DE102004057758A1 - Synergistic composition containing arginine and folic acid, useful for treatment and prevention of e.g. arterial hypertension and arteriosclerosis - Google Patents

Abstract

Composition (A) comprising arginine (I) and folic acid (II) and/or their salts, is new. Independent claims are also included for the following: (1) dietetic food, food supplement and functional food that contains (A); and (2) preparation, in the form of capsules, powder, tablets (optionally coated, effervescent or chewable), beverage, bar or granules that contain (A). ACTIVITY : Hypotensive; Antiarteriosclerotic; Analgesic; Nootropic; Tranquilizer; Cardiant. No details of tests for these activities are given. MECHANISM OF ACTION : None given.

Description

The The invention relates to the use of a combination of arginine and folic acid or a combination of arginine, folic acid and magnesium or each their physiologically acceptable Salts for the preparation of an agent and for prophylaxis and / or Therapy of increased arterial blood pressure, general arteriosclerosis, tension-type headache, Dysstress, declining mental performance, especially of lack of concentration, as well to reduce the cardiovascular risk.

Especially is the inventively prepared Means a medicinal, a dietary Food, a complementary balanced diet, a dietary supplement or a functional food.

Cardiovascular diseases belong the most common Disease and cause of death.

high blood pressure damages both the heart and the vessels. The Consequences of hypertension are e.g. Angina, heart attack, other circulatory disorders, kidney damage and stroke. Hypertension and other cardiovascular diseases represent the preventive and curative medicine face increasingly bigger problems, given the possibilities On the one hand, the intervention is insufficiently perceived and on the other hand due to the risks of synthetic antihypertensives are limited. preventive Applications of synthetic blood pressure products are due to divorce the risk of adverse reactions so far largely. The application of In addition, synthetic hypertension is currently worldwide with many preparations high treatment costs. After the definition of European Society of Hypertension from 2003 is an optimal systolic / diastolic Blood pressure below values of 120/80 mmHg, normal blood pressure in the range 120-129 / 80-84 mmHg, a high normal blood pressure in the range 130-139 / 85-89 mmHg, a mild high pressure in the range 140-159 / 90-99 mmHg, a moderate high pressure in the range 160-179 / 100-109 mmHg and a heavier High pressure at values over 180/110 mmHg ago (ESH J. Hypertens 2003, 21: 1011-1053). Hypertension is a central cardiovascular Risk factor that can be identified in the presence of other risk factors (such as smoking, Dislipoproteinämie, Diabetes) can already cause a high overall cardiovascular risk, if the blood pressure readings are still in the high normal or tired area (Eur. Soc. Hypertension, J. Hypertens 2003, 21: 1011-1053). For this reason, it is necessary, even the low blood pressure to fight. This risk factor applies through well-tolerated, low-side-effect substances, ideally as a dietary ingredient, to reduce or switch off. The primary goal of all against hypertension directed measures is the best possible Reduction of the long-term risk of cardiovascular morbidity and mortality. Lowering blood pressure probably also reduces the risk of Dementia.

Of the Type 2 diabetes is the most common Form of diabetes mellitus. In diabetics occur endothelial Dysfunction and atherosclerotic vascular changes in the form of Micro and macroangiopathies are particularly early on and are accelerating. at Type 2 diabetes increases the ADMA concentrations (Lin et al. Circulation 2002; 106: 987-992). Therefore, it is the type 2 diabetes in particular, cardiovascular Risk factors through well-tolerated, low-toxicity substances, ideally as a dietary component, to reduce or turn off.

task of the present invention is balanced diets, dietary supplements, to provide functional foods or drugs which compared to conventional Antihypertensives and atherosclerosis agents are equally effective, but with drastically less side effects and thus, dependent on the severity of the disease, alone or in addition to conventional Means within the complex measures for cardiovascular diseases also over long Time can be safely used.

task The present invention is further, more economical forms the treatment of hypertension and general arteriosclerosis as she is present available are.

These objects are achieved, according to the invention, by providing a composition comprising a combination of arginine, folic acid or a combination of arginine, folic acid and magnesium, each ingredient independently being a physiologically acceptable salt thereof. In the context of the present invention, "magnesium" is always to be understood as meaning a physiologically compatible magnesium compound. Optionally, the composition may comprise a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable adjuvant. More particularly, the present invention relates to the use of a combination of arginine and folic acid or a combination of arginine, folic acid and magnesium, each ingredient independently as a physiologically acceptable salt, for the preparation of an agent for the prophylaxis and / or therapy of increased arterial blood pressure. general arteriosclerosis, tension head pain, dysstress, diminishing mental performance, especially lack of concentration or / and to reduce the cardiovascular risk. Preferred are combinations of arginine and folic acid or a combination of arginine, folic acid and magnesium, which also contain vitamins B6 and B12. The composition according to the invention can be used for balanced diets, dietary supplements, functional foods or as medicaments.

It is known to be the amino acid L-arginine stimulates the synthesis of nitric oxide, which an improvement in the function of the vascular endothelium, for vascular relaxation and results in an improvement in arterial perfusion. In patients with essential hypertension, administration of L-arginine resulted but not to a significant lowering of blood pressure (Lekakis et al. Int.J.Cardiol. 2002; 86: 317-323). In patients with type II diabetes, which have a reduced nitric oxide formation, could high Arginine doses of 3 g per hour the systolic blood pressure of on average 135 to 123 mmHg and diastolic blood pressure from an average of 86.9 to 80.7 mmHg (Huynh and Tayek, J.Am.Coll.Nutr., 2002; 21: 422-427). Even in kidney transplant patients with high blood pressure could With 9 g L-Arginin per day significant blood pressure reductions are achieved (Kelly et al .. JPEN J.Parenter.Enteral Nutr. 2001; 25: 194-202). at mild forms of hypertension is the hypotensive effect of orally administered L-arginine low.

A similar Situation is folic acid in front. It is known that folic acid has a Reduction of homocysteine concentration in the blood also the function of the vascular endothelium improved. Increased homocysteine concentrations are used today as a risk factor for discussed arterial hypertension. An optimal supply of the Organism with folic acid can reduce homocysteine and thus against cardiovascular diseases protect and reduce coronary risk (Neal et al., Eur.Heart J. 2002; 23: 1509-1515; Vermeulen et al. Lancet 2000; 355: 517-522). It is special known to be folic acid also the raised one lowers arterial blood pressure slightly. In high-risk individuals leads one 4 week Administration of folic acid to decrease the mean blood pressure from 88 to 83 mmHg (Mangoni et al. J.Intern.Med. 2002; 252: 497-503)). To this small To achieve a fall in blood pressure, must be a comparatively high amount of folic acid of 5 mg per day. The German Nutrition Society (DGE), the Austrian Organisation for; society for; party for nutrition (ÖGE) the Swiss Society for Nutrition Research (SGE) and the Swiss Association for nutrition (SVE) recommend as daily Feed for Adults only 400 micrograms folic acid (D.A.C.H. for the Nutrient intake, 1st edition., Hsg: DGE, ÖGE, SGE, SVE., Review Braus VerlagVerl., Frankfurt a.M. ISBN: 3-8295-7114-3 2000).

Orally Magnesium can also cause a slight decrease of hypertension. In patients with low to moderate high blood pressure After administration of 20 mmol of magnesium per day, reductions were average around 2.5 mmHg systolic and 1.4 mmHg diastolic at 24-hour measurement (Kawano et al., Hypertension 1998; 32: 260-265). A Meta-analysis of 20 studies with a total of 1,220 participants showed that a hypotensive effect of orally ingested magnesium at dosages of daily 486 to 927 milligrams is expected. Per 243 mg of magnesium decreases thus systolic pressure on average by 4,3 mmHg and the diastolic blood pressure increased by 2.3 mmHg (Jee et al., Am.J.Hypertens. 2002; 15: 691-696). However, there are no detectable hypotensive effects at lower levels Dosages of up to 350 milligrams of magnesium (Jee et al., Am.J.Hypertens. 2002; 15: 691-696).

Surprisingly has now been found in the context of the present invention that a combination of arginine and folic acid as well as a combination of arginine, folic acid and magnesium capable is a much stronger one Lowering the increased To cause blood pressure as the sum of the effects of the individual components. Surprisingly was further found that the combinations in particular in the Are able to decrease mental ability, especially lack of concentration, as well To significantly improve tension-type headache and dysstress. In the combinations according to the invention is arginine component as the D- and / or L-isomer of arginine preferred, is the use of L-arginine. If mixtures are used from D and L isomer, so they can the isomers in any In particular, the combinations of present invention, a racemic mixture.

Although the individual substances of the combination attributed hypotensive properties, there was so far no indication that a combination of the components arginine and folic acid or arginine, folic acid and magnesium leads to a synergistic effect and thus has a stronger effect than the sum the effects of the individual components is obtained. The combinations according to the invention are therefore usable in particular as a supplemental balanced diet, dietary supplement, functional food or drug. So far there was no indication that the combination according to the invention has the properties mentioned and thus to Therapy and prophylaxis of those forms of arterial hypertension and general arteriosclerosis can be used, which were previously inaccessible to drug prophylaxis and therapy due to benefit / risk considerations. Furthermore, there is no indication in the prior art that a combination of arginine and folic acid or arginine, folic acid and magnesium can lead to an improvement in decreasing mental performance, in particular concentration deficiency, as well as tension-type headache and dysstress.

Especially is the subject matter of the present invention advantageously as a supplementary balanced Diet Atherosclerosis can be used, especially in mild forms of high blood pressure in conjunction with other antihypertensive measures one qualitatively novel contribution to long-term prophylaxis and therapy of arterial high pressure. In particular, she can also used for long-term prophylaxis and therapy of those forms of hypertension which are not usually or still with the conventional ones be treated with synthetic blood pressure.

The compounds to be used according to the invention and their physiologically tolerable salts can be processed in a manner known per se to, for example, orally administrable pharmaceutical and food forms, in particular in the form of capsules, tablets, film-coated tablets, chewable tablets, dragees, effervescent tablets, drinking preparations, bars, granules, powders , Arginine can be used as a D-isomer or L-isomer or as a mixture of both isomers, preferably arginine in its L-form is used. The agent according to the invention is preferably administered orally. Preferably, combinations having the following composition per dosage unit are administered:
Arginine from 0.2 g to 12 g, preferably from 0.6 g to 5 g and more preferably from 0.4 g to 2 g. Folic acid from 10 μg to 900 μg, preferably from 2 μg to 800 μg, more preferably from 40 μg to 150 μg, even more preferably from 20 μg to 100 μg. Magnesium of from 5 mg to 400 mg, preferably from 10 mg to 300 mg, more preferably from 15 mg to 350 mg, more preferably from 20 mg to 150 mg, even more preferably from 30 mg to 100 mg.

These Quantities are generally for a 1 to 8 times, especially for a 2 to 4 times application thought per day. If necessary, the total amount can be once a day be administered.

The used according to the invention Combinations can also as a component of combinations with other ingredients be administered. Preference is given as further components that Vitamin B6 (pyridoxine), more preferably from 0.1 mg to 600 mg, more preferably from 0.2 mg to 10 mg, and the vitamin B12 (cyanocobalamin), more preferably of 0.1 μg up to 5000 μg, more preferably 0.5 μg up to 200 μg, per dose unit.

The The following examples are intended to explain the invention in more detail:

Example I:

Each 600 mg of L-arginine, each containing 40 μg of folic acid and 25 mg of magnesium oxide (corresponding to 15.1 mg of magnesium) are filled into a hard gelatin capsule.

Example II:

Each 4800 mg of L-arginine, each with 310 μg of folic acid and 200 mg of magnesium oxide (equivalent to 120.6 mg magnesium) as a powder in a sachet filled.

Example III:

Each 600 mg L-arginine are pressed into a film-coated tablet with 150 μg folic acid each time.

Example IV:

Each 600 mg of L-arginine are mixed with 150 μg of folic acid and 0.75 mg of vitamin B6 (Pyridoxine HCl) and 1.5 μg Vitamin B12 (cyanocobalamin) pressed into a film-coated tablet.

Claims (11)

Composition comprising a combination of Arginine and folic acid, each component being each independently physiologically acceptable Salt may be present. Composition according to Claim 1, characterized that in addition a physiologically tolerable Contains magnesium compound. Composition according to Claim 1 or 2, characterized that in addition physiologically compatible Contains compounds of vitamin B6 and vitamin B12. Pharmaceutical composition according to claim 1, 2 or 3, wherein arginine is L-arginine. Use of a combination of arginine and folic acid and optionally magnesium compound and vitamin B6 and vitamin B12, each component independently being physiologically may be present for the preparation of an agent for the prophylaxis and / or treatment of increased arterial blood pressure, general arteriosclerosis, tension headache, dysstress, diminishing mental performance, in particular concentration deficiency, or / and to reduce the cardiovascular risk. Use according to claim 5 for the preparation of a By means of prophylaxis and / or long - term therapy of those forms of Hypertension, which due to the low severity normally not or still with the conventional ones be treated with synthetic blood pressure. Use according to claim 5 for the preparation of a By means of prophylaxis and / or long - term therapy of those forms of Hypertension due to drug intolerances not with the conventional ones be treated with synthetic blood pressure. Use according to one of claims 5 to 7 for the preparation a dietary one Food, especially for a complementary one balanced diet. Use according to one of claims 5 to 7 for the preparation a food supplement. Use according to one of claims 5 to 7 for the preparation a functional food. Use according to one of claims 5 to 10 for the production of an agent in the form of capsules, powders, tablets, film-coated tablets, Dragees, effervescent tablets, chewable tablets, drink preparations, bars, or Granulates.