RU2408383C1 - Composition with antineoplastic and adaptogenic activity (versions) and based drug (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: invention refers to pharmacology, particularly to a composition with antineoplastic and adaptogenic activity. The composition with antineoplastic and adaptogenic activity containing: reishi mushroom bracket, raw roots of common licorice or Ural licorice, fennel seeds, refined Altai mumijo, yellow melilot herb. The composition with antineoplastic and adaptogenic activity containing: reishi mushroom bracket, raw roots of common licorice or Ural licorice, fennel seeds, refined Altai mumijo, yellow melilot herb, shelf fungus, common valerian roots, common nettle leaves, motherwort herb, aerial wormwood, spiny eleutherococcus roots. The composition with antineoplastic and adaptogenic activity containing: reishi mushroom bracket, raw roots of common licorice or Ural licorice, fennel seeds, refined Altai mumijo, yellow melilot herb, kidney bean valves, common St. John's wort herb, fibre flax seeds, hop cones, common nettle leaves, whortleberry leaves, aerial wormwood. A drug with antineoplastic and adaptogenic activity (vesions). ^ EFFECT: composition improves tolerance to etiotropic therapy in oncological patients. ^ 21 cl, 9 ex

Description

FIELD OF THE INVENTION

The invention relates to medicine and relates to a composition of natural raw materials that helps to improve the well-being and quality of life of cancer patients, as well as facilitate the tolerance of radiation therapy and chemotherapy.

BACKGROUND

Oncological diseases and their accompanying complications take the second place among the causes of death of the adult population. The etiotropic treatment of cancer with known surgical, radiotherapeutic and chemotherapeutic methods is hindered by numerous side effects. The negative consequences of such treatment in relation to the quality of life, health and survival of cancer patients are often commensurate with the consequences of the underlying disease or even worse. In this regard, it remains relevant to create tools to improve the quality of life of cancer patients, increase the tolerability of etiotropic treatment and reduce the severity of side effects.

Known potent cytotoxic and cytostatic antitumor agents are characterized by high systemic toxicity, immunosuppression, hepatotoxicity, anti-mitotic effects on normal stem cells, and allergic reactions. Side effects of medical, surgical and radiotherapy can be so severe that their use is contraindicated in debilitated patients due to the high risk to life. The creation of non-toxic adaptogens based on natural raw materials suitable for prolonged use can reduce mortality during the etiotropic treatment of debilitated patients.

The specific action of adaptogens is aimed at increasing the body's resistance to infections, in particular to opportunistic infections, at increasing overall stamina, and at reducing feelings of tiredness and fatigue. In general opinion, the adaptogenic activity of drugs is associated with their positive effect on the functions of the immune system (immunomodulatory effect), on the detoxification function of the liver (hepatoprotective effect), on the ability of excretory systems to eliminate toxins, on the processes of cellular respiration (antihypoxic activity) and in general metabolic processes (for example, by filling the deficiency of vitamins and minerals).

Advantage of adaptogens over potent antitumor drugs is expressed in the absence of noticeable side effects, good tolerance, compatibility with other therapeutic factors and drugs, which is especially important in combination therapy of comorbid pathologies. Adaptogens allow you to safely maintain physiological parameters within normal limits, thereby increasing the quality of life, reducing the risk of complications and increasing the tolerability of side effects of potent antitumor drugs.

Their use makes it possible to provide an effective prophylactic and general healing effect at the initial stage of treatment and at the recovery stage, as well as in the complex treatment of sluggish chronic diseases between the courses of basic treatment.

The composition is analogous to antitumor phytotherapeutic collections of medicinal plants with a nonspecific effect on tumor cells (i.e., not having a pronounced effect on microtubules and nucleic acid synthesis) introduced into the State Pharmacopoeia of the Russian Federation or used in traditional medicine.

The disadvantage of most known phytotherapy fees is that they relate to medicines and require medical prescription and control, strict adherence to dosage and accounting for contraindications. In addition, a common known drawback of phytotherapy fees is poor tolerance to patients who have an allergic reaction to individual components of herbal remedies. Thus, it remains relevant to create alternative means of the same purpose for the treatment of patients with allergic reactions to known herbal remedies.

The proposed compositions relate to collections based on natural raw materials containing the body of the fungus Ganoderma lucidum, and may additionally include one or more components that enhance the main type of activity or give additional types of activity, depending on the patient’s diseases associated with cancer.

The activity of the proposed compositions is due to the selected new combination of components, so it is not possible to single out the only closest analogue among the known collections of the same purpose. The total effect of the combination of the selected components in a predetermined ratio exceeds the effect of treatment with the individual components of the composition and the expected effect of summing the effects of several components. This is due to the fact that the components of the composition affect various biochemical pathways and mutually compensate for unwanted side effects.

SUMMARY OF THE INVENTION

The invention relates to an antitumor and adaptogenic composition based on natural raw materials for independent use and as an adjuvant in the treatment of cancer.

The composition according to the invention can be used in preparing the body for treatment, simultaneously with the treatment, to smooth out the negative effects of treatment, to prevent relapse of the tumor and metastasis and for the prevention of neocarcinogenesis.

As an adjuvant, the composition according to the invention can be used at various stages of anticancer therapy associated with the action of various stressful treatment factors, in particular, surgical removal of the tumor, radiation therapy, administration of drugs containing radioisotopes, chemotherapeutic treatment with antimetabolites, alkylating agents , antiestrogens, antiandrogens, cytotoxic agents, cytotoxic antibodies, tubulin stabilizers, radioisotopes.

At various stages of treatment, various types of therapeutic effects of the composition are important. In preparing for treatment, the adaptogenic activity of the composition, increasing the body's resistance to infections, creating a reserve of vitamins and irreplaceable biologically active substances, and reducing oxidative stress in the cells play the most important role. In this case, the action of the composition is aimed at replenishing the body’s reserves, undermined by the developing tumor, combating weight loss, restoring the deficit of limiting metabolic factors in healthy body tissues. When carrying out antitumor treatment, the hepatoprotective, detoxification and diuretic activity of the composition becomes most important. To enhance the therapeutic effect of pathogenetic therapy, as well as after the therapeutic effect and during treatment intervals, the antineoplastic activity of the composition, the prevention of secondary carcinogenesis, tumor relapse and metastasis are of the greatest importance.

The strengthening effect of the composition allows to increase the tolerance of treatment and patients' compliance with the prescribed dosage regimen of chemotherapeutic drugs.

As follows from the foregoing, the objective of the present invention is to provide a composition with adaptogenic and antitumor activity for use as an adjuvant in the complex treatment of cancer with stressful treatment factors or potent chemotherapeutic agents.

This problem is solved by the fact that in its first aspect according to the invention, the antitumor and adaptogenic effects inherent in the components separately are enhanced in an extra-additive manner when they are jointly introduced into the composition containing in mass parts, calculated on the dry weight:

the body of the fungus Ganoderma lucidum (Fr.) Karst (varnished tinder) from 20 to 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis Fisch (Ural licorice) from 2 to 6 seeds of Foeniculum vulgare Mill (fennel ordinary) from 10 to 50 Altai mummy peeled from 0.1 to 0.4 grass Melilotus officinalis L. (sweet clover medicinal) from 10 to 60

Hereinafter, unless otherwise indicated by the context, references to a composition should be understood as a reference to a composition of the present invention. In the present text, the composition according to the invention can also be referred to as the Equilibrium Vita composition or the biocorrector of the Equilibrium Vita homeostasis.

As mentioned above, one of the components of the composition is the body of the fungus Ganoderma lucidum (also known as Reishi, Ling-Zhi, varnished tinder). This mushroom of the class Basidiomycetes has long been used in traditional Chinese medicine as an immunomodulating and antitumor agent. Currently, G. lucidum is one of the most studied basidiomycetes.

It is known about the immunostimulating, antitumor, antiviral, antibiotic, lipid-lowering, hypoglycemic, hepatoprotective, gene-protective, anti-inflammatory, anti-allergenic, anticoagulant, hypotensive and antioxidant effects of G. lucidum.

A detailed review of current information on the immunomodulatory activity of G. lucidum is presented in Lin Z.B. "Cellular and Molecular Mechanisms of Immuno-modulation by Ganoderma lucidum," J. Pharmacol. Sci., 2005, 99: 144-53.

A detailed review of current evidence of the antitumor activity of G. lucidum is presented in Lin Z.B. et al. "Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms," Acta Pharmacol. Sin., 2004, 25 (11): 1387-95.

The hepatoprotective, hypoglycemic and anticoagulant activity of G. lucidum is described, in particular, in the article Lien, E.-J. "Fortschritte der Arzneimittelforschung Progress des researcges pharmaceutiques", Birkhauser Verlaq, Basel, 1990, 34: 395-420. Antihypertensive and antitumor activity is described, in particular, in the article Shiao M.S. et al. "In Food photochemicals for Cancer Prevention: II" (Ho C.T., Osawa T., Huang M.T., Rosen R.T., Eds., American Chemical Society, Washington D.D., 1994, pp.342-354).

Another component of the composition of the invention is the crude roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis Fisch (Ural licorice). It is known about the antimetastatic activity of licorice and the ability of licorice to enhance the effectiveness of chemotherapy (Amosova E. N. "Antimetastatic activity of drugs of natural origin," dissertation for the degree of Doctor of Biological Sciences, Tomsk, 2007, State Research Institute of Pharmacology, Tomsk Scientific Center SB RAMS). The specific activity of licorice preparations is associated with the presence of a large number of glycosides, primarily glycyrrhizin.

It is also known about the ability of licorice glycosides to enhance the activity of various chemotherapeutic drugs (see the article by Tolstikova T.G. et al. “Towards low-dose drugs,” Vestnik RAN, 2007, 77 (10): 867-74, where the use of glycyrrhizic acid is disclosed as a clathrating agent to increase the therapeutic index of psychotropic, cardiotropic, anti-inflammatory drugs and prostaglandins).

The antiproliferative activity of one of the licorice chalcone A licorice was shown (see Jin-Hee Park et al. “Anti-proliferative Effect of Licochalcone A on Vascular Smooth Muscle Cells”, Biol. Pharm. Bull., 2008, 31 (11): 1996 -2000).

Despite the widespread use of licorice glycosides in pharmaceuticals, its effectiveness as an adjuvant of anticancer drugs based on natural raw materials has not been practically studied to date.

The next component of the composition according to the invention are the seeds of Foeniculum vulgare Mill (common fennel).

Fennel has antioxidant, analgesic, and anti-inflammatory activity (see Choi E.M., Hwang J.K., Antiinflammatory, Analgesic and Antioxidant Activities of the Fruit of Foeniculum vulgare, Fitoterapia 2004, 75 (6): 557-65).

Common fennel gives the composition a general strengthening effect due to the high content of vitamin C, carotene, vitamins B, E, and PP in seeds (see the monograph “Plant Resources of the USSR”, Leningrad, Nauka, 1987).

In addition, fennel in the composition has a positive effect on the functions of the excretory systems of the body, which is associated with its choleretic, antispasmodic, diuretic activity and increased gastric secretion. To date, fennel has not been used in medicine to treat tumors or to enhance the action of antitumor drugs based on natural raw materials.

Another component of the composition is the herb Melilotus oficinalis L. (Melilotus officinalis). Melilotus officinalis contains melilotin, coumarin, coumaric and melilotic acid, glycoside melilotoside and essential oil. The pharmacodynamic properties of sweet clover are due primarily to the coumarins contained in it.

It is known that clover coumarins inhibit the central nervous system and have an anticonvulsant effect.

It is also known about the immunomodulating activity of sweet clover, in particular about the ability of clover clover to increase the number of leukocytes (mainly due to granulocytes and, to a lesser extent, due to lymphocytes) in case of leukopenia caused by radiation.

It is well known about the antitumor activity of coumarins as a class of substances, as well as their antispasmodic, coronary expansion and anticoagulant activity (Sokolov S.Ya., Zamotaev I.P. Handbook of medicinal plants (Phytotherapy), Moscow, Medicine, 1988). In particular, the antitumor activity of M. oficinalis L. is disclosed in Smith G. et al. ("Correlation of the in vivo anticoagulant, antithrombotic and antimetastatic efficacy of warfarin in the rat", Thromb. Res., 1988, 50: 163-74), Thornes R. D. ("Anticoagulant therapy in patients with cancer", J. Irish Med. Assoc., 1969, 62: 426-9), Finn G.J. et al. (“Study of the in vitro cytotoxic potential of natural and synthetic coumarin derivatives by using human normal and neoplastic skin cell lines”, Melanoma Res., 2001, 11: 461-7) and Maucher A. et al. ("Antitumor activity of coumarin and 7-hydroxycoumarin against 7, 12-dimethylbenz [a] anthracene-induced rat mammary carcinomas", J. Cancer Res. Clin. Oncol., 1994, 120: 502-4).

Article by Hamta Madari et. al. ("Dicoumarol: A Unique Microtubule Stabilizing Natural Product that Is Synergistic with Taxol", Cancer Research, 2003, 63: 1214-20) discloses the dose-dependent inhibition of microtubule depolymerization by dicumarin M. oficinalis L. and the synergistic activity of dicumarin to stabilize microtubule paclitaxel. The antitumor activity of M. oficinalis L. is due to its effect on the association of tubulin in the mitotic spindle.

In addition, sweet clover has a soothing, calming and hypotensive effect.

Another component of the composition of the invention is mummy. The composition of the mummy includes a complex of organic and mineral substances: zoomelanoedic, humic, fulvic and amino acids, terpenoids, steroids, vitamins of groups B and P, polyphenolic compounds, as well as macro- and microelements (copper, zinc, cobalt, manganese, etc.) . Mumiye has a bactericidal and bacteriostatic, anti-inflammatory, general strengthening property. The dissertation by A.Sh. Shakirov (“Some Oriental Methods for the Treatment of Bone Fractures”, Tashkent, 1953) describes the use of mummies to restore mineral balance in the body.

In addition, the mummy has a regenerative effect on toxic liver damage caused by chemotherapy, and also stimulates microsomal oxidation. The hepatoprotective properties of the mummy are described in the monograph by A. Shvetsky. “Mumiye is a non-specific biogenic stimulant: its properties and history from antiquity to the present day”, Krasnoyarsk, 1990. It is known about the ability of the mummy to stimulate erythropoiesis. Hepatoprotective and erythropoietic activity of the mummy is extremely important to compensate for the negative effects of antitumor chemotherapy.

There is evidence of hypoglycemic activity of the mummy.

The introduction of the mummy in the composition according to the invention allows you to make up for the deficiency of mineral substances caused by the tumor and associated syndromes. Although the authors would not like to be bound by any theory, it is suggested that the polyphenolic compounds contained in the mummy can inhibit the growth of cancer cells. This assumption is in good agreement with numerous data on the antitumor activity of plant-derived polyphenols.

In a private embodiment, the composition according to the invention additionally contains the body of the fungus Fungus betulinus (chaga) in an amount of from 20 to 100 mass parts.

Chaga has adaptogenic activity, stimulates the central nervous and neurohumoral systems of the body, improves metabolism, including activates metabolism in the brain tissue, restores the activity of inhibited enzyme systems, regulates the activity of the cardiovascular and respiratory systems, stimulates blood formation (increases the level of white blood cells) , acts as a general strengthening agent, increases the body's resistance to infectious diseases, has anti-inflammatory properties, enhances the cytostatic activity of antitumor drugs, inhibits the growth of tumors, causes their gradual regression and slows down the development of metastases, i.e. has a cytostatic effect. Chaga restores the body's resistance and its protective mechanisms aimed at combating malignant growth. In addition, chaga has antispasmodic, diuretic, antimicrobial, regenerative properties, normalizes the activity of the gastrointestinal tract and intestinal microflora, promotes scarring of stomach and duodenal ulcers, and exhibits pronounced gastroprotective properties (see, for example, Sahakyan K.R., Vashchenko K .F., Darmogray R.E. "Chaga (black birch mushroom) Fungus Betulinus", Pharmacist, 2004, issue 16).

In one particular embodiment, the composition further comprises the root Valeriana officinalis L. (Valerian officinalis) in an amount of from 10 to 100 parts by weight.

Valerian is known to be effective in treating insomnia, anxiety, and overexcitation (see Andreatini R. et al., “Effect of valepotriates (valerian extract) in generalized anxiety disorder: a randomized placebo-controlled pilot study,” Phytother. Res., 2002, 16 (7): 650-4). These properties of valerian can facilitate the psycho-emotional state of cancer patients.

In another particular embodiment, the composition further comprises a sheet of Urtica dioica L. (dioica nettle) in an amount of from 6 to 20 parts by weight.

Nettle leaves contain gallic and formic acids, urticin glycoside, gum, tannins and protein substances, mineral salts, iron, vitamins A, C, K and volatile. Nettle increases blood coagulability, increases the amount of hemoglobin, platelets and red blood cells, reduces the concentration of sugar in the blood, has a diuretic, anti-inflammatory and restorative effect.

Nettle's antiproliferative activity is known (Durak I. et al. "Aqueous Extract of Urtica Dioica Makes Significant Inhibition of Adenosine Deaminase Activity in Prostate Tissue from Patients with Prostate Cancer", Cancer Biology & Therapy, 2004, 3 (9): 855-7) .

In another particular embodiment, the composition of the invention further comprises a root of Eleutherococcus senticosus (prickly Eleutherococcus) in an amount of from 6 to 20 parts by weight.

Studies have shown that Eleutherococcus increases resistance to stress, attention, metabolism and adaptogenic properties of the body, physical and mental performance and appetite, normalizes blood pressure, enhances visual acuity and normalizes blood sugar, as well as hemoglobin in the blood.

The normalizing effect of eleutherococcus in combination with antibiotics for the cancer process and radiation sickness has been established. It was shown that the components of eleutherococcus inhibit cyclin-dependent kinases in cancer cells, which allows us to rely on the strengthening of specific antitumor treatment.

The antioxidant and cytotoxic activity of eleutherococcus is known (Yu C. Y. et al. "Intraspecific relationship analysis by DNA markers and in vitro cytotoxic and antioxidant activity in Eleutherococcus senticosus", Toxicol In Vitro, 2003, 17 (2): 229-36).

In a private embodiment, the composition according to the invention further comprises Herba Leonuri (motherwort herb) in an amount of from 10 to 100 parts by weight.

The antioxidant and cardioprotective activity of motherwort herb has been proven (Sun J. et al. "Anti-oxidative stress effects of Herba leonuri on ischemic rat hearts", Life Sci., 2005, 76 (26): 3043-56).

In addition, motherwort normalizes heart rate, increases heart rate, has a sedative, hypotensive, antispasmodic and mild diuretic effect and improves digestion.

In one particular embodiment, the composition of the invention further comprises an aerial part of Artemisia vulgaris (common wormwood) in an amount of from 6 to 20 parts by weight.

To enhance the adaptogenic and antitumor activity of the composition and to give it additional therapeutic properties, one or more of the above ingredients is introduced into its composition: the body of the fungus Fungus betulinus (chaga), the root of Valeriana officinalis L. (Valerian officinalis), the leaf of Urtica dioica L. (nettle dioecious), Herba Leonuri (motherwort herb), aerial part of Artemisia vulgaris (common wormwood) and the root of Eleutherococcus senticosus (prickly eleutherococcus).

In a second aspect, the invention relates to a composition with adaptogenic and antitumor activity, comprising the following ingredients in parts by weight, based on dry weight:

the body of the fungus Ganoderma lucidum (Fr.) Karst (varnished tinder) from 20 to 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis fisch (Ural licorice) from 2 to 6 seeds of Foeniculum vulgare Mill (fennel ordinary) from 10 to 50 Altai mummy peeled from 0.1 to 0.4 grass Melilotus officinalis L. (sweet clover medicinal) from 10 to 60 the body of the fungus Fungus betulinus (chaga) from 20 to 100 root Valeriana officinalis L. (valerian medicinal) from 10 to 100 Urtica dioica L. leaf (dioica nettle) from 6 to 20 Herba Leonuri (motherwort herb) from 10 to 100 aerial part of Artemisia vulgaris (wormwood ordinary) from 6 to 20 Eleutherococcus senticosus root (Eleutherococcus prickly) from 6 to 20

In the present text, the composition according to the second aspect of the invention may also be referred to as the Equilibrium-Onco composition or the biocorrector of the Equilibrium Onco homeostasis.

To enhance the adaptogenic and antitumor activity of the above compositions and to give them additional medicinal properties, one or more of the following components is introduced into its composition: Valvae fructum Phaseoli vulgaris (leaflet of common bean fruit), grass Hypericum perforatum L. (Hypericum perforatum L., Linum usitatissimum seeds L. (sowing flax), cones of Lupuli strobulus (common hop), Urtica dioica L. leaf (dioica nettle), Vaccinium myrtillus L. leaf (common blueberry), aerial part of Artemisia vulgaris (common wormwood).

In a particular embodiment, the compositions further comprise Valvae fructum Phaseoli vulgaris (cusps of common bean) in an amount of from 10 to 100 parts by weight.

The leaves of the common bean fruit additionally give the composition a hypoglycemic, diuretic, antihypertensive and antimicrobial activity.

In one particular embodiment, the compositions of the invention further comprise Hypericum perforatum L. (Hypericum perforatum) in an amount of from 2 to 6 parts by weight.

St. John's wort grass contains hypericin, nicotinic acid, ceryl alcohol, tannins, essential oil, carotene, vitamins C and PP, volatile. St. John's wort additionally gives the composition hemostatic, antiseptic, anti-inflammatory, analgesic, diuretic and hepatoprotective activity. St. John's wort is known to enhance digestion, increase appetite and act as a sedative.

In another particular embodiment, the compositions of the invention further comprise Linum usitatissimum L. (sowing flax) seeds in an amount of from 20 to 60 parts by weight.

Sowing flax seeds contain a large number of glycosides (in particular, linamarine) and additionally give the composition an enveloping, emollient and anti-inflammatory effect, which is useful for concomitant inflammatory diseases of the digestive tract. Seeds of flax seed allow you to regulate the secretory and motor functions of the intestine and to correct such concomitant digestive disorders as diarrhea and constipation. The high content of unsaturated fatty acids in the seeds additionally gives the composition antioxidant and radioprotective activity.

In another particular embodiment, the compositions of the invention further comprise ordinary hop cones (Lupuli strobulus) in an amount of from 10 to 100 parts by weight.

Hop cones additionally give the composition a calming, hypnotic and anticonvulsant effect, increase appetite, and have weak antidepressant activity, which helps to correct the anxiety, insomnia and tension inherent in cancer patients. In addition, hop cones enhance digestion, diuresis and have a weak analgesic effect.

In a particular embodiment, the compositions of the invention further comprise a sheet of Vaccinium myrtillus L. (common blueberry) in an amount of from 2 to 6 parts by weight.

Blueberry leaves contain a large amount of antioxidants and are a source of vitamins. Blueberry leaves additionally give the composition hypoglycemic activity, which is especially important in the treatment of cancer patients suffering from diabetes mellitus. In addition, the introduction of blueberry leaves in the composition gives it anti-inflammatory, analgesic, and fixing properties.

In another particular embodiment, the composition of the invention further comprises an aerial part of common wormwood (Artemisia vulgaris) in an amount of from 6 to 20 parts by weight.

Common wormwood additionally gives the composition according to the invention a restorative, analgesic, diaphoretic, choleretic, sedative and antihistamine activity. Keeping wormwood in the composition helps to improve the appetite and digestion of cancer patients, enhances hematopoiesis.

Antitumor activity of wormwood is known (see Myun-Ho Banga et al. "Cytotoxic and Apoptosis-Inducing Sesquiterpenoid Isolated from the Aerial Parts of Artemisia princeps Pampanini (Sajabalssuk)", Chem. Pharm. Bull., 2008, 56 (8): 1168-72).

In a third aspect, the invention relates to a composition with adaptogenic and antitumor activity, comprising the following ingredients in parts by weight, based on dry weight:

the body of the fungus Ganoderma lucidum (Fr.) Karst (polypore varnished) from 20 to 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis fisch (Ural licorice) from 2 to 6 seeds of Foeniculum vulgare Mill (fennel ordinary) from 10 to 50 Altai mummy peeled from 0.1 to 0.4 grass Melilotus officinalis L. (sweet clover medicinal) from 10 to 60 Valvae fructum Phaseoli vulgaris (Bean Sash ordinary) from 10 to 100 herb Hypericum perforatum L. (Hypericum perforated) from 2 to 6 seeds of Linum usitatissimum L. (flax) from 20 to 60 cones of Lupuli strobulus (common hop) from 10 to 100 Urtica dioica L. leaf (dioica nettle) from 2 to 6 leaf of Vaccinium myrtillus L. (blueberries ordinary) from 2 to 6 aerial part of Artemisia vulgaris (wormwood ordinary) from 6 to 20

In the present text, the composition according to the third aspect of the invention may also be referred to as the Equilibrium-Dia composition or the biocorrector of the Equilibrium-Dia homeostasis.

The selected combination of additional components can enhance the adaptogenic and antitumor activity of the composition.

In yet another aspect, the present invention relates to a capsule-containing drug with antitumor and adaptogenic activity, comprising an effective amount of a composition with adaptogenic and antitumor activity according to the invention and, optionally, a pharmaceutically acceptable excipient.

In another aspect, the invention relates to a medicament with antitumor and adaptogenic activity in the form of a tablet, containing an effective amount of a composition with adaptogenic and antitumor activity according to the invention and, optionally, a pharmaceutically acceptable excipient.

As pharmaceutically acceptable excipients are suitable, in particular, excipients, solvents, diluents, carriers, auxiliary, distributing and perceptive agents, delivery vehicles, preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, known in this capacity, pharmaceutically acceptable and pharmacologically compatible with the composition. , suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged-release regulators tavki.

The number and types of excipients are selected based on known rules depending on the desired properties of the composition. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example aluminum monostearate and gelatin. Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and dispensers are starch, alginic acid and its salts and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.

The effective amount of the composition depends on the patient’s body weight, gender and age, dosing regimen, fasting or after eating. These parameters can be determined and / or optimized by a competent specialist in the art using routine methods according to well-known rules, in particular, taking into account the dose-effect dependence and / or the concentration of the active component in the blood serum as a function of time from the moment of administration and dose.

Information on effective amounts obtained in laboratory animals is consistent with the results obtained with the introduction of drugs to humans. Given the absence of any pronounced toxic effects of the proposed compositions in a wide range of doses, the effective dose for humans is from 10 to 50 mg / kg, from 50 to 100 mg / kg, from 100 to 200 mg / kg, from 200 to 400 mg / kg or from 400 to 1000 mg / kg. The frequency of administration of the preparations according to the invention is preferably from 1 to 5 times per day. The duration of the drug depends on the specific purpose of treatment and is usually from 3 to 60 days and longer, preferably from 7 to 15 days.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are given only to illustrate the ideas of the present invention. Nothing in this section of the description should be construed as limiting the scope of the claims. It should be clear that the average person familiar with the ideas of the present invention, can use its main distinguishing features and make equivalent replacements to achieve the task and without deviating from the spirit and scope of the present invention.

EXAMPLE 1

Hard gelatin capsule

Samples of powdered natural raw materials are mixed in the following ratio:

the body of the fungus Ganoderma lucidum (Fr.) Karst one hundred unrefined roots of Glycyrrhiza glabra L. 6 seeds of Foeniculum vulgare Mill fifty Altai mummy peeled 0.2 herb Melilotus officinalis L. 60 Valvae fructum phaseoli vulgaris one hundred grass Hypericum perforatum L. 6 Linum usitatissimum L. seeds 60 cones Lupuli strobulus one hundred Urtica dioica L. leaf 6 leaf of Vaccinium myrtillus L. 6 aerial part of Artemisia vulgaris twenty

The resulting mixture in a dose of 0.4 g is placed in gelatin capsules in

in accordance with TU 9291-016-42897814-03.

EXAMPLE 2

Tablet

Samples of powdered natural raw materials are mixed in the ratio of example 1 and molded in the form of a cylindrical tablet with a diameter of 5 mm or more.

EXAMPLE 3

Composition "Equilprium-Vita"

Samples of powdered natural raw materials are mixed in the following ratio:

the body of the fungus Ganoderma lucidum (Fr.) Karst one hundred unrefined roots of Glycyrrhiza glabra L. 6 seeds of Foeniculum vulgare Mill fifty Altai mummy peeled 0.4 herb Melilotus officinalis L. 60

EXAMPLE 4

Composition "Equilibrium-Onco"

Samples of powdered natural raw materials are mixed in the following ratio:

the body of the fungus Ganoderma lucidum (Fr.) Karst one hundred unrefined roots of Glycyrrhiza glabra L. 6 seeds of Foeniculum vulgare Mill fifty Altai mummy peeled 0.4 herb Melilotus officinalis L. 60 the body of the fungus Fungus betulinus one hundred root Valeriana officinalis L. one hundred Urtica dioica L. leaf twenty Herba leonuri one hundred aerial part of Artemisia vulgaris twenty Eleutherococcus senticosus root twenty

EXAMPLE 5

Composition "Equibrpum-Dia"

The components of the composition are mixed in the ratio specified in example 1.

EXAMPLE 6

Pretreatment with the composition of the invention increases the lethal dose of cyclophosphamide

Outbred mice weighing 20 g intragastrically through a tube are administered the compositions of Example 3, 4 and 5 in an amount of 300 mg / kg in distilled water daily for 14 days. Distilled water was administered to control mice. Then mice inoculate melanoma B-16. 7 days after inoculation, mice are injected intraperitoneally with cyclophosphamide at a dose of 150 mg / kg. Equivolume amounts of distilled water are administered to control mice. In the control group, LD ₅₀ was 450.0 mg / kg. In the group after therapy, the LD ₅₀ was approximately 540.0, 570.0 and 630.0 mg / kg for the compositions of examples 3, 4 and 5, respectively.

With the introduction of the composition according to example 3, not containing G. lucidum, LD ₅₀ was 470.0 mg / kg When processing the composition according to example 3, not containing sweet clover, LD ₅₀ amounted to 460.0. Thus, it was shown that the components of the composition in the selected ratio synergistically compensate for the acute toxicity of chemotherapeutic drugs and can increase their therapeutic dose and / or improve tolerance to treatment.

EXAMPLE 7

Pretreatment with the composition of the invention improves energy metabolism in cells (energy-saving activity)

Male rats weighing 250-260 g are randomized into 4 groups: (1) intact animals, (2) the same as (1), but the animals daily receive the composition of example 3 at a dose of 300 mg / kg in distilled water through an intragastric tube , (3) and (4) are similar to (1) and (2), but the animals are additionally subjected to physical activity, namely, swimming for 30 minutes every other day at a water temperature of 27 ° C (according to the method of Ostrovskaya P.U. et al. , 1981). Intact animals receive an equivalent volume of water.

After 2 months, animals from groups (1) - (4) are decapitated, the myocardium, liver and skeletal muscles are frozen in liquid nitrogen, after which the content of glycogen, lactate, pyruvate and adenine nucleotides in them and the content of glucose and lactate in blood serum are determined by known methods. Excess lactate is calculated by Huckbee W.C. The redox potential is determined by Atkinson D.E.

In group (2), the content of glycogen, pyruvate and lactate in the myocardium increases by 9.7 ± 0.3%, 35.1 ± 0.7%, 35.0 ± 0.1%, respectively, compared with group (1). In group (4), in comparison with group (3), the content of glycogen and pyruvate increases by 19.1% and 17.1%, the content of lactate and excess lactate decreases by 15% and 8%, respectively. The redox potential in the myocardial tissue of group (4) increases by 3-5 millivolts compared to group (3). This indicates the predominance of aerobic oxidation of carbohydrates in the myocardium and an increase in the rate of utilization of lactic acid.

In groups (3) and (4), the effect of the composition is more pronounced than in groups (1) and (2). The ratio of glucose and lactate in blood serum and the content of adenine nucleotides of group (4) are higher, and the ratio of lactate and pyruvic acid is lower than in group (3). The glycogen content in the myocardium, liver and skeletal muscle in groups (2) and (4) is higher than in the corresponding groups (1) and (3).

The duration of swimming to the limit (with a load of 5% of body weight) in group (4) increases by 1.3 times compared with group (3). Thus, there is an improvement in the tolerance of the body to oxygen starvation and an increase in energy resources in the tissues and, as a result, the overall endurance of the body and resistance to stress increase. These properties of the compositions according to the invention can effectively combat the sensation of fatigue and rapid fatigue, which are characteristic of cancer patients receiving chemotherapy.

EXAMPLE 8

Compositions of the invention possess hepatoprotective activity

Hepatoprotective activity of the compositions according to example 3, 4 and 5 is evaluated according to the method disclosed in the article Saratikov A.S. et al. (“Correction of cyclophosphamide toxicity by hepatoprotectors of polyphenolic nature”, Bulletin of Siberian Medicine, 2001, 1: 52-6).

Outbred rats are randomized into 5 groups: (1) intact animals, (2) control animals receiving only cyclophosphamide (CF), (3) - (5) animals receiving the compositions of Examples 3, 4 and 5 and CF. CF is administered intraperitoneally at a dose of 20 mg / kg daily for 10 days. The compositions of examples 1, 2 and 3 are administered intragastrically through a probe at a dose of 300 mg / kg as a suspension in distilled water. Animals of the control group receive an equivalent volume of solvent. The day after the last administration of CF and compositions, rats are decapitated. Hepatoprotective activity is assessed by the ratio of the activity of hepatic enzymes in blood serum in animals receiving only CF and animals additionally receiving the compositions according to examples 3, 4 and 5.

The activity of alanine aminotransferase (AlAT), aspartate aminotransferase (AcAT), alkaline phosphatase (ALP), the content of bilirubin, total lipids, the concentration of protein, glucose, the content of lipid peroxidation products (diene conjugates and malondialdehyde) in rat serum are determined by known methods.

Compared with group (1), the activity of aminotransferases AsAT and AlAT in the blood serum of group (2) increases by 2.3 and 3.0 times, respectively. The ratio of AcAT / AlAT is reduced by 40%. The activity of alkaline phosphatase decreases by 2.2 times. Total bilirubin increases by 2.1 times, indirect bilirubin increases by 8.5 times. The glucuronidation coefficient of bilirubin is reduced by 76%. Total protein and lipids are reduced 2.2 and 1.8 times, respectively (hypoproteinemia and hypolipidemia). Serum glucose does not change. The concentration of diene conjugates in serum is reduced by 1.6 times, and the content of malondialdehyde does not change.

In groups (3) - (5), mortality is observed 22% lower than in group (2). The activity of AcAT and AlAT in the blood decreased by 21-25% and 35-38%, respectively, compared with the group (2). The ratio AsAT / AlAT decreases by 98-115% compared with group (2). The concentration of total bilirubin is reduced by 1.7-1.8 times, the concentration of indirect bilirubin is reduced by 2.0-2.5 times. Glucuronidation of bilirubin is restored to a level of 15% worse than normal. The protein content in the blood increases by 1.3-1.5 times. The amount of malondialdehyde increases by 1.5-1.7 times. The activity of alkaline phosphatase is restored to a level of 1.2 times worse than normal.

Thus, the compositions of examples 3, 4 and 5 exhibit pronounced hepatoprotective activity during cyclophosphamide therapy.

EXAMPLE 9

Compositions of the invention possess antioxidant activity

Male rabbits weighing 2.5-3.0 kg 14 days daily orally administered 300 mg / kg of the compositions according to examples 3-5. Then myocardial infarction is caused by ligation of the left descending coronary artery, after which the compositions continue to be administered for another 3 days. Lipid peroxidation products (diene conjugates (DC) and malondialdehyde (MDA)) are determined by known methods. Animals of the control group receive the known antioxidant ionol orally at a dose of 120 mg / kg.

The compositions of examples 3-5 reduce the content of DC and MDA in the ischemic zone of the myocardium by 30.8-35.3% and 35.2-37.4%, respectively, compared with the control. In the zone remote from ischemic damage, the concentration of MDA decreases by 25.3-27.2%, the content of DC slightly differs from the norm.

Thus, the compositions according to the invention can effectively reduce the level of oxidative stress in the tissues of the body, which is especially important for cancer patients receiving radiation and chemotherapy.

EXAMPLE 10

The compositions of the invention have antitumor activity.

Female outbred white mice weighing 20 g at the age of 3 months were transplanted with Lewis lung carcinoma (3LL, Hellman K., 1984) according to the method of Sof'ina Z.P. et al. (“Experimental Evaluation of Antineoplastic Drugs in the USSR and the USA”, Moscow, Medicine, 1980). The animal groups (1) to (3) receive the compositions according to examples 3-5, the group (4) receives the composition according to example 3, not containing G. lucidum, the group (5) receives the composition according to example 3, not containing sweet clover. The introduction of the compositions begin 7 days after inoculation of 3LL and continue for 11 days. Compositions are administered at a dose of 300 mg / kg via an intragastric tube as a suspension in distilled water. Animals from groups (1) - (5) receive etiotropic therapy with cyclophosphamide 72 hours after inoculation once intramuscularly at a dose of 150 mg / kg. Control mice received equivolume amounts of solvent on the days of drug administration.

One day after the last administration of the compositions, the mice are decapitated, the volume and mass of the primary tumor, the mass of the lungs with metastases are determined, the number and area of metastases in the lungs are calculated, the inhibition of tumor growth (%), the frequency of metastasis and the metastasis inhibition index (%) are calculated (Arkhipov S. A., Junker VM Change in the intensity of metastasis to lungs of transplanted tumors of mice depending on the size of the transplant dose of tumor cells. Research on the induction and metastasis of tumors in an experimental animals, Novosibirsk, 1984, pp. 14-32). On the 3rd day after the administration of CF, the number of leukocytes in the peripheral blood of mice was counted.

Inhibition of tumor growth during therapy with CF alone is 35%. With the introduction of only the compositions of the invention, inhibition of tumor growth in groups (1) - (3) was 21%, 25% and 29%, in group (4) and (5) it was 5% and 10%. When introduced together with the CF - 61%, 67%, 71%, 41% and 49%, respectively.

The frequency of metastasis in animals receiving only the composition did not differ from the control, the metastasis inhibition index in animals receiving the composition and CF was 89%, that is, significantly higher than CF monotherapy.

Thus, the compositions of the invention have antitumor activity, and when combined with cytostatics, they can inhibit metastasis.

Claims (21)

1. A composition with antitumor and adaptogenic activity, including the following ingredients, parts by weight based on dry weight:
the body of the fungus Ganoderma lucidum (Fr.) Karst. (tinder fungus varnished) 20 - 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis fisch (Ural licorice) 2 - 6 seeds of Foeniculum vulgare Mill (common fennel) 10 - 50 Altai mummy peeled 0.1 - 0.4 herb Melilotus officinalis L. (Melilotus officinalis) 10 - 60 2. The composition according to claim 1, further comprising the body of the fungus Fungus betulinus (chaga) at a content of from 20 to 100 parts by weight 3. The composition according to claim 1, additionally including the root of Valeriana officinalis L. (Valerian officinalis) at a content of from 10 to 100 parts by weight 4. The composition according to claim 1, additionally comprising a sheet of Urtica dioica L. (dioica nettle) at a content of from 6 to 20 parts by weight 5. The composition according to claim 1, further comprising Nerba Leonuri (motherwort herb) with a content of from 10 to 100 parts by weight 6. The composition according to claim 1, additionally including the aerial part of Artemisia vulgaris (common wormwood) with a content of from 6 to 20 parts by weight 7. The composition according to claim 1, additionally including the root of Eleutherococcus senticosus (prickly Eleutherococcus) with a content of from 6 to 20 parts by weight 8. The composition according to claim 1, additionally including Valvae fructum Phaseoli vulgaris (leaflet of common bean fruit) with a content of from 10 to 100 parts by weight 9. The composition according to claim 1, further comprising a herb Hypericum perforatum L. (Hypericum perforatum) at a content of 2 to 6 parts by weight 10. The composition according to claim 1, additionally including seeds of Linum usitatissimum L. (flax seed) with a content of from 20 to 60 parts by weight 11. The composition according to claim 1, further comprising cones of Lupuli strobulus (common hop) at a content of from 10 to 100 parts by weight 12. The composition according to claim 1, further comprising a sheet of Vaccinium myrtillus L. (common blueberry) with a content of from 2 to 6 parts by weight 13. A composition with antitumor and adaptogenic activity, including the following ingredients, parts by weight based on dry weight:
the body of the fungus Ganoderma lucidum (Fr.) Karst. (tinder fungus varnished) 20 - 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis fisch (Ural licorice) 2 - 6 seeds of Foeniculum vulgare Mill (ordinary fennel) 10 - 50 Altai mummy peeled 0.1 - 0.4 herb Melilotus officinalis L. (Melilotus officinalis) 10 - 60 the body of the fungus Fungus betulinus (chaga) 20 - 100 root Valeriana officinalis L. (Valerian officinalis) 10 - 100 Urtica dioica L. leaf (dioica nettle) 6 - 20 Herba Leonuri (motherwort herb) 10 - 100 aerial part of Artemisia vulgaris (common wormwood) 6 - 20 Eleutherococcus senticosus root (Eleutherococcus prickly) 6 - 20 14. The composition according to p. 13, further comprising Valvae fmctum Phaseoli vulgaris (leaflet of common bean fruit) at a content of from 10 to 100 parts by weight 15. The composition according to item 13, further comprising a herb Hypericum perforatum L. (Hypericum perforatum) at a content of 2 to 6 parts by weight 16. The composition according to item 13, further comprising seeds of Linum usitatissimum L. (flax sowing) at a content of from 20 to 60 wt.h. 17. The composition according to item 13, further comprising cones of Lupuli strobulus (ordinary hop) with a content of from 10 to 100 parts by weight 18. The composition according to item 13, further comprising a sheet of Vaccinium myrtillus L. (common blueberry) with a content of from 2 to 6 parts by weight 19. A composition with antitumor and adaptogenic activity, including the following ingredients, parts by weight based on dry weight:
the body of the fungus Ganoderma lucidum (Fr.) Karst. (varnished tinder) 20 - 100 unrefined roots of Glycyrrhiza glabra L. (licorice) or Glycyrrhiza uralensis fisch (Ural licorice) 2 - 6 seeds of Foeniculum vulgare Mill (common fennel) 10 - 50 Altai mummy peeled 0.1 - 0.4 herb Melilotus officmalis L. (Melilotus officinalis) 10 - 60 Valvae fructum Phaseoli vulgaris (Bean Sash ordinary) 10 - 100 grass Hypericum perforatum L. (Hypericum perforatum) 2 - 6 seeds of Linum usitatissimum L. (flax) 20 - 60 cones of Lupuli strobulus (common hop) 10 - 100 Urtica dioica L. leaf (dioica nettle) 2 - 6 leaf of Vaccinium myrtillus L. (common blueberries) 2 - 6 aerial part of Artemisia vulgaris (common wormwood) 6 - 20 20. A drug with antitumor and adaptogenic activity in the form of a capsule containing an effective amount of a composition with adaptogenic and antitumor activity according to any one of claims 1, 13 or 19 and, optionally, a pharmaceutically acceptable excipient. 21. A medicament with antitumor and adaptogenic activity in the form of a tablet containing an effective amount of a composition with adaptogenic and antitumor activity according to any one of claims 1, 13 or 19 and, optionally, a pharmaceutically acceptable excipient.