MXPA00012907A - Carnitine and inositol phosphate-containing composition useful as dietary supplement or drug - Google Patents

Abstract

A composition is disclosed suitable for the prevention and/or treatment of cardiovascular and neurocerebral disorders, tissue anoxic forms, muscular energy deficits, inflammatory-type abnormalitites, alterations of blood coagulation such as thrombosis, and tissue proliferation forms, that 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;and (b) an inositol phosphate, particularly the inositol hexaphosphate (IP6).

Description

COMPOSITION CONTAINING CARNITINE AND USEFUL INOSITOL PHOSPHATE AS A DIET OR MEDICINE SUPPLEMENT DESCRIPTION OF THE INVENTION The present invention relates to a composition for the prevention and / or treatment of cardiovascular and neurocerebral disorders, various anoxic tissue forms, energetic muscle deficiencies, inflammatory type abnormalities, blood coagulation disorders such as thrombosis, and forms of tissue proliferation. Accordingly, the composition can take the form and exercise of the action of a dietary supplement or an effective medicine, depending on the action of support or prevention, or the strictly therapeutic action, which is intended to exercise the composition in relation to the particular individuals in which it will be used. More particularly, the present invention relates to an orally administrable composition, parenterally, rectally or transdermally, which comprises in combination as characterizing ingredients: Ref: 125746 .3 ¿^, t. , - 'St ^ tsi & .ti -' '¿geaga-e. a) propionyl-L-carnitine or a pharmacologically acceptable salt thereof, optionally in combination with another "carnitine", wherein by "carnitine" is meant L-carnitine or an alkanoyl-L-carnitine selected from the group consisting of acetyl- L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine or their pharmacologically acceptable salts; and b) an inositol phosphate selected from the group comprising inositol monophosphate, inositol tetraphosphate, inositol pentaphosphate, particularly inositol hexaphosphate (IP6). Carnitines and inositol hexaphosphate are well known for their important metabolic and pharmacological effects which have led to numerous favorable pharmacological and clinical findings. With regard to carnitines, the role they play in the processes of ß-oxidation of fatty acids and the synthesis of ATP is well known. These are also endowed with important antioxidant activity, as demonstrated by its protective effect against the lipoperoxidation of the phospholipid cell membranes and against the ^ »^ A». : & ¿i¡? ~? *) &islífe * oxidative stress induced at the level of myocardial and endothelial cells. These biochemical effects of carnitines are reflected in the favorable results obtained in clinical practice when they are used in the treatment of various forms of atherosclerosis, iocardial ischemia, peripheral vascular disease or diabetes. Also with respect to inositol hexaphosphate (IP6), numerous research studies of a biochemical and clinical nature have been published, which highlight their activities and use in the prevention and treatment of various pathological changes. Although the interest in this compound dates back many years, when the ability of certain vegetable seeds that contain high percentages of IP6 to maintain their germinative capacity intact for very long periods of time, was attributed to the antioxidant action of IPß, it was only Recently, the researchers began to detect its antithrombotic and anti-atherosclerotic properties and its cardioprotective ability against damage caused by infarction, as well as its ability to provide protection against the onset of tumor processes. These properties may be related in part to their high antioxidant capacity and, on the other hand, to their ability to interfere with the release of cytokines and other products induced by the activation of receptors that regulate cell transduction systems. It is well known, in fact, that inositol hexaphosphate, IP6 or phytin, is present in high percentages in all tissues and cells. IP6 constitutes 1-5% by weight of many cereals and legumes, such as, for example, rice, wheat and soybeans, in which this constitutes approximately 50% of the phosphorus reserve. In clinical practice, the main areas in which IP6 has been successfully used refer above all to the treatment of hypercholesterolemia and atherosclerosis, as well as hypercalcemia and the resolution of kidney stones. Experimentally promising results have also been achieved with their use in the inhibition of platelet aggregation induced by ADP, or damage by reperfusion of organs such as the heart. Its incorporation in the erythrocytes, in addition, leads to a greater availability of usable oxygen in those situations where the oxygen utilization capacity seems to be reduced, as in organ ischemia, hemolytic anemia, pulmonary insufficiency and erythrocytosis. It should be emphasized that the main factor underlying this activity of IP6 is its powerful antioxidant action related above all to its iron chelating ability. With respect to the vasculoprotective, neuroprotective and anti-anoxic effects of IP6, its incorporation into erythrocytes increases its stability to the iron ions that can be released within the erythrocytes themselves and, furthermore, by the increase of their affinity for oxygen, they make larger quantities of oxygen available at the tissue level, which have become anoxic. 5 Although the antioxidant effect of IP6 may explain its favorable activity at the metabolic and cardiovascular level, other mechanisms revealed in recent studies have to be taken into consideration with respect to its anti-inflammatory, immunostimulatory and anticancer properties. IP6 and inositol pentaphosphate, IP5, are among the main inositol phosphates present in cells. In addition to modifying the affinity of hemoglobin for oxygen and acting J -. . - > - ^ ¿S »-» »- - '-': - * ~ £ & ** l & * Íd &? * ~ '-, > - «, _,« «& - '^ w .. ^ i * - ~ ^' as neurotransmitters, they play an important role in the transduction of signals from the surface of the cell to its interior, in the activation of genes and in the formation of cytokines and factors that regulate cell growth. In the case of IP6 anticancer activity, dephosphorylation of IP6 to IP5 and IP3, and a decrease in the combination of inositol phosphates characterized by lower phosphorylation are postulated, the prevalence of which regulates or inhibits cell development. IP6, in addition, is capable of blocking the activity of phosphatidylinositol-3-kinase (PI-3-kinase) and thus blocking the Epidermal Growth Factor and transduction of extracellular signals regulated by the activation of protein kinase . Another factor with a presence on the anti-cancer activity of IP6 is that its dephosphorylation to IP3 is considered to be related to the opening of the related calcium channels, an increase in which it is not only a critical element in cell proliferation, but also a important factor in the induction of cellular apoptosis. It has also been found that IP6 competes with the Factor's receivers of insulin growth (IGF-II), and as a result it has been shown that its gene overexpression gives rise to different tumor lines. The IGF receptors, in any case, have been found to be important at the beginning of cellular hyperplasia. In the anti-inflammatory, immunostimulatory and anticancer action of IP6, then, two different mechanisms can be considered. One is peculiar for antioxidant agents which, like salicylic acid, inhibit the activation of the gene transmission via the NK-kb-IkB system, and the other of which, via the combination of inositol phosphate, regulates the factors of growth. From the practical point of view, in the anti-cancer field, the use of IP6 has proven to be effective in the inhibition of colon cancers induced in animals by azoxymethane with a dose-dependent activity. Its use has also appeared to be equally effective in breast carcinoma induced by 7, 12-dimethylbenzanthracene (DMBA) or by methylnitrosourea. Favorable results have also been obtained with the use of IP6 in cancers of the lung, prostate, and liver. Tests 25 conducted human subjects, mainly on yft ^ "dff'-fe" **. * - »«. ir * -.? - - - < - - * - -aa ««? «w?» il «a ~« "^« - - • - ü = -_ £ - • ** - ™ '* * - - - «• ^ t'? * - - - adenocarcinoma and leukemia cells have verified the anticancer efficacy of IP6. It has now surprisingly been found that a combination composition containing as its 5 characterizing components: a) propionyl-L-carnitine or one of its pharmacologically acceptable salts; and b) an inositol phosphate, selected from the group consisting of inositol monophosphate, Inositol tetraphosphate, inositol pentaphosphate and, particularly, inositol hexaphosphate (IP6) is extremely effective in the prevention and / or treatment of cardiovascular and neurocerebral disorders and various forms of anoxia. tissue, inflammatory-type abnormalities, muscular energy deficiencies and forms of tissue proliferation, as a result of the powerful unexpected synergistic effect exerted by its components. It has also been found that, advantageously, the compound (a) can also comprise another "carnitine", selected from the group consisting of L-carnitine, acetyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine and isovaleryl-L-carnitine, or its salts pharmaceutically acceptable or mixtures thereof, and that component (b) may further contain inositol. The preferred weight ratio of component (a) to component (b) may be in the range of 1:10 to 1: 1. Component (b) may be present in the compositions in the form of a plant product or an extract of plant products containing high percentages of inositol phosphates. Suitable vegetable products are, for example, bran and brown rice. The composition according to the invention can be used as a diet supplement or a nutritional supplement substance with a mainly preventive action, and as a medicine for the treatment of frank disease conditions. The surprising synergistic effect that is achieved with the combination of "carnitines" and inositol phosphates, and particularly propionyl-L-carnitine and IP6, has been confirmed by various pharmacological tests (some of which are described later in this ) selected in such a way as to provide highly predictive indications for the practical use of ^. ^. This composition in the preventive / nutritional field and as a strictly therapeutic agent.

Toxicology tests It is known that L-carnitine and propionyl-L-carnitine and inositol hexaphosphate (IP6) are characterized by low toxicity and good tolerability. These favorable characteristics were confirmed by a simple oral administration to rats and mice of L-carnitine and IP6 doses corresponding to 1 g / kg and 750 mg / kg, respectively, and doses of propionyl-L-carnitine and IP6 corresponding to 750 mg / kg and 500 mg / kg, respectively, without any toxic reaction or intolerance that is detected. The intraperitoneal administration of 500 mg of propionyl-L-carnitine and 300 mg of inositol hexaphosphate in rats was also well tolerated and no toxic effects were detected. These favorable low toxicity characteristics were also confirmed by the results of the tests involving the daily oral administration of 300 mg / kg of propionyl-L-carnitine together with 200 mg / kg of IP6 to rats for thirty consecutive days. At the end of these tests In the absence of any detectable reduction in the growth of the animals treated in this way, no detectable changes were seen in the hematocrit values or in the other variables of blood chemistry, particularly glucose. serum, BUN and cholesterol. In addition, no major or histological abnormalities of the major parenchymal tissues of the organs examined could be detected at autopsy.

Anti-inflammatory activity evaluated by carrageenan edema test To evaluate the anti-inflammatory effect of the new composition, the carrageenan edema test was used, in which the legs of the rats are injected with carrageenan. Injection of 0.1 mg of a 1% carrageenan solution (Sigma Chemical, Saint Louis, MO, USA) in the subplantar area of the right leg of the rat induced marked edema of the paw that reached its maximum intensity 4-5 hours after the injection. The edema was measured by mercury plethysmography at different time intervals until the «A» jj-S a} - fourth hour after the injection of carrageenan. Propionyl-L-carnitine (250 mg / kg) and IP6 (250 mg / kg) were orally administered half an hour before injection of subplantar carrageenan. The results of this test (See Table 1) show that propionyl-L-carnitine and inositol hexaphosphate exerted a slight inhibitory action on the inflammatory reaction induced by carrageenan, while its combined use was able to almost completely inhibit edema induced by carrageenan, which demonstrates an unexpected and surprising synergistic effect of propionyl-L-carnitine and inositol hexaphosphate. 15 Table 1 Anti-inflammatory activity assessed by the carrageenan edema test 20; of inhibition after 1 hour 2 hours 4 hours Propionyl-L-carnitine 15 ± 0. 3 8 ± 0. 9 250 mg / kg IP6 250 mg / kg 15 ± 1. 1 20 ± 2. 1 15 ± 0. 6 Propionyl-L-carnitine 250 00 ± 4.8 80 ± 7.1 50 ± 3.9 mg / kg + IP6 250 mg / kg Anti-inflammatory activity assessed by the collagen-induced arthritis test Confirmation of the anti-inflammatory effects of the composition according to the invention was obtained using as a test type II arthritis induced by collagen according to the technique described by Trentham (Trentham DR, J_ ^ Exp. Med., 146: 857, 1977). In this test, a group of mice were immunized by intradermal injection at the base of the tail of 100 μg of natural collagen emulsified in complete Freund's adjuvant (Difco Labs., Detroit, USA). After three weeks, the animals treated in this way were again injected intraperitoneally with the same dose of emulsified collagen. Treatment with propionyl-L-carnitine (200 mg / kg) or with inositol hexaphosphate (200 mg / kg) or with the two compounds in combination was administered orally from the day of the collagen injection until the end of the sixth week .

One group of animals received no treatment and served as a control group. The intensity of the edema was evaluated by assigning grades from 1 to 4. The results of this test also demonstrate a powerful synergism between propionyl-L-carnitine and inositol hexaphosphate. In fact, while propionyl-L-carnitine alone showed no inhibitory effect on collagen-induced edema and IP6 induced only a slight reduction (approximately 20%), when the two compounds were combined, the inhibition of edema was higher than 80% Platelet anti-aggregation activity The platelet anti-aggregation activity of the composition according to the invention was evaluated in blood samples from healthy volunteers. The samples were treated with sodium citrate and centrifuged (145 x g for 5 minutes at 22 ° C) and the number of platelets counted (CA 580 = 4 Platelet Counter - DelCon). This number was brought to a value of 300,000 platelets / ml by the addition of PPP (Poor Platelet Plasma), as necessary, obtained by centrifugation of the blood at 1,600 x g for 10 minutes at 22 ° C. The aggregation agent used was collagen (2.5 ng / ml, 5 ng / ml) and the induced aggregation was measured photometrically according to the method described by Born (Born G.V., Nature, 194: 927, 1962). Platelet aggregation was measured under baseline conditions and after 10 minutes of incubation with propionyl-L-carnitine and IP6 alone or in combination. The doses of propionyl-L-carnitine used were 10 ng and 20 ng / ml, while the doses of IPß were 4 ng and 8 ng / ml. The results of the tests indicate that while propionyl-L-carnitine alone does not inhibit the aggregation action of collagen, IP6 only reduces it to 40%. The combination of the two compounds, however, reveals the complete inhibition of the aggregation activity (100%) which is a indicator of the effective synergistic action that occurs between propionyl-L-carnitine and IP6.

Anti-atherosclerotic activity The antiateroesclerotic activity of the new composition was evaluated in various groups of 5 rats (male Wistar rats) which were administered with an atherogenic diet for six weeks consecutively, consisting of 24% casein, 1% cholesterol, 15% oil cotton, 60% sugar and Vitamin D2 200 mUst / g diet according to the regime proposed by Melinow (Melinow M.R., Atherosclerosis, 48: 105, 1983). At the end of the sixth week of treatment, marked atherosclerotic vascular lesions had been formed which were particularly pronounced at the level of the abdominal aorta. The severity of these lesions was evaluated by a morphometric method, which measures the thickness of the abdominal aorta and the intensity of the stain induced by Sudan IV with a progressive grading system of 1 to 5. In these tests, the rats received daily administrations of 150 mg / kg of propionylcarnitine and 100 mg / kg of IP6, together with their atherogenic diets. The results of the examinations carried out on the rats treated in this way showed that, while propionyl-L-25 carnitine and IP6 alone produce only a slight protective effect, administration of the two compounds in combination almost completely inhibits the occurrence of atherosclerotic lesions as indicated by the morphometric examination and staining with Sudan IV, thus demonstrating, in this case also, the powerful synergistic effect of the Propionyl-L-carnitine and IP6 combined.

Effects on muscle exercise 10 Since IP6, which is rich in phosphate groups, is a useful energy reserve, a series of tests were conducted to establish whether its administration can increase the time of resistance to swimming in mice subjected to swimming forced in a rectangular tank filled with water, according to the technique described by Zheng (Zheng RL, Acta Pharmacol. Sinica, 14: 47 1993) and if its effect could be improved by using it in combination with a carnitine, such as, for example, propionyl-L-carnitine. The tests were performed in various groups of animals treated with propionyl-L-carnitine (200 mg / kg) or with IP6 (100 mg / kg) alone or with the two compounds in combination. ^ -aAtv c sa. », ^ ugly» »a. ^ *« M * ^. ffla - e É d átE: - * ¿í J sa aj ^^ »a» _ as. ^. s í¿ ^ _z < SfT? ¡** Compounds were administered orally in the three days preceding the test. In the animals treated in this way, the time of resistance to swimming was measured in comparison to the control animals. The time of resistance to swimming, medium, was slightly increased in rats treated with propionyl-L-carnitine and in those treated with IP6 alone, while a remarkable lengthening of swimming time was found in the animals treated with the combination of propionyl- L-carnitine and IP6, demonstrating in this way an evident synergistic effect (see Table 2). In another series of tests, the effect of the combination of propionyl-L-carnitine and IP6 on forced muscular exercise was evaluated, which, as is known, can generate reactive oxygen species (ROS), inflammation and damage to muscle structures. . Forced muscular exercise was tested in various groups of rats by running them on a mobile band at controlled speed and at an angle of inclination, as described by Li (Li .X., Acta Pharmacologica Sinica, 20: 126, 1999) and Husain (Husain K., Pathophysiology, 4_: 69, 1997). The animals were run on a slope of z &lM? í &SM? ß & fo '** •' * & < s ** '- «-" ^ - - ^ ^ ^ ^ ^ - ^^ fe about 5o and at a band speed of 28 m / minute The stamina or vigor of the animals reached the point of exhaustion after approximately 85 minutes of exercise 5 The test was carried out on groups of animals which, during the three days preceding exercise, received 200 mg / kg of propionyl-L-carnitine or 100 mg / kg of IP6 alone or in combination. and thirty minutes, respectively, after the end of the exercise, samples were taken from the gastrocnemius muscle of the sacrificed animals, and it was used to measure the malondialdehyde content (MDA) as a marker for the level of lipoperoxidation by means of the Reaction with thiobarbituric acid according to the method described by Ohkawa (Ohkawa H., Anal. Biochem., 95: 351, 1979). As it is apparent from the results given in Table 3, propionyl-L-carnitine and IP6 alone were able to reduce muscle lipoperoxidation levels in muscle homogenates, as detected by the smaller increase in MDA, which, in contrast, was very marked in the control mice five minutes after the end of the exercise. The combination of propionyl-L-carnitine and IP6, on the other hand, provides almost total protection against lipoperoxidation in the muscles of treated animals, thus demonstrating in this case, too, the synergistic effect of propionyl-L-carnitine and IP6.

Table 2 Swim resistance test Treatment Swimming time (minutes) Controls 98 ± 15 Propionyl-L-carnitine 116 ± 19 IP6 136 ± 16 Propionyl-L-carnitine + IP6 184 ± 22 Table 3 Muscle fatigue tests Treatment of MDA content in muscle [nanomol. g-1 (P P)] After After 5 minutes 30 minutes Controls 234 ± 9 225 ± 11 Propionyl-L-carnitine 210 ± 10 212 ± 14 IP6 200 ± 16 205 + 8 Propionyl-L-carnitine + IP6 175 ± 12 181 ± 12 Effects on neuronal hypoxia To evaluate the protective activity of the composition according to the invention on the damage induced by hypoxia at the neuronal level, tests were performed on cultures of chicken brain neurons in which the reduction in cellular respiration was induced by the introduction of NaCN in the cultures. The metabolism energy of neuronal cultures was evaluated by measuring ATP concentrations present in cultures without treatment, or in cultures in which propionyl-L-carnitine or IP6 were added at doses of 100 and 50 mg / liter, respectively. Cultures of brain neurons were prepared according to the technique described by Pettman (Pettman B., Nature, 281: 378, 1979). Cytotoxic hypoxia was induced by the addition of NaCN to the culture medium at a final concentration of 1 mmol / liter. After 120 minutes the medium was replaced by a NaCN-free medium, and the metabolism of the cells was blocked by washing with a buffer solution with ice. The ATP assay was performed according to the procedure described by Erner (Werner A.J., Chromatogr. Biomed, Appl., 421: 257, 1987). The results of these tests are shown in Table 4. The measurement of ATP shows that ATP levels are substantially reduced by anoxia and remain low even after reoxygenation of 30 minutes, whereas, when propionyl-L-carnitine or IP6 are present alone or in combination, there is less reduction of ATP levels as well as faster restoration of ATP levels.

Table 4 Effect on neuronal hypoxia ATP treatment nmol / g of protein after reoxygenation time 0 30 minutes Controls 9.2 ± 0.9 14.4 ± 1.2 Propionyl-L-carnitine H.l ± l.6 16.3 + 2.2 IP6 12.4 ± 2.1 16.9 ± 1.9 Propionyl-L-carnitine + IP6 15.8 ± 2.4 23.7 ± 2.3 5 Anti-proliferative activity In view of the numerous research studies regarding anticancer activity Preventive chemotherapy, experimentally demonstrated by IP6, particularly against colon and breast cancers, the antiproliferative activity of the composition according to the invention was evaluated in relation to proliferation of experimentally induced skin tissue in mice by subcutaneous injection of teleocidin which, like phorbol myristates, is capable of provoke skin proliferative abnormalities, similar to cancer (Fujiki A., Biochem. Biophys. Res. Comm., 90: 976, 1979). Since the cutaneous reactions induced by teleocidin are accompanied by an increase in the activity of ornithine decarboxylase, this enzyme can be considered as a marker for the proliferative reaction and its different degrees of severity. For these tests, teleocidin was injected subcutaneously into the depilated backs of the mice at a dose of 5 μg / mouse. One week before the injection of the teleocidin, the various groups of animals received oral administrations of propionyl-L-carnitine (200 mg / kg) or IP6 (100 mg / kg) or the two compounds in combination. Five hours after the injection of teleocidine, the ornithine decarboxylase assay was carried out on homogenized epidermis of the treated animals according to the method described by O'Brien (O'Brien TG, Cancer Res. 42, 2841, 1982) . The evaluation of the concentration of ornithine-decarboxylase in epidermal extract protein was carried out according to the technique described by Lowry (Lowry O.H., J. Biol. Chem., 193: 265, 1951). As is apparent from the results in Table 5, the increase in ornithine decarboxylase induced by teleocidin was significantly reduced by the previous administration of propionyl-L-carnitine or IP6 alone. However, when the two compounds were used in combination, the reduction in ornithine decarboxylase activity became marked and highly significant.

Table 5 Antiproliferative activity Treatment Activity of ornithine decarboxylase nMool of CO2 / 60 minutes / mg of protein Controls 0.055 ± 0.004 Teleocidine 2.6 ± 0.4 Propionyl-L-carnitine 2.1 ± 0.2 IP6 1.95 ± 0.2 Propionyl-L-carnitine 0.58 ± 0.9 IP6 What is meant by The pharmacologically acceptable salt of L-carnitine or alkanoyl-L-carnitine is any salt of these active ingredients with an acid that does not cause unwanted toxic or collateral effects. These acids are well known to pharmacy experts. Non-limiting examples of suitable salts are the following: chloride; bromide; I last; aspartate, aspartate acid; 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 Phar. 33, (1986), 201-217; this latter publication is incorporated by reference herein. The composition according to the invention can also comprise vitamins, coenzymes, mineral substances and antioxidants. Suitable excipients that are to be used to prepare the compositions that are of interest for the specific route of administration, . »^. ^ -. - ^ á- ^ > -A ^ ..,. , •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• . ^ ^ - »Qj &-fc _'rt • * ..

They will be apparent to experts in pharmacy and the food industry.

Illustrative, non-limiting examples of the compositions according to the invention are reported below. 1) Propionyl-L-carnitine 250 mg Inositol hexaphosphate 250 mg L-carnitine 150 mg Propionyl-L-carnitine 150 mg Inositol phosphate 300 mg 3) Carnitine mixture (75 mg of L-300 mg carnitine, 75 mg of acetyl-L-carnitine, 75 mg of propionyl-L-carnitine, 75 mg of isovaleryl-L-carnitine) inositol hexaphosphate 300 mg 4) Propionyl-L-carnitine 200 mg Inositol hexaphosphate 200 mg Inosine 100 mg) Carnitine mixture (50 mg L-200 mg carnitine, 50 mg acetyl-L-carnitine, - < ..J »c -»? Tw ?. "" ."• TO-. '. *. - »• '^ i.J ^ l ^^ A ^ - ^ fa ^ ... and _ ^ _ ^ ^ ^^^^^. propionyl-L-carnitine, 50 mg of isovaleryl-L-carnitine) Inositol phosphate complex (100 mg 200 mg inositol hexaphosphate, 50 mg inositol phosphate, 50 mg inositol tetraphosphate) Inosine 100 mg ) Acetyl-L-carnitine 200 mg Propionyl-L-carnitine 200 mg Inositol hexaphosphate 400 mg Inosine 200 mg ) Propionyl-L-carnitine 200 mg Inositol hexaphosphate 200 mg Inosine 100 mg Coenzyme Q10 20 mg Vitamin E 5 mg ß-carotene 10 mg Bioflavonoids 25 mg Vitamin C 25 mg Selenium 50 mg Vegetable fibers 50 μg Magnesium stearate 5 mg Propionyl-L-carnitine 200 mg Inositol hexaphosphate 200 mg Inosine 100 mg Creatine 100 mg Vitamin Bi 1 mg Vitamin B2 3 mg Vitamin B6 5 mg Nicotinamide 5 mg Vitamin E 5 mg ß-carotene 10 mg Vitamin B 2 2 μg Folic acid 700 μg It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

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Claims (17)

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

1. A composition in combination, characterized in that it comprises: a) propionyl-L-carnitine or a pharmacologically acceptable salt thereof; and b) an inositol phosphate.

2. The composition according to claim 1, characterized in that the inositol phosphate is selected from the group consisting of inositol monophosphate, inositol tetraphosphate, inositol pentaphosphate and inositol hexaphosphate (IP6).

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

4. The composition according to claims 1-3, characterized in that the ingredient (b) further comprises inositol.

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

6. The composition according to any of the preceding claims, characterized in that the ingredient (b) appears as a vegetable product or extract of plant products containing the same.

7. The composition according to claim 6, characterized in that the vegetable product is bran or brown rice and / or its extracts.

8. The composition according to any of the preceding claims, characterized in that the pharmacologically acceptable salt of L-carnitine or alkanoyl-L-carnitine is ^^ JJ ^ * S3 ^ & ^ -. S .- \ 'Á.Á & sMS! L - ^^^ íli ^^? Í ^ Á, ^ ^ * - -atea- & w "selects from the group comprising: chloride; bromide; I last; aspartate, aspartate acid; 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.

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

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

11. The composition according to any of the preceding claims 1-9, characterized in that it is administrable orally, parenterally, rectally or transdermally, in the form of a medicament.

12. The dietary supplement according to claim 10, for the prevention of anoxic tissue forms, cardiac or nervous disturbances, muscular energy deficiencies, fatigue and asthenia, inflammatory type abnormalities, and forms of tissue proliferation.

13. The medicament according to claim 11, characterized in that it is for the therapeutic treatment of pathologies induced by free radicals, for the treatment of cardiovascular or cerebral disorders due to tissue anoxia or aging, alterations of blood coagulation such as thrombosis , inflammatory type abnormalities, muscular energy deficiencies accompanied by asthenia and fatigue, and as an adjuvant in the treatment of tissue proliferation forms.

14. The dietary supplement according to claim 12, characterized in that it is in the form of tablets, pills, capsules, granules or syrups.

15. The medicament according to claim 13, characterized in that it is in the form of tablets, pills, capsules, granules, syrups, suppositories, flasks or drops.

16. The use of a composition in combination comprising as characterizing active ingredients: a) propionyl-L-carnitine or a pharmacologically acceptable salt thereof; b) an inositol phosphate selected from the group consisting of inositol monophosphate, inositol tetraphosphate, inositol pentaphosphate and inositol hexaphosphate (IP6) 15 for the preparation of a dietary supplement or a medicine useful for the prevention and / or treatment of cardiovascular or neurocerebral disorders due to chronic or acute tissue anoxia, energy deficiencies, abnormalities 20 inflammation, nervous and muscular asthenia, and forms of tissue proliferation.

17. The use according to claim 16, characterized in that the The ingredient (a) further comprises a "carnitine" selected from the group comprising L-carnitine, acetyl-L-carnitine, butyryl-L-carnitine, valeryl-L-carnitine, isovaleryl-L-carnitine or their pharmacologically acceptable salts or mixtures thereof and ingredient (b) further comprises inositol