Therapeutic agent and method of treating vegetative-vascular dystonia, dizziness syndrome of various origins, and kinetosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to neurology, and concerns treating vegetative-vascular dystonia, dizziness syndrome of various origins, and kinetosis. That is ensured by administering a therapeutic agent containing an activated-potentiated form of brain-specific protein S-100 antibody and using the activated-potentiated form of endothelial NO-synthase antibodies as an additional exalting agent.

EFFECT: invention provides the effective treatment of the above pathological conditions by the synergetic effect of the ingredients of the therapeutic agent.

9 cl, 16 tbl, 4 ex

 

The invention relates to medicine and can be used to treat dystonia, accompanied by increase and reduction in blood pressure, syndrome of vertigo of various origins and kinetosis.

The prior art known to the treatment of syndrome of a vegetative dystonia drug "TenTen" on the basis of the activated-potentiated form of antibodies to meshoperations protein S -100 (Lobov M. A., Borisova, M. N., Osipov, O. C. Drug Tenoten (child) in the treatment of children with a syndrome of a vegetative dystonia. Neurology: current issues. Sixth interregional scientific-practical conference, devoted to related issues of neurology and psychiatry. Novosibirsk, Tomsk, Russia, 27-28 may 2009. Articles and abstracts, page 100). However, this drug in the treatment of vegetative-vascular dystonia of various origins may not provide sufficient therapeutic efficacy.

The invention is aimed at expanding therapeutic range drugs on the basis of the activated-potentiated form of antibodies to endothelial NO-synthase and improving the treatment of vegetative-vascular dystonia of various origins, syndrome of vertigo of various origins and kinetosis.

The solution of this problem is provided by the fact that the drugs are for Les is possible dystonia, syndrome of vertigo of various origins and kinetosis containing the activated-potentiated form of antibodies to meshoperations protein S-100, according to the invention made in the form of pharmaceutical compositions and contains extra reinforcing component activated-potentiated form of antibodies to endothelial NO-synthase.

When this activated-potentiated form of antibodies to endothelial NO-synthase and the activated-potentiated form of antibodies to meshoperations protein S-100 is used in the form of 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 endothelial NO-synthase and activated-potentiated form of antibodies to meshoperations protein S-100, and pharmaceutically acceptable additives, which include lactose, microcrystalline cellulose is magnesium stearate.

When this aqueous or aqueous-alcoholic solutions of the activated-potentiated form of antibodies to endothelial NO-synthase and meshoperations protein S-100 is obtained by repeated consecutive dilution and external influences - vertical shaking of every dilution of matrix solutions, respectively affinity purified antibodies to endothelial NO-synthase and meshoperations protein S-100 concentration of 0.5÷5.0 mg/ml

Moreover, 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 method for the treatment of dystonia syndrome dizziness of various origins and kinetosis by introducing into the body an activated-potentiated form of antibodies to meshoperations protein S-100, according to the invention, optionally (at the same time and sachetana) 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 endothelial NO-synthase and the activated-potentiated form of antibodies to meshoperations protein S-100 is used in the form of activated-potenzirovannogo the water or water-alcohol solution of each component, activity 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.

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

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 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 2-4 times a day.

In the treatment of vegetative-vascular dystonia of various origins 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 solid Lekarstvo the x forms (tablets), each of which contains 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 activated-potentiated forms of 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 exposure - repeated vertical shaking of every dilution (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 methods of treatment of vegetative-vascular dystonia of various origins), provides an unexpected synergistic therapeutic effect, confirmed adequate (valid) experimental models and clinical studies, which is to improve the effectiveness of treatment of vegetative-vascular dystonia of various origins. This technical result is due to the increased is of the neuroprotective activity of antibodies to protein S-100, increased 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 mental performance, restores the processes of learning and memory, normalizes somatovegetative symptoms, increases cerebral blood flow and, consequently, enhances therapeutic range drugs and improving the treatment of vegetative-vascular dystonia of various origins, including the syndrome of dizziness and kineticom, dystonia, accompanied by increase and reduction in blood pressure. At the same time declared the drug, as its components, does not have a sedative and miorelaksantnoe action, do not cause addiction and habituation. Including the claimed medicinal product can be used in complex therapy.

In addition, the claimed medicinal product expands the Arsenal of drugs intended the military to treat dystonia, dizziness of various origins and kinetosis.

The drug is prepared mainly as follows.

For making an activated-potentiated form of active components, using monoclonal or predominantly 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 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.

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. The result is rosedene such procedures have monospecific antisera with high content of antibodies, which is used to produce the activated-potentiated forms of components. If necessary, conduct the purification of antibody present in anticigarette, for example, by the method of affinity chromatography by the 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 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. In carrying out the stated drugs in solid dosage form on a neutral carrier - lactose - can be applied to the mixture of these components in a volume ratio of 1:1.

Preferred for the preparation of the claimed medicinal preparation is the use of polyclonal antibodies to endothelial is Oh NO-synthase and meshoperations protein S-100, 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 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 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 APFRGFWQER LHDIESKGLQ PHPMTLVFGC RCSQLDHLYR

DEVQDAQERG VFGRVLTAFS

1081 REPDSPKTYV QDILTELAA 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 FRTWNSQLVRYAGYRQQDGS 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 LCMDEYDWS LEHETLWLW TSTFGNGDPP

ENGESFAAAL MEMSGPYNSS

601 PRPEQHKSYK IRFNSISCSD PLVSSWRRKR KESSNTDSAG

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 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 EAGDVIGVLRDQQRYHEDIF GLTLRTQEVT SRIRTQSFSL

QERQLRGAVP WAFEPPGSDT

1201 NSP

It is possible to obtain polyclonal antibodies to endothelial NO-synthase using in Kacha is the firmness of the 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 (4°C) overnight. The next day remove the clot adhered to the spatula, and centrifuged remaining liquid at 13,000 g for 10 min. the Supernatant (supernatant) is anticorodal. The resulting anticavity should be yellow. Add to anticigarette 20% (weight concentration) NaN3what about final concentration of 0.02% and stored until use in a frozen state at -20°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 NaCl 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-synthase, which is insoluble matrix followed by elution with concentrated salt solutions.

Thus obtained 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÷3,0 mg/ml, used as a matrix (primary) solution for the subsequent preparation of the activated-potentiated form on homeopathic technology.

To obtain polyclonal antibodies to meshoperations b is the LCA of 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 proteins;

- 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 what efudex 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 - rabbit - back into the region in the amount of 1-2 ml per 8-th, 15-th day is 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 uniform is menichini 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 (at least 10 times) vertical shaking ("dynamics") of each received cultivation and use separate containers for each subsequent breeding until you get the desired potency - ratio cultivation on homeopathic technology (see, for example, W. Schwabe. "Homeopathic medicines", M, 1967, S. 14-29).

For example, for the preparation of the 12th centesimal dilution With 12 one part of the mentioned matrix solution of antibodies to NO-synthase (or meshoperations protein S-100) 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 C 12. 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 NO-synthase 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 sootvetstvujushej multiplicity cultivation is performed to obtain a dilution C30 and C200.

When used as a component (for example, an activated-potentiated form of antibodies to meshoperations protein S-100) a mixture of various, mainly centesimal, dilutions, each dilution of the component (for example, C12, C30, C200) prepare separately for the above-described technology to their penultimate cultivation (respectively, to obtain C11, C29, C199) and then bring in one container, one portion of each received the penultimate cultivation 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, prepared by Sverrisdottir matrix solution, respectively, in the 10012, 10030and 100200time equivalent mixture of centesimal dilutions C12, C30 and C200, on homeopathic technology.

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.

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

To obtain the claimed pharmaceutical compositions are aqueous or aqueous-alcoholic solutions of active components, mixed mainly 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 endothelial NO-synthase and activated-potentiated form of antibodies meshoperations protein S-100, and pharmaceutically acceptable additives, including mainly lactose, cellulose microcrystalline and magnesium stearate.

For solid oral forms of the claimed medicinal product produced in the plant fluidized bed (for example, type "Hüttlin Pilotlab" production company Hüttlin 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 activated-potentiated form of antibodies to endothelial synthase nitric oxide (NO-synthase) and meshoperations protein S-100, mainly the inratio 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. 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 in the number of 3-8 wt. parts by weight of the total load from the mass of solid oral forms. Then to this mixture 25 to 45 mass. parts by weight of the total load "unsaturated" pure lactose (to reduce the cost and some simplification and acceleration of the 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, predominantly weight of 300 mg. After tabletting get tablets impregnated with a water-alcohol solution of the activated-potentiated form of antibodies to NO-synthase and meshoperations protein S-100 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 C12, C30 and C200, prepared according to homeopathic technology.

Preferably the claimed pharmaceutical composition Ryoko is endued take 1-2 tablets 2-4 times a day.

Example 1.

The study of the impact of the integrated product, which consists of 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 C12, C30, C200, in the ratio of 1:1 (ULD anti-S100+anti-eNOS), as well as components that are included in its composition - activated-potentiated forms 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 C12, C30, C200, and activated-potentiated forms 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 [3N]pentazocine with recombinant Sigma-1 Rotz the torus person 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, signaling, 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, mental and affective disorders, 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, and cilities, 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+anti-eNOS or 10 ál MD AT to S100 or 10 ál MD AT to NOS. 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 MD AT to S100 and MD AT to NOS 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 µg protein) homogenate membrane of the cell line Jurkat (line leukemic T-lymphocytes person), and finally 20 μl of radioligand tritium-labeled [3N]pentazocine (15 nm).

To measure nonspecific binding instead of drugs or potentiated water in incubationperiod contributed 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 (as 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 dimensionULD anti-S100+anti-eNOS20 ál48,435,542,058,0
ULD anti-S10010 ál67,363,165,234,8
ULD anti-eNOS10 ál147,5owed 161.1154,3-54,3
Potentiated water20 ál98,175,886,913,1
Potentiated water10 ál14 0,110 6,21 23,2-23,2
Note:
% specific binding in control=(specic binding of experience / specific binding control)*100%;
% inhibition of the special is practical binding in control=100% -(specific binding experience / specific binding control)*100%).

The results, reflecting the inhibition above 50% represent significant effects of the investigated compounds; inhibition from 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: complex drug ULD anti-S100+anti-eNOS more effective 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 of the person;

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 [3N]pentazocine with recombinant Sigma 1 R is zeptogram person.

Example 2.

Been studied drug in the form of tablets weighing 300 mg impregnated with a water-alcohol solution (3 mg/tab.) the activated-potentiated forms 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 medicinal product is in the form of tablets weighing 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 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 C12, C30, C200 (ULD anti-S100+anti-eNOS); the medicinal product is in the form of tablets weighing 300 mg impregnated with a water-alcohol solution (3 mg/tab.) the activated-potentiated forms of polyclonal rabbit antibodies to endothelial NO-synthase, purified on antigen, in ultra-low dose (ULD anti-eNOS), resulting from the dilution of initial matrix solution (with concentration of 2.5 mg/ml) at 100 12, 10030, 100200time equivalent mixture of centesimal homeopathic dilutions C12, C30, C200. Placebo were used tablet weight of 300 mg, containing excipients: lactose (lactose monohydrate) - 267 mg microcrystalline cellulose 30 mg, magnesium stearate 3 mg

The effectiveness of the studied drugs in the treatment of dizziness (vertigo) and other symptoms of motion sickness were evaluated on the model of kinetosis, or motion sickness/motion sickness, which is different Vestibulo-vegetative disorders. Dizziness is a common symptom of a lesion of the vestibular analyzer of various origins, including dysfunction of the vestibular nerve cochlear and vestibular system, disorders of blood circulation in the vertebral-basilar system, pathology of the Central nervous system (CNS) and other Vertigo as a manifestation of kinetosis accompanied by other Vestibulo-vegetative disorders, including three types of reactions: vestibulomotor (nystagmus and reactions deviation), Vestibulo-touch (besides the dizziness is nystagmus (or reaction potvrdenia), protective motion) and vegetative (nausea, vomiting, sweating, palpitations, feeling hot, the oscillation pulse and blood pressure).

Double-blind, placebo-controlled comparative clinical and the following parallel groups efficacy protivoukachiwauschee properties of the composition ULD anti-S100+anti-eNOS, drug ULD anti-S100 and anti-eNOS, conducted with the participation of 15 somatically healthy volunteers - men and women aged 15 to 60 years (mean age of 33.3±0,75 years) low (n=5, 33%) or moderate (n=10; 67%) degree of resistance to motion sickness.

For modeling the state of motion and evaluate the effectiveness of investigational drugs have used the most appropriate and generally accepted model of kinetosis - sample with continuous cumulative impact of Coriolis accelerations (NCUC). Source portability samples NCUC all participants in the study was no more than 5 minutes. Vestibulo-vegetative disorders caused by the kinetic impact (NCUC), recorded with the use of a complex of diagnostic methods, including patient assessment, quantitative assessment of disorders of the Vestibulo-vegetative sensitivity Scale (Halle), analysis of heart rate variability (HRV), a self-assessment of functional status (SAN health, activity, mood). As criteria of effectiveness of therapy was evaluated dynamics tolerability and duration of the recovery period when kinetic effects, the change in intensity of sensory-motor reactions (nystagmus), indices of HRV (using Biocom Wellness Scan, developed by AWS, LLC in accordance with the International standard Europe the Russian Association of cardiology and the North American society of Electrophysiology and data SAN. Safety criteria were the nature, severity and time of occurrence of possible adverse reactions (AR) in the period of therapy associated with the drug; the influence of the studied drugs on the indicators of the function of the Central nervous system (the reaction to a moving object [WFD], simple motor responses [VPTR]); dynamics of physical and functional parameters (heart rate [HR], systolic [GARDEN] and diastolic [DBP] blood pressure, sample Rod, samples Genc); exercise tolerance index (Harvard step test). Safety was assessed when receiving the test dose, and in exchange receive within 7 days.

All participants within 1 month prior to inclusion in the study were not taking any medications. After a screening visit, participants were randomizirovannoe into 4 groups depending on the received product (1 - ULD anti-S100+anti-eNOS, 2 - ULD anti-S100; 3 - ULD anti-eNOS; 4 placebo).

On the first day of the study (Visit 1) were recorded original functional and physiological status of volunteers, then performed a 5-fold test dose, then ran the sample NCUC, recorded the duration of the test, using a comprehensive diagnostic examination revealed associated with the achivaniem vegetative vestibular disorders and NYA. In the next 2-6 days, the volunteer has been assigned to the drug per 1 tablet 3 times a day. 7 day (Visit 2) the patient took the drug on the first day, they were re-range of diagnostic studies before and after samples NCUC. The study was organized in such a way that the research team worked with only one subject. The study was a parallel and was conducted in the first half of the day with usually 4 people a day, one person on the drug or a placebo. Following 3 weeks was a wash period, the outcome of which patients in each subgroup was prescribed a new drug/placebo research cycle was repeated (Visit 1, course taking the drug; Visit 2). Thus, in the course of the study, each volunteer participated in the four cycles of the study. When this track to all the subjects participated in the evaluation of each of the three drugs and placebo, which helped to mitigate the influence of individual characteristics of the test on the effect of therapy. Analysis of the effectiveness of the drugs was carried out according to all the subjects who completed the full course of treatment with study drug in accordance with the study Protocol (n=15).

Indicators of severity of symptoms of motion sickness (dizziness, nausea, weakness, pale skin, sweating, etc.) after CIN the political impact (NCUC) on the background of the day of receiving the study drug testified all study participants had reached approximately the same state of motion as the severity evaluated by the physician-investigator on a scale Halle symptoms of autonomic dysfunction was not significantly different in all groups (table 2, Visit 1). However, time kinetic impact that caused similar symptoms of motion sickness, differed among the four groups and depended on drugs, which was attended by the participants in the study (table 3, Visit 1). One day the medication ULD anti-S100+anti-eNOS resulted in the most distinct protivoukachiwauschee effect, which is manifested not only in significantly more time endurance tests NCUK (104,10±13,14 sec against 68,50±6,57 sec in the group of ULD anti-S100; 75,00±6,79 sec - in the company of ULD anti-eNOS and B1,30±3,15 sec in the placebo group), but in the least time nystagmus (9,90±1,20 sec against 13,50±1,51; 16,10±1,68 and 13,30±1,12 sec, respectively) and fast recovery (96,90±13,54 sec against 194,20±of 18.45; 202,50±21,72 and 241,70±38,41 sec, respectively).

Roughly similar rates were reported at Visit 2 after the course of medication. To achieve similar symptoms of motion sickness (table 2, Visit 2) longest kinetic impact applied to the volunteers who received within 7 days composition ULD anti-S100+anti-eNOS (table 3, Visit 2). Most of the code in the config protivoukachiwauschee effect of the composition ULD anti-S100+anti-eNOS was expressed in significantly less time nystagmus (9,50±1,38 sec; p<0.01) and the duration of the recovery period (117,90±15,65 s; p<0,01). Protivoukachiwauschee action had a monocomponent preparation ULD anti-S100, as evidenced by better than in the placebo group, tolerability samples NCUC, time nystagmus and recovery (table 3, Visits 1 and 2), however, the effectiveness of the drug ULD anti-S100 inferior composition ULD anti-S100+anti-hedgehog)8. Single drug ULD anti-eNOS did not show protivoukachiwauschee effect, because the test results NCUC and subsequent recovery period had no significant differences from the placebo group (table 3, Visits 1 and 2).

Comparative analysis of samples NCUC in groups of ULD anti-S100+anti-eNOS and ULD anti-S100 day when the medication showed that the addition of ULD anti-eNOS increased tolerance kinetic effects on 52%, reduced time nystagmus by 27% and reduced recovery period after the end of the kinetic impact by 50%, including the duration of the vertigo - 49%. However, the greatest contribution component ULD anti-eNOS contributed to the effectiveness of a combined preparation (composition ULD anti-S100+anti-eNOS) in exchange reception, which was reflected in the excess of 30% of the result achieved in the group of ULD anti S100 on tolerability kinetic impact and DL the activity of nystagmus (for each parameter). In addition, the growth effect on Visit 2 in terms of endurance tests NCUC and duration of nystagmus data regarding Visit 1 when receiving the composition ULD anti-S100+anti-eNOS compared with single drug ULD anti S100 was expressed to a greater extent, which was confirmed by the change of these indicators by 30% and 4% (vs. 21% and 0% in the group of ULD anti-S100).

When evaluating the effectiveness protivoukachiwauschee properties of drugs and special attention was paid to the possible effect on the stability of the autonomic nervous system (ANS), in particular a change in the balance between the sympathetic and parasympathetic divisions. To this end, each visit was analyzed indices of HRV at rest and when performing functional tests (respiratory and orthostatic tests).

The analysis of HRV at rest (sitting) before and after the test NCUK (table 4) found that in patients receiving the study drug had a tendency to increase in SDNN index, which indicated the increase in HR variability due to parasympathetic influence on heart rhythm. In response to kinetic effects in all the groups studied had increased the value of the RMS-SD, describing the activity of the parasympathetic component of the autonomic regulation. In the groups receiving the composition ULD anti-S100+eNOS and ULD anti-S100 has been an increase in HF, what also testified to the shift of the autonomic balance towards parasympathetic. Thus, after the sample NCUC in all the groups studied were increasing parasympathetic influences on heart rate.

HRV analysis under transient conditions showed that one-day admission composition ULD anti-S100+anti-eNOS increased reaction time (13,9±1,14; p≤0.05) and the stabilization time (24,2±1,28; p≤0,05) in comparison with ULD anti-S100 and placebo (table 5). These figures exceeded the values of the placebo group and after kinetic effects that have demonstrated a positive effect of combined drug and ANS reactivity (increased tolerance to changes in body position). The smallest difference between the maximum and minimum heart rate respiratory test (table 6) confirmed the best compromise between the two divisions of the ANS after a one-day admission composition ULD anti-S100+anti-eNOS (25,1±2,66 beats./min; p≤0,05). By the end of week of therapy stabilizing effect on the balance of the ANS after sample NCUK (with orthostatic and breathing test) were also noted in the group receiving the composition ULD anti-S100+anti-eNOS (Tables 5, 6).

The results of the self-assessment of functional status (health-activity-mood) volunteers, which the participants of the studies were performed after modeling Usachev the deposits (samples NCUC) at the beginning and end of therapy, testified to the fact that subjects in all study groups gave average scores for each of the parameters (table 7). Thus, on a background of reception of preparations portability samples NCUC was satisfactory. The greatest increase compared with the placebo group by the end of 7-day intake (>10%) was noted in group composition ULD anti-S100+anti-eNOS.

In the safety analysis included data from all volunteers participating in the study. During the whole period of observation there was a good tolerability of the investigational drugs. Adverse events associated with drugs that have not been identified. All volunteers studied groups completed treatment in the terms established by the study Protocol prematurely eliminated from the study was not.

On physical examination, including performance curves, sad and dad, and also according to the Harvard step test, the subjects were not registered any pathological abnormalities in the time of the survey (table 8). All identified changes do not exceed normal values. While all subjects subjectively noted the satisfactory feeling.

Along with hemodynamic data to assess the safety of the investigational drugs, their adverse impact on higher nervous options and, the volunteers investigated the psychophysiological indicators (WFD, ITDR, HC, S, COUVE). In addition, samples were Post and Genc for evaluation of tolerance to hypoxia.

According to the results (table 9), nor day, nor of course the medication had no significant influence on the estimated parameters. Indicators of sensorimotor coordination (WPDR, WFD) did not differ from results of a placebo group before and after samples NCUC on both visits. Data on the study of such complex functions, such as volume and stability of attention, testified that the investigational drug both before and after samples NCUC did not change the degree of concentration and flexibility of attention, not different from the placebo group.

The analysis of indicators of standard stress tests with breath showed a tendency to increase endurance test hypoxia (table 9). When the breath on the inhale the duration of the sample Rod was increased after administration of the study drugs, but receive only the composition ULD anti-S100+anti-eNOS allowed significantly longer to resume breathing after kinetic impact (68,1±18,8 sec source and of 91.7±27,4 sec after sample NCUC; p<0,05). Increased tolerance of hypoxia was also observed when performing tests of Genc (the breath on the exhale; p>0,05).

Thus, the first study using an experimental motion sickness demonstrated protivoukachiwauschee the effectiveness of the composition ULD anti-S100+anti-eNOS and monocomponent preparation ULD anti-S100. Study drugs increase the stability of the subjects to the kinetic effects after playback clinical and physiological effects of motion sickness, facilitating easier for clinics motion and earlier restoration of the subjects after cessation of exposure. In addition, it was shown that protivoukachiwauschee the combined action of the drug (composition ULD anti-S100+anti-eNOS) is greater than the efficiency of individual components. The effectiveness of the composition ULD anti-S100+anti-eNOS in control of the Vestibulo-autonomic and sensory reactions in experimental motion sickness increases in exchange welcome. It should be noted that ULD anti-eNOS as monotherapy has not protective against motion effect, but when combined with ULD anti-S100 significantly enhances protivoukachiwauschee effects that occurs during the day, and with a short course of medicine. Better ability to adjust transients, i.e. to influence the reactivity of the parasympathetic and sympathetic divisions of the ANS, as well as the adaptive capacity of the ANS in the state of motion (to increase tolerance to abrupt changes in body position), was observed in the composition ULD anti-S100+anti-eNOS, which is an important component protivoukachiwauschee is waist medicines. Composition ULD anti-5100+anti-em and monocomponent preparation ULD anti-S100 when using them as protivoukachiwauschee tools, including when performing camera functions, safe and not have a negative impact on physical and physiological parameters.

Composition ULD anti-S100+anti-eNOS and ULD anti-S100 can be recommended for the prevention and relief of motion sickness when motion sickness (including sea, air, transport disease) individuals with low and medium degree of resistance. Preparations differ high safety and no adverse effects on the quality of professional activity.

Table 2
The score Halle depending upon the drug after the test NCUC
MedicationScale Halle (points)
Visit 1 (day admission)(n=15; M±SE)Visit 2 (course administration)(n=15; M±SE)
ULD anti-S100+ anti-eNOS12,00±0,6312,30±0,59
ULD anti-S10013,30±0,65 12,30±0,46
ULD anti-eNOS13,10±0,7812,0010,55
Placebo13,40±0,7713,30±0,45

Table 3
Dynamics of indicators of the sample NCUC depending on accepted drug
MedicationVisit 1 (day reception)
Portability samples NCUC, sec (n=15; M±SD)Time nystagmus,sec (n=15; M±SD)The time of the recovery, sec (n=15; M±SD)
ULD anti-S100+anti-eNOS104,10±13,14**9,90±1,20*96,90±13,54***
ULD anti-S10068,50±6,57 ×13,50±1,51194,20±of 18.45×××
ULD anti-eNOS75,00±6,7916,10±1,68202,50±21,72×××
Placebo61,30±3,15 13,30±1,12241,70±38,41
The P value on the criterion of Kruskal-Wallis'0,01820,06580,0001
Visit 2 (directional reception)
ULD anti-S100+anti-eNOS134,70±20,24**9,50±1,38**117,90±15,65 **
ULD anti-S100at 82.70±10,3313,50±1,69167,50±14,72 ×
ULD anti-eNOS74,30±9,49 ×17,30±2,40×××209,20±21,62××
Placebo63,70±3,9115,00±1,47199,60±31,19
The P value on the criterion of Kruskal-Wallis10,03410,02440,0061
Note:
1to determine significant differences between groups we used the criterion of Kruskal-Wallis. If the criterion showed the reliability, R&l; 0,05; for comparison between groups was the criterion used Mann-Whitney.
* the significance of differences compared with placebo, p<0,05; ** significance of differences compared with placebo, p<0,01; *** significance of differences compared with placebo, p<0,001.
× the significance of differences compared with ULD anti-S100+anti-eNOS, p<0,05;
×× the significance of differences compared with ULD anti-S100+anti-eNOS, p<0,01;
××× the significance of differences compared with ULD anti-S100+anti-eNOS, p<0,001.

Table 4
HRV parameters of study participants at rest before and after kinetic impact
IndexVisit 1 (day reception)Visit 2 (directional reception)
After dosingAfter sample NCUCAfter dosingAfter sample NCUC
Group ULD anti-S100+anti-ery (M±SD)
SDNN, MS 57,7±5,5168,2±7,4259,4±5,0365,6±4,66
RMSSD, msec43,1±6,7751,4±which 9.2247,0±6,2147,6±5,33
TR MS2979,0±186,061678,3±397,11#1067,2±167,241381,0±166,30
LF, MS2437,5±709,6709,6±178,72391,9±75,61to 588.5±87,48
HF, MS2which is 171,5±51,08228,4±76,79206,5±58,32218,5±at 43.96
LF/HF,.E.4,2±0,824,9±0,833.3V±0,834,2±0,91
Group MD anti-S 100 (M±SD)
SDNN, MS60,9±4,6270,9±5,9059,1±4,8068,8±4,87
RMSSD, msec44,3±5,39 50,6±6,5642,4±4,6347,8±5,57
TR MS2832,2±124,93*1342,8±217,09841,4±149,931288,0±163,52#
LF, MS2315,2±52,38*550,9±72,44#313,6±66,71540,7±87,57#
HF, MS2151,4±41,19247,0±69,53#138,3±38,42187,1±39,80
LF/HF,.E.3,0±0,544,0±0,722,8±0,534,0±0,52
Group ULD anti-eNOS (M±SD)
SDNN, MS67,4±7,7378,6±6,1465,8±8,6869,0±5,23
RMSSD, msec53,0±8,8658,4±7.68 per59,6±12,4552,2±5,30
TR MS2 1841,1±359,79#1232,3±292,511275,4±172,47
LF, MS2576,5±167,07849,9±194,2#527,2+167,07562,1±89,38
HF, MS2313,3±139,90285,3±65,92218,9174,78216,3±63,72
LF/HF,.E.3,6±0,873,9±0,823,7±1,143,8±0,58
The placebo group (M±SD)
SDNN, MS64,6±6,10to 75.7±6.42 per61,1±6,7270,8±6,79
RMSSD, msec50,9±7,7453,1±6,6244,6±6,6344,3±5,31
TR MS21062,2+150,021917,8±318,96#898,8±169,621418,5±227,59#
LF, MS2 440,6±77,30832,4±181,15334,8±75,94611,4±113,64#
HF, MS2253,9±59,95USD 266.7±61,94166,0±48,14174,1±44,96
LF/HF,.E.3,4±0,725,0±1,333,4±0,934,8±0,83
Note:
* the significance of differences compared with placebo, p≤0,05);
# the significance of differences compared with baseline, p≤0,05.

Table 5
HRV parameters of study participants when conducting orthostatic test before and after kinetic impact
IndexVisit 1 (day reception)Visit 2 (directional reception)
After dosingAfter sample NCUCAfter dosingAfter sample NCUC
Group ULD anti-S100+anti-ery (M±SD)
The reaction to the load.E.1,30±0,061,40±0,041,30±0,061,40±0,06
Reaction time, sec13,9±1,14*×12,7±1,24*11,8±0,5711,7±1,09
Stabilization time, sec24,2±1,28*×of 21.9±1,44*20,6±0,7422,4±1,44 *×
Group ULD anti-S100 (M±SD)
The reaction to the load.E.1,40±0,041,30±0,041,30±0,041,30±0,05
Reaction time, secof 7.60±1,0510,6±1,559,7±1,2110,0±1,73
Stabilization time, sec15,1±1,16*18,3±1,4318,0±1,1818,0±1,80
Group ULD anti-eNOS (M±SD)
The reaction to the load.E.1,30±0,041,30±0,041,50±0,121,30±0,04
Reaction time, sec8,20+0,949,10±1,129,2±0,778,3±0,70
Stabilization time, sec16,5±1,0217,1±1,3319,0±2,0416,7±0,98
The placebo group (M±SD)
The reaction to the load.E.1,30±0,041,30±0,041,40±0,061,30±0,06
Reaction time, sec9,5±1,288,1±0,9010,4±1,588,8±1,09
Stabilization time, sec18,3+0,941B,8±1,0918,0±1,3716,5±1,11
Note:
* the significance of differences compared with placebo, p<0,05);
× the significance of differences compared to SEE the anti-S100, p≤0,05.

Table 6
HRV parameters of study participants when conducting a breath test before and after kinetic impact
IndexVisit 1 (day reception)Visit 2 (directional reception)
After dosingAfter sample NCUCAfter dosingAfter sample NCUC
Group ULD anti-S100+anti-eNOS (M±SD)
The ratio of max HR/ min HR,.E.1,5±0,05*1,5±0,061,5±0,051,5±0,05
The difference max HR min HR, beats./min25,1±2,66*26,5+2,7726,5±2,3724,9±2,24*
Group ULD anti-S100 (M±SD)
The ratio of max HR / min HR,.E.1,5±0,061,6±0,05 1,5±0,041,6±0,06
The difference max HR min HR, beats./min27,7±2,6827,2±2,4025,7±2,2426,9±2,67
Group ULD anti-eNOS (M±SD)
The ratio of max HR / min HR,.E.1,5+0,051,5±0,0 41,5±0,061,6±0,05
The difference max HR min HR, beats./min26,7±2,4426,2±2,0427,7±2,4727.3±2,12
The placebo group (M±SD)
The ratio of max HR/ min HR,.E.1,6±0,071,6±0,061,5±0,051,6±0,05
The difference max HR min HR, beats./min31,2±3,0628,2±2,5027,7±2,3729,2±2,44
Note: * significance of differences compared with placebo, p≤0,05

Table 7
The dynamics of self-assessment of functional status (health-activity-mood) of study participants
IndexVisit 1 (day reception)Visit 2 (directional reception)
Group ULD anti-S100+anti-eNOS (M±SE)
Health4,3±0,264,6±0,27
Activity4,2±0,204,2±0,22
Mood5,0±0,165,2±0,13
Group ULD anti-S100 (M±SE)
Health3,7±0,214,3±0,22
Activity3,6±0,174,0±0,19
Mood4,5+0,164,9±0,19
Group ULD anti-eNOS (M±SE)
Health3,9±0,254,1±0,26
Activity3,8±0,253,9±0,23
Mood4,4±0,194,6±0,19
The placebo group (M±SE)
Health4,0±0,244,0±0,24
Activity3,8±0,203,7±0,26
Mood4,3±0.204,7±0,24

Table 8
Dynamics of physical performance and exercise tolerance study participants before and after the kinetic impact
Index1 visit (one day admission)visit 2(directional reception)
After dosingAfter sample NCUCAfter dosingAfter sample NCUC
Group ULD anti-S100+anti-eNOS (M±SE)
heart rate(tank/min)74,6±3,3668,4±3,6774,1±3,1067,7±2,62
GARDEN (mm RT.CT.)123,4±2,83125,9±4,08the level of 121.8±2,65128,3±4,25
DBP (mm RT.CT.)74,0±3,0979,3±2,6276,2±2,4380,3±3,30
The index of the step-test-53,6±2.60-52,3±2,09
Group ULD anti-S100 (M±SE)
Heart rate(tank/min)73,5±2.57 m69,7±2,7872,1±2,8467,7±2,39
GARDEN (mm RT.CT.)of 127.5±2,55to 133.5±4,77127,1±2,55129, 9mm±5,06
DBP (mm RT.CT.)75,5±2,6582,6±3,31of 74.9±2,41 82,3±3,19
The index of the step-test-50,6±1,71-53,0±1,63
Group ULD anti-eNOS (M±SE)
Heart rate(tank/min)76,5±2,5967,3±1,98for 77.3±2,0270,1±3,23
GARDEN (mm RT.CT.)RUB 127.3±3,14131, 5mm±5.16to 123.5±3,06to 129.3±4,13
DBP (mm RT.CT.)75,2±2,2480,3±2,6673,9±2,8381,0±3,22
The index of the step-test-51,8±2,12-51,2±2,21
The placebo group (M±SE)
Heart rate(tank/min)74,5±2.7868,9+of 3.4673,9±3,23to 72.3±to 3.58
GARDEN (mm RT.CT.)to 125.3±3,30133,3±4,73 124,3±2,83126,9±3.95
DBP (mm RT.CT.)76,2±2,1581,7±2,8375,4±1,8679,7±3,03
The index of the step-test-50,0±2,03-50,1±1,99

Sample Genc
Table 9
Dynamics of indicators of the physiological status of study participants before and after the kinetic impact
Index1 visit (one day admission)visit 2 (directional reception)
After dosingAfter sample NCUCAfter dosingAfter sample NCUC
Group ULD anti-S100+anti-hedgehog)8 (M±SE)
WPDR257,5±8,67268,9±10,18269,6±9,75279,9±12,24
The WFD. .E.50,1±3,9249,5±4,5047,3±4,8647,0±3,54
The WFD, % hitting the target3,0±0,954,5±1,155,3±1,584,0±1,11
HC, s5,2±0,345,2±0,355,2±0,415,1±0,40
Attention span, s41,7±2,3639,9±2,3838,1±2,1737,5±2,04
COUVE17,4±1,6617,2±1,5118,0±1,7118,8±1,72
Sample Post68,1±4,8591,7±7,07*71,8±6,02to 85.5±9,36
Sample Genc47,1±4,0350,1±3,9446,7±3,2848,1±to 4.52
Group ULD anti-S100 (M±SE)
WPDR 258,9±9,95282,4±13.56MHz268,4±11,37279,1±9,20
Art,.E.58,1±6,4057,5±6,3455,1±5,0653,8±5,02
The WFD, % hitting the target3,7±1,502,0±0,822,3±0,835,0±1,69
HC, s6,0±0,406,4±0,526,2±0,426,0±0,41
Attention span, s42,6±2,6842,1±2,2742,7±2,3041,9±2,52
COUVE14,5±1,1614,9±1,2615,3±1,1315,4+1,18
Sample Post59,0±4.09 to72,6±to 6.1964,5±4.9375,9±5,67
Sample Genc47,1±4,4849,4±4,6948,3±4,30 48,8±4,14
Group ULD anti-eNOS (M±SE)
WPDR257,7±8,49279,4±14,23USD 266.7±13,19275,5±11,44
Art,.E.48,3±3,6751,9±4,3952,5±4,7949,6±4,22
The WFD, % hitting the target2,3±0,832,0±0,823.3V±1,265,7±1,68
HC, s5,9±0,256,0±0,345,5±0,245,9±0,33
Attention span, s41,9±2,1043,8±2,3941,3±2,0042,5±2,22
COUVE13,7±1,3414,8±1,31the 15.6±1,2414,1±1,40
Sample Post62,5±5,4969,5±5,0956,7±3,3473,1±7,98
43,1±3,51of 45.7±3,1543,4±of 3.7745,8±4,03
The placebo group (M±SE)
WPDRof 267.6±of 7.64290,1±11,33281,119,78263,3±6,85
Art,.E.60,7±8,3154,1±5,5751,1±3,6952,6±5,38
The WFD, % hitting the target3.7±1.033,7±1,243.3V±0,934,3±1,61
HC, s6,1±0,715,7±0,365,5±0,325,9±0,71
Attention span, s41,9±2,0942,4±2,8141,3±2,1839,6±2.26 and
COUVE14,5±1,6414,5±1,7915,3±1,5515,9±1,58
Sample Post 63,7±4,7167,9±6,9064,8±5,9483,0±12,24
Sample Genc44,7±2,5247,1±3,3043,7±2,7147,8±3,78

During the research the following methods were used and determined the following status options:

- Test with continuous cumulative impact of Coriolis accelerations (NCUC) (Margaryan, S. C., Oganov E. M., Sidelnikov I. A. Vestibular sampling method continuous cumulation of Coriolis accelerations // Military. the honey. Journe. 1966. No. 9. S. 59-62; research Methods for medical and flight review. - M.: Voenizdat, 1972).

The test can identify the resistant effect of the Coriolis acceleration and, thus, may indicate exposure to this subject motion sickness.

The order of execution of the sample. The subject sitting in a chair baranyi or electroparadise chair, takes this position, torso, and head to the axis of rotation is along the torso. Eyes closed. Against the background of continuous uniform rotation chairs at 180 deg/sec (one revolution in two seconds) surveyed at the end of the fifth turnover begins to tilt your head from the right shoulder to the left or the left to right and back at an angle not less than 30 degrees in each direction from the vertical. The bending is carried out continuously, without excessive muscle tension in the neck and head rotations during the entire period of rotation. Every movement of his head from shoulder to shoulder running smoothly for 2 seconds without stopping in extreme and mean positions. The speed of tilt is controlled by a metronome or cast time figures 21 and 22, which should correspond to 2 seconds. The countdown run the sample, you must begin with the moment of the first swinging movement of the head.

Before the test the examinee is instructed, in particular, indicate that he should inform the doctor about the appearance of the illusion swing, feelings of heat, fever, salivation, nausea that may occur during the test. Before the test is performed a few test head movements, so that the subject received the skill of controlling the speed of swinging movements and learned the correct position of the head at the moment of movement.

The appearance of the evident Vestibulo-autonomic disorders (pallor, rash, nausea, retching and vomiting) during continuous run tests NCUC are the criteria for ultimate portability influence of Coriolis accelerations. Recorded time of occurrence of Vestibulo-vegetative reactions from the beginning of the run samples NCUC and the time of their termination after the sample NCUC. Tests on the case is the cost of Coriolis accelerations were conducted in the first half of the day, not earlier than 2 hours after eating and only once a day. On the day of the test the subject is no longer exposed to other influences (in the chamber, the centrifuge and others).

The method for quantitative evaluation of disorders of the Vestibulo-vegetative sensitivity (Scale Halle) (Quantitative evaluation of disorders of the Vestibulo-vegetative sensitivity // Space biology and aerospace medicine, 1981. No. 3.- S. 72-75). Based on the assessment of the severity (in points) Vestibulo-vegetative symptoms (dizziness, nausea, sweating, pallor of the skin, drowsiness and other) arising from the conduct of the sample NCUC, the method allows to detect the degree of transferability of human Coriolis acceleration (poor, satisfactory, good, excellent).

- Study the variability of the heart rhythm (HRV) (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart Rate Variability standards of measurement, physiological interpretation, and clinical use. Cir. 1996; 93:1043 1065).

For data collection HRV used Biocom Wellness Scan system developed by AWS, LLC. It was created in accordance with the International standard of the European Association of cardiology and the North American society of Electrophysiology (International Task Force consisting of the European Society of Cardiology and the North American Society for Pacing and Electrophysiology, 1996).

The system contains the following components:

1. Personal computer is the software (PC) with a Windows operating system.

2. Photoplethysmograph HRM-02 (PPG).

3. Ear sensor (PPG ear-clip).

4. Software Biocom Wellness Scan Software on the CD.

5. Guidance on the use of in electronic format (PDF).

Study on the establishment of a database of patient included three tests assessing autonomic balance: the 5-minute recording of HRV at rest; respiratory test; orthostatic test.

The stages of the research HRV

1. The researcher gives the subject a brief description of each test prior to start.

2. The subject sits comfortably, while in a relaxed state.

3. Ear sensor is wiped with alcohol solution and placed on the ear lobe. Earrings, if any, must be removed before the test.

4. The researcher selects the 5-minute recording of HRV at rest (Short-term Resting HRV Test) for execution.

5. The researcher followed the instructions to run the test.

6. As soon as the test is completed and the data recorded in the database, the researcher selects respiratory (Metronome Breathing Test) or orthostatic test (Orthostatic Test).

7. The researcher follows the instructions of the respiratory or orthostatic test.

8. As soon as the test is completed and the data recorded in the database, the researcher reviews the results of all performed tests to determine whether they are acceptable. If any of the data do not satisfy the requirements of the study,the researcher repeats the test.

9. After viewing the data, the test ends and the ear sensor is removed from the ear of the subject.

Description the 5-minute recording of HRV at rest:

Short test of HRV is used to evaluate the balance between the sympathetic and parasympathetic branches of the autonomic nervous system. It is a 5-minute PPG recording in a sitting position without provocative maneuvers. During the test, the subject breathes randomly with a respiratory rate of not less than 9 breaths per minute to obtain valid HRV parameters. The system calculates the following HRV parameters:

1. The parameters in the time domain:

1. HR

2. Mean NN

3. SDNN

4. RMS-SD

2. The parameters in the frequency domain:

5. Total Power

6. VLF

7. LF

8. HF

9. LF/HF Ratio

10. LF Norm

11. HFNorm

All HRV parameters in the time domain are calculated on the normal minitower intervals (NN) due to normal sinus contraction of the heart recorded during the test.

Frequency HRV parameters are calculated from the density power spectrum (PSD), calculated using the fast Fourier transform (FFT).

The parameters in the time domain:

HR is the average heart rate calculated for the entire recording of the heart rhythm. HR is measured in beats per minute (BPM).

Mean NN is the mean value minitower intervals throughout the recording. Mean NN measures the I in milliseconds.

SDNN is the standard declination NN intervals, which is the square root of the variance of NN. Since the quantity under the root mathematically equivalent to the total power in the spectral analysis, SDNN reflects all the cyclic components responsible for variability. The real value of SDNN depends on the record length - the longer the record, the higher the value of SDNN. Thus, in practice it is impossible to compare the values of SDNN, calculated at different time intervals. SDNN is measured in milliseconds.

RMS-SD is the square root of the differences between successive NN intervals. This indicator assesses the high-frequency component of heart rate variability, which is associated with the parasympathetic regulation of the heart. RMS-SD measured in milliseconds.

The parameters in the frequency domain:

Total Power (TP) is the estimation of the density power spectrum in the range from 0 to 0.4 Hz. This indicator reflects the total activity of the autonomic nervous system and the sympathetic activity makes the greatest contribution. Total Power is calculated in milliseconds squared (MS2).

Very Low Frequency (VLF) is the density power spectrum in the range between 0.0033 and 0.04 Hz. The physiological nature of this indicator is that it is an indicator of the overall activity of the various slow mechanisms of regulation. VLF is calculated in milliseconds is x squared (MS 2).

Low Frequency (LF) is the density power spectrum in the range between 0.04 and 0.15 Hz. This indicator reflects both sympathetic and parasympathetic activity. He is a good indicator of sympathetic activity in long-term recordings of HRV. Parasimpaticski influence is represented in LF when the respiratory rate is less than 9 breaths per minute. LF is calculated in milliseconds squared (MS2).

High Frequency (HF) is the density power spectrum in the range between 0.15 and 0.4 Hz. This indicator reflects parasympathetic activity. HF is also known as "breathing" component, as corresponds to the variation of NN intervals due to breathing (this phenomenon is known as respiratory sinus arrhythmia (RSA)). Heart rate increases during inhalation and decreases during exhalation. HF is calculated in milliseconds squared (MS2).

LF/HF Ratio is the ratio between the density power spectrum in the range of LF and HF. This indicator reflects the overall balance between sympathetic and parasympathetic activity. High values of this index is an indicator of the dominance of sympathetic activity, while low - parasympathetic. LF/HF Ratio is calculated in normalized units.

Normalized Low Frequency (LFnorm) is the ratio between the absolute value of LF and TP without regard to VLF. This pokazatel which minimizes the effect of VLF in the total power spectrum and allocates changes in sympathetic regulation. LFNorm calculated in percentage.

Normalized High Frequency (HF norm) is the ratio between the absolute value of HF and TP without regard to VLF. This measure minimizes the effect of VLF in the total power spectrum and allocates changes in parasympathetic regulation. HFnorm calculated in percentage.

Breath test:

This test is designed to assess the parasympathetic branch of the autonomic nervous system. The test gives a positive stimulation of the parasympathetic regulation of heart rhythm.

During this test, the subject breathes deeply and evenly with a respiratory rate of 6 breaths per minute. During the test, it is very important to exclude any events that may affect random breath, such as talking, coughing, sighing, etc., This interference can cause undesirable fluctuations of heart rate and can distort the results. The subject was instructed to breathe for 1 minute, following the movement of Pazera depicted on the computer screen. Calculate the following test parameters:

1. Minimal HR (bpm)

2. Maximal HR (bpm)

3. Standard Deviation of HR (bpm)

4. Mean ratio of HR max / HR min (ATE Ratio)

5. Maximal Variance of HR during the test (bpm)

- Orthostatic test

This test is used to assess the influence of the parasympathetic regulation of the heart rhythm. The test is based on the change of body position of the subject. The subject must be in a relaxed state in the sitting position After a minute recording the heart rhythm of the subject is given the command to stand, avoiding any sudden movements. The subject remains standing for another minute. Monitoring heart rhythm continues throughout the test. The purpose of recording the baseline and maneuver rising to estimate nonstationary transition process in the rhythm of the heart, caused by changes in body position. HR monitories up until a new stationary state of the heart rhythm is not detected. Calculate the following test parameters:

1. 30:15 Ratio (the ratio between the maximum value of the heart rate within the first 15 seconds after standing up to the minimum value of the heart rate within the first 30 seconds after getting up, or the reaction to the load.E.).

2. The time to reach maximum values of heart rate after standing up (or reaction time, sec.)

3. The time to reach HR 75% of baseline (or stabilization time, in seconds).

4. The minimum value of the heart rate (ID/s).

5. The maximum value of the heart rate (ID/s).

- Self-assessment of functional status (SAN) (Duskin C. A., Lavrent'eva N. A., Miroshnikov N. P., Sharay Century B. Test differentiated self-assessment of functional status // Questions of psychology, 1973. No. 6. - S. 141-145).

The method allows to quantify the performance of the subjective state, describing three categories of signs: health, activity and mood (SAN), which are defined using a special form. the form and there are 30 pairs of words with opposite meanings and between evaluation scale. Depending on the subjective assessment of his state of the subject notes the severity of a certain variable on a seven-point scale. Signs by numbers characterize: 1-2, 7-8, 13-14, 19-20, 25-26 - health; 3-4, 9-10, 15-16, 21-22, 27-28 - activity; 5-6, 11-12, 17-18, 23-24, 29-30 - mood. When processing the results of the mood assessment recoded from 7 to 1 from left to right, and activity - right-to-left.

For each characteristic (health, activity, mood) calculated the arithmetic mean of the value of its error and standard deviation. This allows the integral to evaluate the subjective state. The arithmetic mean value is immediate subjective response of functional status and health, but in terms of the range of estimates within one group of features (standard deviation), it is possible to judge the reliability of the results.

- Psychometric tests

Were performed on computers on the program "EYE" (the operational control of the operator), designed for this kind of research management specialists "Habitability and medical support personnel, Navy" Central research Institute of shipbuilding Russian Ministry of defense, under the direction of Professor Rybnikov C. Y.

Define the following physiological parameters:

in response to a moving object (WFD);

- simple motor responses (WPDR);

- attention span (S);

- attention span (HC).

Due to the high variability psychophysiological indicators of their measurement was performed several times and then calculated the arithmetic mean of the entire series of values. In particular, the assessment WPDR was repeated 50 times, the WFD - 20, S and HC 5 times. In the test of the WFD also of 20 values were counting the number of hits the target and then calculated the percentage of accurate hits. In the test HC investigated the average execution time of the test, the number of correct responses in percent to the total number performed by the volunteer.

To integrate these indicators was determined by the ratio of sustained attention (IMC), which was calculated by dividing the percentage of correct answers on average run time of the test.

In response to a moving object (WFD) (preservation of the health of the floating part of the Navy. A guide for physicians // Under the General editorship Zheglov centuries, Sapova I. A., Shchegolev B. C. - M.: Voenizdat. - 1990. - 192 S.).

Reaction to a moving object allows you to define the precision of examinee response to a stimulus and to judge the balance of the processes of excitation and inhibition in the cerebral cortex. The essence of the response is the need of recovering is to pour a fast moving object in a pre-fixed point. This may be used include remotely by the experimenter electrochemi, the potential participant must stop exactly at the mark "O" button on your remote. This test can also be performed using special software on the PC. The response of the examinee may be premature - arrow electroeconomy not reached "On", the trailing-arrow overshot the mark "O", exact - arrow stopped at the mark "O". Each premature or delayed reaction is a quantitative characteristic in absolute units. To assess the results of the sample is calculated relative accuracy of responses (in % of the total number of reactions), as well as the average arithmetic and algebraic average values of all submitted responses.

- Simple sensorimotor reaction to light or simple motor responses (WPDR) (preservation of the health of the floating part of the Navy. A guide for physicians // Under the General editorship Zheglov centuries, Sapova I. A., Shchegolev B. C. - M.: Voenizdat, 1990. - 192 S.).

Simple motor reaction is one of the informative methods for strength of nervous processes. In simple sensorimotor reaction can distinguish two mental act is: an act of perception (touch point of the reaction) and a reciprocal movement (motor component). Assessment WPDR can be produced in the traditional way (using chronoreflexometric), as well as using special computer programs. The subject tentatively explain the contents and perform the test. Then he sits down on a chair, puts his hands on the table in front of honorifically, the finger of the dominant hand has on its corresponding button. After completion of the test, the physician-researcher submits a command and within 3-10 seconds after it switches on the device. The objective of the test as soon as possible after the occurrence of the signal to respond by pressing the button and extinguish the light. Simple motor reaction is measured (in milliseconds) since the appearance on the monitor screen special object before pressing the test button on the pointing device (keyboard or mouse). WPDR is measured, typically 50 times, and then determined the average value of the index.

- Harvard step test (research Methods in physiology military labor. Manual / edited by B. C. Novikov. - M.: Voenizdat, 1993. - 240 S.)

As functional tests, allowing you to identify the response of the cardiovascular system adverse effects and, in particular, the impact of the Coriolis accelerations, used a 2-minute Harvard step test (Karpman C. L. et al., 1988).

The method is based nocence autonomic changes during physical load submaximal capacity and regenerative capacity of the body to normalize the heart rate.

The magnitude of the step test characterizes the speed of recovery process after intense muscular work. What is recovering faster the pulse, the smaller the value of (P2+P3+P4) and, consequently, the higher the index step of the test.

In athletes, this figure is usually higher than that of untrained people. When toxic effects of drugs should be expected to decrease. At the same time it is increasing evidence that the drug increases the functional reserves of the organism and the ability to endure adverse environmental effects, including kinetic effects.

The test is that the subject for 2 minutes with a frequency of 30 times per minute squats.Immediately after loading it on the 2nd, 3rd and 4th minutes count the pulse for the first 30 seconds of each minute. The index step of the test was calculated by the formula:

The index of the Harvard step test=T*100/(P2+P3+P4)*2,

where T - time load in seconds; P2, P3, P4 - frequency pulse on the 2nd, 3rd, 4th-minute recovery period, and * is the multiplication sign.

Due to the fact that the drugs are intended for those susceptible to motion sickness, including drivers, assessed their safety when executed by a person responsible operator functions. With this purpose were the main predictors of quality activities operatorsto the type what thoroughly examined the functional state of the Central nervous system (in particular, systems coordination and response systems provide high efficiency fine motor components, activities, and attention).

Probe Rod (maintaining the health of the floating part of the Navy. A guide for physicians // Under the General editorship Zheglov centuries, Sapova I. A., Shchegolev B. C. - M.: Voenizdat.- 1990. - 192 S.).

The essence of the complete sample is breath after three breaths 3/4 full depth of the breath. To test the examinee on the nose wears a clip or the subject holds his nose with his fingers. The delay time is recorded by stopwatch. The test may be carried out twice at intervals of 3-5 minutes between definitions. For the duration of the breath sample is estimated as follows:

- less than 39 seconds - unsatisfactory;

- 40 to 49 s - satisfactory;

more than 50 seconds - well.

- Sample of Genc (maintaining the health of the floating part of the Navy. A guide for physicians // Under the General editorship Zheglov centuries, Sapova I. A., Shchegolev B. C. - M.: Voenizdat.- 1990. - 192 S.).

The essence of the complete sample is in the breath on the exhale after three breaths. The test of Genc in the supine position, the duration of breath holding in healthy people R udaetsya 25-30 sec. When it comes again after the measured amount of foot (44 m within 30 seconds), the duration of breath-holding is reduced to 17-22 sec, while the functional failure of the body to 5-15 seconds. Evaluation tests were conducted as follows:

less than 34 sec - unsatisfactory;

- 35-39 s - satisfactory;

more than 40 seconds - well.

Example 3. To study the efficacy of treatment of patients with the Syndrome of Vegetative Dysfunction (SVD) psychophysiological and dishormonal Genesis declared drug 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 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 C12, 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 forms of polyclonal rabbit antibodies to mathoperation the WMD 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

Design the study was a single center, open, randomized, comparative clinical study of the efficacy and safety of using medications ULD anti-S100+anti-eNOS and ULD anti-S100, used as monotherapy in the treatment of patients with the Syndrome of Vegetative Dysfunction (SVD) psychophysiological and dishormonal Genesis.

The study included 12 patients with a diagnosis of SVD psychophysiological Genesis" and "SVD dishormonal Genesis", ranging in age from 23 to 61 years. The average age of the patients was 49,25±12,63 year.

After determining the compliance of the patient inclusion criteria and exclusion Protocol patients were randomized into one of two study groups: group ULD anti-S100+anti-emo-6 patients (3 patients with SVD psychophysiological and 3 patients SVD dishormonal Genesis). The average age of the patients group ULD anti-S100+anti-eNOS was 41,33±12.5 years (17.7% of men and 82.3% of women); group ULD anti-S100 - 6 patients (3 patients with SVD psychophysiological and 3 patients SVD dishormonal Genesis).

Cf is dni patient age group ULD anti S100 was 57,16±4.35 years (17.7% of men and 82.3% of women).

In this study there were 4 visit to the research center. The treatment phase lasted from Visit 1 to Visit 3. Visit 3 (Day 56±5) was the first endpoint of the study, after which began the phase follow-up observations. Phase follow-up observations continued until Visit 4 (Day 84±5).

In the safety analysis included data from all patients participating in the study (n=12). During the whole period of observation of the patients showed good tolerance of the drug. Adverse events were absent. One patient did not come for the second visit, contact with it is lost. The patient was not included in the analysis. 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 manifestations of the SVD, and anxiety-depressive disorders (Beck depression inventory), was identified improving the quality of life of patients, expressed in a statistically significant increase in the total score of the questionnaire SF-36 (podskalo "physical health" 38,04±2,44 to 47,84±1,27, p=0.005, podskalo "mental health" - with 57,88±3,94 to 72,75±1,64, p<0.01), and as well as a statistically significant reduction in the total score on the Beck depression inventory (from 11.0±1.4 to 5.5V±1,37, p<0,02)

When evaluating on istia drug ULD anti S100 on the main manifestations of the SVD, and anxiety-depressive disorder patients (Beck depression inventory) were identified improving the quality of life of patients, expressed in a statistically significant increase in the total score of the questionnaire SF-36 (podskalo "mental health" - 56,107±1,36 up to 70.7±1,39, p<0,001). Trends increase the total score of podskali "physical health" in this group have been identified.

When analyzing the dynamics of anxiety and depressive disorders in a group of ULD anti-S100 statistically significant reduction in total score on the Beck depression inventory (from 10.5±1,04 to 5.33±1,5, p<0,02) (table 10).

Table 10
SF-36 (physical health)SF-36 (mental health)The Beck depression inventory
ULD anti-S100+anti-eNOS before the treatment38,04±2,4457,88±3,9411,0±1,4
ULD anti-S100+anti-eNOS after treatment47,84±1,27*72,75±1,64**5,5±1,37***
ULD anti-S100 before the treatment46,99±8,0956,07±1,36 10,5±1,04
ULD anti-S100 after treatment49,17±2,68to 70.7±1,39****5,33±1,5***
*- R from ex.=0,005
**- R from ex.<0,01
***- R from ex.<0,02
****- R. from Ref.<0,001

Reliable inter-group differences after treatment on these indicators are not identified. When planning the study and the recruitment of patients, the groups were divided into the following subgroups:

1. Patients with a diagnosis of Vegetative Dysfunction Syndrome psychophysiological Genesis (chronic stress), who will receive the drug ULD anti-S100+anti-em as monotherapy.

2. Patients with a diagnosis of Vegetative Dysfunction Syndrome psychophysiological Genesis (chronic stress), who will receive the drug ULD anti-S100 as monotherapy.

3. Patients with a diagnosis of Vegetative Dysfunction Syndrome dishormonal (climacteric) Genesis, who will receive the drug ULD anti-S100+anti-eNOS as monotherapy.

4. Patients with a diagnosis of Vegetative Dysfunction Syndrome dishormonal (climacteric) Genesis, which will be p in order to obtain the drug ULD anti-S100 as monotherapy.

The analysis of the obtained data subgroup trends were consistent with those in the whole group analysis, though, and had less confidence that, probably due to small number of observations (table 11, 12).

Table 11
SVD dishormonal (climacteric) Genesis
SF-36 (physical health)SF-36 (mental health)The Beck depression inventory
ULD anti-S100+anti-eNOS before the treatment38,5±2,9957,9±4,4211,0±2,0
ULD anti - S100+anti-eNOS after treatment47,99±1,48*72,75±1,85*5,33±0,57***
ULD anti-S100 before the treatment47,39±8,3556,79±1,2310,0±1.0
ULD anti-S100 after treatment48,96±3,1670,71±1,68**4,66±0.057****
*- Rotich.<005
**- R from ex.<0,005
***- R from ex.=0,053
****- R from ex.=0,01

Table 12
SVD psychophysiological (chronic stress)Genesis
SF-36 (physical health)SF-36 (mental health)The Beck depression inventory
ULD anti-S100+anti-eNOS before the treatment37,57±2, 3157,85±4,3911,0±1,0
MD anti-5100+anti-eNOS after treatment47,69±1, 32*72,73±1,82* *5,B6±2,08****
ULD anti-S100 before the treatment47,39±8, 35to 55.42±1,3111,0±1,0
ULD anti-S100 after treatment48,96±3, 1670,b±1,65* **6,0±2,0****
* - R from ex.<0,02
**- R from ex.<0,05
***- R from ex.=0,002
****- R from ex.=0,082

When intergroup and intragroup analysis of the dynamics of blood pressure, integrative autonomic indicators, indicators variational pulsometry statistically significant trends were not identified, except for the tendency to reduce the Index of Autonomic Balance (IIA). This is likely due to insufficient number of observations.

IIA - integrative index calculated as the ratio of the amplitude of the Mo (the number of R-interval corresponding to the range of fashion) to the Variation of the Amplitude (difference between maximum and minimum values of R-R). The decrease of this index indicates a shift of the autonomic balance from sympathicotonia to normal - and vagotonia, i.e., about the increasing influence of the parasympathetic divisions of the autonomic nervous system (ANS).

In the group dishormonal SVD statistically significant tendency to decrease IIA subgroup ULD anti-S100+anti-eNOS. While statistically significant (p<0.05) difference between the subgroup of ULD anti-S100+anti-eNOS and a subgroup of ULD anti-S100 (table 13).

Dishormonal SVD
Table 13
PSI before the treatmentIOM after treatment
ULD anti-S100+anti-eNOS721,1+38,52416,86±73,72*#
ULD anti-S100 after treatment48,96±3,16696,26±B1,85
* - R from ex.<0,05
# - R.. with ULD anti-S100.<0,05

Thus, clinical research claimed medicines ULD anti-S100+anti-eNOS shown a positive impact on the quality of life of patients with the Syndrome of Vegetative Dysfunction (SVD) psychophysiological and dishormonal Genesis, a positive effect on anxiety-depressive disorder patients. Demonstrated a positive effect of the drug on autonomic nervous system. In addition, confirmed the high portability of the claimed medicinal preparation. Adverse events were absent.

Example 4.

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 decrease cogniti the different functions, 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. This is based on 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 deterioration of 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 4 studied the efficiency with scopolamine amnesia the AI rats claimed medicinal product in the form of a composition, contains 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-hedgehog)8).

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) was used 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 accordingly 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 educational cess is Yu in the maze Morris (4 consecutive test every 60 seconds). 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, it was placed 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 and 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, C is acetelyne increased (Table 14, 15). 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 16). The introduction of ULD anti S100 in the group # 2 did not lead to the improvement of the studied parameters (Table 14, 15, 16). The introduction of ULD anti-S100+anti-em 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 14) and overcome distances (table 15) within 4 days of training, and improved memory, which was reflected in the increase in time spent in the place where was the platform (table 16).

Table 14
The latent period of search platforms, sec
GroupTraining
1 dayday 23 dayday 4
Intact e,n=1254,7±6,230,8±2,826,9±5,120,5±3,6
Control,n=12100,1±6,8*** to 92.4±9,3***81,4±1 0,7***to 77.7±9,4***
ULD anti-S100, n=12106,8±7,0of 99.3±7,8is 95.6±9,080,4±1 1,1
ULD anti-S100+anti-eNOS, n=1294,4±7,290,7±8,278,3±8,660,1±1 0,2
* * * the difference from the intact significantly, p<0,05

Table 15
The distances covered in search of a platform, cm
Groups andTraining
1 dayday 23 dayday 4
Intact, n=121055,7±94,6659,5±62,2564,8±119,340B,1±B1,2
Control, n=122587,1±217,2 ***2559,6±250,5***2397,9±312,6 2366,1±293,8***
ULD anti-S100,n=122797,2±208,9B,2±255,12857,0±300,82457,4+to 344.4
ULD anti-S100+anti-eNOS, n=122434,3±222,82529,9±282,72344,2±283,01905,1±343,7
* * * the difference from the intact significantly, p<0,05

Table 16
The time spent in the place where once stood the platform, s
GroupSample
0-30 sec30-60 sec0-60 sec
Intact, n=1240,8±4,136,8±3,638,5±2,6
Control, n=1218,4±2,8***18,8±1,9***18,8±1,7***
ULD anti-S100,n=1213,3±2,121,5±2,b 17,6±1,3
ULD anti-S100+anti-eNOS, n=12of 19.1±4.823,8±2,221,2±2,5
* * * the difference from the intact significantly, p<0,05

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

1. Pharmaceutical composition for the treatment of dystonia syndrome dizziness of various origins and kinetosis 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 endothelial NO-synthase and the activated-potentiated form of antibodies to meshoperations protein S-100 is used in the form of 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 according to p. 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 solutions of the activated-potentiated form of antibodies to endothelial NO-synthase and activated-potentiated form of antibodies to meshoperations protein S-100, 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 endothelial NO-synthase and meshoperations protein S-100 is obtained by repeated consecutive dilution in conjunction with external cause - shaking each dilution of the matrix solutions of affinity purified antibodies to endothelial NO-synthase and meshoperations protein S-100 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 degree is Rath.

7. A method for the treatment of dystonia syndrome dizziness of various origins and kinetosis by introducing into the body an activated-potentiated form of antibodies to meshoperations protein S-100, characterized in that additionally at the same time and sachetana enter the activated-potentiated form of ultra-low doses of affinity purified antibodies to endothelial NO-synthase.

8. The method according to p. 7, characterized in that the activated-potentiated form of antibodies to endothelial NO-synthase and the activated-potentiated form of antibodies to meshoperations protein S-100 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 - shaking of every dilution.

9. The method of treatment on p. 7 or p. 8, characterized in that use is prepared in the form of a single drug - single dosage form a mixture of different dilutions of antibodies to endothelial NO-synthase in combination with a mixture of various dilutions of antibodies to meshoperations protein S-100, prepared according to homeopathic technology.



 

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