Medication for treating alzheimer's disease and method of treating alzheimer's disease

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurology, and deals with treatment of Alzheimer's disease. For this purpose pharmaceutical composition, which contains activated potentiated form of antibodies to brain-specific protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase, is introduced.

EFFECT: introduction of claimed composition provides efficient treatment of Alzheimer's disease due to synergic neuroprotective, anti-ischemic and anxiolytic action of composition components.

9 cl, 5 tbl, 3 ex

 

The invention relates to medicine and can be used for the treatment of Alzheimer's disease.

In the prior art it is known neurotropic drug on the basis of antisera to meshoperations protein S-100 (RU2156621 C1, A61K 39/395, 27.09.2000).

It is also known study of the drug on the basis of ultra-low doses of antibodies to meshoperations protein S-100 in violation of cognitive functions, emotional, and neurological status in conditions of experimental models of Alzheimer's disease, which showed that the drug has the ability to restore impaired cognitive function, improves emotional state, reduces anxiety and may be promising for the prevention and treatment of Alzheimer's disease (Voronina T. A., long, M. C. and others Effect of ultra-low doses of antibodies to S-100 in violation of cognitive functions, emotional, and neurological status in conditions of experimental models of Alzheimer's disease. Bulletin of experimental biology and medicine. 2009, No. 8, Annex, S. 174-176).

The invention is directed to the creation of effective means for the prevention and treatment of Alzheimer's disease.

The solution of this problem is provided by the fact that drug for the treatment of Alzheimer's disease containing the activated potentiated form of antibodies crashesplugin.mo protein S-100, according to the invention, made in the form of pharmaceutical compositions and contains extra reinforcing component of the activated potentiated form of antibodies to endothelial NO-synthase.

When this activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase is used in the form of the activated potentiated aqueous or aqueous-alcoholic solution, 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.

The pharmaceutical composition can be made in solid dosage form and contain an effective amount of particles of a neutral carrier, saturated with a mixture of aqueous or aqueous-alcoholic solutions of the activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase, and pharmaceutically acceptable additives, including lactose, cellulose microcrystalline and magnesium stearate.

Moreover, aqueous or aqueous-alcoholic solutions of the activated potentiated form of antibodies to meshoperations protein S-100 and endothe territorial NO-synthase obtained by repeated consecutive dilution in conjunction with external cause - vertical shaking of every dilution of the matrix solutions of affinity purified antibodies to meshoperations protein S-100 and to endothelial NO-synthase with a concentration of 0.5÷5.0 mg/ml

Preferably each of the components of ultra-low doses of affinity purified antibodies are used in the form of a mixture of various, mainly centesimal, dilutions, prepared according to homeopathic technology.

The solution of this problem is provided by the fact that in the treatment of Alzheimer's disease by introducing into the body of the activated potentiated form of antibodies to meshoperations protein S-100, according to the invention, optionally (at the same time and combined) introducing the activated potentiated form of ultra-low doses of affinity purified antibodies to endothelial NO-synthase.

When this activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase is used in the form of the 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.

Preferably the use is prepared in the form of a single - drug one dosage form a mixture of different dilutions of antibodies to meshoperations protein S-100 in combination with a mixture of various dilutions of antibodies to endothelial NO-synthase, prepared according to homeopathic technology.

In addition, the drug contains active components in a volume ratio of 1:1, with each component used in the form of a mixture of three corresponding matrix solutions, diluted, respectively, in the 10012, 10030and the 100200once that is equivalent to boast of dilutions C12, C30, C200, prepared according to homeopathic technology.

The claimed pharmaceutical composition is recommended, preferably, 1-2 tablets 2-6 times a day.

In the treatment of Alzheimer's disease may separate, but combined and simultaneous use (organism) of the claimed pharmaceutical compositions in the form of two separately prepared drugs in the form of solutions and in solid dosage forms (tablets), each of which contains the activated potentiated form of ultra-low doses of affinity purified antibodies to meshoperations protein S-100 and, accordingly, the activated potentiated form of ultra-low doses of affinity purified antibodies to endothelial NO-synthase.

The proposed combination of the activated potentiated Faure the antibodies to meshoperations protein S-100 and to endothelial NO-synthase in the pharmaceutical composition (i.e., forms antibodies to meshoperations protein S-100 and to endothelial NO-synthase, prepared according to homeopathic technology exponentiation by repeated consecutive dilution and external influences - vertical shaking (see, for example, C. Schwabe "Homeopathic medicinal product", M, 1967, S. 14-29), which have activity caused by potentiation in pharmacological models and/or clinical treatment of Alzheimer's disease) provides an unexpected synergistic therapeutic effect, confirmed adequate (valid) experimental models and clinical studies, which is to enhance the effectiveness of treatment of Alzheimer's disease. This technical result due to increased neuroprotective activity of antibodies to protein S-100, increasing vegetal stabilizing effect, normalization of vegetative status, a synergistic effect of both components in neuronal plasticity and, consequently, increasing the resistance of the brain to toxic effects, which improves the integrative activity and restores interhemispheric communication brain, helps to eliminate cognitive impairment, stimulates reparative processes and accelerates the recovery of functions of the Central nervous system, improves the mind is to promote the health, restores the processes of learning and memory, normalizes somatovegetative symptoms, increases cerebral blood flow, and therefore provides a more effective treatment of Alzheimer's disease.

At the same time declared the drug, as its components, does not have a sedative and miorelaksantnoe action, does not cause addiction and habituation.

In addition, the claimed medicinal product expands the Arsenal of drugs intended for the treatment and prevention of Alzheimer's disease.

The drug is prepared mainly as follows.

For preparation of the 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, edited by G. of Primes, M, "Medicine", 1987, S. 9-33; or, for example, article Laffly, E., R. Sodoyer Hum. Antibodies. Monoclonal and recombinant antibodies, 30 years after. - 2005 - Vol.14. - N 1-2. P. 33-55.

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 of work includes getting brednich cells, producing 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.

Polyclonal antibodies can be obtained by active immunization of animals. For this purpose a specially designed circuit animals make a series of injections required in accordance with the invention substances - antigens: mathoperation protein S-100 and endothelial NO-synthase. As a result of this procedure is to obtain monospecific antisera with high content of antibodies that is used to produce the activated potentiated form of components. 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.

Preferred for the preparation of the claimed pharmaceutical compositions is the use of polyclonal antibodies to meshoperations protein S-100 and to endothelial NO-synthase, which as a matrix (primary) solution with a concentration of 0.5÷5.0 mg/ml, is used for the subsequent preparation of the activated potentiated form.

Preferred for the preparation of each component is the use of a mixture of trihydrate-alcohol-dilution of initial matrix solution of antibodies, diluted, respectively, in the 10012, 10030and 100200time, which corresponds to boast of dilutions 12, C30 and With 200, prepared according to homeopathic technology. In carrying out the stated drugs in solid dosage form on the lactose is applied a mixture of these components.

Preferred for the preparation of the claimed medicinal preparation is the use of polyclonal antibodies to meshoperations protein S - 100 and endothelial NO-synthase, which can be obtained by immunization of rabbits as follows.

For the experimental studies were used antibodies, cooked to order specialized biotechnology firm.

Polyclonal antibodies to endothelial NO-synthase get, using as immunogen (antigen) for immunization of rabbits with adjuvant whole molecule endothelial NO-synthase following sequence:

1 MGNLKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPEPSR ARARATYAN 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 HTGWRGPGL RWYALPAVSN MLLEIGGLEF SAAPFSGWYM

361 STEIGTRNLC DPHRYNILED VAVCMDLDTR TTSSLWKDKA AVEINLAVLH SFQLAKVTIV

421 DHHAATVSFM KHLDNEQKAR GGCPADWAWI VPPIYGSLPP VFHQEMVNYI LSPAFRYQPD

481 PWKGSATKGA GITRKKTFKE VANAVKISAS LMGTLMARV KATILYASET GRAQSYAQQL

541 GRLFRKAFDP RVLCMDEYDV VSLEHEALVL VVTSTFGNGD PPENGESFAA ALMEMSGPYN

601 SSPRPEQHKS YKIRFNSVSC SDPLVSSWRRKRKESSNTDS AGALGTLRFC VFGLGSRAYP

661 HFCAFARAVD TRLEELGGER LLQLGQGDEL CGQEEAFRGW AKAAFQASCE TFCVGEEAKA

721 AAQDIFSPKR SWKRQRYRLS AQAEGLQLLP GLIHVHRRKM FQATVLSVEN LQSSKSTRAT

781 ILVRLDTAGQ EGLQYQPGDH IGISAPNRPG 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 APFRGFWQERLHDIESKGLQ 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 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 CRSAQEMFTY ICNHIKYATN RGNLRSAITV FPQRCPGRGD

241 FRIWNSQLVRYAGYRQQDGS 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 PLVSSWRRKRKESSNTDSAG ALGTLRFCVF GLGSRAYPHF

661 CAFARAVDTRLEELGGERLL QLGQGDELCG QEEAFRGWAQ AAFQAACETF CVGEDAKAAA

721 RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ ATIRSVENLQ SSKSTRATIL

781 VRLDTGGQEG LQYQPGDHIG VCPPNRPGLV EALLSRVEDP PAPTEPVAVE QLEKGSPGGP

841 PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL AEEPREQQEL EALSDPRRY

901 EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY SVSSAPSTHP GEIHLTVAVL

961 AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR LPPDPSLPCI LVGPGTGIAP

1021 FRGFWQERLHDIESKGLQPTPMTLVFGCRC SQLDHLYRDE VQNAQQRGVF GRVLTAFSRE

1081 PDNPKTYVQD ILRTELAAEV HRVLCLERGH MFVCGDVTMA TNVLQTVQRI LATEGDMELD

1141 EAGDVIGVLRDQQRYHEDIF GLTLRTQEVT SRIRTQSFSL QERQLRGAVP WAFEPPGSDT

1201 NSP

It is possible to obtain polyclonal antibodies to endothelial NO-synthase using as 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 Guston, formed in the center of the tube. The blood is placed in a refrigerator (4°C) 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) NaNs to a final concentration of 0.02% and stored until use in a frozen state at -20°C (or without the addition of NaNs - at -70°C). 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 Nad, type of 6.26 g of Na2SO4, mixed and incubated for 12-16 h at 4°C;

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 produce the purification of antibodies by the method of affinity chromatography by attaching the obtained antibodies to endothelial NO, 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 0.5-5.0 mg/ml, preferably 2.0 to 3.0 mg/ml, used as a matrix (primary) solution for the subsequent preparation of the activated potentiated form.

To obtain polyclonal antibodies to meshoperations protein S-100 use mozopacity protein S-100, physico-chemical properties of which are described in the article by M. C. Starostin, S. M. Sviridov. Neurospecific protein S-100. The successes of modern biology, 1977, T. 5, S. 170-178; book M. B. Shtark, Meshoperations proteins /antigens/ and function of neuron, M, "Medicine", 1985; C. 12-14, isolated from brain tissue bull by the following method:

- frozen in liquid nitrogen fabric powdered in a special mill;

extraction of proteins is carried out in a ratio of 1:3 (weight/volume) in the extracting buffer by homogenization;

the homogenate was heated for 10 min at 60°C and cooled to 4°C in an ice bath;

- thermolabile proteins are removed by centrifugation;

- conduct stepwise fractionation with ammonium sulfate, followed by removal of precipitated impurity be the Cove;

- containing protein S-100 fraction precipitated by 100% saturated ammonium sulfate at lower pH to 4.0 and collected by centrifugation;

- dissolved in a minimal volume of buffer containing EDTA and mercaptoethanol, dialoginput against deionized water and freeze-dried;

- fractionation of acidic proteins continue chromatography on ion-exchange media - DEAE cellulose DE-52 and then DEAE-Sephadex a-50;

- collected and otvetsvennii fractions containing protein S-100, divide the molecular weight by gel-filtration on Sephadex G-100;

purified protein S-100 deleteroute and freeze-dried.

The molecular weight of purified mezhoperatorskogo protein S-100 is - 21000 D.

Due to the high content of aspartic and glutamic acids mozopacity protein S-100 is highly acidic and is at the anode position during electrophoresis in a discontinuous buffer system in polyacrylamide gel, which facilitates its identification.

To obtain meshoperations antisera to the selected meshoperations protein S-100 is prepared a mixture of purified protein S-100 (antigen) in complex with methylated bovine serum albumin as a carrier with complete adjuvant's adjuvant, which is injected subcutaneously laboratory animal is the rabbit back into the region in the number -2 ml On the 8th, the 15th day repeated immunization. Blood sampling produce (for example, from a vein of the ear) on the 26th and the 28th day.

The resulting anticavity has a titer of 1:500-1:1000, forms the only band of precipitation with an extract from nervous tissue, but does not react with extracts of heterologous bodies and forms a single peak precipitation with pure protein S-100 and extract the nervous tissue, indicating that monospecificity the obtained antisera.

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) or in 999 parts (for the thousandth breeding M) neutral solvent in combination with multiple vertical (not less than 10 times) by 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 (see, for example, C. Schwabe "Homeopathic medicinal product", M, 1967, S. 14-29).

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

For example, for the preparation of the 12th centesimal dilution With 12 one part of the mentioned matrix solution of antibodies to meshoperations protein S-100 (or NO-synthase) with a concentration of 2.5 mg/ml diluted in 99 parts of a neutral aqueous or aqueous-alcoholic solvent (mainly 15% ethanol) 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 12. Thus, 12th somenoe breeding With 12 represents the solution obtained by diluting consistently in different tanks 12 times the 1st part of the initial matrix solution of antibodies to meshoperations protein S-100 with a concentration of 2.5 mg/ml in 99 parts of a neutral solvent, i.e., a solution prepared by dilution of the matrix solution in the 10012time. Similar operations with a corresponding multiplicity of cultivation is performed to obtain dilutions With 30 and 200.

When used as a biologically active liquid component of the mixture of various, mainly centesimal, dilution of the active substance obtained by homeopathic technology, each component of the composition (for example, C12, C30, C0) is prepared separately as described above, technologyid their penultimate cultivation (respectively, to obtain C11, 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 meshoperations protein S-100 in midget doses received by Sverrisdottir matrix solution, respectively, in the 10012, 10030and 100200time equivalent mixture of centesimal homeopathic dilutions C12, C30 and C200.

You can use each component in a mixture of other various dilutions on homeopathic technology, for example, the decimal or centesimal, (C12, C30 C100; D20, C30 C100 or D20, C30, M100, and so on), the effectiveness of which is determined experimentally.

To obtain the claimed pharmaceutical compositions are aqueous or aqueous-alcoholic solutions of the active components are mixed, predominantly, in a volume ratio of 1:1 and used in liquid dosage form.

The claimed pharmaceutical composition can be used in solid dosage form that contains an effective amount of neutral particles of the carrier is lactose, saturated by soaking up the saturation a mixture of aqueous or aqueous-alcoholic solutions of the activated potentiated form of antibodies to shopelvis.com protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase, and pharmaceutically acceptable additives, including, primarily, lactose, cellulose microcrystalline and magnesium stearate.

For solid oral forms of the claimed medicinal product produced in the plant fluidized bed (for example, type "Hiittim Pilotlab" production company Huttlin GmbH) irrigation until saturation of injected fluid - fluidized bed of particles of neutral matter - of lactose (milk sugar) with a particle size of 150÷300 μm, a pre-obtained aqueous or aqueous-alcoholic solution of the activated potentiated form of antibodies to meshoperations protein S-100 and endothelial synthase nitric oxide (NO-synthase), mainly in the ratio of 1 kg of the solution of antibodies to 5 or 10 kg of lactose (1:5-1:10) with simultaneous drying in a stream supplied under the grate of heated air at a temperature not exceeding 40°C. the Estimated number 0,17÷0,34 by weight of the solid oral form dried particles, saturated activated potentiated form of antibodies, are loaded into the mixer and mixed with microcrystalline cellulose, enter the number 3÷8 mass. parts by weight of the total load from the mass of solid oral forms. Then to this mixture 25÷45 mass. parts by weight of the total load "unsaturated" pure lactose (to reduce the cost and some simplification and acceleration of process the of process without reducing the effectiveness of therapeutic effects) and magnesium stearate in an amount of 0.1÷0.3 mass. parts by weight of the total load. The obtained tablets weight evenly mixed and tabletirujut direct dry pressing (for example, in tablet press Korsch XL 400) with the formation of round tablets weight 150-500 mg After tabletting get a tablet weight of 300 mg, impregnated with a water-alcohol solution of the activated potentiated form of antibodies to meshoperations protein S-100 and NO-synthase in midget doses, each component prepared from a matrix solution, diluted, respectively, in the 10012in the 10030100200that is equivalent to a mixture of centesimal dilutions 12, C30 and C200, prepared according to homeopathic technology.

Preferably the claimed pharmaceutical composition is recommended to take 1-2 tablets 2-6 times a day.

Example 1.

The study of the impact of the integrated product, which consists of the activated potentiated forms of polyclonal affinity purified rabbit antibodies to meshoperations protein S-100 (anti-S100) and to endothelial NO-synthase (anti-eNOS) in ultra-low doses (ULD) obtained by Sverrisdottir initial matrix solution (concentration 2.5 mg/ml) at 10012, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions 12, C30, C200, in the ratio of 1:1 (ULD anti-S100+anti-eNOS), as well as components that make it with the Tav - the activated potentiated form of polyclonal rabbit antibodies to meshoperations protein S-100, purified on antigen, in ultra-low dose (ULD anti-S100) obtained by Sverrisdottir original matrix solution in the 10012,10030, 100200time equivalent mixture of centesimal homeopathic dilutions 12, C30, C200 and the activated potentiated form of polyclonal rabbit antibodies to endothelial NO-synthase, purified on antigen, in ultra-low dose (ULD anti-eNOS), obtained by Sverrisdottir original matrix solution in the 10012, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions C12, C30, C200, performed in vitro binding standard ligand [3H]pentazocine with recombinant Sigma 1 receptor human was assessed by radioligand method.

The Sigma-1 receptor - intracellular receptor localized in cells of the Central nervous system, the cells of most peripheral tissues and immune cells. Receptors demonstrate a unique ability to transloziruetsa, which is called by many psychotropic drugs. Dynamics of Sigma-1 receptors are directly connected with different influences, carried out by the drugs under the action of Sigma-1 receptors. These effects include the regulation of channel activity, ecosites, transmission of the signals, remodeling of the plasma membrane (formation of rafts) and transport of lipids/metabolism. All this can contribute to the development of plasticity of neurons in the brain. There is evidence that Sigma-1 receptors have a modulating effect on all of the major neurotransmitter systems: noradrenergic, serotonergic, dopaminergic, cholinergic system and NMDA-regulated glutamate effects. The Sigma-1 receptor plays an important role in the pathophysiology neurodegenerative diseases, including Alzheimer's, participates in the processes of learning and memory. In this regard, the ability of drugs to influence the efficiency of interaction of ligands with the Sigma-1 receptor indicates the presence of neuroprotective, anti-ischemic, anxiolytic, antidepressant, antiasteniceski components in the spectrum of their pharmacological activity, that allows to consider these drugs as effective medicines, including for the treatment of cerebrovascular diseases.

As a control test compounds were tested potentiated distilled water (a mixture of homeopathic dilutions C12+C30+C200).

In the experiment (to measure total binding) in the incubation medium was brought to 20 μl of the integrated product ULD anti-S100+ant the-eNOS or 10 ál of ULD anti-S100 or 10 ál of ULD anti-eNOS. Thus, the number of ULD anti-S100+anti-eNOS inserted in the pilot hole during testing of the integrated product was identical to the number of ULD anti-S100 and ULD anti-eNOS, tested as plain products, which allows to compare the effectiveness of the complex of the drug with its individual components included in its composition. Potentiated distilled water was introduced into the incubation medium in a volume of 20 μl and 10 μl.

Then he made 160 ál (~200(-ig protein)) homogenate membrane of the cell line Jurkat (line leukemic T-lymphocytes person), and finally 20 μl of radioligand labeled with tritium [3H]pentazocine (15 nm).

To measure nonspecific binding instead of drugs or potentiated water in the incubation medium was brought to 20 μl of unlabeled ligand haloperidol (10 μm).

Radioactivity was measured on a scintillation counter (Topcount, Packard) using a scintillation mixture (Microscint 0, Packard) after incubation for 120 minutes at a temperature of 22°C in 50 mm Tris-HCl buffer (pH 7,4) and filtration on glass fiber filters (GF/B, Packard). Specific binding (in the experiment or control) was calculated as the difference between total (experience or control) and nonspecific binding.

The results are presented as percent inhibition of specific binding in control (the quality of the ve control used distilled water) (table 1).

Table 1
The influence of drugs and potentiated water binding standard radioligand [3H]pentazocine with recombinant Sigma 1 receptor human
Experimental groupThe number inserted in the pilot hole% of specific binding of radioligand in control% inhibition of binding of radioligand in control
1st dimension2nd dimensionAverage
ULD anti-S100+anti-eNOS20 ál48,435,542.058,0
ULD anti-S10010 ál67,363,165,234,8
ULD anti-eNOS10 ál147, 5owed 161.1 -54,3
Potentiated water20 ál98,175,886,913,1
Potentiated water10 ál140, 1106,2of 123.2-23,2
Note:
% specific binding in control=(specific binding in the experience of specific binding in control)* 100%;
% inhibition of specific binding in control=100% - specific binding in the experience of specific binding in control) * 100%).

The results, reflecting the inhibition above 50% represent significant effects of the investigated compounds;

inhibition of 25% to 50%, testify about the effects of a weak to moderate; inhibition of less than 25% are considered insignificant effects of the investigated compounds and are within the background level.

Thus, in this experimental model, it is shown that: holistic medicine MD anti-5100+anti-eNOS more effective is, than its individual components (ULD anti-S100 and ULD anti-eNOS) inhibits the binding of standard radioligand [3H]pentazocine with recombinant Sigma 1 receptor human; ULD anti-S100, made in experimental well in a volume of 10 µl, inhibit the binding of standard radioligand [3H]pentazocine with recombinant Sigma 1 receptor human, but the effect is inferior to the severity of the effect of the integrated product ULD anti-S100+anti-eNOS; ULD anti-eNOS made in experimental well in a volume of 10 µl, had no effect on the binding of standard radioligand [3H]pentazocine with recombinant Sigma 1 receptor human; potentiated water introduced into the pilot hole in the volume of 10 ál or 20 ál, had no effect on the binding of standard radioligand [3H]pentazocine with recombinant Sigma 1 receptor human.

Example 2.

The study included patients with a diagnosis of Alzheimer's disease.

To study the properties of the claimed medicinal product for the treatment of Alzheimer's disease were used tablet weight of 300 mg, impregnated with a pharmaceutical composition comprising a water-alcohol solution (6 mg/tab.) the activated potentiated forms of polyclonal affinity purified rabbit antibodies to mathoperation is the protein S-100 (anti-S100) and to endothelial NO-synthase (anti-eNOS) in ultra-low doses (ULD), received Sverrisdottir initial matrix solution (with concentration of 2.5 mg/ml) at 10012, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions 12, C30, C200 (ULD anti-S100+anti-eNOS).

As a control group used a group of patients receiving the drug in the form of tablets weighing 300 mg impregnated with a water-alcohol solution (3 mg/tab.) the activated potentiated form of polyclonal rabbit antibodies to meshoperations protein S-100, purified on antigen, in ultra-low dose (ULD anti-S100) obtained by Sverrisdottir initial matrix solution (concentration 2.5 mg/ml) at 10012, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions 12, C30, C200.

The study was an open randomized comparative study of efficacy and safety of investigational therapy (drugs ULD anti-S100 and ULD anti-S100+anti-eNOS) in two parallel groups in patients with Alzheimer's disease mild to moderate severity.

The study included 6 patients with a diagnosis of Alzheimer's disease" mild and moderate severity, ranging in age from 55 to 64 years. The average age of the patients was 59,0±to 3.58 years.

The study examined the compliance of patients to sleduyuscheey include and exclude.

Inclusion criteria:

1. Patients with Alzheimer's disease mild to moderate severity, confirmed the results of medical history, neurological examination and medical documentation.

2. The immutability of concomitant therapy for at least months prior to Visit 1.

3. No grounds for any change in neurological concomitant therapy during the whole observation period.

4. The absence of the preconditions for the purpose of immunomodulating drugs in the next 6 months.

5. The level of education and understanding of the patient sufficient to adequately communicate with the investigator and study coordinator.

6. Patients are evaluated by the researcher as a reliable, ready to fulfill all scheduled clinical visits, tests and procedures specified by the Protocol.

7. Patients have a valid home address.

Exclusion criteria:

1. History of surgery on the brain.

2. Stroke in anamnesis.

3. The diagnosis of psychosis, bipolar disorder or schizoaffective disorder in history.

4. Major depressive disorder according to the criteria of the depression module of the international mini neuropsychiatric interview (MINI).

5. Factors/condition, medical or otherwise, which, according to issledovatel is, may affect the test results of the patient in this study.

6. Answers "2A", "2B", "2B" or "3" in the heading And the Beck depression inventory (active suicidal thinking with some intent to act, without specific plan or active suicidal thinking with specific plan and intent).

7. Autoimmune disease in history.

8. Acute liver failure or expressed cirrhosis (class C according To Child-Pugh).

9. Uncorrected thyroid gland.

10. Uncompensated arterial hypertension in history.

11. Severe or decompensated cardiovascular disease, liver disease, kidney disease, metabolic, respiratory, or hematologic disease, symptomatic peripheral vascular disease, or other medical or psychiatric condition which, in the opinion of the investigator, may affect patient participation in the study or may result in prolongation of hospitalization or re-hospitalization of the patient in the course of the study.

12. 3abolevaniya and States that, in the opinion of the investigator, may interfere with participation of the patient in the study.

13. The drug Impaza (ULD anti-eNOS) or Tenoten (ULD anti-S100) to participate in the study.

14. The antidepressants of any group not excluding herbal and homeopathic medicines.

15. Receiving anxiolytics any group, including herbal and homeopathic medicines.

16. Receiving immunomodulators, including herbal and homeopathic medicines.

17. Systemic treatment with steroids within 1 month or less before the

18. Visit 1.

19. Vaccinations, including flu.

20. Participation in the study drugs Impaza (ULD anti-eNOS) or Tenoten (ULD anti-S100), if patients took at least one dose of the drug.

21. Participation in other clinical study within 1 month prior to inclusion in this study.

22. Pregnancy, breast-feeding, inability to use adequate contraception during the study and within one month after the last dose of study drug.

23. The presence of Allergy/intolerance to any component of the medications used in treatment, including lactose intolerance.

24. Drugs, neuroleptics, alcoholism, mental illness of the patient.

25. Patients are staff directly associated with the study and/or are family members of the staff of the research center, directly associated with the study. The concept of "family" includes spouse, parents, children, brothers (sisters) - related to both biological and legal is their relationship,

26. Participation in the judicial process, or estimated compensation or participation in the judicial process, according to the researcher.

After determining the compliance of the patient inclusion criteria and exclusion Protocol, patients were randomized into two groups investigated: group ULD anti-S100 (3 men, women 100% men, 0%, mean age 59±3.6 years) and a group of ULD anti-S100+anti-eNOS (3 people, women 66,66%, men - 33,33%, mean age 59±4,36 year).

This research was conducted in 5 visits to the research center. The treatment phase lasted from Visit 1 to Visit 4 for 84±5 days. Visit 4 (Day 84±5) was the first endpoint of the study, after which began the phase follow-up observations. Phase follow-up observations continued to Visit 5 (Day 168±5).

In the safety analysis included data from all patients participating in the study (n=6). During the whole period of observation of the patients showed good tolerability of the study drug. Adverse events were absent. All patients studied groups completed treatment in the terms established by the study Protocol, early leavers patients was not.

When evaluating drug action ULD anti-S100+anti-eNOS on the main neuropsychiatric symptoms of Alzheimer's disease (naraps the hierarchical questionnaire NPI, section severity), the severity of associated distress caring for a patient person (neuropsychiatric questionnaire NPI, section distress), the activity of the patient's daily life (questionnaire ADS-ADL) and cognitive function of the patient (MMSE questionnaire), it was revealed improvement in major neuropsychiatric manifestations of Alzheimer's disease, expressed in a statistically-significant decrease in the total score section "severity" neuropsychiatric questionnaire NPI (24,33±4.73 to 12,0±of 3.46, p<0,05) to Visit 4 (table 2).

Also, there was a trend to decrease distress caring person, and the increased activity of the patient's daily life, which, however, did not reach statistically significant values to the end of therapy, which might be related to insufficient number of patients.

Along with this, there was a trend to improvement in cognitive function, exemplified by the increase in the assessment on MMSE 23,B6±3,21 points to 26,66+1,53 points, which, however, did not reach statistically significant values to the end of therapy, which may also be connected with the insufficient number of patients.

Similar indicators in the group of patients treated with ULD anti-S100, showed trends toward improvement, with the exception of a statistically implausible improve the score on the MMSE with cushion 22.66±0,577 points to 23.33±0,577 points.

In this case, the difference m the waiting groups on the total score of the MMSE scale by the end of therapy, was reliable with probability p<0,05.

Thus, clinical research combined drug ULD anti-S100+anti-eNOS shown a positive impact on major neuropsychiatric symptoms of Alzheimer's disease and the possible impact on cognitive function in patients with Alzheimer's disease. In addition, confirmed the high tolerability of the drug. Unwanted effects when taking the drug was absent.

Example 3.

The effectiveness of drugs when scopolamine amnesia in rats (a model of Alzheimer's disease).

Alzheimer's disease (ad) is a neurodegenerative disease and is characterized by a decline in cognitive function, memory impairment, confusion, changes in emotional background. Although the main reason for the development of this disease at the present time is the accumulation of beta-amyloid, leading to the formation of beta-amyloid plaques and neurofibrillary tangles in brain tissue, BA is also accompanied by a deficiency of cholinergic system. On this basis, one of the most common ways of modeling ad in animals with cholinergic antagonist system of scopolamine. The introduction of scopolamine experimental animals (usually rats or mice) disrupts the ability to learn and leads to uh is dsiney memory.

To evaluate the cognitive functions of rats and mice use different methods, in particular water maze Morris. The essence of this test is that the vessel with opaque water animals that are released into the water from different points, have to search for hidden stationary platform. The advantage of this method is that it allows a user to observe the learning process of the animal (the formation of his ideas about the spatial location of the platform regardless of where it was lowered into the water), and to assess the strength of memory (to do this, hold the test sample when the platform is removed).

In the Example below, 3 studied the efficiency with scopolamine amnesia in rats claimed medicinal product in the form of a composition containing activated potentiated forms of polyclonal affinity purified on antigen rabbit antibodies to meshoperations protein S-100 (anti-S100) and to endothelial NO-synthase (anti-eNOS) in ultra-low doses (ULD) obtained by Sverrisdottir initial matrix solution (with concentration of 2.5 mg/ml) at 10012, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions 12, C30, C200 (ULD anti-S100+anti-eNOS).

In a study of the effectiveness of the drug ULD anti-S100+anti-eNOS at scopolamine amnesia in rats (a model of Alzheimer's disease) which was used in 48 rats-males line Rj: Wistar (NAP) (mass 180-280 g). Within 4 days the rats were injected subcutaneously with saline (n=12, intact) or scopolamine dose of 0.5 mg/kg (n=36) (scopolamine-induced amnesia). Rats with scopolamine-induced amnesia were divided into 3 groups and injected them, respectively, distilled water (7.5 ml/kg, n=12, control group # 1), ULD anti-S100 (7.5 ml/kg, n=12, group # 2) and ULD anti-S100+anti-eNOS (7.5 ml/kg, n=12, group # 3) intragastrically for 9 days (4 days before injection of scopolamine, 4 days on the background of the introduction of scopolamine and 1 day after the injection of scopolamine).

Within 4 days of administration of scopolamine after 60 minutes after administration of test drugs and 30 minutes after administration of scopolamine conducted a training session in the maze Morris (4 consecutive test intervals 60). Maze Morris is a circular vessel (diameter 150 cm, height 45 cm, 30 cm filled with water (26-28°C). At 18 cm from the edge of the vessel is the hidden platform (15 cm diameter), recessed 1.5 cm below the water level. Water make muddy, adding a non-toxic dye (e.g., milk powder), making the invisible platform. For each test animal was placed in the maze at one of the starting points that are equidistant from a hidden platform, and gave them the opportunity to find her. If the animal could not find the platform within 120 seconds, e is put on the platform for 60 seconds and then started a new test. During 4 trials in a random order, the animals began passing through the maze twice with each source point. The tests were recorded on videotape, and then analyzed the distances covered in search of a platform in each test and the latent period of the search platform.

5 day sample: the platform was removed from the maze, the rat gave to swim freely for 60 seconds. We registered the time spent in the place where once stood the platform.

The introduction of scopolamine significantly impaired the ability of animals to learn: in the control group No. 1 the time spent by animals in search of the platform and the distance that the animals went in search of a platform, was significantly increased (Tables 3, 4). The test showed that the memory of the animals of the control group No. 1 has deteriorated significantly: in the place where once stood the platform, they were less time than intact rats (table 5). The introduction of ULD anti S100 in the group # 2 did not lead to the improvement of the studied parameters (Table 3, 4, 5). The introduction of SMD aHTH-S100+anti-eNOS in the group # 3 has resulted in a slight improvement of education, which was reflected in the shortening of the latency time search platform (table 3) and overcome distances (table 4) within 4 days of training, and improved memory, which was reflected in the increase of time, providinng is in place, where was the platform (table 5).

Thus, used in models of Alzheimer's disease, the use of complex ULD anti-S100+anti-echos was more effective than isolated introduction of ULD anti-S100.

1. Pharmaceutical composition for the treatment of Alzheimer's disease containing the activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase.

2. The pharmaceutical composition under item 1, characterized in that the activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase is used in the form of the activated potentiated aqueous or aqueous-alcoholic solution, 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 - shaking of every dilution.

3. The pharmaceutical composition under item 1 or 2, characterized in that the solid dosage form and contains an effective amount of granules neutral media saturated with a mixture of aqueous or aqueous-alcoholic R. the cross-sections of the activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase, and pharmaceutically acceptable additives.

4. The pharmaceutical composition under item 1 or 2, characterized in that an aqueous or aqueous-alcoholic solutions of the activated potentiated form of antibodies to meshoperations protein S-100 and to endothelial NO-synthase obtained by repeated consecutive dilution in conjunction with external cause - shaking each dilution of the matrix solutions of affinity purified antibodies to meshoperations protein S-100 and to endothelial NO-synthase with a concentration of 0.5÷5.0 mg/ml

5. The pharmaceutical composition under item 1 or 2, characterized in that each of the components on the basis of ultra-low doses of affinity purified antibodies are used in the form of a mixture of various, mainly centesimal, dilutions, prepared according to homeopathic technology.

6. The pharmaceutical composition according to p. 3, characterized in that the pharmaceutically acceptable additives include lactose, cellulose microcrystalline and magnesium stearate.

7. A method of treating Alzheimer's disease by introducing into the body of the activated potentiated form of antibodies to meshoperations protein S-100, characterized in that additionally at the same time and combined introducing the activated potentiated form of ultra-low doses of affinity purified antibodies to endothelial NO-synthase.

8. Pic is b on p. 7, characterized in that the activated potentiated form of antibodies to meshoperations protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase is used in the form of the activated potentiated aqueous or aqueous-alcoholic solution of each component, the activity of which is due to the process of repeated dilution in water or water-alcohol solvent in combination with an external mechanical impact - shaking of every dilution.

9. The method of treatment according to p. 7, characterized in that use is prepared in the form of a single drug - single dosage form a mixture of different dilutions of antibodies to meshoperations protein S-100 in combination with a mixture of various dilutions of antibodies to endothelial NO-synthase, prepared according to homeopathic technology.



 

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