Method for correction of endothelial dysfunction

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and cardiology, and concerns correction of the endothelial dysfunction. That is ensured by administering an activated potentiated form of antibodies to endothelial nitrogen oxide synthase in a combination with an activated potentiated form of antibodies to a C-terminal fragment of AT1 angiotensin II receptor.

EFFECT: this combined effect provides effective correction of the endothelial function by the synergetic effect of the activated potentiated form of the antibodies.

4 cl, 1 tbl, 1 ex

 

The invention relates to medicine, in particular cardiovascolari, and can be used for the correction of endothelial dysfunction.

The prior art method of correction of endothelial dysfunction with a mixture of solutions of homeopathic dilutions of polyclonal antibodies to endothelial synthase nitric oxide person (EN 2306953, C1, A61K 39/395, 2007). However, the disadvantage of this invention is that the claimed method is effective in endothelial dysfunction associated with low levels of endothelial NO-synthase, and may not provide therapeutic efficacy in endothelial dysfunction with normal production of NO-synthase.

The invention is aimed at creating an effective and safe method of correction of endothelial dysfunction in preventing inflammation of the vessel wall and the development of endothelial dysfunction.

The solution of the problem provided by the fact that the method of correction of endothelial dysfunction, characterized by the fact that the body is injected simultaneously activated - potentiated form of antibodies to endothelial synthase nitric oxide in combination with an activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II.

When this activated - potentiated form of antibodies to endotheli is through NO-synthase and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II is used in the form of activated - potentiated aqueous or aqueous-alcoholic solution of each component, the activity of which is due to the sequential process of repeated dilution in water or water-alcohol solvent in combination with an external mechanical impact - vertical shaking of every dilution.

And use prepared in the form of a single (combined) of the medicinal product - a single dosage form a mixture of different dilutions of antibodies to endothelial NO-synthase in combination with a mixture of various dilutions of the antibody - terminal fragment AT1receptor of angiotensin II, prepared according to homeopathic technology.

Aqueous or aqueous-alcoholic solutions of the activated potentiated form of antibodies to endothelial synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II can be obtained by repeated consecutive dilution in combination with external mechanical impact - vertical shaking of every dilution of the matrix solution of antibodies with a concentration of 0.55.0 mg/ml

When this activated - potentiated form of antibodies to an endo who lialei the synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment of the ATI receptor of angiotensin II is used in the form of a mixture of various, mainly centesimal, in homeopathic dilutions technology.

The claimed method can be used for the correction of L-Name-induced endothelial dysfunction in rats male Wistar amid intraperitoneal administration of L-Name at a dose of 12.5 mg/kg by daily injection of 2 times per day 4.5 ml/kg (9 ml/kg/day) intragastrically mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide in the form of a mixture of solutions of homeopathic dilutions C12, C30, C200 and 4.5 ml/kg (9 ml/kg/day) and a mixture of solutions of homeopathic dilutions of antibodies to C-terminal the fragment AT1receptor of angiotensin II in the form of a mixture of solutions of homeopathic dilutions C12, C30, C200.

In addition, the activated - potentiated form of antibodies to endothelial synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II is used in the form of a mixture of different dilutions, prepared according to homeopathic technology, mainly in the form of a mixture of the three solutions were prepared from a matrix solution, diluted, respectively, in the 10012, 10030and 100200once that is equivalent with the military dilutions C12, C30, C200, prepared according to homeopathic technology.

When correction of endothelial dysfunction may separate, but combined and simultaneous use (organism) an activated - potentiated form of antibodies to endothelial synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II in the form of two separately prepared drugs in the form of solutions and in solid dosage forms (tablets), each of which contains activated - potentiated form of ultra-low doses of antibodies to endothelial NO-synthase and, accordingly, the activated - potentiated form of ultra-low doses of antibodies to C-terminal fragment AT1receptor of angiotensin II.

The proposed combination of activated - potentiated form of antibodies to endothelial NO-synthase and C-terminal fragment AT1receptor of angiotensin II in medicine (i.e. form of antibodies to endothelial NO-synthase and C-terminal fragment AT1receptor of angiotensin II, prepared according to homeopathic technology exponentiation by repeated cultivation and external mechanical impact - repeated vertical shaking of every dilution (see, for example, Usabe "Homeopathic medicines is", M., 1967, p.14-29), which have activity caused by potentiation in pharmacological models and/or clinical correction of endothelial dysfunction) provides increased eNOS leads to blockade angiotensinogen receptor type 1, eliminates the effects of angiotensin II (conversion of nitric oxide in peroxynitrate, stimulation of the synthesis of endothelin-stimulated production of cytokines, resulting in inflammation does not occur in the vascular wall, hyperactively the renin-angiotensin aldosteronoma system (RAAS)), leading to formation of endothelial dysfunction.

The activated - potentiated form of antibodies to endothelial NO-synthase and C-terminal fragment AT1receptor of angiotensin II are prepared as follows. For making an activated - potentiated form of active components, using monoclonal or, mostly, polyclonal antibodies, which can be obtained by known technologies - techniques are described, for example, in the book: Immunological methods, Ed. by Grimes, M, "Medicine", 1987, p.9-33; or, for example, article Laffly E., R. Sodoyer Hum. Antibodies. Monoclonal and recombinant antibodies, 30 years after. - 2005 - Vol. 14. - N1-2. P.33-55.

Polyclonal antibodies can be obtained by active immunization of animals. For this purpose a specially designed circuit belly is haunted by doing a series of injections required in accordance with the invention substances - antigens: endothelial NO-synthase and C-end fragment AT1receptor of angiotensin II. As a result of this procedure is to obtain monospecific antisera with high content of antibodies that is used to produce the activated - potentiated forms. If necessary, conduct the purification of antibody present in anticigarette, for example, by the method of affinity chromatography, by application of salt fractionation by precipitation or ion exchange chromatography.

Monoclonal antibodies receive, for example, using hybridoma technology. Moreover, the initial stage of the process includes immunization, based on the principles already developed in the preparation of polyclonal antisera. Further stages include obtaining hybrid cells that produce clones of the same specificity of antibodies. Their separation into individual form is carried out in the same manner as in the case of polyclonal antisera.

Preferred for the preparation of activated - potentiated form of antibodies to endothelial NO-synthase and C-terminal fragment AT1receptor angiotensin II is the use of polyclonal antibodies to endothelial NO-synthase and C-terminal fragment AT1receptor of angiotensin II, which as a matrix(primary) solution with a concentration of 0.55.0 mg/ml, used for the subsequent preparation of the activated - potentiated form.

Preferred for the preparation of each component is the use of a mixture of three aqueous-alcohol dilutions of the initial matrix solution of antibodies, diluted, respectively, in the 10012, 10030and the 100200time, which corresponds to boast of dilutions C12, C30 and C200, prepared according to homeopathic technology.

Polyclonal antibodies to endothelial NO-synthase can be obtained by using as an immunogen (antigen) for immunization of rabbits adjuvant and whole molecules of endothelial NO-synthase following sequence:

1 MGNLKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPEPSR APAPATPHAP DHSPAPNSPT

61 LTRPPEGPKF PRVKNWELGS ITYDTLCAQS QQDGPCTPRR CLGSLVLPRK LQTRPSPGPP

121 PAEQLLSQAR DFINQYYSSI KRSGSQAHEE RLQEVEAEVA STGTIHLRES ELVFGAKQAW

181 RNAPRCVGRIQWGKLQVFDA RDCSSAQEMF TYICNHIKYA TNRGNLRSAITVFPQRAPGR

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 WTSTFGNGD 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 GPPPSWVRDPRLPPCTVRQA LTFFLDITSP PSPRLLRLLS TLAEEPSEQQ ELETLSQDPR

901 RYEEWKLVRC PTLLEVLEQF SVALPAPLL 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 LRDQQRYHEDIFGLTLRTQE VTSRIRTQSF SLQERHLRGA VPWAFDPPGP 1201 DTPGP

It is possible to obtain polyclonal antibodies to endothelial NO-synthase using as immunogen (antigen) of whole molecules of endothelial NO-synthase following sequence:

1 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR APASLLPPAP EHSPPSSPLT

61 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL GSLVFPRKLQ GRPSPGPPAP

121 EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT GTYQLRESEL VFGAKQAWRN

181 APRCVGRIQW GKLQVFDARD CRSAQEMFTYICNHIKYATN 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 AQS YAQQLGR

541 LFRKAFDPRV LCMDEYDVVS LEHETLWLW TSTFGNGDPP ENGESFAAAL MEMSGPYNSS

601 PRPEQHKSYKIRFNSISCSD PLVSSWRRKR KESSNTDSAG ALGTLRFCVF GLGSRAYPHF

661 CAFARAVDTR LEELGGERLL QLGQGDELCG QEEAFRGWAQ AAFQAACETF CVGEDAKAAA

721 RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ ATIRSVENLQ SSKSTRATIL

781 VRLDTGGQEG LQYQPGDFflG VCPPNRPGLV EALLSRVEDP PAPTEPVAVE QLEKGSPGGP

841 PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL AEEPREQQEL EALSQDPRRY

901 EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY SVSSAPSTHP GEIHLTVAVL

961 AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR LPPDPSLPCILVGPGTGIAP

1021 FRGFWQERLH DIESKGLQPT PMTLVFGCRC SQLDHLYRDE VQNAQQRGVF GRVLTAFSRE

1081 PDNPKTYVQDILRTELAAEV HRVLCLERGH MFVCGDVTMA TNVLQTVQRI LATEGDMELD

1141 EAGDVIGVLR DQQRYHEDIF GLTLRTQEVT SRIRTQSFSL QERQLRGAVP WAFEPPGSDT

1201 NSP

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

1192-1195

PWAF

1189-1192:

GAVP

1185-1205:

RHLRGAVPWAF DPPGPDTPGP

1194-1205:

AF DPPGPDTPGP

1186-1196:

HLRGAVPWAF D

1186-1205:

HLRGAVPWAF DPPGPDTPGP

Before taking the blood sample for 7-9 days spend 1-3 intravenous injection for raising antibodies. In the process of immunization in rabbits take small blood samples to estimate the number of antibodies. The maximum level of immune response to the introduction of most soluble antigens is achieved in 40-60 days after the first injection. After completion of the first cycle immunization of rabbits for 30 days to give to restore health and are reimmunization including 1-3 intravenous injection. To obtain antisera from immunized rabbits collect the blood in a centrifuge tube with a volume of 50 ml using a wooden spatula to remove from the walls of the tube formed clots and put the wand in the clot formed in the center of the tube. The blood is placed in a refrigerator (4C) overnight. The next day remove the clot adhered to the spatula, and centrifuged remaining liquid at 13000g for 10 minutes the Supernatant (supernatant) is anticorodal. The resulting anticavity should be yellow. Add to anticigarette 20% (weight concentration) NaN3D. the final concentration of 0.02% and stored until use in a frozen state at -20C (or without addition of NaN 3- at -70C). For allocation from the antisera of antibodies to endothelial NO-synthase produce absorption in the solid phase in the following sequence:

1. 10 ml of rabbit antisera diluted 2 times with 0.15 M NaCl type of 6.26 g of Na2SO4, mixed and incubated for 12-16 h at 4C;

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

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

4. the fraction of antibodies determined by measuring the optical density of the eluate at 280 nm.

Then make a clearance antibodies, for example, by the method of affinity chromatography by attaching the obtained antibodies to endothelial NO-synthase, which is insoluble matrix followed by elution with concentrated salt solutions.

Obtained, thus, the buffer solution of polyclonal rabbit antibodies to endothelial NO-synthase, purified on antigen, with a concentration of 0.55.0 mg/ml, preferably 2,03,0 mg/ml, used as a matrix (primary) solution for the subsequent preparation of the activated - potentiated form on homeopathic technology.

The polyclonal antibodies is and to C-terminal fragment AT 1receptor of angiotensin II can be obtained similar to the above method, using as immunogen (antigen) for immunization of rabbits, for example, adjuvant and C-terminal fragment AT1receptor of angiotensin II select, for example, from the following groups:

GKKFK RYFLQLLKYI PPKAKSHSNL STKMSTLSYR PSDNVSSSTK KPAPCFEVE

LNPF FYVFFGKNFK KYFLQLIKYI PPNVSTHPSL TTKMSSLSYR PPENIRLPTK KTAGSFDTE

QLLKYI PPKA

SSLSYR PPENIR

QLIKYI PPNVSTHP

SNL STKMSTLSYR PSDNVSSSTK KPAPCF

It is possible to obtain polyclonal antibodies to C-terminal fragment AT1receptor of angiotensin II using as immunogen (antigen) C-terminal fragment of the ATI receptor of angiotensin II person added to the N end of a Cysteine (C):

CGKKF KRYFL QLLKY IPPKA KSHSN LSTKM STLSY RPSDN VSSST CCRR CFEVE

The activated - potentiated form of each component is prepared by uniformly reducing the concentration in the serial dilutions 1 of the above matrix solution of 9 parts (for decimal dilution (D) or 99 parts (for centesimal dilution (C) or in 999 parts (for the thousandth breeding M) neutral solvent with multiple vertical shaking ("dynamics") of each received cultivation and use separate containers for each subsequent breeding until you get the desired potency - ratio cultivation in homeopathic method (the m, for example, Usabe "Homeopathic medicinal product", M, 1967, p.14-29).

External processing in the process of reducing the concentration can be realized by ultrasound, electromagnetic or other physical effects.

For example, for the preparation of the 12th centesimal dilution C12 one part of the mentioned matrix solution of antibodies to endothelial NO-synthase (or C-terminal fragment AT1receptor angiotensin II) with a concentration of 3.0 mg/ml diluted in 99 parts of a neutral aqueous or aqueous-alcoholic solvent and repeatedly (10 times or more) vertically shaken - potentiate received 1st somenoe C1 breeding. From the 1st centesimal C1 breeding prepare 2nd somenoe breeding C2. This operation is repeated 11 times, getting 12th somenoe breeding C12. Thus, 12th somenoe breeding C12 represents the solution obtained by diluting consistently in different tanks 12 times the 1st part of the initial matrix solution of antibodies to endothelial NO-synthase with a concentration of 3.0 mg/ml in 99 parts of a neutral solvent, a solution prepared by dilution of the matrix solution in 100 times. Similar operations with a corresponding multiplicity of cultivation is performed to obtain a dilution C30 and C200.

When used as a biologically active liquid component of the mixture of various,mainly centesimal, dilutions of the active substance prepared according to homeopathic technology, each component of the composition (for example, C12, C30, C200) prepare separately for the above-described technology to their penultimate cultivation (respectively, to obtain the joint venture, s, S) and then applied in accordance with the composition of the mixture in one container, one part of each component and mixed with the required amount of solvent (respectively, with 97 parts for centesimal dilution). You get the activated - potentiated form of antibodies to endothelial NO-synthase in midget doses received by Sverrisdottir matrix solution, respectively, 10012, 10030 and 100200 times, equivalent to a mixture of centesimal dilutions C12, C30 and C200, prepared according to homeopathic technology.

You can use the active substance in the form of a mixture of other various dilutions, for example, decimal, and/or centesimal, (D20, C30, C100 or C12, C30, with50 etc.), prepared according to homeopathic technology, the effectiveness of which is determined experimentally.

When potentiation instead of shaking in the process of reducing the concentration can also be external effects of ultrasound, electromagnetic or other physical effects.

For experimental studies have used polyclonal antibodies, prigot is undertaken by order of the specialized biotechnology firm.

Example 1.

For experimental study of correction of endothelial dysfunction experiments were carried out on white rats male Wistar weighing 250-300 g were divided into 4 groups: group 1 - control, received distilled water 9 ml/kg/day (daily intragastric administration.), group 2 - received L-NAME (12.5 mg/kg), group 3 - received L-NAME (12.5 mg/kg)+ mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial NOS man - C12, C30, C200 (9 ml/kg/day), group 4 - received L-NAME(12.5 mg/kg)+mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial NOS man - C12, C30, C200 (9 ml/kg/day)+a mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragment of the ATi receptor of angiotensin II - C12, C30, C200 (9 ml/kg/day).

Endothelial dysfunction in rats caused a (simulated) by the intraperitoneal administration of N-nitro-L-arginine methyl ester (L-NAME) at a dose of 12.5 mg/kg/day for 28 days. On the 29th day from the beginning of the experiment under General anesthesia (sodium thiopental (50 mg/kg) catheter in the left carotid artery for recording blood pressure (BP), a bolus of pharmacological agents in the right femoral vein. Hemodynamic parameters: systolic blood pressure (SBP), diastolic blood pressure (YES who) and heart rate (HR) was measured continuously by a sensor TSD104A and hardware-software complex MP 100 production Biopac System, Inc., USA. Functional tests: endothelium-dependent vasodilatation (ESV) - intravenous administration of acetylcholine (ach) at a dose of 40 mcg/kg, endothelium-independent vasodilatation (ANSW) - intravenous sodium nitroprusside (NP) at a dose of 30 g/kg

The degree of development of endothelial dysfunction was assessed by the coefficient of endothelial dysfunction, which is the ratio of the area of the triangle above the trend of the reduction reaction of blood pressure (BP) in response to the introduction of sodium nitroprusside (NP) to the area of the triangle above the trend of the reduction reaction of blood pressure in response to the introduction acetylcholine (ach).

When the statistical processing of the data was calculated the mean value, the standard deviation value. The differences were considered significant at p<0,05.

Processing of experimental data when carrying out functional tests on endothelium-dependent (acetylcholine 40 g/kg) and endothelium-independent (nitroprusside 30 mg/kg/in) relaxation of blood vessels in experimental animals have found that intraperitoneal injection of L-Name at a dose of 12.5 mg/kg for 28 days caused an increase of the coefficient of endothelial dysfunction to 3.50,5 used (PL. 1), whereas in the control group of animals (intragastric administration of distilled water at a dose of 9 ml/kg/day) QED was 1.20,1 usled

In the group of animals, the which within 28 days were administered L-Name at a dose of 12.5 mg/kg, intragastrically mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide person, at a dose of 9 ml/kg - C12, C30, C200 in complex with a mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragment AT1receptor of angiotensin II - C12, C30, C200 QED amounted to 1,80,2 usled

In the group of animals that within 28 days were administered L-Name at a dose of 12.5 mg/kg and was administered intragastrically mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide person (at a dose of 9 ml/kg/day) - C12, C30, C200 in complex with a mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragment AT1receptor of angiotensin II (at a dose of 9 ml/kg/day) - C12, C30, C200 QED amounted to 1.40,1), which is significantly lower than in the group of animals which were administered L-Name, and in the group of animals with mono correction with a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide person at a dose of 9 ml/kg - C12, C30, C200.

Thus, the obtained results confirm the possibility of correction L-Name-induced endothelial dysfunction in rats by L-Name at a dose of 12.5 mg/kg by intragastric administration of a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide person - C12, C30, C200 in complex with a mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragmented receptor of angiotensin II - C12, C30, C200 in the dose of 9 ml/kg each of them, resulting in the reduction of QED in this group of animals to the level of 1,40,1 usled, close to the level of QED in the control group of animals - 1,20,1 usled

The data obtained allow us to conclude about the possibility of effective correction of endothelial dysfunction in humans.

Table 1

Dynamics of parameters of blood pressure and coefficient of endothelial dysfunction in the simulation of L-Name-induced endothelial dysfunction and correct it with a mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial synthase nitric oxide person, at a dose of 9 ml/kg - C12, C30, C200 in complex with a mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragment of the receptor of angiotensin II - C12, C30, C200 in the dose of 9 ml/kg/day.
Groups of animalsFunctional testGARDEN, mm HgDBP, mm Hg's vascular reactions when conducting EDVD with AH and AND with NP, usledQED, the river. units
The checkpoints for important locations the I (daily, intragastric administration of distilled water and 9 ml/kg/day)Source159,25,4to 124.24,7
OHto 96.96,752,03,03071,2501,11,20,1
NP113,86,1552,43617,2560,1
Treated with L-NAME (12.5 mg/kg)Source204,810*164,25,9*
OH111,37,464,74,3*3700,2536,93,50,5*
NP118,29,961,44,411922,81838,9*
L-NAME (12.5 mg/kg)+mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial NOS man - C12, C30, C200 (9 ml/kg/day)And the output 230,18,8*175,16,4*
OH116,44,0*73,53,5*5826,0801,2**1,80,2**
NP108,14,6603,69628,5970,1*
L-NAME(12.5 mg/kg)+mixture of solutions of homeopathic dilutions of polyclonal rabbit antibodies to endothelial NOS man - C12, C30, C200 (9 ml/kg/day) +mixture of solutions of homeopathic dilutions of antibodies to C-terminal fragment AT1receptor of angiotensin II - C12, C30, C200 (9 ml/kg/day)Source213,64,6*166,82,7*
OH116,95,5*73,33,4*3295,3201,41,40,1**
NP122,34,670,54,5*4546,2299,4**
When echange: * - p<0,05 in comparison with the control group; ** - p<0,05 in comparison with the group of L-NAME. GARDEN - systolic blood pressure, DBP - diastolic blood pressure, S is the area above the curve recovery of blood pressure when conducting pharmacological tests, CED - factor for endothelial dysfunction.

1. Method of correction of endothelial dysfunction, characterized by the fact that the body is injected simultaneously activated - potentiated form of antibodies to endothelial synthase nitric oxide in combination with an activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II.

2. The method according to claim 1, characterized in that the activated - potentiated form of antibodies to endothelial NO-synthase and the activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II is used in the form of activated - potentiated aqueous or aqueous-alcoholic solution of each component, the activity of which is due to the sequential process of repeated dilution in water or water-alcohol solvent in combination with an external mechanical impact - vertical shaking of every dilution.

3. The method according to claim 2, characterized in that an aqueous or aqueous-alcoholic solutions of the activated - potentiated form of antibodies to endothelial synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II are obtained by repeated consecutive dilution in conjunction with external cause - vertical shaking of every dilution of the matrix solution of antibodies with a concentration of 0.55.0 mg/ml

4. The method according to claim 1 or 2, characterized in that the activated - potentiated form of antibodies to endothelial synthase nitric oxide and activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II is used in the form of a mixture of various, mainly centesimal, in homeopathic dilutions technology.

5. The method according to claim 1 or 2, characterized in that for the correction of L-Name-induced endothelial dysfunction in rats induced by injection of L-Name at a dose of 12.5 mg/kg, are used simultaneously activated - potentiated form of antibodies to endothelial synthase nitric oxide in combination with an activated - potentiated form of antibodies to C-terminal fragment AT1receptor of angiotensin II in the form of a mixture of solutions of homeopathic dilutions C12, C30, C200.



 

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14 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: invention relates o medicine and can be applied in treating varicose disease of veins of lower extremities with application of endovenous laser vein coagulation (ELVC). For this purpose skin area, which is subjected to operation, is processed with antiseptic solution. Under control of ultrasonic apparatus into vessel lumen introduced is catheter, through which light-conductor is passed to saphenofemoral fistula. After that, tumescent anesthesia is performed by creation of water "cushion", at that applying cold, ozonised 0.9% physiological solution with temperature 5-7C, ozone concentration 4-5 mcg/ml and time of saturation with ozone 5-8 minutes. Or ozonised 0.1% lidocaine solution with temperature 5-7C, ozone concentration 4-5 mcg/ml and time of saturation with ozone 5-8 minutes is introduced. After that, pathological vessel is exposed to laser energy. If necessary, applications of 50 ml ozonised heparin-containing gel are made after procedure in projection of coagulated vein with exposition 60-90 minutes until ozone concentration of gels reaches 6500-7000 mcg/ml.

EFFECT: method ensures effective treatment of said pathology due to selection of most optimal type of anesthesia and following therapy, which contribute to reduction of pains, local manifestations of inflammation, activation of processes of focal and marginal epithelisation processes.

2 cl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and concerns a multimodality therapy for diabetic foot. That is ensured by a local and infusion therapy. The local therapy involves using the ointments Curiosin and Levomecol. The infusion therapy involves administering rheopolyglucin 5.3 ml/kg and 2% trental 1.3 mg/kg, 0.9% NaCl 300 ml and Cytoflavin 10 ml; 0.9% NaCl 300 ml and vitamin C 9 mg/kg in daily doses for degree I ulcers; the infusion therapy is combined with a magnetic therapy generated by MAGNET-Med TeKo apparatus at magnetic induction intensity 75% for 16 minutes. Degree II ulcers require doses of the infusion preparations, except for 0.9% NaCl, to be doubled, while the magnetic therapy is performed at magnetic induction intensity 100%, length of exposure 32 minutes; the therapeutic course is 10 procedures.

EFFECT: method provides higher effectiveness and reduced length of treating ensured by the correction of oxidation-reduction processes and improvement of tissue regeneration.

1 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental cardiology, and concerns the L-NAME-induced endothelial dysfunction correction. That is ensured by introducing the mixture of solutions of homoeopathic dilutions of rabbit monoclonal antibodies to human endothelial nitrogen oxide synthase C12, C30, C200 (9 ml/kg/day) in complex with the mixture of solutions of homoeopathic dilutions of angiotensin II receptor C-terminal fragment antibodies C12, C30, C200 in a dose of 9 ml/kg/day.

EFFECT: method provides the effective endothelial dysfunction correction in the specific experimental environment.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to cardiology, and concerns the endothelial dysfunction correction. That is ensured by a therapeutic agent containing an activated potentiating form of vascular endothelium growth factor (VEGF) antibodies. The activity of the therapeutic agent is related to the process of multiple serial dilutions in an aqueous or aqueous-alcohol solution in a combination with an external mechanical vertical agitation of each dilution.

EFFECT: method provides the effective L-NAME-induced endothelial dysfunction correction in experiment.

6 cl, 1 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology and medicine. What is described is an active immunostimulating vaccine containing at least one RNA, preferentially iRNA coding at least two antigens evoking the immune response in a mammal and used for treating lung cancer, first non-small cells lung cancer (NSCLC), preferentially specified among three primary subtypes, squamous cell carcinoma, adenocarcinoma and large-cell lung carcinoma, or NSCLS-related disorders.

EFFECT: there are produced kits, first containing the active immunostimulating vaccine.

21 cl, 34 dwg, 1 tbl, 8 ex

FIELD: veterinary medicine.

SUBSTANCE: method for production of anti-luteolytic blood - AlB is that luteolisate is administered subcutaneously to gelding twice with an interval of 14 days at a dose of 20 ml each, containing parts of the corpus luteum of pregnancy of cows, and after 14 days after the second administration the blood is taken from the jugular vein. The method of treatment and prevention of persistent corpus luteum, subinvolution of uterus and postpartum endometritis in cows comprises at the background of general therapy the use of anti-luteolytic blood that is administered subcutaneously in the neck region twice at a dose of 10 ml each with an interval of 6 days.

EFFECT: use of anti-luteolytic blood promotes the resorption of the corpus luteum of pregnancy and shortens the duration of postpartum involution of genitals that enables to prevent and reduce the time of treatment of ill cows with persistent corpus luteum, subinvolution of uterus and postpartum endometritis.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to therapy and pharmacology, and can be used to increase pharmacological activity and therapeutic efficacy of drug preparations of activated-potentiated forms of hyperdiluted antibodies. That is ensured by administering a pharmaceutical composition containing activated potentiated pathogenic antigen and endothelial NO-synthase antibodies.

EFFECT: administering this composition provides higher therapeutic efficacy ensured by a synergetic effect of the ingredients of the composition.

10 cl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and veterinary science and concerns a method for producing the purified antigen of Dirofilaria immitis. The presented method involves mechanical homogenisation, centrifugation of a homogenate, collection of a supernatant to be used as an antigen; the homogenisation involves a 2-cm head end of a mature female of Dirofilaria immitis placed in an aqueous solution of saccharose 0.25 M in a ratio of 1:3, frozen at a temperature of -18C, that is followed by mechanical homogenisation and protein extraction in the aqueous solution of saccharose 0.25 M at 4C for 12 hours, wherein 3 cycles of five 30-second ultrasonic homogenisations of the supernatant is performed at 70 kHz every 30 seconds at 0C; the supernatant prepared after ultrasonic homogenisation is dissolved in cooled acetone at a temperature of 0C in a ratio of 1:20 with exposition for 1 hour at a temperature of 4C.

EFFECT: presented invention enables producing the high-sensitivity and specificity antigen and can be used in diagnosis of dirofilariasis in humans and animals.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and deals with an application of an antibody, which binds with residues of 1-5 or 3-7 A-beta, to reduce vascular amyloid in a patient with cerebral amyloid angiopathy, with the antibody being introduced intravenously or subcutaneously.

EFFECT: invention provides purification of the patient's vessels from amyloid deposits.

9 cl, 2 ex, 6 dwg

FIELD: biotechnology.

SUBSTANCE: strain Moraxella bovoculi has antigenic, virulent properties and immunogenic activity. It is deposited under the number "SH-Ch6 N-DEP" in the All-Russian State Collection of strains of microorganisms used in veterinary medicine and animal husbandry FSBI "Russian national centre of quality and standardisation of drugs for animals and feed". The strain can be used in manufacture of diagnostic preparations and vaccines against infectious keratoconjunctivitis of cattle.

EFFECT: invention enables to produce diagnostic preparations and vaccines against infectious keratoconjunctivitis of cattle.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and veterinary science.

EFFECT: using RPE (ribosomal protein extract) together with Th1-activating adjuvant for preparing a drug for treating or preventing a parasitic disease provides cross-protective immunity against different Leishmania species.

13 cl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to therapy, and concerns treating viral infections. That is ensured by administering a drug containing active ingredients presented by an activated-potentiated form of human gamma-interferon antibodies and an activated-potentiated form of CD4 receptor antibodies.

EFFECT: administering this combined drug provides effective treatment of viral diseases ensured by the synergetic antiviral effect of the active ingredients of the drug.

10 cl, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a preparation, stimulating antigen-independent differentiation of B-lymphocytes, from a raw material of an animal origin. The method of obtaining the preparation, stimulating antigen-independent differentiation of B-lymphocytes, from the raw material of the animal origin includes homogenisation of the preliminarily frozen at -40C tissue of porcine endometrium with further extraction for 36 hours in 3% solution of acetic acid with a ratio 1 part of the raw material to 5 parts of an acetic acid solution and addition of zinc chloride in dose 1 g per 1 l of 3% acetic acid at pH 3.5-4.0, in which the obtained extract is filtered, centrifuged at 3000 rev/min for 20 min, a supernatant liquid is poured into the cooled acetone with a ratio 1:5, a sediment is formed for 12 hours at -4C, precipitated with acetone, the target product is additionally purified by ultrafiltration with the limit of molecular retention 5kD, with further filtration and lyophilisation.

EFFECT: extension of the assortment of highly efficient medications, stimulating antigen-independent differentiation of B-lymphocytes.

5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions discloses a pharmaceutical composition and a kit containing type II anti-CD20 antibodies and a proteasome inhibitor applicable in treating cancer expressing CD20. Also, the group of inventions refers to using type II anti-CD20 antibodies for obtaining a drug preparation applicable for treating cancer expressing CD20 in a combination with the proteasome inhibitor.

EFFECT: group of inventions is characterised by using the antibodies possessing high antibody-dependent cell-mediated cytotoxicity and efficacy in the therapy of cancer diseases.

13 cl, 3 dwg, 4 tbl, 3 ex

FIELD: immunotherapeutic agents.

SUBSTANCE: antigenic preparations are obtained from keratinophilic fungi Trichophiton or Microsporum species or yeast species Candida by alkali hydrolysis techniques. Thus obtained preparations can be, in particular used, as vaccines and for treating allergy and modulating immune response.

EFFECT: expanded immunotherapeutic possibilities.

17 cl, 5 dwg, 12 tbl, 20 ex

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