RU2523557C2 - Method of treating vegetovascular dystonia and pharmaceutical composition for treating vegetovascular dystonia - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to therapy, and concerns treating vegetovascular dystonia (VVD). That is ensured by administering a pharmaceutical composition containing activated potentiated angiotensin II receptor antibodies and activated potentiated endothelial NO-synthase antibodies.

EFFECT: method provides effective treatment of vegetovascular dystonia ensured by the synergetic action of the ingredients of the pharmaceutical composition.

1 ex, 1 tbl

Description

The invention relates to medicine and can be used for the effective treatment of vegetovascular dystonia (VVD).

The prior art preparation for the treatment of hypertension, based on the activated forms of ultra-low doses of antibodies to the angiotensin II receptor (Application of ultra-low doses of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor (Cardos) in the treatment of arterial hypertension. Epstein O.I. 2006). However, this drug does not provide sufficient therapeutic efficacy in the treatment of various disorders in the body with VSD.

The invention is aimed at creating an effective complex preparation in the form of a pharmaceutical composition and increasing the effectiveness of the treatment of vegetovascular dystonia.

The solution to this problem is provided by the fact that in the method of treating vegetovascular dystonia, by introducing into the body a drug based on an activated - potentiated form of ultra-low doses of affinity-purified antibodies to the angiotensin II receptor, prepared by repeated serial dilution and external exposure, according to the invention, additionally simultaneously the activated - potentiated form of ultra-low doses of affinity-purified antibodies to endothelial NO synthase is combined.

In this case, an activated - potentiated form of antibodies to the C-terminal fragment of AT! - angiotensin II receptor and activated - potentiated form of antibodies to endothelial NO synthase.

In addition, the activated — potentiated form of antibodies to the C-terminal fragment of the AT ₁ angiotensin II receptor II and the activated — potentiated form of antibodies to the endothelial NO synthase are used in the form of an activated — potentiated aqueous or aqueous-alcoholic solution of each component obtained in the process of sequential multiple dilution in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical action - vertical shaking.

In this case, a mixture of various homeopathic dilutions of antibodies to the C-terminal fragment of the AT ₁ receptor of angiotensin II in combination with a mixture of various homeopathic dilutions of antibodies to endothelial NO synthase is prepared in the form of a single drug.

It is possible to use a pharmaceutical composition based on an activated - potentiated form of ultra-low doses of affinity-purified antibodies to the C-terminal fragment of the AT ₁ angiotensin II receptor and to endothelial NO synthase in combination with known standard drugs used to treat diseases of the cardiovascular system of the following groups : ACE inhibitors incl. combined, diuretics, β-blockers, nitrates, cardiac glycosides, lipid-lowering drugs, antiplatelet agents, antihypoxants, anticoagulants.

The solution to this problem is also provided by the fact that the drug for the treatment of vegetative vascular dystonia based on the activated - potentiated form of ultra-low doses of affinity-purified antibodies to the angiotensin II receptor, according to the invention, is made in the form of a pharmaceutical composition and additionally contains an activated - potentiated form of antibodies as an enhancing component to endothelial NO synthase.

In this case, the activated - potentiated form of antibodies to the angiotensin II receptor and to endothelial NO synthase is used in the form of an activated - potentiated aqueous or hydroalcoholic solution obtained by sequential multiple dilution of a matrix solution of the corresponding antibodies in an aqueous or hydroalcoholic solvent and an intermediate external mechanical impact - vertical shaking.

In addition, the pharmaceutical composition may be in solid dosage form and contain an effective amount of a neutral carrier saturated with a mixture of the activated — potentiated form of antibodies to the angiotensin II receptor and the activated — potentiated form of antibodies to endothelial NO synthase, and pharmaceutically acceptable additives, which may include lactose, microcrystalline cellulose and magnesium stearate.

In this case, aqueous or aqueous-alcoholic solutions of activated - potentiated forms of antibodies to the angiotensin II receptor and to endothelial NO synthase were obtained by repeated serial dilution and intermediate external exposure from matrix solutions of affinity purified antibodies to angiotensin II receptor and to endothelial NO synthase with a concentration 0.5 ÷ 5.0 mg / ml.

Moreover, each of the components of ultra-low doses of affinity-purified antibodies is used in the form of a mixture of various, mainly hundred, homeopathic dilutions.

In addition, the pharmaceutical composition contains active ingredients: an activated - potentiated form of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor and to endothelial NO synthase in a 1: 1 ratio, each component being used in an ultra-low dose in the form of a mixture of three corresponding matrix solutions diluted 100 ¹² , 100 ³⁰ , and 100 ²⁰⁰ times, which is equivalent to hundreds of homeopathic dilutions of C12, C30, C200.

It is possible that the claimed pharmaceutical composition based on the activated form of ultra-low doses of affinity-purified antibodies to diseases of the C-terminal fragment of the AT ₁ angiotensin II receptor and endothelial NO synthase be used in combination with known standard drugs used to treat diseases of the cardiovascular system of the following groups :

- ACE inhibitors including combined (enap, enalapril, kapoten, renitek, prestarium (berlipril, diroton, kapoten, quadropril, monopril, renitek, prestarium, noliprel-forte, enap-H));

- diuretics (furosemide, veroshpiron, hypothiazide, arifon retard, indapamide, hypothiazide, diuver, indap, indapamide);

- β-blockers (egilok, atenolol, concor, betalok ZOK);

- nitrates (dilaside, cardicet, cardicet retord, mitrolinate, MonoMack, monochinque, nitroglycerin, nitrosorbide, olicardium, pectrol, sydnopharm);

- cardiac glycosides (digoxin);

- calcium antagonists (normodipine, cordoflex, amlovas, amlodipine, amlovas, amlotop, cardilopin, cordaflex, cordipin CL);

- lipid-lowering drugs (vasilip, lypimar, liptonorm, simvageksal, simvastol, simvokard, simgal, tulip)

antiplatelet agents (aspirin, cardiASA, cardiomagnyl, thromboass);

- antihypoxants (preductal MB, preductal, trimectal);

- anticoagulants (warfarin).

The claimed pharmaceutical composition is recommended to be taken, preferably, 1-2 tablets 2-4 times a day.

When treating the treatment of vegetovascular dystonia, it is possible to use separately in the form of two separately prepared preparations, both in the form of solutions and in solid dosage forms (tablets), each of which contains an activated - potentiated form of ultra-low doses of affinity-purified antibodies to diseases of the C-terminal fragment of AT ₁ receptor angiotensin II and, accordingly, the activated potentiated form of ultra-low doses of affinity purified antibodies to endothelial NO synthase

The proposed pharmaceutical composition based on the activated - potentiated form of ultra-low doses of affinity-purified antibodies to diseases of the C-terminal fragment of the AT ₁ angiotensin II receptor and to endothelial NO synthase (i.e., the forms of antibodies to the C-terminal fragment of the AT ₁ angiotensin II receptor and to endothelial NO synthase prepared according to the homeopathic technology of potentiation by repeated serial dilution and intermediate external action - vertical shaking, which has activity in rmakologicheskih models and / or clinical treatments of vascular dystonia) provides an unexpected synergistic therapeutic effect, verified experimentally, which consists in normalizing effect on vegetative status in patients with vegetative dystonia and asthenia in anxiolytic and antidepressant activity.

Moreover, the use of the claimed pharmaceutical composition in the treatment of patients with diseases of the cardiovascular system leads to an improvement in the quality of life, in particular, patients have improved quality of life, assessed by the criteria of depression, anxiety, duration of walk, increased exercise tolerance, etc.

In addition, the claimed technical solution expands the arsenal of drugs intended for complex therapy of VSD.

The pharmaceutical composition is prepared mainly as follows.

For the preparation of the activated - potentiated form of the active components, monoclonal or, mainly, polyclonal antibodies are used, which can be obtained by known technologies - methods described, for example, in the book: Immunological methods, ed. G. Fremel, M., "Medicine", 1987, S. 9-33; or, for example, in an article by Laffly E., Sodoyer R. Hum. Antibodies. Monoclonal and recombinant antibodies, 30 years after. - 2005 - Vol.14. - N 1-2. P.33-55.

Monoclonal antibodies are obtained, for example, using hybrid / home technology. Moreover, the initial stage of the process includes immunization, based on the principles already developed in the preparation of polyclonal antisera. Further stages of the work include obtaining hybrid cells producing clones of antibodies of the same specificity. Their isolation in an individual form is carried out by the same methods as in the case of polyclonal antisera.

Polyclonal antibodies can be obtained by active immunization of animals. To this end, according to a specially developed scheme, the animals are given a series of injections of the substance required by the invention, an antigen: endothelial NO synthase and the C-terminal fragment of AT ₁ angiotensin II receptor. As a result of this procedure, a monospecific antiserum with a high antibody content is obtained, which is used to obtain the activated potentiated form. If necessary, the antibodies present in the antiserum are purified, for example, by affinity chromatography, using fractionation by salt precipitation or ion exchange chromatography.

Preferred for the preparation of the claimed pharmaceutical composition is the use of polyclonal antibodies to endothelial NO synthase and to the C-terminal fragment of AT ₁ angiotensin II receptor, which are used as a matrix (primary) solution with a concentration of 0.5 ÷ 5.0 mg / ml for subsequent preparation of the activated - potentiated form.

Preferred for the preparation of each component is the use of a mixture of three water-alcohol dilutions of the primary matrix solution of antibodies diluted 100, ¹² , 100, ³⁰ , and ^100,200 times, respectively, which corresponds to hundreds of homeopathic dilutions of C12, C30 and C200. When performing the claimed drug in solid dosage form, a mixture of these components is applied to lactose.

Preferred for the preparation of the claimed drug is the use of polyclonal antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor and endothelial NO synthase, which can be obtained by immunization of rabbits as follows.

To obtain polyclonal antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor, an adjuvant and the C-terminal fragment of AT ₁ angiotensin II receptor selected, for example, from the following group are used as immunogen (antigen) for immunization of rabbits:

GKKFK RYFLQLLKYI PPKAKSHSNL STKMSTLSYR PSDNVSSSTK KPAPCFEVE

LNPF FYVFFGKNFK KYFLQLIKYI PPNVSTHPSL TTKMSSLSYR

PPENIRLPTK

KTAGSFDTE

QLLKYI PPKA

SSLSYR PPENIR

QLIKYIPPNVSTHP

SNL STKMSTLSYR PSDNVSSSTK KPAPCF

It is possible to obtain polyclonal antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor using the C-terminal fragment of the AT1 receptor angiotensin II as an immunogen (antigen) with cysteine (C) added to the N end:

CGKKF KRYFL QLLKY IPPKA KSHSN LSTKM STLSY RPSDN VSSST KKRAR CFEVE

Before blood sampling for 1-3 days, 1-3 intravenous injections are performed to increase the level of antibodies. During immunization, small blood samples are taken from rabbits to evaluate the amount of antibody. The maximum level of the immune response to the administration of most soluble antigens is achieved 40-60 days after the first injection. After the end of the first cycle of immunization of rabbits for 30 days, they restore health and re-immunization, including 1-3 intravenous injections. To obtain antisera from immunized rabbits, blood is collected in a 50 ml centrifuge tube. Using a wooden spatula, the formed clots are removed from the walls of the tube and the wand is placed in the clot formed in the center of the tube. Blood is placed in a refrigerator (temperature 4 ° C) at night. The next day, the clot attached to the spatula is removed and the remaining liquid is centrifuged at 13000 g for 10 minutes. The supernatant (supernatant) is an antiserum. The resulting antiserum should be yellow. Add to the antiserum 20% (weight concentration) NaN ₃ to a final concentration of 0.02% and store until use in a frozen state at a temperature of -20 ° C. To isolate antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor from antiserum, absorption on the solid phase is carried out in the following sequence:

1. 10 ml of rabbit antiserum are diluted 2 times with 0.15 M NaCl, 6.26 g of Na ₂ SO ₄ are added, stirred and incubated for 12-16 hours at 4 ° C;

2. The precipitate formed is removed by centrifugation, dissolved in 10 ml of phosphate buffer and then dialyzed against the same buffer overnight at room temperature;

3. after removal of the precipitate by centrifugation, the solution is applied to a column with DEAE-cellulose, balanced with phosphate buffer;

4. The antibody fraction is determined by measuring the optical density of the eluate at 280 nm.

The antibodies are then purified by affinity chromatography by attaching the obtained antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor, which is located on an insoluble matrix, followed by elution with concentrated salt solutions.

Thus obtained buffer solution of polyclonal rabbit antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor, purified on antigen, with a concentration of 0.5 ÷ 5.0 mg / ml, preferably. 2.0 ÷ 3.0 mg / ml, used as a matrix (primary) solution for the subsequent preparation of the activated - potentiated form.

Polyclonal antibodies to endothelial NO synthase are obtained in a similar manner to the above, using as an immunogen (antigen) for immunization of rabbits an adjuvant and a whole molecule of endothelial NO synthase of the following sequence:

1 MGNLKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPEPSR ARARATRNAR DHSPAPNSPT

61 LTRPPEGPKF PRVKNWELGS ITYDTLCAQS QQDGPCTPRR CLGSLVLPRK LQTRPSPGPP

121 PAEQLLSQAR DFINQYYSSI KRSGSQAHEE RLQEVEAEVA STGTIHLRES ELVFGAKQAW

181 RNAPRCVGRI QWGKLQVFDA RDCSSAQEMF TYICNHIKYA TNRGNLRSAI TVFPQRAPGR

241 GDFRIWNSQL VRYAGYRQQD GSVRGDPANV EITELCIQHG WTPGNGRFDV LPLLLQAPDE

301 APELFVLPPE LVLEVPLGAP HTGVVRGPGL RWYALPAVSN MLLEIGGLEF SAAPFSGWYM

361 STEIGTRNLC DPHRYNILED VAVCMDLDTR TTSSLWKDKA AVEINLAVLH SFQLAKVTIV

421 DHHAATVSFM KHLDNEQKAR GGCPADWAWI VPPIYGSLPP VFHQEMVNYI LSPAFRYQPD

481 PWKGSATKGA GITRKKTFKE VANAVKISAS LMGTLMAKRV KATILYASET GRAQSYAQQL

541 GRLFRKAFDP RVLCMDEYDV VSLEHEALVL VVTSTFGNGD PPENGESFAA ALMEMSGPYN

601 SSPRPEQHKS YKIRFNSVSC SDPLVSSWRR KRKESSNTDS AGALGTLRFC VFGLGSRAYP

661 HFCAFARAVD TRLEELGGER LLQLGQGDEL CGQEEAFRGW AKAAFQASCE TFCVGEEAKA

721 AAQDIFSPKR SWKRQRYRLS AQAEGLQLLP GLIHVHRRKM FQATVLSVEN LQSSKSTRAT

781 ILVRLDTAGQ EGLQYQPGDHIGISAPNRPG LVEALLSRVE DPPPPTESVA VEQLEKGSPG

841 GPPPSWVRDP RLPPCTVRQA LTFFLDITSP PSPRLLRLLS TLAEEPSEQQ ELETLSQDPR

901 RYEEWKLVRC PTLLEVLEQF PSVALPAPLL LTQLPLLQPR YYSVSSAPNA HPGEVHLTVA

961 VLAYRTQDGL GPLHYGVCST WLSQLKTGDP VPCFIRGAPS FRLPPDPYVP CILVGPGTGI

1021 APFRGFWQER LHDIESKGLQ PHPMTLVFGC RCSQLDHLYR DEVQDAQERG VFGRVLTAFS

1081 REPDSPKTYV QDILRTELAA EVHRVLCLER GHMFVCGDVT MATSVLQTVQ RILATEGDME

1141 LDEAGDVIGV LRDQQRYHED IFGLTLRTQE VTSRIRTQSF SLQERHLRGA VPWAFDPPGP

1201 DTPGP

It is possible to obtain polyclonal antibodies to endothelial NO synthase using the following sequence as an immunogen (antigen) of a whole molecule of endothelial NO synthase:

1 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT

61 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP

121 EQLLSQARDFINQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN

181 APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD

241 FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT PGNGRFDVLP LLLQAPDDPP

301 ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML LEIGGLEFPA APFSGWYMST

361 EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV EINVAVLHSY QLAKVTIVDH

421 HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF HQEMVNYFLS PAFRYQPDPW

481 KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA TILYGSETGR AQSYAQQLGR

541 LFRKAFDPRV LCMDEYDVVS LEHETLWLVV TSTFGNGDPP ENGESFAAAL MEMSGPYNSS

601 PRPEQHKSYK IRFNSISCSD PLVSSWRRKR KESSNTDSAG ALGTLRFCVF GLGSRAYPHF

661 CAFARAVDTR LEELGGERLL QLGQGDELCG QEEAFRGWAQ AAFQAACETF CVGEDAKAAA

721 RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ ATIRSVENLQ SSKSTRATIL

781 VRLDTGGQEG LQYQPGDHIG VCPPNRPGLV EALLSRVEDP PAPTEPVAVE QLEKGSPGGP

841 PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL AEEPREQQEL EALSQDPRRY

901 EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY SVSSAPSTHP GEIHLTVAVL

961 AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR LPPDPSLPCI LVGPGTGIAP

1021 FRGFWQERLH DIESKGLQPT PMTLVFGCRC SQLDHLYRDE VQNAQQRGVF GRVLTAFSRE

1081 PDNPKTYVQD ILRTELAAEV HRVLCLERGH MFVCGDVTMA TNVLQTVQRI LATEGDMELD

1141 EAGDVIGVLR DQQRYHEDIF GLTLRTQEVT SRIRTQSFSL QERQLRGAVP WAFEPPGSDT

1201 NSP

It is possible to obtain polyclonal antibodies to endothelial NO synthase using, as an immunogen (antigen), a synthetic peptide of endothelial NO synthase, selected, for example, from the following amino acid sequences:

1192-1195

Pwaf

1189-1192:

Rgavp

1185-1205 ^∧

RHLRGAVPWAF DPPGPDTPGP

1194-1205:

AF DPPGPDTPGP

1186-1196:

HLRGAVPWAF D

1186-1205:

HLRGAVPWAF DPPGPDTPGP

The activated - potentiated form of each component is prepared by uniformly decreasing the concentration as a result of successive dilution of 1 part of the matrix solution in 9 parts (for decimal dilution) or in 99 parts (for hundredth dilution) or in 999 parts (for thousandth dilution) of a neutral solvent with multiple vertical shaking ("dynamization") of each dilution obtained and using separate containers for each subsequent dilution to obtain the desired potency - to breeding rates according to the homeopathic method (see, for example, V. Schwabe "Homeopathic medicines", M., 1967, p.14-29).

For example, to prepare a 12th hundred-fold dilution of C12, one part of the aforementioned matrix solution of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor with a concentration of 3.0 mg / ml is diluted in 99 parts of a neutral aqueous or aqueous-alcoholic solvent (mainly 70% ethyl alcohol) and repeatedly (10 or more times) vertically shake - potentiate the obtained 1st hundredth C1 dilution. From the 1st hundredth C1 dilution, a second hundredth C2 dilution is prepared. This operation is repeated 11 times, obtaining the 12th hundredth dilution of C12. Thus, the 12th hundredth dilution of C12 is a solution obtained by diluting successively in different containers 12 times of the first part of the initial matrix solution of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor with a concentration of 3.0 mg / ml in 99- te parts of a neutral solvent, i.e. a solution prepared from a matrix solution diluted 100 times, which is equivalent to a hundred-percent homeopathic dilution of C12. Similar operations with the appropriate dilution ratio are carried out to obtain dilutions of C30 and C200.

When using as a biologically active liquid component a mixture of various homeopathic, mainly hundred, dilutions, active ingredients, each component of the composition (for example, C12, C30, C200) is prepared separately according to the technology described above to the penultimate dilution (respectively, to obtain C11, C29, C199) and then, in accordance with the composition of the mixture, in one container, one part of each component is added and mixed with the required amount of solvent (respectively, with 97 parts for hundred-percent dilution). In this case, an activated - potentiated form of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor in an ultra-low dose of each component is prepared, prepared from a matrix solution diluted in 100 ¹² , in 100 ³⁰ in 100 ²⁰⁰ , which is equivalent to a mixture of hundred-percent homeopathic dilutions C12, C30 and C200.

It is possible to use the active substance in the form of a mixture of various different homeopathic dilutions, for example, decimal and or hundredths (D20, C30, C100 or C12, C3O, C50, etc.), the effectiveness of which is determined experimentally.

When potentiating instead of shaking in the process of decreasing the concentration, it is also possible to exert external influence by ultrasound, electromagnetic or other physical action

To obtain the claimed pharmaceutical composition, aqueous or aqueous-alcoholic solutions of the active ingredients are mixed, mainly in a ratio of 1: 1 and used in liquid dosage form. Preferably, the pharmaceutical composition comprises an activated - potentiated form of antibodies to the C-terminal; fragment AT _{1 of} the angiotensin II receptor and to endothelial NO synthase in an ultra-low dose of each component in an ultra-low dose of each component prepared from a matrix solution diluted in 100 ¹² , in 100 ³⁰ in 100 ²⁰⁰ , which is equivalent to a mixture of hundreds of homeopathic dilutions C12, C30 and C200.

The claimed pharmaceutical composition can also be used in solid dosage form, which contains an effective amount of granules of a neutral carrier - lactose, saturated by soaking in an activated - potentiated form of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor to a mixture of aqueous or aqueous-alcoholic solutions, and activated - potentiated form of antibodies to endothelial NO synthase, and pharmaceutically acceptable additives, including, mainly, lactose, microcree cellulose and the metallic magnesium stearate.

To obtain a solid oral form of the claimed medicinal product, a fluidized bed is installed (for example, Huttlin Pilotlab type manufactured by Huttlin GmbH) until the granules of a neutral substance - lactose (milk sugar) introduced into the fluidized - boiling layer are saturated with a particle size of 150 ÷ 300 um, preformed aqueous or aqueous-alcoholic solution of activated - potentiated forms of antibodies to the C-terminal fragment of AT ₁ receptor of angiotensin II and endothelial nitric oxide synthase (NO-synthase) becom venno in a ratio of 1 kg of antibody solution to 5 or 10 kg of lactose (1: 5-1: 10) with simultaneous drying in a heated air stream supplied under the grate at a temperature of not higher than 40 ° C. The estimated amount of 0.17 ÷ 0.34 of the mass of solid oral form) of dried granules saturated with the activated - potentiated form of antibodies is loaded into a mixer and mixed with microcrystalline cellulose introduced in an amount of 3-8 mass. parts of the total mass of the load - from the mass of solid oral form. Then 25 ÷ 45 masses are added to this mixture. parts of the total mass of the load of "unsaturated" pure lactose (to reduce the cost and some simplification and acceleration of the process without reducing the effectiveness of the therapeutic effect), magnesium stearate in an amount of 0.1 ÷ 0.3 mass. parts of the total mass of the load and microcrystalline cellulose in an amount of 3 ÷ 8 mass. parts of the total mass of the load. The resulting tablet mass is uniformly mixed and tabletted by direct dry pressing (for example, in a Korsch-XL400 tablet press) with the formation of round tablets weighing 150 ÷ 500 mg. After tabletting, 300 mg tablets are obtained, impregnated with an aqueous-alcoholic solution (3.0-6.0 mg / tablet) with an activated, potentiated form of antibodies to the C-terminal fragment of AT ₁ angiotensin II receptor and NO synthase in an ultra-low dose, each a component prepared from a matrix solution diluted in 100 ¹² , in 100 ³⁰ in 100 ²⁰⁰ , which is equivalent to a mixture of hundred-percent homeopathic dilutions C12, C30 and C200.

Preferably, the claimed pharmaceutical composition is recommended to take 1-2 tablets 2-4 times a day.

For experimental studies were used antibodies prepared by order of a specialized pharmaceutical company.

Example 1

The clinical efficacy and safety of the use of a pharmaceutical composition based on a component of activated - potentiated forms of antibodies in ultra-low doses (SMD) to the C-terminal fragment of AT ₁ angiotensin II receptor and to endothelial NO synthase (a mixture of homeopathic dilutions C12, C30, C200) was studied in 60 patients of both sexes (men - 26.7% (n = 16), women - 73.3% (n = 44) of the total number of patients) with asthenia (more than 12 points on the item "general asthenia" on the subjective asthenia scale MFI-20 (Multidimensional Fatigue Inventory)) and vegetovascular dystonia (pain her 15 points on the vegetative change scale) aged 29 to 64 years (average 47.1 ± 1.77 years) in a double-blind, placebo-controlled, randomized clinical trial in parallel groups.

Patients were randomized into two groups (n = 30 each). Patients of group 1 received the claimed drug in 1 tablet 3 times a day. Group 2 patients received placebo 1 tablet 3 times a day. The total duration of taking the drug and monitoring patients was 6 months.

The effectiveness of the therapy was evaluated by the dynamics of the indicators of the subjective asthenia assessment scale, questionnaires for assessing the level of anxiety and depression (Spielberger and Beck scales), sleep assessment questionnaires, and a vegetative changes questionnaire.

The dynamics of changes in the autonomic and psychological status, quality of life of patients on the background of the therapy is presented in table 1.

It was shown that the use of the claimed drug for 6 months led to a statistically significant decrease in the level of asthenia in all MFI-20 subscales. The following indicators improved most significantly: general asthenia (from 12.9 ± 0.21 to 10.9 ± 0.27 points, p <0.01 from the placebo group), physical asthenia (from 12.3 ± 0.56, to 10.2 ± 0.39 points, p <0.05 from the placebo group), mental asthenia (from 10.2 ± 0.47 to 8.9 ± 0.41 points, p <0.05 from the placebo group). After 1 month of therapy, in the main group 1, a statistically significant decrease in the severity of vegetative changes was noted (according to the data of a specialized questionnaire), after 6 months of treatment the achieved results (reduction in the total score from 28.9 ± 1.66 to 17.6 ± 0.76) statistically significant (p <0.05) differed from the placebo group (reduction in total score from 32.1 ± 3.36 to 22.4 ± 2.08).

Also, the use of the claimed drug contributed to improving the psychological status of patients. A statistically significant decrease in the level of anxiety and depression was noted after 1 month of taking the drug, with continued treatment, positive changes increased. At the end of 6 months in group 1, the level of reactive anxiety on the Spielberger scale (decrease from 39.3 ± 1.02 to 32.4 ± 0.76 points) and the level of depression according to the Beck questionnaire (decrease from 9.2 ± 0.44 to 7.8 ± 0.31 points) is statistically significant. (p <0.05), differed from the corresponding indicators of the placebo group (decrease from 42.7 ± 2.65 to 37.6 ± 1.81 and from 11.1 ± 1.43 to 9.9 ± 0.90 points respectively). The results were confirmed by the positive dynamics (p <0.001 from the initial values) of the indicators of the sleep assessment questionnaire, after 6 months of treatment, the total score in group 1 (increase from 16.9 ± 0.44 to 19.4 ± 0.29) was statistically significant ( p <0.05) higher than in the placebo group (increase from 16.6 ± 0.67 to 18.2 ± 0.47).

During the entire period of monitoring the patients, the drug was well tolerated, adverse events were absent.;,

Thus, the study showed that a pharmaceutical composition based on antibodies to the C-terminal fragment of AT1 angiotensin II receptor (a mixture of homeopathic dilutions C12 + C30 + C200) and SMD antibodies to endothelial NO synthase (a mixture of homeopathic dilutions C12 + C30 + C200) possesses antiasthenic action, has a normalizing effect on the vegetative status in patients with vegetovascular dystonia and asthenia, has anti-anxiety and antidepressant activity.

Table 1. Indicator Combined preparation, n = 30 Placebo, n = 30 Visit 1 Visit 2 (4 weeks) Visit 3 (12 weeks) Visit 4 (24 weeks) Visit 1 Visit 2 (4 weeks) Visit 3 (12 weeks) Visit 4 (24 weeks) General asthenia (MFI-20 scale) M ± m 12.9 ± 0.21 12.3 ± 0.29 11.5 ± 0.35 *** # 10.9 ± 0.27 *** ## 13.1 ± 0.26 12.9 ± 0.23 12.5 ± 0.17 *** 11.9 ± 0.19 *** Physical asthenia (MFI-20 scale) M ± m 12.3 ± 0.56 11.7 ± 0.49 ** 11.2 ± 0.45 ** 10.2 ± 0.39 *** # 12.3 ± 0.38 12.1 ± 0.29 11.7 ± 0.29 ** 11.4 ± 0.21 ** Decreased activity (MFI-20 scale) M ± m 10.3 ± 0.50 10.1 ± 0.47 9.5 ± 0.42 * 9.1 ± 0.28 * 10.6 ± 0.63 10.1 ± 0.53 * 9.7 ± 0.50 ** 9.5 ± 0.38 ** Decreased motivation (MFI-20 scale) M ± m 9.60 ± 0.55 9.5 ± 0.47 8.6 ± 0.32 * 8.3 ± 0.27 * 9.9 ± 0.75 9.7 ± 0.57 9.4 ± 0.51 9.3 ± 0.48 Mental asthenia (MFI-20 scale) M ± m 10.20 ± 0.47 9.7 ± 0.44 * 9.5 ± 0.42 * 8.9 ± 0.41 ** # 10.8 ± 0.51 10.6 ± 0.43 10.5 ± 0.40 10.3 ± 0.38 Questionnaire of vegetative changes (total score) M ± m 28.9 ± 1.66 25.3 ± 1.26 ** 22.1 ± 1.26 *** 17.6 ± 0.76 *** # 32.1 ± 3.36 29.5 ± 2.57 * 25.9 ± 2.42 *** 22.4 ± 2.08 *** Sleep assessment form (total score) M ± m 16.9 ± 0.44 18.4 ± 0.42 ** 18.9 ± 0.34 *** 19.4 ± 0.29 *** # 16.6 ± 0.67 17.5 ± 0.56 ** 18.1 ± 0.47 *** 18.2 ± 0.47 *** Personal anxiety (Spielberger scale) M ± m 37.6 ± 2.03 35.6 ± 1.42 * 35.1 ± 1.64 ** 32.9 ± 1.23 *** 39.1 ± 3.05 38.7 ± 2.78 36.9 ± 2.45 * 36.9 ± 2.46 * Reactive Anxiety (Spielberger Scale) M ± m 39.3 ± 1.02 35.7 ± 0.72 *** # 34.5 ± 1.02 *** 32.4 ± 0.76 *** # 42.7 ± 2.65 40.3 ± 1.99 ** 38.3 ± 1.87 ** 37.6 ± 1.81 ** Beck Depression Questionnaire (total score) M ± m 9.2 ± 0.44 8.4 ± 0.25 * 8.3 ± 0.27 * 7.8 ± 0.31 ** # 11.1 ± 1.43 10.5 ± 1.19 * 10.0 ± 0.93 9.9 ± 0.90 * Significance of differences compared with the initial indicator: * p <0.05, ** p <0.01, *** p <0.001. Significance of differences compared with the placebo group: * p <0.05, ## p <0.01, ### p <0.001.

Claims (11)

1. A method of treating a vegetation pump with a dystonia diet by administering a drug based on an activated, potentiated form of affinity-purified antibody to the angiotensin II receptor, prepared by repeated serial dilution and external exposure, characterized in that an activated, potentiated form of an affinity is additionally introduced at the same time. purified antibodies to endothelial NO synthase. 2. The method according to claim 1, characterized in that they use the activated - potentiated form of antibodies to the C - terminal fragment of AT ₁ - angiotensin II receptor and the activated - potentiated form of antibodies to endothelial NO synthase. 3. The method according to claim 1 or claim 2, characterized in that the activated - potentiated form of antibodies to the C - terminal fragment of AT ₁ - angiotensin II receptor and the activated - potentiated form of antibodies to endothelial NO synthase are used in the form of activated - potentiated aqueous or an aqueous-alcoholic solution of each component obtained in the course of successive multiple dilutions in an aqueous or aqueous-alcohol solvent and an intermediate external mechanical action - shaking of each dilution. 4. The treatment method according to claim 1 or claim 2, characterized in that they use a pharmaceutical composition prepared in the form of a single drug - one dosage form, which includes a mixture of different homeopathic dilutions of antibodies to the C - terminal fragment of AT ₁ - angiotensin II receptor in combination with a mixture of different homeopathic dilutions of antibodies to endothelial NO synthase. 5. The treatment method according to claim 1 or claim 2, characterized in that they use a pharmaceutical composition based on the activated β-potentiated form of affinity purified antibodies to the C - terminal fragment of AT ₁ - angiotensin II receptor and to endothelial N0 synthase in combination with known standard drugs used to treat diseases of the cardiovascular system of the following groups: ACE inhibitors including combined, diuretics, (3-adrenergic blockers, nitrates, cardiac glycosides, calcium antagonists, lipid-lowering drugs, antiplatelet agents, antihypoxants, anticoagulants. 6. A drug for treating a vegetosuos with a dystonia diet according to claim 1, based on an activated - potentiated form of affinity-purified antibodies to the angiotensin II receptor, characterized in that it is made in the form of a pharmaceutical composition and additionally contains an activated - potentiated form of antibodies to endothelial as an enhancing component NO synthase. 7. The drug according to claim 6, characterized in that the activated - potentiated form of antibodies to the angiotensin II receptor and to endothelial NO synthase is used in the form of an activated - potentiated aqueous or aqueous-alcoholic solution obtained in the course of successive multiple dilutions of the matrix solution of the corresponding antibodies in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical action - shaking each dilution. 8. The drug according to claim 6 or claim 7, characterized in that the pharmaceutical composition is in solid dosage form and contains an effective amount of an activated — potentiated form of antibodies to the angiotensin II receptor and an activated — potentiated form of antibodies to the endothelial NO synthase granules neutral carrier and pharmaceutically acceptable additives. 9. The drug according to claim 6 or claim 7, characterized in that aqueous or aqueous-alcoholic solutions of activated - potentiated forms of antibodies to the angiotensin II receptor and to endothelial NO synthase are obtained by repeated serial dilution and intermediate external exposure from matrix solutions affinity purified antibodies to the angiotensin II receptor and to endothelial NO synthase with a concentration of 0.5 ÷ 5.0 mg / ml. 10. The drug according to claim 6 or claim 7, characterized in that each of the components of the affinity purified antibodies is used as a mixture of various, mainly hundred, homeopathic dilutions. 11. The drug of claim 8, characterized in that the pharmaceutically acceptable additives include lactose, microcrystalline cellulose and magnesium stearate.