RU2701567C1 - Agent possessing hepatoprotective activity - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a herbal raw material agent possessing hepatoprotective action. Proposed agent represents a collection of milk thistle fruits pulp, rhizomes and roots of elecampane, chicory roots, rosehips, mint leaves, nettle leaves, common yarrow herb taken in certain proportions.

EFFECT: disclosed agent exhibits marked hepatoprotective activity and extends the range of hepatoprotector agents.

1 cl, 3 tbl

Description

The invention relates to the pharmaceutical industry, namely to a tool based on plant materials with hepatoprotective activity.

It is known that in the environment, in the consumed products there is a huge amount of hepatotoxic xenobiotics with which a person has been in contact throughout his life.

In recent decades, the proportion of diseases of the gastroenterological pathology has increased and has a further tendency to spread, about half of which are liver diseases. Hepatoprotective agents for the pathogenetic therapy of acute and chronic diseases of the hepatobiliary system normalize the structure, metabolism, and function of the liver parenchyma.

It is known that chronic alcohol consumption is accompanied by liver damage (fatty infiltration, hepatitis). The main biological effect of ethanol is associated with impaired tissue and cellular metabolism, suppression of the immune system, and toxicity (Collier, J.A. B. et al. Oxford Handbook for Clinicians., Moscow: Medicine, 2000).

The use of synthetic drugs (antibiotics, NSAIDs) does not always provide the desired effect, in some cases exacerbates the course of the disease. In this regard, the development and use of herbal medicines that are quite pronounced efficacy and safety in the treatment and prevention of alcoholic liver damage is relevant.

The therapeutic effect is achieved due to a wide range of pharmacological properties of medicinal plants: hepatoprotective, choleretic, anti-inflammatory, antimicrobial, astringent, immunomodulating, etc.

The liver and kidneys are the main organs involved in metabolism and excreting drugs that are not subjected to intensive metabolism and excretion in the liver (Therapeutic University of Washington. Ed. Woodley M. and Whelan A.M., 1995, p. 422- 423). Phytopreparations meet all these requirements.

Very often, for the treatment of chronic liver diseases arising from the use of various drugs, hepatoprotective drugs are used: essentialia, betamine citrate, as well as vitamins of various groups.

For the treatment of chronic alcoholic hepatitis, the drug Hofitol, obtained from the extract of fresh artichoke leaves, is used. Chophytol has a direct effect on the liver and kidneys, as well as on other organs and systems of the body. At the same time, the drug improves the antitoxic function of the liver, increases the production of coenzymes by hepatocytes, and affects the metabolism of lipids and cholesterol (Loranskaya I.D., Rakitskaya L.G. Mamedova L.D. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2005, No. 3, p. 83). However, this drug has a mild clinical effect and is not effective enough in the treatment of drug hepatitis.

For the treatment of liver diseases, hepatoprotective collection No. 1 is used: sandy immortelle grass (1 part), bird highlander (1 hour), spotted milk thistle grass (1 hour), burlap grass (1 hour), ordinary cuff grass (1 hour) ), cinnamon rose hips (1 h). A tablespoon of the mixture must be poured with 1 cup of boiling water, insisted for 3-6 hours in a thermos, strain. To use 1 / 3-1 / 2 cups three times a day 20-30 minutes before meals (Ivanchenko V.A. Natural medicine. M., 2004, p. 242). However, this collection does not have a pronounced therapeutic effect due to insufficient hepatoprotective effect, and with prolonged use, side effects of spotted milk thistle grass on heart activity are possible. In addition, the collection is in a thermos for 3-6 hours, which weakens the effect of some active substances in medicinal raw materials.

Hepatoprotective collection No. 2 is also used: crushed roots and rhizomes of elecampane large - 1 hour, grass of the initial letter - 1 hour; semi-dyed grass - 1 hour; large plantain grass - 2 hours; cuff grass - 1 hour; shredded rhizomes of the beetle - 1 hour; barberry fruits - 1 hour; common chicory herb - 1 hour; large celandine grass - 1 hour; licorice roots naked - 1 hour. A tablespoon of the mixture must be poured 1/5 cup water, boil for 10 minutes, insist - 1 hour, cool. To use 1 / 3-1 / 2 glasses three times a day before meals (Ivanchenko V.N. Natural Medicine. M., 2004, p. 242). However, hepatoprotective collection No. 2: it is not recommended for patients with increased acidity of gastric juice due to the relatively high content of large plantain grass - 2 parts. In addition, in some patients, a toxic reaction to grass of large celandine is not excluded - 1 h.

Tea from the following collection is also used for the treatment of chronic hepatitis: St. John's wort, perforated - 40.0 g, knotweed grass - 20.0 g, wild chicory grass - 30.0 g, sandy immortelle flowers - 40.0 g, pharmacy chamomile flowers - 10.0 g, buckthorn bark - 30.0 g, marigold flowers - 40.0 g. 20.0 g of the mixture in the evening pour 400 ml of raw water, insist night, boil for 5-7 minutes in the morning, insist 20 minutes, consume for of the day (Lavrenova G.V. Medicinal herbs. M., 1996, book 2, p. 367-368). This collection does not cause a sufficiently pronounced clinical effect in the treatment of drug-induced hepatitis due to the relatively high content of sandy Helichrysum flowers - 40.0 g, and it is inappropriate to use in patients with hyperacid gastritis and chronic colitis due to the high content of buckthorn bark.

Also known are hepatoprotectors of plant origin, legalon (silymarin, silibinin), carlsil, obtained from the fruits of milk thistle, which are closest in pharmacological activity to the proposed hepatoprotective collection from medicinal plant materials and are recommended as comparison drugs in the study of hepatoprotective drugs (Khabiev R. U. Guidelines for the experimental (preclinical) study of new pharmacological substances, Moscow, 2005, pp. 683-691).

Known plant collection with hepatoprotective activity and used for the treatment of patients with drug hepatitis, containing, in addition to other components, a dioica nettle leaf, peppermint leaf, elecampane root (RU 2419449 C1, 05.27.2011). The disadvantage of this collection is the multicomponent composition, insufficiently high hepatoprotective activity.

A collection of plant materials, which has a pronounced hepatoprotective activity and consists of a cake of milk thistle fruit, 30 mass%, rhizome and elecampane root, 10 mass%, chicory root, 15 mass%, rosehip fruit, 10 mass%, mint leaves, 10 mass %, nettle leaves-10 mass%, yarrow grass-15 mass%.

The technical result consists in creating an agent having a pronounced hepatoprotective effect, as well as in expanding the arsenal of agents with hepatoprotective activity.

The technical result is achieved by the fact that the proposed tool is a herbal collection, including cake of milk thistle, rhizome and root of elecampane, chicory root, rose hips, mint leaves, nettle leaves, yarrow, with the following ratio of components, in mass%:

cake of milk thistle - 30,

rhizome and root of elecampane - 10,

chicory root - 15,

rose hips - 10,

mint leaves - 10,

nettle leaves - 10,

yarrow grass - 15.

The composition of the proposed product includes medicinal plants that are approved for use in medical practice: milk thistle fruit cake (TU 64-4-99-93), rhizome and elecampane root (GF XI, issue 2, Article 73), chicory root (GOST 13031-67), rosehips (GF XI, issue 2, Art. 38), mint leaves (GF XI, Iss. 2, Art. 18), nettle leaves (GF XI, Iss. 2, Art. 25), yarrow herb (GF XI, issue 2, Art. 53).

The proposed ratio of medicinal plants included in the collection is selected empirically and represents the most appropriate quantitative combination of components, in which the proposed tool is characterized by the most pronounced hepatoprotective effect.

The milk thistle included in the cake has a hepatoprotective effect, the silybin and silymarin contained in it stabilize the hepatocyte cell membranes, preventing the release of enzymes from the cells, and inhibit the penetration of various toxins into the cells. Fatty oils (32%), biogenic amines (tyraimn, histamine) provide liver cells with valuable compounds, contributing to the formation of new cells.

Chicory root containing polysaccharides improves carbohydrate metabolism, due to the presence of a large amount of inulin in it, it has a powerful choleretic effect.

Yarrow herb is rich in vitamin K, which provides a hemotoxic effect, preventing bleeding, this is especially valuable for cirrhosis.

Nettle leaves contain a complex of biologically active substances. Nettle leaves contain vitamins and iron salts, which normalize lipid metabolism in liver cells, have an anti-inflammatory effect, improve regeneration processes, and also restore the body's resistance to various environmental and internal factors.

Rose hips contain a large amount of vitamin C, carotene, vitamin B2, vitamin K, 18% sugar, tocopherols, all these vitamins normalize metabolic processes in the liver.

Elecampane root contains essential oils (up to 4.3%), has a bactericidal antiviral effect, due to which it is used as an additional tool for viral hepatitis. Elecampane root accelerates cell repair processes, has choleretic activity. Rich in inulin (44%), which regulates carbohydrate metabolism.

Peppermint leaves are rich in essential oils. The therapeutic effect is due to the menthol essential oil (60%), which has a moderate sedative, antispasmodic, antitoxic and choleretic effect. Peppermint essential oil improves digestion of the gastrointestinal tract by acting on the smooth muscles of the bile duct.

Herbal components of the collection in the complex have a normalizing effect on the metabolism in the liver and its detoxification function. The proposed collection has the ability to restore cell membranes, the structure of cells, removes cholesterol from the body. The water infusion of the proposed collection has a pronounced hepatoprotective activity, not inferior to the reference drug - carlsyl. The ability of this collection to effectively prevent and eliminate the effects of toxic liver damage was identified during experimental studies.

The technology for preparing the collection consists in the fact that each type of plant material that meets the requirements of the Gosfarmakopeia is crushed to a size of 5-7 mm. Then the medicinal raw materials are weighed and thoroughly mixed in certain parts until a uniform mixture is filtered and dusted out through a sieve with a hole diameter of 0.18 mm, packaged.

The tool is used in the form of a herbal tea, for the preparation of which 2 teaspoons of the collection are filled with 200 ml of boiling water, insisted for 10-15 minutes, cooled at room temperature, filtered. The obtained filtrate is used to determine pharmacological properties.

Membrane-protective activity was observed in the model of acute carbon tetrachloride poisoning. In the integrated test, the microviscosity of the membranes was assessed by the mobility of the fluorescence probe of pyrene in the erythrocyte membranes (Table 1). The structure of biomembranes in the pathogenesis of most pathological conditions is violated due to the intensification of lipid peroxidation, during which hydroperoxide groups are formed in hydrophobic fatty acid lipid residues. The interaction of these groups with other polar structures of biomembranes leads to an increase in microviscosity of cell and subcellular membranes, which, as a result, leads to disruption of intracellular metabolism. As can be seen from table 1, the collection by its action occupies an intermediate position between the control (intact animals) and untreated. Thus, the collection has a certain membrane protective effect (table. 1).

At the next stage of the studies, a comparative study of the therapeutic and prophylactic effect of the developed collection, collection from the patent RU 2419449 and the reference drug - carzil in CCl ₄ -induced toxic hepatitis was carried out. The study was performed on 60 white outbred male rats weighing 220-240 g, randomly distributed in 4 groups:

1st group - intact rats (n = 22);

2nd group - control group (n = 22);

3rd group - experimental, claimed collection (n = 28);

4th group - experimental, collection from patent RU 2419449 (n = 28).

5th group - experimental, reference preparation - carlsil (n = 28).

Animals were kept under standard vivarium conditions on a standard feeding diet. The first experimental group for three weeks received water extract from the claimed collection. The second experimental group received water extraction from the collection of RU 2419449 for three weeks. During the first two weeks of the experiment, the experimental animals received the infusion under conditions of free soldering, on average, 30 ml of infusion per day per animal. The third experimental group received Karsil (Sopharma, Bulgaria) at a dose of 200 mg / kg intragastrically as a suspension, as a reference preparation with hepatoprotective activity. Animals from the control and intact groups received ad librum water.

On the 15th day of the experiment, toxic hepatitis was induced in the experimental and control groups of animals by intraperitoneal administration of CCl ₄ in the form of a 25% solution in olive oil, once at a dose of 0.2 ml / kg (in terms of CCl ₄ ). After which the animals continued to receive hepatoprotectors for another 7 days. Thus, in the experiment, the therapeutic and prophylactic use of hepatoprotectors was simulated.

The hepatoprotective effect of the test collection was evaluated using a thiopental test. Thiopental was administered intraperitoneally at a dose of 50 mg / kg and the duration of thiopental anesthesia was recorded according to the “lateral position” indicator. The test allows us to estimate the metabolic rate of thiopental carried out by cytochrome P-450-dependent monooxygenase system of hepatocytes.

The results of the experiment were processed using t-student criterion and are presented in table 2.

CCl ₄ hepatitis is characterized by the development of collicative necrosis, protein and fatty degeneration of hepatocytes, localized mainly in the central zone of the hepatic lobule, where the maximum activity of cytochrome P-450 monooxygenases is maximal and the production of damaging hepatotoxin metabolites predominates. From the data obtained in the experiment, it is seen that the duration of thiopental anesthesia in animals exposed to hepatotoxin (control), the duration of thiopental anesthesia was almost 3 times higher than that of intact. The therapeutic and prophylactic use of the studied collection completely prevented these CCl ₄ -induced changes. It should be noted that a comparison of the hepatoprotective effect for this indicator (duration of thiopental anesthesia) did not reveal a significant difference from the same indicator of the comparison drug - carzil. This indicates less liver damage in the experimental group (the claimed collection) and the preserved function of the cytochrome P-450-dependent monooxygenase system of hepatocytes.

Some biochemical and enzymatic blood parameters were also used as informative criteria for assessing the safety of liver tissue and the hepatoprotective effectiveness of the proposed collection.

In experimental animals that were not exposed to thiopental, on the 21st day from the start of the experiment, after decapitation, blood was taken to determine cholesterol, bilirubin (total, direct, indirect), ALT, ACT. Blood was centrifuged for 10 min at 3000 rpm on a Scanspeed mini centrifuge (USA). Plasma was taken and blood biochemical parameters were evaluated using kits from Intermedica (USA), according to the manufacturer's instructions on a biochemistry analyzer from Biochem (USA) (see table 3).

As can be seen from the results shown in table 2, in the control group CCl ₄ hepatitis there was a significant increase in the level of liver enzymes, cholesterol, total, direct and indirect bilirubin, caused by exposure to hepatotoxin. In the group that received the claimed collection against hepatitis, the indicated shifts were significantly less pronounced, including in comparison with the collection according to the patent RU 2419449. It should be noted that the data obtained in the CCl ₄ + declared collection group are only slightly inferior to the results, obtained in the group of animals "CCl ₄ + karsil."

Thus, the data obtained in the experiment indicate the presence of pronounced hepatoprotective properties in the collection consisting of oilcake milk thistle, rhizome and root of elecampane, chicory root, rosehips, mint leaves, nettle leaves, and yarrow grass.

Claims (2)

A tool with hepatoprotective activity, which is an herbal collection containing cake of milk thistle, rhizome and root of elecampane, chicory root, rosehips, mint leaves, nettle leaves, yarrow, in the following ratio of components, in mass%: milk thistle thirty rhizome and root of elecampane 10 chicory root fifteen dog-rose fruit 10 mint leaves 10 nettle leaves 10 yarrow grass fifteen