC14 poisoning exerted by glutathione, propionyl L-carnitine and its use and combination is determined by titration of the culture supernatant for both alanine aminotransferase (Ala AT) and of aspartate aminotransferase (Asp AT) (Beckman Automatic Biochemistry Rating System 700-Encore 2) The cytological examination of liver cells is carried out both in an electron microscope and in an optical one after fixation in 3% formalin and paraffin for microscopy Optical and 3% glutaraldehyde and 1% osmium tetroxide for electron microscopy. The results of these analyzes (see Tables 4, 5, and 6) show that both glutathione and propionyl L-carnitine are able to reduce the toxic effects of carbon tetrachloride. Surprisingly, a greater effect of the glutathione combination is obtained together with the PLC. In this case, the percentage of dead cells is reduced to practically zero. The increase in enzyme concentrations indicative of metabolic functional damage (Ala AT - Asp AT) is also substantially and unexpectedly reduced by the combination of glutathione and propionyl L-carnitine. Confirmation of the intense synergistic effect of glutathione and propionyl L-carnitine is also provided by histological examinations that, in light microscopy, reveal the virtually complete disappearance of necrotic cells and, in electron microscopy, show the preservation of intracellular structures and , in particular, of the mitochondrial structures and the number of ribosomes.

Table 4 Protection against cultures of hepatic cells intoxicated with CC14 Treatment% of dead cells CC14 85 ± 4 Glutathione 55 + 5 Propionyl L- 10 ± 1 carnitine Glutathione + 5 ± 3 Propionyl L-carnitine Table 5 Protection on cultures of liver cells intoxicated with CC1. Concentrations of alanine aminotransferase (Ala AT nmol .min "1 L" 1) and aspartate aminotrans era¡sa (Asp AT nmol .1min-1 L'1) in the supernatant after a period of 4 hours Treatment Ala AT Asp AT CC14 26.5 ± 3.1 9.08 ± 0.7 Glutathione 19.7 ± 2.5 7.5 ± 5.4 Propionyl L-carnitine 22.4 ± 2.8 8.9 + 0.9 Glutathione + Propionil 7.7 + 1.9 3.4 ± L-carnitine 2.1 Analysis Intoxication Induced Hepatic carbon tetrachloride Another indicator CC14 toxicity in the liver is provided by increased hepatic concentration of triglycerides. In this analysis, too, the protective activity of glutathione, propionyl L-carnitine, amino acids and yeast, both alone and in combination with the composition according to the invention, is demonstrated. CC14 poisoning is induced when administering to rats fasting an intraperitoneal injection of 1 ml. kg "1 of a suspension of CC14 at 20% in olive oil. Before the CC14 poisoning the rats are subjected to treatment for 3 consecutive days with glutathione (G = 50 mg / kg), or with propionyl L- carnitine (PC = 100 mg / kg), or with yeast containing 10% glutathione (YG = 500 mg / kg), or with a combination of amino acids (AA = 50 mg glutamic acid, 25 mg cysteine, 50 mg glycine, magnesium 5 mg), or with the complete combination CC (CC = PC + G + AA), or with the complete combination of yeast CYC (CYC = PC + YG + AA). After the administration of CC14 / the livers are removed of decapitated animals and are used to quantify the concentration of triglycerides according to the method described by Donabedian (Donabedian RK, Clin.Chem., 20: 632, 1974) .The results of these analyzes also reveal a substantial synergism between glutathione and glutathione. Propionyl L-carnitine by protecting the liver against CC14 poisoning. Marking is the protective effect of the combination of propionyl L-carnitine with yeast and the amino acid complex. In this case, in fact, the hepatic infiltration by triglycerides is virtually non-existent, also demonstrating the powerful synergism achieved by the composition according to the invention (see Table).

Table 6 Analysis of the increase in hepatic triglycerides induced by CC14 CC14 (ml.kg-1) Treatments Triglyceride s (mg.g-1) 0 5.9 ± 0.4 1 26.9 ± 1.1 PC 20.2 ± 1.9 G 18.7 + 2.1 1 YG 16.5 ± 1.2 1 AA 20.4 ± 2.1 1 CC 12.5 + 1.4 1 CYC 9.9 ± 0.6 Protection against Experimental Hypertriglyceridemia in the Rat The method used for this analysis is described by Carlson (Carlson L. A.V., J. Atheroscl. Res., 8 ^: 667, 1968) and modified as described in Atherosclerosis, _16 > : 349, 1972. According to this analysis the oral administration of 3 g / kg of fructose in the rat induces a substantial increase in both liver and serum triglycerides five hours after administration. The objective of this analysis is to evaluate whether the administration of the components of the composition according to the invention, when used alone or in combination, are capable of reducing triglyceride abnormality which is considered to be severe underlying hepatic dysfunction as well as a Atherosclerosis To this end, various groups of rats are treated with glutathione (G = 50 mg / kg), with propionyl L-carnitine (PC = 50 mg / kg), or with a yeast containing 10% glutathione (YG = 500 mg / kg), or with a mixture of amino acids (AA = glutamic acid 50 mg / kg, cysteine 25 mg / kg, glycine 100 mg / kg, magnesium 5 mg / kg), ^ ^^ M ^^^^^^? ^^^^^ ^ ti ^ tse¡Smá ß ^ or a combination of these various components (at the same doses) without yeast (CC) or with yeast ( CYC). The treatment is given orally during the 3 days preceding the administration of fructose and for 3 hours after its administration. Five hours after the administration of fructose all the animals are sacrificed and the samples are used in lines to evaluate the triglycerides according to the method described by Donabedian (Donabedian R. K., Clin. Chem., 20: 632, 1974). The results of these analyzes indicate that both glutathione and propionyl L-carnitine have a small efficacy on the serum levels of triglycerides induced by the administration of fructose, but a marked effect is obtained when these compounds are given in combination, particularly in the presence of yeast A substantial reduction in triglycerides is, in fact, observed in the blood of rats to which the complete combination has been administered together with yeast and amino acids, and therefore demonstrates the powerful synergism between the various components of the combination. (see Table 7).

Table 7 Analysis on hypertriglyceridemia (mg / lOOml) induced in the rat Controls 190 + 6.7 G 180 ± 5.9 YG 175 + 6.9 PC 185 ± 7.1 YG + PC 155 ± 8.1 AA 185 ± 6.5 CC 140 ± 4.3 CYC 133 ± 6.3 Experimental Analysis of Atherosclerosis The method used in this analysis is described by Manilow (Manilo M.R., Atherosclerosis, 4_8: 105, 1983). According to this analysis, administration for six weeks consecutively to male Wistar rats of an atherogenic diet consisting of 10% cottonseed oil, 24% casein, 1% cholesterol, 60% sugar, and vitamin D2 200 mUST / g diet induces pronounced vascular atherosclerotic lesions. These are determined at the level of the aorta by quantifying the thickness of the abdominal aorta using the morphometric method and the intensity of the stain induced by Sudan IV and evaluating the severity with a scoring system of 1 to 5. The morpho-ethical evaluations of intensity of Sudan IV staining again reveal, in these analyzes, also a substantial synergism between glutathione (25 mg / kg) and propionyl L-carnitine (100 mg / kg), but the protective effect is even more marked when the complete combination of yeast is used. In the group of rats subjected to treatment with CYC, the occurrence of vascular atherosclerotic lesions seems, in fact, to be completely inhibited, which demonstrates in this case, also the synergistic activity of the various components of the combination according to the invention.

Activity against Glycerol-Induced Nephropathy The method used in this analysis is the one described by Young (Young J. H. K., Meth., Find. Exp. jfej M ^^^^ í ^^^^^ ** ^^ m Clin. Pharmacol., _13: 23, 1991). According to this analysis, an injection of glycerol induces renal failure and nephropathy in the rat. This method is used to evaluate the protective effects of the combination according to the invention on the kidney. Male Sprague-Dawley rats are used, which, after depriving themselves of water for drinking for 24 hours, are injected with 10 cc / kg of a 50% w / v solution of glycerol and water. After the injection, the treated animals are allowed to drink. After a period of 24 hours, samples are taken in animal lines, and after centrifugation, the plasma concentration of creatinine is assessed (according to the method described by Taussky HH, Clin.Chem.Acta, _1: 210, 1956) and also urea by means of a reaction with diacetyl monoxime (Henry RY, Cannon DC Eds., Clinical Chemistry, 2nd Ed. Harper &Rowe, London, 1974). Propionyl L-carnitine (100 mg / kg), glutathione (50 mg / kg) or yeast containing glutathione (500 mg / kg), amino acids (25 mg / kg each), yeast (500 mg / kg) and a combination of these at the same doses are administered daily during the 3 days preceding the analysis. The results of this analysis (see Table 8) '* 2 * ^ * • indicate that both propionyl L-carnitine and glutathione have a good enough protective effect against renal lesions induced by glycerol, but greater efficiency is obtained through their combined use, particularly in the presence of yeast. With the presence of amino acids, in addition to yeast, the protection that is conferred is practically total, which demonstrates the effective potentiation of the activity obtained by the combination and not only the synergism that exists between propionyl L-carnitine and glutathione, but also the favorable action exerted by yeast and amino acids in this combination.

Table 8 Protective activity against kidney failure induced by glycerol in rats Urea Creatinine Treatment (mg / ml) (mg / lOOml) Witnesses 56.8 ± 7.7 22.2 ± 1.9 Glicerol 360.4 ± 116.7 ± 55.2 19.4 Propionyl L-carnitine 280.5 ± 88.5 ± 22.5 11.5 Glutathione 240.8 ± 79.9 + 20.9 9.9 Propionyl L-carnitine + 185.5 ± 60.2 ± Glutathione 19.2 6.5 Propionyl L-carnitine + 160.8 ± 52.5 ± Yeast (10% Glutathione) 16.8 6.1 Amino Acids 320.4 ± 105.5 ± 50.6 14.9 Propionyl L-carnitine + 95.4 ± 9.2 38.4 ± Glutathione + Amino Acids + 4 1 Yeast Effects on the concentration of glutathione (GSH) in elderly rats Since the metabolic and enzymatic activity of glutathione is known to be reduced in elderly rats and this reduction is taken as one of the causes of aging, the effect of the administration of the new composition or its individual components on the glutathione concentrations in the plasma and liver of young and elderly rats are evaluated. Two different groups of rats are used for this analysis: young rats (2-3 months) and elderly rats (8-10 months). The concentration of glutathione (GSH) is clated in both groups according to the technique described by Morón (Morón MS, Biochem Biophys. Acta, 582: 67, 1979) both before the start of the analysis and after 15 days of a daily administration of propionyl L-carnitine (100 mg / kg), glutathione (50 mg / kg), propionyl L-carnitine with glutathione or with yeast containing 10% glutathione (500 mg / kg), amino acids (500 mg / kg) or the combination according to the invention . After 15 days of treatment, the assessment of glutathione concentrations that are present both in the liver (see Table 9) and in the plasma (see Table 10) show the reciprocal potentiation of propionyl L-carnitine and glutathione to restore normal concentrations of glutathione in elderly rats. However, the synergism is even more marked in the presence of the yeast and the amino acids when they are mixed in the composition according to the invention.

Table 9 Effects on the concentration of glutathione (GSH ng / mg protein) in livers of young and elderly rats Treatment Young rats Older rats Time Ti-me 0 15 days 0 15 days Witnesses 11.55 ± 12.75 ± 8.70 ± 8.10 ± 0.88 0.91 0.72 0.63 Propionyl L-carnitine 11.25 ± 12.90 ± 7.9 ± 9.3 ± 0.41 0.71 0.51 0.46 Glutathione 12.1 ± 12.85 ± 8.82 ± 9.90 + 0.36 0.66 0.69 0.76 Propionyl L-carnitine 12.70 ± 13.05 ± 8.10 ± 10.50 ± + Glutathione 0.64 0.55 0.71 0.40 Propionyl L-carnitine 11.73 ± 13.75 ± 8.75 ± 10.80 ± + Yeast (10% 0.49 0.62 0.41 0.71 glutathione) Amino Acids 11.25 ± 12.68 ± 8.90 ± 9.15 ± 0.68 0.41 0.57 0.68 Propionyl L-carnitine 11.35 ± 12.45 ± 8.25 ± 11.95 ± + Glutathione + 0.77 0.59 0.61 0.85 Amino Acids + Yeast Table 10 Effects on the concentration of glutathione (GSH) (GSH mg / dL) in the plasma of young and elderly rats Treatment Rats Rats of young people old Time Time 0 15 0 15 days days Testicles 2.12 2.25 1.39 1.35 ± 0.59 0.39 0.49 0.55 Propionil L- 2.22 2.39 1.40 1.75 carnitine ± ± 0.29 0.50 0.22 0.20 Glutathione 2.09 2.35 1.26 1.80 ± + ± + 0.31 0.35 0.31 0.41 Propionil L- 2.14 2.40 1.22 1.95 1.95 carnitine + ± ± ± + Glutathione 0.21 0.40 0.21 0.35 Propionil L- 2.20 2.48 1.35 2.05 carnitine + ± ± ± + Yeast (10% 0.19 0.33 0.33 0.29 glutathione) Amino Acids 2.27 2.40 1.33 1.40 ± ± ± 0.27 0.29 0.21 0.34 Propionil L- 2.10 2.36 1.25 2.25 carnitine + ± ± ± Glutathione + 0.16 0.26 0.16 0.39 Amino Acids + Yeast Effects on Glutathione Uptake and Blood Concentration of Animals with Drastic Glutathione Reduction The objective of these analyzes is to demonstrate that the composition according to the invention favors the uptake of glutathione as a result of the presence of the yeast. To this end, the glutathione content in the blood of a group of male Sprague-Dawley rats is reduced by the administration of diethyl maleate (DEM), a depletor of glutathione levels, according to the technique described by Plummer (Plummer J ., Chemical depletion of glutathione "in vivo", Methods in Enzymology, 77: 50,1981). The DEM is administered intraperitoneally to fasting rats at a dose of 1 cc / kg. After a period of half an hour after injection of diethyl maleate, glutathione is administered orally alone (50 mg / kg), or a yeast containing 10% glutathione (500 mg / kg), or 50 mg / kg glutathione together with 500 mg of yeast that does not contain glutathione. Another group of rats receives the glutathione precursor amino acids (glutamic acid 50 mg / kg, glycine 50 mg / kg, cysteine 50 mg / kg, magnesium 10 mg / kg) or the ^ 8 ~ £ ^. -.._... tfXiÜ * ... - ..,. The complete combination according to the invention at the same doses as described above. After a period of 4 hours, the blood samples of the treated animals are taken and the plasmatic concentration of glutathione is quantified. The results of these analyzes (see Table 11) indicate that the uptake of glutathione is substantially increased by the presence of the yeast, whether the yeast contains glutathione or is simply used in combination with the glutathione. The presence of yeast causes a significant increase in plasma concentrations of glutathione in rats where these concentrations have been reduced by the injection of DEM. This effect is even more marked when the animals devoid of glutathione are administered the complete combination according to the invention.

Table 11 Effects on the concentration of glutathione (GSH) in the plasma (GSH mg / dl) in rats with depleted levels of glutathione when injecting diethyl maleate (DEM). The values are quantified 4 hours after the injection Glutathione (GSH mg / dl) Indicators 2.70 ± 0.41 DEM 0.61 ± 0.74 Propionyl L-carnitine 0.70 ± 0.54 Glutathione 0.95 ± 0.88 Yeast (10% glutathione) 1.65 ± 0.90 Glutathione + Yeast 1.85 ± 0.80 Amino acids 1.10 ± 0.66 Propionyl L-carnitine + Glutathione 2.15 ± 1.1 + Amino Acids + Yeast Some non-limiting examples of the composition according to the invention are indicated below. 200 mg carnitine mixture (L-carnitine 50 mg, acetyl L-carnitine 50 mg) Yeast (titrated with 7-10% of 200 mg glutathione) Glutamic Acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg 200 mg carnitine mixture (L-carnitine 50 mg, acetyl L-carnitine 50 mg, propionyl L-carnitine 50 mg, isovaleryl L-carnitine 50 mg) Glutathione (GSH) 50 mg Glutamic Acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg Yeast . { Saccharomyces 200 mg cerevisiae)) Propionyl L-carnitine 200 mg Yeast (titrated with 7-10% of 200 mg glutathione) Glutamic Acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg ) Propionyl L-carnitine 200 mg Glutathione (GSH) 50 mg Glutamic acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg Yeast (Saccharomyces 200 mg cerevisia) ) Propionyl L-carnitine 200 mg Glutathione (GSH) 100 mg Glutamic acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg Yeast. { Saccharomyces 200 mg cerevisia) ) Propionyl L-carnitine 200 mg Yeast (titrated with 7-10% of 300 mg glutathione) Glutamic Acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg ) Propionyl L-carnitine 200 mg Glutathione (GSH) 100 mg Glutamic acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg β-carotene 5 mg a-carotene 5 mg Coenzyme Q 0 0 mg ¿¿¿¿¿¿¿¿¿Í í iiíái ^ i- Selenium methiotina 20 μg Yeast (Saccharomyces 200 mg cerevisia) 8) Propionyl L-carnitine 200 mg Yeast (7-10% Glutathione) 300 mg Glutamic acid 50 mg L-cysteine 50 mg Glycine 50 mg Magnesium Citrate 10 mg β-carotene 5 m < 3 a-carotene 5 mg Coenzyme Qio 10 mg Vitamin PP 25 mg Vitamin B6 25 mg Vitamin Bi2 250 μg Selenium methionine 20 μg What is meant by a pharmacologically acceptable salt of L-carnitine or of the alkanoyl L-carnitine is any salt of these active ingredients with an acid that does not give rise to undesired toxic or secondary effects. These acids are well known to pharmaceutical experts. Non-limiting examples of suitable salts are the following: chloride; bromide; I last; aspartate; acid aspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate, acid maleate; orotato; oxalate, oxalate acid; sulfate, acid sulfate; trichloroacetate, trifluoroacetate and methanesulfonate. A list of pharmacologically acceptable salts approved by the FDA is given in Int. J. of Pharm. 33, (1986), 201-217; this latest publication is incorporated herein for your reference. The composition according to the invention can also comprise vitamins, coenzymes, mineral substances and antioxidants. Suitable excipients to be used to prepare the compositions that are related to the specific route of administration will be apparent to the pharmaceutical and food industry experts.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (22)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A composition of a combination, characterized in that it comprises: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; and (b) glutathione or yeast containing glutathione; (c) a glutathione-free yeast if component (b) consists of glutathione.

2. The composition according to claim 1, characterized in that the ingredient (a) further comprises a "carnitine" selected from the group comprising L-carnitine, acetyl L-carnitine, valeryl L-carnitine, isovaleryl L-carnitine or its salts pharmacologically acceptable or mixtures thereof.

3. The composition according to claim 2, characterized in that ingredient (a) comprises a mixture of L-carnitine, acetyl L-carnitine and propionyl L-carnitine or their pharmacologically acceptable salts.

4. The composition according to claims 1-3, characterized in that the glutathione-containing yeast contains from 7 to 10% by weight of glutathione.

5. The composition according to claims 1-4, characterized in that the weight ratio (a): (b): (c) is from 100: 1: 100 to 1:10:10 and preferably from 10: 1: 10 to 1: 1: 1.

6. The composition according to claims 1-5, characterized in that it further comprises: (d) at least one of the precursors for the biosynthesis of glutathione, selected from the group comprising glutamic acid, cysteine and magnesium.

7. The composition according to claim 6, characterized in that the weight ratio (a): (d) is from 1: 1 to 1: 0. 5 .

8. The composition according to claims 1 and 6, characterized in that it comprises: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; (b) glutathione (c) a glutathione-free yeast, selected from the group comprising Saccharomyces cerevisiae and Saccharomyces fragilis; (d) glutamic acid, glycine, cysteine and magnesium.

9. The composition according to claims 1, 4-6, characterized in that it comprises: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; (b) a yeast containing 7-10% by weight of glutathione; (c) glutamic acid, glycine, cysteine and magnesium.

10. The composition according to claims 1, 3-6, characterized in that it comprises: (a) a mixture of L-carnitine, acetyl L-carnitine, propionyl L-carnitine or its pharmacologically acceptable salts; (b) glutathione; (c) a glutathione-free yeast selected from the group comprising Saccharomyces cerevi si ae and Saccharomyces fragilis; (d) glutamic acid, glycine, cysteine and magnesium.

11. The composition according to claims 1, 3-6, characterized in that it comprises: (a) a mixture of L-carnitine, acetyl L-carnitine, propionyl L-carnitine or its pharmacologically acceptable salts; (b) a yeast containing 7-10% by weight of glutathione; (c) glutamic acid, glycine, cysteine and magnesium.

12. The composition according to any of the preceding claims, characterized in that the pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine are selected from the group comprising: chloride; bromide; I last; aspartate; acid aspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate; fumarate; acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate, acid maleate; orotato; oxalate acid; sulfate, acid sulfate; trichloroacetate, trifluoroacetate and methane sulfonate.

13. The composition according to any of the preceding claims, characterized in that it also comprises vitamins, coenzymes, mineral substances and antioxidants.

14. The composition according to any of the preceding claims, characterized in that it is orally administrable, in the form of a dietary supplement.

15. The composition according to any of the preceding claims, characterized in that it is oral, parenteral, rectal, or transdermally admmistrable in the form of a medicament.

16. The dietary supplement according to claim 14, characterized in that it is for the prevention of hepatosis, nephropathies and cardiovascular or cerebral damage due to an altered metabolism of the corresponding organs or caused by toxic substances.

17. The dietetic medicine according to claim 15, characterized in that it is for the therapeutic treatment of a hepatosis, nephropathies and cardiovascular or cerebral damages due to an altered metabolism of the corresponding organs or caused by toxic substances.

18. The dietary supplement according to claim 16, characterized in that it is in the form of tablets, dragees, pills, capsules, granules or j arabs. • - • '- * s - ~~

19. A medicament according to claim 17, characterized in that it is in the form of tablets, dragees, pills, capsules, granules, syrups, suppositories, in bottles or drops.

20. The use of a combination composition characterized in that it comprises: (a) propionyl L-carnitine or a pharmacologically acceptable salt thereof; and (b) glutathione or yeast containing glutathione; (c) a glutathione-free yeast if component (b) consists of glutathione; to prepare a dietary supplement or a medicine useful for increasing the absorption of tissue concentrations of glutathione.

21. The use of the composition according to claim 20, characterized in that the combination further comprises: (e) at least one of the precursors for the biosynthesis of glutathione, selected from the ?? I? ß ^ group comprising glutamic acid, glycine, cysteine and magnesium.

22. The use according to claim 20 or 21, characterized in that the dietary supplement or the drug is useful for preventing / treating hepatosis, nephropathies and cardiovascular or cerebral damage due to an altered metabolism of the corresponding organs or caused by toxic substances.