DE102015214644A1 - COMPOSITION FOR THE TREATMENT OF INCREASED CHOLESTEROL, CORTISOL OR TRIGLYZERID VALUES - Google Patents

Abstract

The invention relates to a composition for the prophylaxis or treatment of abnormal levels of total cholesterol and / or LDL-cholesterol and / or cortisol and / or triglycerides in the body of animals and humans, said composition containing at least one isoquinoline alkaloid.

Description

Technical area

The present invention relates to an agent for the prevention and treatment of elevated cholesterol, cortisol and / or triglyceride levels in humans and animals.

State of the art

Cortisol is a stress hormone that activates catabolic metabolic processes and thus provides the body with high-energy compounds. Cortisol is a steroid hormone of the adrenal cortex. It promotes protein breakdown and converts amino acids into glucose (gluconeogenesis) with the aim of increasing blood sugar levels to be better prepared for the stress. Due to these principles of action, cortisol increases the physical performance in the short term. However, if the level of cholesterol is significantly increased over time (for example due to hereditary factors, long-term stress or other causes), a large number of adverse health consequences occur. Without stress, the cortisol release follows a typical course of the day: The cortisol formation begins more in the second half of the night and stored cortisol is relieved in the early morning, so that the body is immediately capable of getting up in the morning. The cortisol release repeats itself several times in the morning and subsides during the day. In the evening practically no cortisol is released and only about 10 percent are detectable in the blood. The lows are reached around midnight.

Cholesterol, also known as cholesterol, is a vital sterol and an important component of the plasma membrane. It increases the stability of the membrane and, together with proteins, contributes to the infiltration and transport of signaling substances into the cell membrane. A high total cholesterol concentration, in particular a high LDL cholesterol concentration in the blood is an important risk factor for cardiovascular diseases esp. Of the heart and vessels.

Triglycerides are compounds of glycerol and organic acid molecules. The organic acids may in particular be saturated and / or unsaturated fatty acids, the triglycerides are then "lipids". Increased triglyceride levels increased the risk of vascular disease, especially atherosclerosis and the formation of blood clots and the associated sequelae (thrombosis, heart attack, stroke). Pathologically elevated triglyceride levels may be e.g. This may be due to a lipid metabolism disorder, diabetes mellitus, hyperchylomicronemia, hypothyroidism, kidney disease, chronic alcohol abuse or obesity.

Vascular diseases are among the leading causes of death in industrialized countries. Risk factors include elevated levels of cholesterol, cholesterol and triglycerides.

The isoquinoline alkaloids sanguinarine and chelerythrine are known from various publications as antimicrobial secondary plant components. For example, describes the WO 93/16602 (Neufeld) improved livelihoods of livestock based on an antimicrobial effect of sanguinarine on the intestinal flora, which - similar to synthetic antibiotics - achieve better growth rates.

Also known is the use of sanguinarine in oral hygiene. Again, the expected effect is based on the antimicrobial effect of sanguinarine on the unwanted oral flora of humans.

Technical problem and basic solutions

In contrast, the invention has the task of improving the health of humans and animals, in particular with regard to vascular diseases and their causes.

• a) Gesamtcholesterol und/oder
• b) LDL-Cholesterol und/oder
• c) Cortisol und/oder
• d) Triglyzeridwerten

bei Menschen oder Tieren.Composition having one or more isoquinoline alkaloids for use in the prophylaxis or treatment of abnormal levels of:

• a) total cholesterol and / or
• b) LDL cholesterol and / or
• c) Cortisol and / or
• d) triglyceride values

in humans or animals.

The use of the above-mentioned composition may be advantageous, since a reduction in pathologically increased levels of several substances, each of which may cause various diseases and negative symptoms, is effected by a single composition. It has e.g. It has been pointed out that a pathologically elevated cholesterol concentration and a pathologically increased triglyceride concentration may significantly increase the overall risk of vascular disease more than would have been expected given a simple summation of the risks arising from the individual risk factors. Unlike this, e.g. when assessing a blood glucose or creatinine value commonly perceived as isolated risk factors, LDL-cholesterol, total cholesterol, triglyceride levels and cortisol levels are factors that influence a global health risk, in particular for cardiovascular diseases. A particularly high risk of vascular disease arises when a patient has both elevated LDL cholesterol levels and elevated triglyceride levels.

The use of isoquinoline alkaloids can thus be used both prophylactically and therapeutically against each of the above-mentioned pathologically increased substances, but can also be used in a particularly advantageous manner against vascular and other diseases which are a consequence of several of the abovementioned factors a) -d ) are.

In another positive aspect, no negative side effects were observed in humans or animals. Some positive side effects are known, e.g. the increase in performance when using such a composition as a feed or feed additive for livestock.

According to embodiments, the isoquinoline alkaloids are quaternary benzophenanthridine alkaloids, preferably selected from the group consisting of sanguinarine, chelerythrine and their salts.

The isoquinoline alkaloids may be of natural or synthetic origin. For example, the isoquinoline alkaloids may be derived from parts or extracts of a plant selected from the group consisting of Sanguinaria canadensis, Macleaya spp. like Macleaya cordata, Argemone mexicana, Chelidonium majus and Eschscholzia californica. The alkaloids may also be derived from cell cultures, fermentation with suitable bacteria and fungi, or synthetically produced.

The extracts which can be used in the context of the invention can be prepared by any known method, and it is possible, for example, to use aqueous and / or alcoholic extracts and / or CO ₂ extracts.

According to embodiments, the entirety of all components of the composition which are not isoquinoline alkaloids or isoquinoline alkaloid salts, a salt content of at least 0.001 wt.%, Preferably above 0.01 wt%. These salts include in particular NaCl, MgCl, CaCl and / or other salts, preferably salts which are physiologically compatible and which furthermore preferably trigger a salty taste in mammals. This can be advantageous since the composition or the beverage obtained from the composition, drinking water, drinking water, feed or food is thereby improved in taste.

According to some embodiments, the composition contains at least 4 mg of sodium per kg of the composition, the sodium preferably being present as NaCl.

In embodiments, the total of all components of the composition that are not isoquinoline alkaloids or isoquinoline alkaloid salts includes a weight fraction of magnesium of at least 5 mg per kilogram of the composition. The magnesium is preferably present as magnesium sulfate. However, other magnesium compounds are possible. Magnesium compounds are particularly useful as carriers for the isoquinoline alkaloids and facilitate homogeneous mixing of the isoquinoline alkaloids and other components of the composition during production.

According to embodiments, the lowering of one or more of the substances a) -d) serves for the prophylaxis of arteriosclerosis in humans or animals.

The benzophenanthridine alkaloids used according to the invention can be present in their water-insoluble form and can be processed or administered in this form.

They can also be added directly to drinking water in water-soluble systems or added to drinks. Furthermore, they can also be further processed as a gel, as a powder, as a long-term slow-release bolus or as granules. If the alkaloids used are of natural origin, they are usually present as Alkaloidmischungen. These alkaloid mixtures are adjusted by mass spectrometry and HPLC for their content of the alkaloids sanguinarine and chelerythrine and standardized.

According to embodiments, the isoquinoline alkaloids are in salt form, preferably as chlorides or sulfates.

According to embodiments, the composition further contains one or more antioxidants.

According to embodiments, the at least one isoquinoline alkaloid is adjusted to the amount of composition typically absorbed by humans or animals per day such that when consuming an amount of the composition per animal or person per day recommended, 0.02 mg to 1000 mg isoquinoline alkaloid (s) or salts of which per animal or person and day are taken up.

According to embodiments, the at least one isoquinoline alkaloid is so tailored to the amount of composition typically absorbed by humans or animals per day that when consumed one for the purpose of treating one or more pathologically increased concentrations of the substances a) -d) per animal or human and Day 50 mg to 1000 mg isoquinoline alkaloid (s) or salts thereof per animal or human and day are included.

• – Arteriosklerose, Herzinfarkt, Schlaganfall, Ablagerungen in den Sehnen oder in der Haut als Folge von a), b) oder d);
• – Schädigung der Nebenniere, Konzentrationsstörungen, Gefäßverengung, Bluthochdruck, Durchblutungsstörungen, erhöhter Blutzuckerspiegel und Insulinspiegel, Förderung der Entwicklung von Diabetes Typ II, Osteoporose, Schädigung von Gelenkknorpeln, Schwächung des Immunsystems, Unterdrückung der Schilddrüsenfunktion, Verringerte Bildung von Geschlechtshormonen, Cushing-Syndrom als Folge von d).

According to embodiments, the composition is used for the treatment or prevention of diseases caused by an increased blood value of one of the substances a) -d). These diseases include:

• - Arteriosclerosis, myocardial infarction, stroke, deposits in the tendons or in the skin as a result of a), b) or d);
• - adrenal gland, impaired concentration, vasoconstriction, hypertension, circulatory disorders, elevated blood sugar and insulin levels, promotion of development of type II diabetes, osteoporosis, damage to articular cartilage, weakening of the immune system, suppression of thyroid function, reduced production of sex hormones, Cushing's syndrome as a result from D).

According to embodiments, the composition includes at least one acid. The type and amount of at least one acid is chosen and matched with the nature and amount of the remaining ingredients of the composition such that the composition, including the acid, has a pH below 6.8, preferably below 6.5. The composition may preferably be a liquid, in particular an aqueous solution, e.g. Drinking water, drinking water, beverages, liquid dairy products with Isochinolinalkaloidzusatz or act an aqueous pharmaceutical composition.

This may be advantageous because an acidic pH increases the chemical stability of isoquinoline alkaloids in aqueous solution and additionally increases solubility. On the one hand, the shelf life of a liquid isoquinoline alkaloid composition is increased because deposition of isoquinoline alkaloids on vessel walls and sedimentation of isoquinoline alkaloid aggregates with other components of the composition is prevented. The improved shelf life results in a simplified handling and a lower price at the end user. It has also been observed that such an acidified solution is particularly well suited for administration to livestock via the drinking water, since the corresponding lines and valves of the drinking water plants do not clog, since the isoquinoline alkaloid is kept in solution by the acid. Also in the administration to humans and pets there are advantages because the drinking or drinking water or corresponding liquid dietary supplements and drinks are better storable, the active ingredient does not settle or settle at the vessel turning and thus contamination of the drinking vessel and a Reduction of the dissolved Alkaloidgehalts in drinking or drinking water or beverage is prevented.

According to embodiments, the composition is a liquid or solid concentrate, from which by addition of further substances, in particular liquid substances such as water, juice, milk, lemonades or other suitable for human or animal enjoyment of liquids, a diluted form of the composition is obtained, which then only for administration to the animal or the human is determined. In this case, the type and amount of the at least one acid is chosen and matched with the type and amount of the remaining ingredients of the composition including the other liquid substance (s) that the diluted composition including the acid has a pH below 6.8 , preferably below 6.5.

The acid may be a carboxylic acid. This has the advantage that many carboxylic acids are themselves very readily soluble in water and are suitable for consumption by animals and humans. The acidity is often lower than the acidity of more aggressive acids such as e.g. Hydrochloric acid or sulfuric acid, but sufficient for the required pH value reduction usually.

Preferably, the at least one acid is water-soluble.

Preferably, the at least one acid is an amphiphilic organic acid, in particular an amphiphilic carboxylic acid.

According to embodiments, the at least one acid is an acid, i.e., an acid that is both water-soluble and lipophilic-phase-soluble. According to embodiments, the at least one carboxylic acid is selected from a group comprising: an amphiphilic carboxylic acid, an aliphatic carboxylic acid, an aromatic carboxylic acid, a heterocyclic carboxylic acid, a saturated carboxylic acid, an unsaturated carboxylic acid or a combination of two or more of these acids.

The at least one acid may e.g. consist of one of the following acids or a combination of two or more of these acids: malic acid, lactic acid, acetic acid, citric acid, formic acid, sorbic acid, propionic acid, ascorbic acid, fumaric acid, oxalic acid.

Preferably, the at least one acid is powdery. This can facilitate the handling and weighing of the determined amount of acid. For example, malic acid or citric acid are powdery. Preferably, the at least one acid is already mixed in the preparation of the composition in powder form with the other components of the composition. Preferably, to obtain a powdered composition, a powdery acid such as e.g. Malic acid or citric acid used.

According to other embodiments, the at least one acid is liquid. This is e.g. in the case of propionic acid.

For example, 5 grams of water may be added to 5 grams of a powdered composition to produce 10 grams of the liquid composition, also called "concentrate". The 5 grams of water may also contain thickening agents to impart a gelatinous consistency to the resulting composition. Alternatively, the composition may be prepared as a liquid composition, e.g. by adding a liquid acid, e.g. Propionic acid is used as the at least one acid.

• a) Gesamtcholesterin von über 230 mg/dl Blut
• b) LDL-Cholesterin von über 160 mg/dl Blut
• c) Cortisolkonzentration morgens über 24 µg/dl Blut
• d) Triglyceridkonzentration von über 200 mg/dl.

According to statements, in the case of a human adult the following limit values are to be regarded as a pathological increase:

• a) Total cholesterol of over 230 mg / dl blood
• b) LDL cholesterol of over 160 mg / dl blood
• c) Cortisol concentration in the morning above 24 μg / dl of blood
• d) triglyceride concentration of over 200 mg / dl.

The "normal" (i.e., the health-safe level) cortisol level and, correspondingly, the threshold for a "pathologically excessive" cortisol level are time dependent. For example, the "normal" concentration of cortisol in the blood serum of humans is "morning", ie between 7 and 9 o'clock in the morning, at 4.5 to 24.0 μg / dl, between 15 and 17 h at 1.5 to 15 μg / l. The concentration in saliva is typically around 0.15 to 1.00 μg / dl at 8 am and 0.07 to 0.22 μg / dl at 10 pm

The limit values mentioned here are to be understood as examples. Depending on age, gender and other factors, the limit for each of the above substances may also be above or below the values listed here. The question as to the concentration at which a particular substance is classified as hazardous to health can be assessed differently in individual cases (some laboratories already consider a triglyceride level of more than 150 mg / dl of blood to be abnormally high). However, the concentration-lowering effect of isoquinoline alkaloid remains unaffected.

It should also be mentioned at this point that an increased cortisol level in the blood is usually accompanied by a correspondingly high cortisol level in the saliva and urine. The same applies to the other substances mentioned a) -d). Depending on the embodiment, the concentration of the substances a) -d) can thus be measured in the blood, urine or saliva and compared with a corresponding reference value. The reference value may be different for urine or saliva than for blood, but here too a decrease in concentration can be detected.

The increased value of the substances a) -d) can be caused, for example, by oxidative stress, eating habits and / or hereditary factors.

According to embodiments, the composition is one of the following types of composition: feed, feed additive, feed premix, human food, dietary supplement, functional food, human or animal pharmaceutical preparation, drinking water, drinking water, beverage, dairy product. Alternatively, the composition may also be a liquid or solid concentrate for the preparation of any of the types of composition herein.

According to embodiments, each kilogram of the composition formed as feed, feed additive, food, dietary supplement, functional food, human food, drinking water, drinking water, beverage or dairy product contains from 0.05 to 1000 mg of the isoquinoline alkaloid (s) or their salts. This dosage may be particularly advantageous if the abovementioned types of composition are administered or taken regularly and in larger amounts, so that a comparatively low dosage is used here. In particular, this dosage is administered according to embodiments for preventive purposes, ie even if a certain factor (total cholesterol, LDL cholesterol, cortisol, triglycerides) is still in the normal range, but should be prevented from increasing further to a concentration that is harmful to health.

According to embodiments, every kilogram of the composition formed as a dietary supplement or as a pharmaceutical preparation for human or animal contains from 0.05 to 100 000 mg of isoquinoline alkaloid (s) or salts thereof. In particular, 1 kg of the composition may contain 1001 mg to 100,000 mg isoquinoline alkaloid (s) or salts thereof.

In particular, the composition can be in the form of a pharmaceutical preparation for animals or humans, which contains the at least one isoquinoline alkaloid together with pharmaceutically acceptable carriers and / or excipients and optionally together with further pharmaceutical active substances.

The composition may thus contain suitable carriers and additives and be formed as food or feed, remedies, dietary supplements, functional foods, feed additives, drinking water, drinks or medicinal drinks, drinking water, etc., using suitable carriers. Depending on the type of composition, various manufacturing and mixing techniques can be used. For example, the isoquinoline alkaloidal composition of the present invention can be incorporated into a feed premix or other premix for a composition suitable for human consumption, the conventional ingredients selected from the group consisting of vitamins, minerals, trace elements, enzymes, grains or cereal products, proteins , Amino acids and the like. The premix may e.g. a powdered or liquid concentrate. The premix can be made to produce a composition directly for human or animal consumption. According to embodiments, the premix or concentrate contains such a high concentration of the isoquinoline alkaloid that the dilution or depletion in the course of the production process of the administration form suitable for direct consumption sets the concentration of the at least one isoquinoline alkaloid to one of the ranges of values mentioned here.

In the preparation of foodstuffs, the composition of the invention may be added to a concentrate or processed into a concentrate, the concentrate comprising conventional ingredients, for example selected from the group consisting of vitamins, minerals, trace elements, enzymes, emulsifiers, preservatives, colorants, flavorings, stabilizers , Cereals or cereal products, fillers, sweeteners, salts and the like, and that is further processed for the preparation of a human-suitable product, for example as a pharmaceutical, food or dietary supplement. The composition of the invention may also be incorporated into a conventional precursor composition for the preparation of a pharmaceutical composition, wherein the precursor composition comprises pharmaceutically acceptable carriers and having pharmaceutical excipients and optionally pharmaceutical active ingredients. In particular, antioxidants may be added to the composition intended for animal or human consumption. These reduce or prevent oxidative stress. Oxidative stress is one of the causes of elevated levels of cholesterol, cortisol and triglycerides. Antioxidants thus enhance the health-promoting effect of at least one Isochinolinalkaloids in the prophylaxis or treatment of the increased levels of substance according to a) -d) or the resulting damage, diseases or conditions. As non-limiting examples, one can use vitamin C, vitamin E, selenium, zinc, etc. as antioxidants. Some of the antioxidants currently used, such as selenium or zinc, are sometimes known as environmental toxins and are more or less highly toxic, which limits their unlimited and long-term use in humans, for example. Therefore, these substances also have a relatively narrower dosage range between the effective dose and the dose that should not be exceeded for reasons of health, or even have statutory limits.

Antioxidants are e.g. They are known to prevent atherosclerotic lesions in LDL particles and in vascular cells by accumulating in LDL particles and protecting them from oxidation. The excessive formation of oxidized LDL particles is stopped. Antioxidants also accumulate in vascular cells and strengthen the cells of the vascular system against oxidized LDL particles. This prevents reactions such as monocyte adhesion, foam cell formation, cytotoxicity and dysfunction of the vascular cells. Vascular diseases can not be expressed. Since the alkaloids of the composition according to the invention are a natural component of various (medicinal) plants and presumably have reached their environment for millions of years at the death of the plant, degrading systems have developed in the environment which restore the compounds to their starting materials carbon, oxygen, water , Remove nitrogen. In contrast, for example, in large-scale use of zinc and selenium or other heavy metals acting as antioxidants in correspondingly high dosages, there would be a potential enrichment of the environment with such heavy metals.

Thus, the present invention has many advantages over currently used substances or methods both in terms of environmental safety, health compatibility and the subsequent degradation in soil, water or sewage treatment plants.

"Functional foods" are foods that are enriched with additional ingredients and for which a positive effect on health can be proven. For example, milkshakes, beverage powders, cereal jellies with special additives and similar products can be functional foods.

The composition of the invention may, for. B. in the form of pharmaceutical preparations alone or with other active substances. The composition of the invention may, for. B also in animal stables e.g. also be added directly to the drinking water via suitable medicines or via the milk for calves in appropriate dilution and water-soluble form. For fish and shrimp, it has been found to be advisable to choose a water-insoluble formulation in order to delay leaching of the ingredients in the habitat as far as possible until the feed is eaten. Particularly in the case of domestic animals, the lowering of one or more of the stated values may be advantageous, since in domestic animals the natural life expectancy is generally to be fully utilized and a premature death by e.g. Arteriosclerosis, which is promoted by the substances a) -d), a common cause of death for pets such. Dogs and cats is.

• a) Gesamtcholesterol und/oder
• b) LDL-Cholesterol und/oder
• c) Cortisol und/oder
• d) Triglyzeridwerten

bei Menschen oder Tieren. Beispielsweise kann die Zusammensetzung gemäß einer der hier beschriebenen Ausführungsformen zusammengesetzt sein.In a further aspect, the invention relates to a use of a composition comprising one or more isoquinoline alkaloids for the prophylaxis or treatment of abnormally elevated levels of:

• a) total cholesterol and / or
• b) LDL cholesterol and / or
• c) Cortisol and / or
• d) triglyceride values

in humans or animals. For example, the composition may be composed according to one of the embodiments described herein.

According to embodiments, the isoquinoline alkaloids used are quaternary benzophenanthridine alkaloids of natural or synthetic origin, preferably selected from the group consisting of sanguinarine, chelerythrine and their salts. According to further embodiments, the composition used is a composition according to one of the embodiments already described. Thus, for example, an isoquinoline-containing drinking or drinking water, a dietary supplement or one of the other abovementioned types of composition can be used to reduce one or more of the abovementioned substances a) -d).

In the QBA composition according to the invention, the alkaloids may be present in any desired ratio, ie in the range of sanguinarine: chelerythrine = 99%: 1% to 1%: 99%. In a specific embodiment, the alkaloids sanguinarine and chelerythrine are present in the ratio of 1: 0.5, based on the natural ratio of these alkaloids in the vegetable starting material.

The alkaloids are in an advantageous embodiment in the form of salts, for example in their chloride or sulfate form, but they can also take any other salt form which is chemically stable. The alkaloid itself is chemically unstable and can be inactivated by addition of hydroxyl ions. Thus, the alkaloid can potentially serve as a reducing agent.

For the prophylaxis or treatment of symptoms of oxidative stress, preferably 0.02 to 1000 mg of benzophenanthridine alkaloid (s) or their salts are administered per animal or person and day.

According to a feature of the invention, the oxidative stress-causing disease for the prophylaxis or treatment of which the QBA composition according to the invention is used is an elevated cholesterol level, e.g. a cholesterol level measured in the blood plasma.

In the following, "elevated cholesterol levels" is understood as meaning a pathologically increased total cholesterol level or a pathologically elevated LDL cholesterol level. This may vary depending on the species, age, sex and other factors (pregnancy). The average total cholesterol level of adults between 35 and 65 years old in Germany is about 236 mg / dl blood plasma (equivalent to 6.1 mmol / l). According to embodiments, total cholesterol levels above 290 mg / dl of blood plasma are to be regarded as pathologically elevated total cholesterol levels. In some parts of China the average cholesterol level is 94 mg / dl with norm values between 70 mg / dl and 170 mg / dl blood plasma. The lower cholesterol levels are less likely to be associated with heart and cancer, so that, according to embodiments, levels in excess of 170 mg / dl blood plasma may be considered pathologically elevated total cholesterol since these levels increase the risk of cancer and heart disease ( Campbell, T. Colin; Thomas M. Campbell II: The China Study: The Most Comprehensive Study of Nutrition Ever Conducted and the Startling Implications for Diet, Weight Loss, and Long-term Health. Perseus Distribution, June 1, 2006, ISBN 978-1-932100-66-2, p. 444 )

The LDL cholesterol level is subject to a similar age- and sex-dependent distribution as the total cholesterol level. According to embodiments, e.g. a value of 208 mg LDL cholesterol / dl blood plasma in women and a value of 211 mg LDL cholesterol / dl blood plasma in males between 35 and 36 years as morbidly increased.

The corresponding values in various livestock species and hobby and domestic animals (for example, riding horses, ponies, dogs, cats, small animals) can be found in the literature. Despite the fact that the average cholesterol concentration in the blood of a human or animal is dependent on many factors, there are nevertheless limits which the doctor considers disadvantageous and undesirable, taking into account the individual situation of the human or animal.

The composition according to the invention, in experiments with chickens, pigs, dairy cows and fish, has not shown any significant deteriorations of relevant liver, heart, or heart rate during long-term administration over the entire life span or in the case of short-term administration as part of a high dose up to 50 times the doses recommended here. lymphatic tissue or of critical levels in the blood.

A recent rat study in rats has shown that, in the short or long term, up to 2000 mg of the isoquinoline alkaloid composition of the invention could be administered per kg of live weight without any relevant clinical toxicology parameter being responsive, human or animal daily dosages of isoquinoline alkaloid alkaloids of 150 g per person per day, 6 g per chicken, 10 g per cat, 30 to 60 g per dog, 200 g per pig, 100 g per calf, 1000 g per cow, etc. Thus, the composition of the present invention is significantly safer than previous standard measures (e.g., taking antihypertensive agents) and absolutely harmless to health compared to these.

In the context of the present invention, a series of experiments was carried out in which the intended use of the compositions was carried out in the preferred dosages listed in Table 1 below. As can be seen from Table 1, the dosages of the compositions vary widely, depending on a number of factors, including body mass. The dosages can be chosen to be higher, especially when the composition according to the invention is used in humans or animals at already existing elevated levels of total cholesterol, LDL cholesterol, cortisol or triglycerides or diseases and symptoms caused thereby. Thus, the preferred dosage ranges given in Table 1 cover both the prophylactic and curative dosages of the compositions. Table 1: Dosage of Isochinolinalkaloid composition depending on body mass and oxidative stress potential Monogastric in general 0.02 to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in feed or water human 0.02 to 1000 mg of the at least one isoquinoline alkaloid per person per day, dissolved in the diet or in water or drinks or as a tablet, etc. Dog Cat 0.02 to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in the diet or as a dietary supplement Pigs, poultry 0.02 mg to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in feed or water Ruminants in general 0.02 to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in the feed, water or applied as a bolus Cattle, beef cattle, dairy cows 0.02 mg to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in the feed or water or applied as a bolus calves 0.02 to 1000 mg of the at least one isoquinoline alkaloid per animal per day, in the diet or water; When two or more of the substances a) -d) are in a range of serious health concern, more preferably 20 to 50 mg of the at least one isoquinoline alkaloid per animal per day aquaculture 0.02 mg to 1000 mg of the at least one isoquinoline alkaloid per kg of feed Fish, shrimp 0.02 to 1000 mg of the at least one isoquinoline alkaloid per kg of fish feed

The dosage in feed and food based on the experiments is based on the daily consumption of food or food from humans, livestock, hobby, fish or shrimp and is expressed as mg / kg of food or feed or mg per liter of drinking water / drinking water.

As carriers have food and food, z. As well as amino acids, acids, starch, etc., proven.

The prophylactic use in humans or animals can be permanent, but can also last for a few weeks sporadically in case of a problem. Is administered the composition of the invention z. On dietary supplements such as effervescent tablets, powders, granules, which are taken with a glass of drinking water; it can be administered as a medical device in tablet form or in gel and the like.

The prophylactic continuous dosage is in the feed for all animal species, depending on the number of substances a) -d), which are in the health-critical high range and depending on the measured concentration of these substances at 0.05 to 1000 mg Isochinolinalkaloid per kg feed. This is permanently administered to protect the animal over the entire period of use or fattening period before a health-critical increase in the substances a) -d).

The same dosage caused a marked reduction in LSL and total cholesterol levels as well as cortisol and triglyceride levels in the blood in initial trials on humans who took the isoquinoline alkaloid daily over a liquid or solid dietary supplement for several weeks.

The invention will be explained in more detail below with reference to specific embodiments and the drawing.

EXAMPLES

For reasons of reproducibility of the experimental results and the analysis, in the following examples, isoquinoline alkaloid compositions were used in which the alkaloids sanguinarine and chelerythrine were contained in a ratio of 1: 0.5. This ratio is based on the natural ratio of these alkaloids in the vegetable source material. Comparable results are to be expected with mixtures of these alkaloids in any other ratio, since it was found that the two alkaloids show very similar behavior and can be used effectively. In first experiments on individual subjects, a reduction of the stated values a) -d) by ingestion of Isochinolinalkaloiden such. Sanguinarine and chelerythrine observed. For livestock such as pigs and broilers more extensive test series were carried out. The experiments on pigs described below also document the benefits for humans. From experiments with pharmaceutical substances in pigs it is known from experience, from research reports and approval processes that the medical test results obtained for pigs concerning the mode of action of a certain substance can be transferred to humans.

Example 1: Influence of the composition according to the invention on the cortisol level of pregnant pigs

The pigs assigned to the experimental groups received the composition according to the invention during pregnancy, in the last two weeks before the date of birth. The feed containing the composition of the invention in an amount such that 2.25 (VG ₂₎ or 1.125 (VG ₁₎ mg isoquinoline alkaloid (e) were administered per animal per day. Supplementation of the feed was continued until the 35th day after the litter. The control group received no Isochinolinalkaloide or a comparable feed, but did not contain Isochinolinalkaloide.

The stress parameters "cortisol" and "C-reactive protein" measured on the day of the birth showed significantly lower values in the experimental groups (VG ₁ and VG ₂ ) compared to the control group (KG), as shown in Table 2 below: TABLE 2 Control group (KG) Experimental group (VG ₁ ) Experimental group (VG ₂ ) cortisol 27.5 ng / ml 18.6 ng / ml 19.5 ng / ml C-reactive protein 320.6 ng / ml 110.5 ng / ml 140.2 ng / ml

The mortality rate of the piglets during the suckling phase decreased from 6.86% to 6.45% (p <0.05). The weight of all fed piglets per sow on the day of weaning increased from 56.59 kg to 58.67 kg (significance level p <0.05). Overall, the composition according to the invention led to a noticeable improvement in performance and to a 7.46% higher weaning weight per piglet (p <0.05). The stress hormone cortisol was significantly reduced by 50%, the C-reactive protein as a parameter for oxidative stress in the liver was even improved to almost 30% of the original value. Both parameters indicate the demonstrably positive effect of the composition according to the invention on essential health and stress parameters.

Example 2: Effect of the composition according to the invention on the incorporation of fat

The adipose tissue in the body is distinguished on the one hand, the desired intramuscular fat as a lubricant of the muscle fibers and in its function as a physiological separation of various tissues in living animals and humans and as a carrier of the taste in food and on the other hand, the unwanted fat tissue as ballast physiologically questionable effects. The latter group includes in particular excessive abdominal fat ("abdominal fat"). A particularly unfavorable feature of abdominal fat is its hormonal activity. Belly fat releases more than 20 hormones and various other substances into the blood, including hormones that promote cardiovascular disease, vascular disease, diabetes mellitus type 2 and cancer (including leptin and adiponectin, cholesterol and cancer) Triglycerides). The relationships of the adipose tissue and their assessment with regard to their health relevance are certainly similar in humans.

With the composition according to the invention, the following results could be obtained, which show that the unfavorable storage of adipose tissue and the content of cholesterol in the blood are changed positively in terms of health.

The experiments were carried out with cattle beef. The group of experimental animals comprised 19 animals and the group of control animals 20 animals. The dosage of the composition according to the invention was 9 mg isoquinoline alkaloid / animal / day. Both groups also received the antibiotic monensin and the masthormone clenbuterol. The proportion of renal pelvic fat and abdominal fat, which is undesirable and indicates unfavorable physiological states, ie oxidative stress, was reduced by 8% (significance level p <0.05) due to the inventive composition of sanguinarine and chelerythrine.

The reduction was accompanied by an increased formation of valuable muscle meat and a better utilization of the feed. This is due to a more favorable state of the protein-producing cells and the liver in those animals to which the composition according to the invention has been administered.

Example 3: Influence of the composition of the invention on carcass parameters of broilers, e.g. the cholesterol level

• 1) Kontrolle = Antibiotika-frei.
• 2) Positivkontrolle, Antibiotikum Avilamycin (10 mg/kg)
• 3) Isochinolinalkaloide: 0,4 mg/kg Futter,
• 4) Isochinolinalkaloide: 1,0 mg/kg Futter.

The feeding trial was carried out as follows. 840 chickens were divided into 28 groups (four treatment groups, seven repeats, 30 chickens each). The treatment groups were as follows:

• 1) Control = antibiotic-free.
• 2) Positive control, antibiotic avilamycin (10 mg / kg)
• 3) Isoquinoline alkaloids: 0.4 mg / kg feed,
• 4) Isoquinoline alkaloids: 1.0 mg / kg diet.

Table 3 below summarizes the effects of the composition of the invention on various tissue parameters of the chicken. Table 3 tissue Weight of different tissues in g per broiler and depending on the treatment control antibiotic Composition according to the invention 0.4 mg isoquinoline alkaloid / kg feed Composition according to the invention 1.0 mg Isochinoli nalkaloid / kg feed spleen 2.4 g 2 g 2.6 g 2.6 g Bursa gland 3.4 g 4 g 5 g 4.5 g abdominal fat 34 g 28 g 28 g 30 g chest muscle 170 g 185 g 180 g 185 g leg 180 g 180 g 188 g 195 g Total cholesterol 145 mg / 100 ml 136 128 116 NDV titer, log 3.33 4.00 4.33 4.20

As can be seen from Table 3, broilers to which the composition according to the invention has been administered showed significantly less abdominal fat as well as higher weights of bursa, which is the chicken's immune organ (lymphatic organ). The cholesterol levels were significantly positively changed by the composition according to the invention, indicating significantly reduced oxidative stress factors. The immune response of the bursa to a Newcastle Disease Virus (NDV) vaccine was significantly increased by more than 30%.

The results thus show that the animals which had received the composition according to the invention showed a healthier position in all physiological measured values and had a reduced cholesterol level.

Example 4: Test series for activity against an elevated cholesterol concentration

A test series for detecting an isochinolinalkaloidhaltigen aqueous solution according to the invention against elevated cholesterol levels was carried out as follows: Over a period of 60 days, a group of pigs with 20 animals ("experimental group") a sanguninarinhaltige drinking water of concentration 50 mg sanguinarine / liter of drinking water ad libidum provided. The drinking water had been adjusted by malic acid to a pH value below 6.8. A control group received pure water as drinking water. On the 61st day of the experiment the cholesterol levels in the blood of the animals of both groups were determined. The result is given in the table below: Table 4 Sanguinarine [mg / liter of drinking water] Dead. Cholesterol [mg / ml] LDL [mg / ml] HDL [mg / ml] LDL / HDL 0 1.78 0.82 0.77 1.06 50 1.56 * 0.64 * 0.74 0.86 * * statistically significant change

Sanguinarine reduces blood cholesterol levels in pigs statistically significantly by about 20%. Although the concentration of HDL cholesterol, which is considered beneficial, has also been reduced, it is less in proportion than the "harmful" LDL cholesterol. The important ratio of the ratio of LDL to HDL was significantly improved (reduced).

A further series of tests for the detection of an isochinolinalkaloidhaltigen aqueous solution against elevated cholesterol levels was performed on broilers as follows: It was over a period of 70 days a group of broilers with 100 animals ("experimental group") a sanguninarinhaltige drinking water of concentration 50 mg sanguinarine / Liters of drinking water ad libidum provided. The drinking water had been adjusted by malic acid to a pH value below 6.8. A control group received pure water as drinking water. On the 71st day of the experiment the cholesterol levels in the blood of the animals of both groups were determined. The result is given in the table below: Table 5 Sanguinarine [mg / liter of drinking water] Dead. Cholesterol [mg / ml] LDL [mg / ml] 0 3.41 0.66 50 2.72 * 0.59 * * statistically significant change

Sanguinarine thus reduces the blood cholesterol levels in broilers statistically significantly by about 20%.

In addition, it was observed that the concentration of triglycerides in broiler blood was reduced by about 1/3.

Example 5: Experiment with broiler chickens

The housing conditions in the henhouse with high livestock density per square meter and countless interventions in the short life of chickens, multiple vaccinations, high ammonia levels in the air, use of toxic coccidiostats, use of antibiotics and so loss of stable intestinal flora characterized.

In the experiment, a control group without antibiotic supplement was fed. Another group received the antibiotic avilamycin in an amount of 10 ppm (= 10 mg / kg diet). Two more groups received different dosages of an alkaloid composition according to the invention, in which sanguinarine and chelerythrine were contained in the ratio 1: 0.5, namely 0.40 mg isochinolinalkaloid / kg and 1.0 mg Isochinolinalkaloid / kg feed. The diet of all groups contained the recommended levels of classical antioxidants such as zinc, selenium, vitamin E and vitamin C.

The parameters "malondialdehyde" (MDA) and the blood titres of immunoglobulins against Newcastle disease were recorded. In addition, both the frequency of intestinal bacteria was examined to exclude antimicrobial effects, as well as MDA in slaughtered meat after storage in the refrigerated counter. This last-mentioned measured value should show whether the anti-oxidative effect of the active ingredient according to the invention also persists after slaughter and the food reacts less to oxidative stress from the storage conditions until it is consumed; So, for example, if the fatty acids in the meat of the animals are in a more oxidatively stable state than those of the animals that received a placebo or an antibiotic.

Table 6 below shows the effects of the composition of the invention on the total blood cholesterol content. Table 6 control Antibiotic 10 mg / kg Isoquinoline alkaloids 0.4 mg / kg Isoquinoline alkaloids 1.0 mg / kg Cholesterol in the blood mg / 100 ml 145 136 128 117

It can be seen from the measured values that the composition according to the invention, added to a feed which already contained classical antioxidants in all test groups, and administered in doses of 0.40 mg and 1.0 mg isoquinoline alkaloid per kg feed respectively to significantly reduce cholesterol levels in chickens' blood, and more so the more isoquinoline alkaloids were added to the diet.

Brief description of the figures

An exemplary series of tests on the effectiveness of the isoquinoline alkaloid composition and the solubility and efficacy of various compositions are illustrated in the attached drawings and tables. Show:

1 the influence of an isoquinoline alkaloid drinking water on the blood cortisol levels of pigs,

2 the influence of the composition on the pH of water of different initial pH values,

3 the influence of the composition on the pH of water of different degrees of hardness.

1 shows an experiment in which the influence of sanguinarine-containing, acidified drinking water on the salivary cortisol value of livestock was measured. Two groups G1 G2 of 25 pigs each and a control group "Con" with the same number of pigs were all initially treated with pure water as drinking water and reassembled D0 on the first day of the experiment, ie the animals were subjected to regrouping-related stress. One day before the rearrangement (D-1), the averaged cortisol value of all animals of the three groups was determined. The first group G1 was then treated with sanguinarinalkaloid, with malic acid brought to a pH value of below 6.8 drinking water of concentration 1 mg sanguinarine per L drinking water ad libidum, the group G2 received a drinking water with higher Sanguinarinalkaloidkonzentration of 2 mg / L and the control group received pure water. On selected days (D0: immediately after regrouping, D1, D2: on the 1st and 2nd day of the experiment) the cortisol levels in the saliva of the animals were determined. Cortisol is an indicator of mental and oxidative stress. 5 shows that the drinking water leads to reduced cortisol levels (based on the almost identical cortisol levels of the three groups measured at D0 at D0), thus producing less hormonal indicators of stress thanks to the drinking water vapor towards the control group, which delivers pure water was reduced, more clearly and more quickly, with the effect being particularly evident in the group of animals that received a higher dose of alkaloids (G2). The animals therefore displayed fewer stress indicators due to the treatment, which has a positive effect on health and meat quality.

2 and 3 show the influence of the composition on the pH of water of different initial pH values. This in 2 For example, in the context of a preliminary experiment, the diagram shown can be used to determine the amount of carboxylic acid needed to bring a certain composition to a desired pH. The test series were performed with malic acid (malate) as the carboxylic acid and with sanguinarine as the at least one isoquinolialoid. The combination of the at least one isoquinoline alkaloid and the acid may be advantageous as it increases the solubility and chemical stability of the alkaloid. The shelf life and effectiveness of the aqueous Isochinolinalkaloidlösung is thus improved, and a sedimentation of Alkaloidabscheidungen or clogging of valves and pipes that transport a corresponding drinking water is prevented. One

To test the effect of a composition on the pH, a 63 wt% malic acid composition was provided. The remainder of the composition comprised the at least one alkaloid and further, largely pH-neutral fillers and sugar alcohols, which have little or no effect on the pH of water. In order to test the influence of the composition on the pH of water, the following series of experiments was carried out.

Eleven different amounts of the composition (0, 12.5, 25, 40, 50, 75, 100, 500, 1000, 5000, 10000 mg) were measured. In a first series of experiments, one liter of water of different initial pH (5.9, 6.8, 8.5) was mixed with one of the eleven metered quantities of the composition. Both pH test strips and pH measuring electrodes served as a method of pH determination.

As a result, it was found that the composition lowered the pH value of the water or drinking water dose-dependently. This effect takes place even at a lower dosage. The degree of pH reduction is dependent on the starting pH and the amount of the composition used. With already acidified water, the reduction amounts to 0.3-0.5; in basic conditions, this is up to about 1. When dosed into an already acidified medium, the additional effect is limited. This has a protective effect against a stagnation of water intake by livestock (due to the sour taste).

3 shows the influence of for 2 described composition on the pH of water of different degrees of hardness. For this purpose, the following test series was carried out: Eleven different amounts of the composition (0, 12.5, 25, 40, 50, 75, 100, 500, 1000, 5000, 10000 mg) were measured. In a second series of experiments, three different degrees of hardness of water were tested by adding different levels of calcium carbonate (0 (dist.); 1.4; 2.8 mmol / l), which serves as an indicator of water hardness. Both pH test strips and pH measuring electrodes served as a method of pH determination. As a "soft", "medium hard", "hard" and "very hard" water is considered water with the following concentrations: soft: <1.5 mmol _CaCO3 / l; medium: 1.5-2.5 mmol CaCO ₃ / l; hard: 2.5-3.8 mmol CaCo ₃ / l, very hard:> 3.8 mmol CaCo ₃ / l.

As a result, it was found that in harder water the reduction of the pH value by the composition is reduced due to a buffering of the acid effect. Even with hard water, however, a slightly acidic pH is reached. The lowest pH reached was 3.0.

Corresponding series of experiments may also be used for other acids, e.g. Lactic acid or citric acid can be carried out to determine an optimal ratio of alkaloid and acid to provide a composition based on another acid.

test series

In the following, examples ("Composition I-V") for the composition according to embodiments of the invention will be described. Composition I component % By weight of the composition function Macleaya cordata extract (containing: 90% by weight of isoquinoline alkaloids, especially sanguinarine and chelerythrine) 2.37 main components malic acid 63.78 Sorbitol (alcohol) 18.7 Alditols, amino acids, other additives Monosodium glutamate (amino acid, feed additive) 11.2 Sodium bicarbonate (propellant sold as effervescent tablet) 1 Sodium chloride (salt, feed additive) 1 Potassium sorbate (preservative) 1.95 Composition II component % By weight of the composition function Isoquinoline alkaloid: sanguinarine and chelerythrine 0.1 main components malic acid 25 Sorbitol (alcohol): further organic substance 25 Alditols, amino acids, other additives Amino acid, feed additive, salt, preservative, thickener 49.9 Composition III component % By weight of the composition function Isoquinoline alkaloid: sanguinarine and chelerythrine 10 main components malic acid 25 Sorbitol (alcohol): further organic substance 25 Alditols, amino acids, other additives Amino acid, feed additive, salt, preservative, thickener 40 Composition IV component % By weight of the composition function Isoquinoline alkaloid: sanguinarine and chelerythrine 0.1 main components malic acid 10 Sorbitol (alcohol): further organic substance 25 Alditols, amino acids, other additives Amino acid, feed additive, salt, preservative, flavor enhancer 64.9 Composition V component % By weight of the composition function Isoquinoline alkaloid: sanguinarine and chelerythrine 10 main components malic acid 10 Sorbitol (alcohol): further organic substance 25 Alditols, amino acids, other additives Amino acid, feed supplement, salt, preservative, thickener 55

Tests for solubility and alkaloid stability

Of each of compositions I-V of these mixtures, 50 mg, 100 mg, 1000 mg each were diluted in 1 liter of water. By stirring at room temperature, the added amount of composition completely dissolved in the liter of water every few minutes. Even after 6 months, no sedimentation or precipitation of the alkaloid was observable. HPLC analysis showed an unchanged content of alkaloid in the said dilution series even 6 months after preparation of the respective dilutions.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 93/16602 [0006]

Cited non-patent literature

• Campbell, T. Colin; Thomas M. Campbell II: The China Study: The Most Comprehensive Study of Nutrition Ever Conducted and the Startling Implications for Diet, Weight Loss, and Long-term Health. Perseus Distribution, June 1, 2006, ISBN 978-1-932100-66-2, p. 444 [0059]

Claims (18)

Composition having one or more isoquinoline alkaloids for use in the prophylaxis or treatment of abnormal levels of: a) total cholesterol and / or b) LDL cholesterol and / or c) Cortisol and / or d) triglyceride values in humans or animals. The composition of claim 1, wherein the isoquinoline alkaloids are quaternary benzophenanthridine alkaloids, preferably selected from the group consisting of sanguinarine, chelerythrine and their salts. Composition according to any one of the preceding claims, in which all the constituents of the composition which are not isoquinoline alkaloids or isoquinoline alkaloid salts have a salt content of at least 0.001% by weight, preferably more than 0.01% by weight, the salt fraction preferably consisting of sodium chloride. Composition according to one of the preceding claims, - Wherein all the components of the composition which are not isoquinoline alkaloids or isoquinoline alkaloid salts contain a weight proportion of magnesium of at least 5 mg per kilogram of the composition, the magnesium preferably being present as magnesium sulphate. Composition according to one of the preceding claims, wherein the lowering of one or more of the substances a) -d) for the prevention of arteriosclerosis in humans or animals. A composition according to any one of the preceding claims, wherein the isoquinoline alkaloids are derived from parts or extracts of a plant selected from the group consisting of Sanguinaria canadensis, Macleaya spp. like Macleaya cordata, Argemone mexicana, Chelidonium majus and Eschscholzia californica. A composition according to any one of the preceding claims wherein the isoquinoline alkaloids are in salt form, preferably as chlorides or sulfates. A composition according to any one of the preceding claims, wherein the composition further comprises one or more antioxidants. A composition according to any one of the preceding claims wherein the amount to be administered ranges from 0.02 mg to 1000 mg isoquinoline alkaloid (s) or salts thereof per animal or human and day. A composition according to any one of the preceding claims, for the treatment or prevention of diseases caused by an increased blood value of one of the substances a) -e), which diseases include: - Arteriosclerosis, myocardial infarction, stroke, deposits in the tendons or in the skin as a result of a), b) or e); - adrenal gland, impaired concentration, vasoconstriction, hypertension, circulatory disorders, elevated blood sugar and insulin levels, promotion of development of type II diabetes, osteoporosis, damage to articular cartilage, weakening of the immune system, suppression of thyroid function, reduced production of sex hormones, Cushing's syndrome as a result from D). A composition according to any one of the preceding claims, further comprising an acid, wherein the type and amount of acid is chosen and matched with the nature and amount of the other ingredients of the composition such that the composition, including the acid, has a pH below 6.8, preferably below 6.5 having. The composition of claim 11, wherein the acid is a carboxylic acid. A composition according to any one of the claims, wherein the composition is one of the following types of composition: feed, feed additive, feed premix, human food, dietary supplement, functional food, human pharmaceutical preparation or animal, a drinking water, a drinking water, a drink, a dairy product, a liquid or solid concentrate for the preparation of one of these types of compositions. A composition according to claim 13 which is as a feed, feed additive, food, nutritional supplement, functional food, human food, drinking water, drinking water, beverage or dairy product, each kilogram of the composition being 0.05 to 1000 mg of the isoquinoline alkaloid (e) or their salts. A composition according to claim 13, wherein the composition serves as a dietary supplement or as a pharmaceutical preparation for human or animal, each kilogram of the composition containing 0.05 mg to 100 000 mg isoquinoline alkaloid (s) or salts thereof, in particular 1001 mg to 100 000 mg isoquinoline alkaloid (e) or salts thereof. A pharmaceutical preparation according to claim 15, wherein the pharmaceutical preparation contains the at least one isoquinoline alkaloid together with pharmaceutically acceptable carriers and / or excipients and optionally together with other pharmaceutical agents. Use of a composition having one or more isoquinoline alkaloids for the prophylaxis or treatment of abnormally elevated levels of: a) total cholesterol and / or b) LDL cholesterol and / or c) Cortisol and / or d) triglyceride values in humans or animals. Use according to claim 17, wherein the isoquinoline alkaloids are quaternary benzophenanthridine alkaloids, preferably selected from the group consisting of sanguinarine, chelerythrine and their salts.

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