RU2531048C2 - Drug substance for reducing insulin resistance and treating diabetes mellitus and method for providing higher therapeutic effectiveness in diabetes mellitus with insulin and/or antihyperglycemic medications - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to endocrinology, and concerns treating diabetes mellitus. That is ensured by administering a pharmaceutical composition containing activated-potentiated forms of insulin receptor and endothelial NO-synthase antibodies.

EFFECT: invention provides the effective treatment of diabetes mellitus by the synergetic effect of the ingredients of the composition on the pathogenic mechanisms of the disease that are reducing the insulin resistance and the blood glucose level.

20 cl, 6 dwg, 5 ex

Description

The invention relates to medicine and can be used to reduce insulin resistance and for the treatment of diabetes mellitus, as well as to increase the effectiveness of the treatment of diabetes with insulin and / or other hypoglycemic drugs, including insulin-resistant patients.

The prior art knows antidiabetic drug in the form of potentiated insulin prepared according to homeopathic technology (RU 2134122 C1, A61K 39/395, 08/10/1999).

The prior art method for regulating carbohydrate and fat metabolism and a drug based on the activated form of ultra-low doses of antibodies to insulin receptors (RU 2199345 C1, A61K 39/395, 02.27.2003). However, these drugs do not in all cases provide sufficient therapeutic efficacy.

There is also a method of treating patients with diabetes mellitus by administering hypoglycemic drugs and / or insulin or insulin derivatives (RU 2358738 C2, A61K 31/5517, 2006). However, the effectiveness of the treatment of diabetes mellitus with this kind of drug in some cases may be insufficient.

The invention is directed to the creation of a medicinal product in the form of a pharmaceutical composition based on an activated-potentiated form of antibodies to an insulin receptor, which provides a decrease in insulin resistance and effective treatment of diabetes mellitus, as well as to increase the effectiveness of treatment of diabetes with insulin and / or other hypoglycemic drugs

The solution to this problem is provided by the fact that the drug for reducing insulin resistance and for the treatment of diabetes mellitus, containing an activated-potentiated form of antibodies to the insulin receptor, according to the invention is made in the form of a pharmaceutical composition and includes an activated-potentiated form of antibodies as an additional reinforcing component to endothelial NO synthase.

Moreover, the drug may contain an activated-potentiated form of antibodies to the β-subunit of the insulin receptor and an activated-potentiated form of affinity-purified antibodies to endothelial NO synthase.

While the drug preferably contains an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase.

In addition, the drug may contain an activated-potentiated form of antibodies to the α-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase.

Moreover, the activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and the activated-potentiated form of antibodies to the endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution, the activity of which is due to the process of repeated dilution of the matrix solution of the corresponding antibodies in an aqueous or hydroalcoholic solvent in combination with an external mechanical action - repeated shaking of each dilution.

In addition, the pharmaceutical composition may be in solid dosage form and contain an effective amount of a neutral carrier granule saturated with a mixture of an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase, and pharmaceutically acceptable additives that include isomalt, crospovidone and magnesium stearate.

In this case, aqueous or aqueous-alcoholic solutions of activated-potentiated forms of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase can be obtained by repeated serial dilution in combination with an external mechanical action - multiple shaking of each dilution from matrix solutions affinity-purified antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase with a concentration of 0.5 ÷ 5.0 mg / ml

Moreover, each of the components is used in the form of a mixture of various, mainly hundred, dilutions prepared according to homeopathic technology.

The solution to this problem is also ensured by the fact that in the method of reducing insulin resistance and treating type I and type 2 diabetes mellitus, comprising administering to the body an activated-potentiated form of antibodies to the insulin receptor, according to the invention, an additional reinforcing component in the form of activated potentiated forms of antibodies to endothelial NO synthase.

In this case, it is possible to administer the pharmaceutical composition in the form of a single drug - one dosage form containing the activated-potentiated form of antibodies to the β-subunit of the insulin receptor and the activated-potentiated form of antibodies to endothelial NO synthase.

Preferably, the pharmaceutical composition is administered in the form of a single drug - a single dosage form containing an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase.

In addition, it is possible to administer a pharmaceutical composition in the form of a single drug - a single dosage form containing an activated-potentiated form of antibodies to the α-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase.

In addition, it is possible to administer a pharmaceutical composition in the form of a single drug - one dosage form containing an activated-potentiated form of antibodies to the α-subunit of the insulin receptor and an activated-potentiated form of antibodies to the insulin receptor β-subunit in combination with an activated-potentiated form antibodies to endothelial NO synthase.

Moreover, the activated-potentiated form of antibodies to the insulin receptor, or fragments of the insulin receptor, including the C-terminal fragment of the β-subunit of the insulin receptor, and the activated-potentiated form of antibodies to the endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcohol solution, the activity of which is due to the process of repeated dilution of the matrix solution of the corresponding antibodies in an aqueous or aqueous-alcohol solvent in combination with an external mechanical effect ime - shaking each breeding multiple times.

In addition, in the pharmaceutical composition, each of the components is used in the form of a mixture of various, mainly hundred, dilutions prepared according to homeopathic technology.

The solution to this problem is also ensured by the fact that in the method of treating diabetes mellitus by administering insulin and / or hypoglycemic drugs according to the invention, a pharmaceutical composition is additionally introduced into the body containing an activated-potentiated form of antibodies to an insulin receptor, mainly to the C-terminal fragment of the β-subunit of the receptor insulin, and the activated-potentiated form of antibodies to endothelial NO synthase.

In this case, the activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and the activated-potentiated form of antibodies to the endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution of each component, the activity of which is due to the process of repeated dilution in aqueous or hydroalcoholic solvent in combination with an external mechanical action - repeated shaking of each dilution.

Preferably, the pharmaceutical composition is used in the form of a single drug - a single dosage form containing a mixture of different dilutions of the C-terminal fragment of the β-subunit of the insulin receptor in combination with a mixture of different dilutions of antibodies to endothelial NO synthase prepared by homeopathic technology.

In addition, the drug may contain active ingredients in a volume ratio of 1: 1, with each component used in the form of a mixture of three appropriate matrix solutions diluted 100 ¹² , 100 ³⁰ , and 100 ²⁰⁰ times, respectively, which is equivalent to hundreds of dilutions of C 12, C 30, C 200 prepared according to homeopathic technology.

The claimed drug can be used in the treatment of diabetes alone as a hypoglycemic drug or in combination therapy in addition to insulin replacement therapy and / or in conjunction with oral hypoglycemic drugs (biguanides (metformin); sulfonylureas (glibenclamide, glipizide, glyclazide, glycidone), ; thiazolidinediones (rosiglitazone); α-glycosidase inhibitors (acarbose), etc.), as well as in addition to the accompanying therapy of diabetes mellitus for the purpose of ofilaktiki its complications.

The claimed pharmaceutical composition is recommended to be taken, preferably, 1-2 tablets 2-6 times a day (preferably 2-4 times a day).

To reduce insulin resistance and in the treatment and prevention of diabetes mellitus, separate but combined and simultaneous use (introduction into the body) of the components of the pharmaceutical composition of the claimed medicinal product in the form of two separately prepared preparations both in the form of solutions and in solid dosage forms is possible (in tablets), each of which contains an activated-potentiated form of ultra-low doses of affinity-purified antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and, respectively, the activated-potentiated form of ultra-low doses of affinity-purified antibodies to NO-synthase.

The proposed combination of activated-potentiated forms of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and NO synthase in the pharmaceutical composition (i.e., the forms of antibodies to the C-terminal fragment of the α-subunit of the insulin receptor α-subunit and to NO synthase prepared according to homeopathic technology of potentiation by repeated serial dilution in combination with external mechanical action - vertical shaking of each dilution, which is active in pharmacological models and / or clinics methods of treating and preventing diabetes mellitus or reducing insulin resistance) provides an unexpected synergistic therapeutic effect, confirmed by adequate experimental models and clinical studies, which consists in reducing insulin resistance, increasing the effectiveness of insulin therapy in patients with type I diabetes and non-insulin-dependent diabetes mellitus Type II, stabilization of the doses used and reduction of the doses of antidiabetic drugs in the complex oh therapy, reducing the risk of side effects, decrease the severity of diabetes complications, such as cardiovascular disorders, neuropathy, nephropathy, due to an increase in the sensitivity of body cells to insulin due to nonspecific NO-dependent activation of the intracellular signal transduction of insulin receptor.

In addition, the claimed drug expands the arsenal of drugs for the treatment of diabetes, including in complex insulin therapy, both for the prevention of complications and to reduce the side effects of antidiabetic drugs.

Figure 1 presents a graph showing the effect of the tested drugs on the glucose level in the blood plasma of rats with streptozotocin-induced diabetes mellitus; figure 2 shows the effect of the tested drugs on the 14th day of administration on the area under the concentration-time curves (AUC) in the glucose tolerance test in rats with streptozotocin-induced diabetes mellitus; figure 3 shows the effect of the tested drugs on the level of glucose in the blood plasma of rats with spontaneous non-insulin-dependent diabetes mellitus; figure 4 shows the effect of the tested drugs on the 28th day of administration on the area under the concentration-time curves (AUC) in the glucose tolerance test in rats with spontaneous non-insulin-dependent diabetes mellitus; figure 5 shows the dynamics of the level of glucose and glycated hemoglobin in patients with type I diabetes mellitus while taking the drug AT RI + AT NOS; figure 6 shows the dynamics of the level of glucose and glycated hemoglobin in patients with type II diabetes mellitus while taking the complex drug AT RI + AT NOS.

The drug is prepared mainly as follows.

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

Monoclonal antibodies are obtained, for example, using hybridoma technology. Moreover, the initial stage of the process includes immunization, based on the principles already developed in the preparation of polyclonal antisera.

Further stages of the work include obtaining hybrid cells producing clones of antibodies of the same specificity. Their isolation in an individual form is carried out by the same methods as in the case of polyclonal antisera.

Polyclonal antibodies can be obtained by active immunization of animals. To do this, according to a specially developed scheme, animals are given a series of injections with the antigens required by the invention: the C-terminal fragment of the β-subunit of the insulin receptor and NO synthase. As a result of this procedure, monospecific antisera with a high content of antibodies are obtained, which are used to obtain activated-potentiated forms. If necessary, the antibodies present in the antiserum are purified, for example, by affinity chromatography, using fractionation by salt precipitation or ion exchange chromatography.

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

Preferred for the preparation of each component is the use of a mixture of three water-alcohol dilutions of the primary matrix solution of antibodies diluted 100 ¹² , 100 ³⁰ , and 100 ²⁰⁰ times, respectively, which corresponds to hundreds of homeopathic dilutions C 12, C30 and C 200. When performing the claimed drug in solid dosage form, a mixture of these components in a volume ratio of 1: 1 is applied to a neutral carrier - lactose.

Preferred for the preparation of the claimed drug is the use of polyclonal antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to NO synthase, which can be obtained by immunization of rabbits as follows.

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

For immunization of rabbits, it is possible to use as an immunogen (antigen) an adjuvant and a human insulin receptor molecule with the sequence:

1 mgtggrrgaa aapllvavaa lllgaaghly pgevcpgmdi rnnltrlhel encsvieghl

61 qillmfktrp edfrdlsfpk limitdylll frvygleslk difpnitvir gsrlffnyal

121 vifemvhike lglynlmnit rgsvrieknn eicylatidw srildsvedn hivlnkddne

181 ecgdicpgta kgktncpatv ingqfvercw thshcqkvcp tickshgcta eglcchsecl

241 gncsqpddpt kcvacmfyi dgrcvetcpp pyyhfqdwrc vnfsfcqdih hkcknsrrqg

301 chqyvihnnk cipecpsgyt mnssnilctp cigpcpkvch llegektids vtsaqelrgc

361 tvingsliin irggnnlaae leanlgliee isgylkirrs yalvslsffr kirlirgetl

421 eignysfyal dnqnirqlwd wskhnltttq gklffhynpk lclseihkme evsgtkgrqe

481 mdialktng dkascenell kfsyirtsfd killrwepyw ppdfrdllgf mifykeapyq

541 nvtefdgqda cgsnswtvvd idpplrsndp ksqnhpgwim rglkpwtqya ifvktivtfs

601 derrtygaks diiyvqtdat npsvpldpis vsnsssqiil kwkppsdpng nithylvfwe

661 rqaedseife ldyclkglkl psrtwsppfe sedsqkhnqs eyedsagecc scpktdsqil

721 keleessfrk tfedylhnvv fvprktssgt gaedprpsrk rrslgdvgnv tvavptvaaf

781 pntsstsvpt speehrpfek vvnkeslvis girhftgyri elqacnqdtp eercsvaayv

841 sartmpeaka ddivgpvthe ifennvvhim wqepkepngi iviyevsyrr ygdeelhlcv

901 srkhfalerg crirglspgn ysvriratsl agngswtept yfyvtdyldv psniakiiig

961 plifvflfsv vigsiylflr krqpdgplgp lyassnpeyl sasdvfpcsv yvpdewevsr

1021 ekitllreig qgsfgmvyeg nardiikgea etrvavktvn esaslrerie flneasvmkg

1081 ftchhvvrll gvvskgqpti vvmelmahgd lksylrsirp eaennpgrpp ptiqemiqma

1141 aeiadgmayl nakkfvhrdi aamcmvahd ftvkigdfgm trdiyetdyy rkggkgllpv

1201 rwmapeslkd gvfttssdmw sfgvvlweit slaeqpyqgl sneqvlkfvm dggyldqpdn

1261 cpervtdlmr mcwqfnpkmr ptfleivnil kddlhpsfpe vsffhseenk apeseeleme

1321 fedmenvpid rsshcqreea ggrdggsslg fkrsyeehip ythmnggkkn griltlprsn

1381 ps;

or an adjuvant and the α-subunit of the human insulin receptor with the sequence:

28-762:

28 hly pgevcpgmdi mnltrlhel encsvieghl

61 qillmfktrp edfrdlsfpk limitdylll frvygleslk difpnitvir gsrlffnyal

121 vifemvhike lglynlmnit rgsvrieknn eicylatidw srildsvedn hivlnkddne

181 ecgdicpgta kgktncpatv ingqfvercw thshcqkvcp tickshgcta eglcchsecl

241 gncsqpddpt kcvacrnfyi dgrcvetcpp pyyhfqdwrc vnfsfcqdih hkcknsrrqg

301 chqyvihnnk cipecpsgyt mnssnilctp cigpcpkvch llegektids vtsaqelrgc

361 tvingsliin irggnnlaae leanlgliee isgylkirrs yalvslsffr kirlirgetl

421 eignysfyal dnqnirqlwd wskhnltttq gklffhynpk lclseihkme evsgtkgrqe

481 mdialktng dkascenell kfsyirtsfd killrwepyw ppdfrdllgf mifykeapyq

541 nvtefdgqda cgsnswtvvd idpplrsndp ksqnhpgwim rglkpwtqya ifvktivtfs

601 derrtygaks diiyvqtdat npsvpldpis vsnsssqiil kwkppsdpng nithylvfwe

661 rqaedseife ldyclkglkl psrtwsppfe sedsqkhnqs eyedsagecc scpktdsqil

721 keleessfrk tfedylhnvv fvprktssgt gaedprpsrk rr

or an adjuvant and a polypeptide fragment of the a-subunit of the human insulin receptor, selected, for example, from the following sequences:

131-144:

lglynlmnit rgsv;

191-203:

kgktncpatv ing;

441-453:

wskhnltttq gkl;

541-560:

nvtefdgqda cgsnswtvvd;

611-620:

diiyvqtdat npsvpldpis;

702-719:

yedsagecc scpktdsqi

or an adjuvant and the β-subunit of the human insulin receptor with the sequence:

763-1382

763 sigdvgnv tvavptvaaf

781 pntsstsvpt speehrpfek vvnkeslvis girhftgyri elqacnqdtp eercsvaayv

841 sartmpeaka ddivgpvthe ifennvvhim wqepkepngi iviyevsyrr ygdeelhlcv

901 srkhfalerg crirglspgn ysvriratsl agngswtept yfyvtdyldv psniakiiig

961 plifvflfsv vigsiylflr krqpdgplgp lyassnpeyl sasdvfpcsv yvpdewevsr

1021 ekitllreig qgsfgmvyeg nardiikgea etrvavktvn esaslrerie flneasvmkg

1081 ftchhvvrll gvvskgqpti vvmelmahgd lksylrsirp eaennpgrpp ptiqemiqma

1141 aeiadgmayl nakkfvhrdi aamcmvahd ftvkigdfgm trdiyetdyy rkggkgllpv

1201 rwmapeslkd gvfttssdmw sfgvvlweit slaeqpyqgl sneqvlkfvm dggyldqpdn

1261 cpervtdlmr mcwqfnpkmr ptfleivnil kddlhpsfpe vsffhseenk apeseeleme

1321 fedmenvpid rsshcqreea ggrdggsslg fkrsyeehip ythmnggkkn griltlprsn

1381 ps

or an adjuvant and a polypeptide fragment of the C-terminal fragment of the β-subunit of the human insulin receptor, selected, for example, from the following sequences:

1368-1377:

KKNGRILTLP;

1372-1382:

RILTLPRSNPS;

1369-1375:

KNGRILT;

1366-1382:

GGKKNGRILTLPRSNPS;

1365-1382:

NGGKKN GRILTLPRSN PS

Before blood sampling for 1-3 days, 1-3 intravenous injections are performed to increase the level of antibodies. During immunization, small blood samples are taken from rabbits to evaluate the amount of antibody. The maximum level of the immune response to the administration of most soluble antigens is achieved 40-60 days after the first injection. After the end of the first cycle of immunization of rabbits for 30 days, they restore health and re-immunization, including 1-3 intravenous injections. To obtain antisera from immunized rabbits, blood is collected in a 50 ml centrifuge tube. Using a wooden spatula, the formed clots are removed from the walls of the tube and the wand is placed in the clot formed in the center of the tube. Blood is placed in a refrigerator (temperature 4 ° C) at night. The next day, the clot attached to the spatula is removed and the remaining liquid is centrifuged at 13000g for 10 minutes. The supernatant (supernatant) is an antiserum. The resulting antiserum should be yellow. Add to the antiserum 20% (weight concentration) NaN ₃ to a final concentration of 0.02% and store until use in a frozen state at a temperature of -20 ° C (or without adding NaN ₃ at a temperature of -70 ° C). In order to isolate antibodies to the C-terminal fragment of the β-subunit of the human insulin receptor from antiserum, absorption on the solid phase is carried out in the following sequence:

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

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

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

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

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

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

1 MGNLKSVGQE PGPPCGLGLG LGLGLCGKQG PASPAPEPSR

ARARATRNAR DHSPAPNSPT

61 LTRPPEGPKF PRVKNWELGS ITYDTLCAQS QQDGPCTPRR

CLGSLVLPRK LQTRPSPGPP

121 PAEQLLSQAR DFINQYYSSI KRSGSQAHEE RLQEVEAEVA

STGTIHLRES ELVFGAKQAW

181 RNAPRCVGRI QWGKLQVFDA RDCSSAQEMF TYICNHIKYA

TNRGNLRSAI TVFPQRAPGR

241 GDFRIWNSQL VRYAGYRQQD GSVRGDPANV EITELCIQHG

WTPGNGRFDV LPLLLQAPDE

301 APELFVLPPE LVLEVPLGAP HTGVVRGPGL RWYALPAVSN

MLLEIGGLEF SAAPFSGWYM

361 STEIGTRNLC DPHRYNILED VAVCMDLDTR TTSSLWKDKA

AVEINLAVLH SFQLAKVTIV

421 DHHAATVSFM KHLDNEQKAR GGCPADWAWI VPPIYGSLPP

VFHQEMVNYI LSPAFRYQPD

481 PWKGSATKGA GITRKKTFKE VANAVKISAS LMGTLMAKRV

KATILYASET GRAQSYAQQL

541 GRLFRKAFDP RVLCMDEYDV VSLEHEALVL VVTSTFGNGD

PPENGESFAA ALMEMSGPYN

601 SSPRPEQHKS YKIRFNSVSC SDPLVSSWRR KRKESSNTDS

AGALGTLRFC VFGLGSRAYP

661 HFCAFARAVD TRLEELGGER LLQLGQGDEL CGQEEAFRGW

AKAAFQASCE TFCVGEEAKA

721 AAQDIFSPKR SWKRQRYRLS AQAEGLQLLP GLIHVHRRKM

FQATVLSVEN LQSSKSTRAT

781 ILVRLDTAGQ 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 QDILRTELAA EVHRVLCLER GHMFVCGDVT

MATSVLQTVQ RILATEGDME

1141 LDEAGDVIGV LRDQQRYHED IFGLTLRTQE VTSRIRTQSF

SLQERHLRGA VPWAFDPPGP

1201 DTPGP

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

1 MGNLKSVAQE PGPPCGLGLG LGLGLCGKQG PATPAPEPSR

APASLLPPAP EHSPPSSPLT

61 QPPEGPKFPR VKNWEVGSIT YDTLSAQAQQ DGPCTPRRCL

GSLVFPRKLQ GRPSPGPPAP

121 EQLLSQARDF INQYYSSIKR SGSQAHEQRL QEVEAEVAAT

GTYQLRESEL VFGAKQAWRN

181 APRCVGRIQW GKLQVFDARD CRSAQEMFTY ICNHIKYATN

RGNLRSAITV FPQRCPGRGD

241 FRIWNSQLVR YAGYRQQDGS VRGDPANVEI TELCIQHGWT

PGNGRFDVLP LLLQAPDDPP

301 ELFLLPPELV LEVPLEHPTL EWFAALGLRW YALPAVSNML

LEIGGLEFPA APFSGWYMST

361 EIGTRNLCDP HRYNILEDVA VCMDLDTRTT SSLWKDKAAV

EINVAVLHSY QLAKVTIVDH

421 HAATASFMKH LENEQKARGG CPADWAWIVP PISGSLTPVF

HQEMVNYFLS PAFRYQPDPW

481 KGSAAKGTGI TRKKTFKEVA NAVKISASLM GTVMAKRVKA

TILYGSETGR AQSYAQQLGR

541 LFRKAFDPRV LCMDEYDVVS LEHETLWLVV TSTFGNGDPP

ENGESFAAAL MEMSGPYNSS

601 PRPEQHKSYK IRFNSISCSD PLVSSWRRKR KESSNTDSAG

ALGTLRFCVF GLGSRAYPHF

661 CAFARAVDTR LEELGGERLL QLGQGDELCG QEEAFRGWAQ

AAFQAACETF CVGEDAKAAA

721 RDIFSPKRSW KRQRYRLSAQ AEGLQLLPGL IHVHRRKMFQ

ATIRSVENLQ SSKSTRATIL

781 VRLDTGGQEG LQYQPGDHIG VCPPNRPGLV EALLSRVEDP

PAPTEPVAVE QLEKGSPGGP

841 PPGWVRDPRL PPCTLRQALT FFLDITSPPS PQLLRLLSTL

AEEPREQQEL EALSQDPRRY

901 EEWKWFRCPT LLEVLEQFPS VALPAPLLLT QLPLLQPRYY

SVSSAPSTHP GEIHLTVAVL

961 AYRTQDGLGP LHYGVCSTWL SQLKPGDPVP CFIRGAPSFR

LPPDPSLPCI LVGPGTGIAP

1021 FRGFWQERLH DIESKGLQPT PMTLVFGCRC SQLDHLYRDE

VQNAQQRGVF GRVLTAFSRE

1081 PDNPKTYVQD ILRTELAAEV HRVLCLERGH MFVCGDVTMA

TNVLQTVQRI LATEGDMELD

1141 EAGDVIGVLR DQQRYHEDIF GLTLRTQEVT SRIRTQSFSL

QERQLRGAVP WAFEPPGSDT

1201 NSP

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

1192-1195

Pwaf

1189-1192:

Gavp

1185-1205:

RHLRGAVPWAF DPPGPDTPGP

1194-1205:

AF DPPGPDTPGP

1186-1196:

HLRGAVPWAF D

1186-1205:

HLRGAVPWAF DPPGPDTPGP

Thus obtained buffer solutions of each component of polyclonal antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase with a concentration of 0.5-5.0 mg / ml, preferably 2.0-3.0 mg / ml are used as matrix (primary) solutions for the subsequent preparation of activated-potentized forms of the drug.

The activated-potentiated form of each component is prepared by uniformly decreasing the concentration as a result of sequential dilution of 1 part of the matrix solution in 9 parts (for decimal dilution D), or in 99 parts (for hundredth dilution C), or in 999 parts (for thousandth dilution M ) a neutral solvent in combination with multiple (at least 10 times) vertical shaking (“dynamization”) of each dilution obtained and the use of separate containers for each subsequent dilution to Acquiring the required potency - the multiplicity of homeopathic dilution method (see, eg, W. Schwabe "Homeopathic medicines", Moscow, 1967, s.14-29...).

For example, to prepare the 12th hundredth C12 dilution, one part of the matrix solution of antibodies to the C-terminal fragment of the P-subunit of the insulin receptor P (or endothelial NO synthase) with a concentration of 3.0 mg / ml is diluted in 99 parts of neutral aqueous or water-alcohol solvent (mainly 15% ethyl alcohol) and repeatedly (10 or more times) vertically shake - potentiate the obtained 1st hundredth C1 dilution. From the 1st hundredth C1 dilution prepare the 2nd hundredth dilution C2. This operation is repeated 11 times, obtaining the 12th hundredth dilution of C12. Thus, the 12th hundredth dilution of C 12 is a solution obtained by diluting successively in different containers 12 times of the 1st part of the initial matrix solution of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor with a concentration of 3.0 mg / ml in 99 parts of a neutral solvent, i.e. a solution prepared by diluting the matrix solution in 100 ¹² times. Similar operations with the appropriate dilution ratio are carried out to obtain dilutions of C 30 and C 200.

When using as a component (for example, an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor) mixtures of various, mainly hundred, dilutions, each dilution of the component (for example, C 12, C 30, C 200) is prepared separately for of the technology described above to their penultimate dilution (respectively, to obtain C 11, C 29, C 199) and then add one part of each obtained last but one dilution into one container and mix with the required amount of solvent (respectively enno with 97 parts for centesimal dilution). In this case, an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor β-subunit is obtained in an ultra-low dose, prepared by super-dilution of the matrix solution, respectively, 100 ¹² , 100 ³⁰ and 100 ²⁰⁰ times, equivalent to a mixture of hundred-fold dilutions of C 12, C 30 and C 200 by homeopathic technology.

It is possible to use each component in the form of a mixture of other various dilutions according to homeopathic technology, for example decimal and / or hundredths (C 12, C 30, C 100; C 12, C 30, C 50; D 20, C 30, C 100 or D 20 , C 30, M 100, etc.), the effectiveness of which is determined experimentally.

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

To obtain the claimed pharmaceutical composition, aqueous or aqueous-alcoholic solutions of the active ingredients are 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, which contains an effective amount of particles of a neutral carrier (for example, isomalt) saturated by soaking in an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit until saturated with a mixture of aqueous or aqueous-alcoholic solutions the insulin receptor and the activated-potentiated form of antibodies to endothelial NO synthase, and pharmaceutically acceptable additives, including mainly isomalt, cro povidone and magnesium stearate.

To obtain a solid oral form of the claimed medicinal product, a fluidized bed is installed (for example, a Huttlin Pilotlab type manufactured by Huttlin GmbH) irrigation until saturation of particles of a neutral substance - isomalt - pre-mixed with aqueous or aqueous-alcoholic solutions, introduced into the fluidized bed activated-potentiated forms of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase, mainly in the ratio of 1 kg of antibody solution per 5 or 10 kg isomalt (1: 5-1: 10) with simultaneous drying in a stream of heated air supplied under the grate at a temperature not exceeding 40 ° C. The estimated amount of 9.5 ÷ 30 mass. parts of dried particles saturated with the activated-potentiated form of antibodies are loaded into the mixer and mixed with 60 ÷ 88 mass. parts of unsaturated pure isomalt. Then, 1 ÷ 5 masses are added to this mixture. parts of crospovidone with 0.1 ÷ 1 mass. part of magnesium stearate. The resulting tablet mass is uniformly mixed and tabletted by direct dry pressing (for example, in a Korsch tablet press - XL 400) with the formation of round tablets weighing 150 ÷ 500 mg, mainly weighing 250 mg.

It is possible to prepare a solid oral form of the claimed drug by saturating a neutral carrier - lactose (10 ÷ 34 parts by weight of the total mass of the load or the mass of the solid oral form) with an aqueous or aqueous-alcoholic solution of activated-potentiated forms of antibodies to the C-terminal fragment of P- subunits of the insulin receptor and endothelial NO synthase, followed by mixing with microcrystalline cellulose β-10 mass. parts of the total charge mass), “unsaturated” pure lactose (25 ÷ 85 parts by weight of the total charge mass), magnesium stearate (0.1 ÷ 1 parts by weight of the total charge mass). The resulting tablet mass is uniformly mixed and tabletted by direct dry pressing (for example, in a Korsch tablet press - XL 400) with the formation of round tablets weighing 150 ÷ 500 mg, mainly weighing 300 mg.

Glucose, sucrose, maltose, starch, isomaltose, isomalt and other monosaccharides, oligosaccharides and polysaccharides used in the manufacture of pharmaceuticals, as well as technological mixtures based on the latter with the addition of lubricants, disintegrants, binders and dyes, can also be used as a neutral carrier.

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

In the following Examples 1 and 2, we studied the effect of activated-potentiated forms of polyclonal affinity-purified antibodies on the antigen to the C-terminal fragment of the β-subunit of the insulin receptor in an ultra-low dose obtained by super-dilution of the initial matrix solution (concentration of 2.5 mg / ml) in 100 ¹² 100 ³⁰ 100 ²⁰⁰ time (aT RI), the activated-potentiated form of polyclonal affinity-purified antibodies on an antigen to endothelial NO-synthase in the ultra low dose received sverhrazvedeniem initial matrix solution (2.5 mg / l) 100 ¹² 100 ³⁰ 100 ²⁰⁰ time (AT NOS), and the claimed drug in the form of a composition comprising activated-potentiated form of polyclonal affinity purified antibody antigen to the C-terminal fragment of β-subunit of the insulin receptor in the ultra low dose obtained by super-dilution of the initial matrix solution (concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, and activated-potentiated forms of polyclonal affinity-purified antibodies to endothelial NO synthase at an ultra-low dose obtained by super-dilution each matrix solution (concentration 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times (AT RI + AT NOS) on the glucose level in the blood plasma of rats with streptozotocin-induced diabetes mellitus. Impaired glucose tolerance (reducing its utilization by the body) is one of the most important indicators in the treatment and diagnosis of diabetes.

According to WHO criteria, diabetes mellitus (types I and II) is characterized by an increase in blood glucose (hyperglycemia) and impaired glucose tolerance. The latter may be caused by a violation of insulin secretion and / or a decrease in peripheral tissue insulin sensitivity. A sensitive method for assessing impaired glucose tolerance of the body tissues is the glucose tolerance test, based on a dynamic assessment of the ability of the body tissues to utilize glucose.

Example 1

The study used 150 male Wistar rats (weight at the beginning of the study 250-300 g, age 3.5-4 months). 10 rats were intact (control group). The rest were injected with streptozotocin at a dose of 50 mg / kg to simulate an experimental model of diabetes mellitus. The administration of streptozotocin led to a significant increase in glucose in the blood plasma of rats compared with intact animals (18 mmol / L vs 3.5 mmol / L, p <0.05). 72 hours after the administration of streptozotocin, rats with a blood glucose level of at least 12 mmol / l were divided into 7 groups (20 rats each), which were administered distilled water (w / w, 1 time per day, 5 days) ml / kg / day), insulin ("Insulin", Actrapid, Denmark) (s / c, 2 times a day, 8 units / kg / day), rosiglitazone ("Roglit", Gideon Richter, Hungary) (comparison drug, v / f, 2 times a day, 8 mg / kg / day), AT RI (v / f, 1 time per day, 2.5 ml / kg / day), AT RI + AT NOS (v / f, 1 once a day, 5 ml / kg / day), rosiglitazone and insulin (according to the schemes corresponding to the isolated administration of each pr the drug), AT RI + AT NOS and insulin (according to the schemes corresponding to the isolated administration of each drug). On the 7th, 14th and 21st days of drug administration in rats on an empty stomach, the plasma glucose level was measured by enzymatic (glucose oxidase method) using the Glucose PKD kits (Russia). After 14 days of drug administration, glucose was orally administered (1 g / kg) and a glucose tolerance test was performed.

In the group administered with AT RI, after 7, 14 and 21 days, the glucose level was lower than in the control by 22-28%, however, the differences did not reach the level of reliability. The claimed drug AT RI + AT NOS was more effective - the decrease in glucose levels on the 14th and 21st day of the study reached 47% and 42%, respectively (p <0.05 relative to the control). The comparison drug rosiglitazone also reduced glucose levels on the 14th and 21st day of the study, and the significant effect was recorded only on the 14th day of the study (36%, p <0.05 relative to the control). Insulin administered at ½ effective dose (selected in the preliminary study) most effectively reduced glucose levels at all observation times (to the level of intact control) (Figure 1). It should be borne in mind that short-acting insulin was used in the study and plasma glucose was measured 1 hour after its administration, which determined the pronounced effect of ½ dose of insulin on the blood glucose level, against which it was not possible to identify the effect of the combined use of insulin in these periods of the study with rosiglitazone or AT RI + AT NOS.

Figure 2 shows the effect of the test drugs on day 14 of administration on the area under the concentration-time curves (AUC) in the glucose tolerance test in rats with streptozotocin-induced diabetes mellitus.

Thus, in the oral sugar load test (14th day of drug administration), the claimed drug AT RI + AT NOS and insulin when administered alone were most effectively increased in glucose tolerance. Rosiglitazone reduced the area under the concentration-time curve (increased glucose tolerance), however, its effectiveness was not significant relative to the intact control group (Figure 2).

Example 2

The study used 36 male rats of the Goto-Kakizaki line (weight at the beginning of the study 250-280 g, age 10-12 weeks). Rats of this line are characterized by spontaneous development of non-insulin-dependent diabetes. The animals were divided into groups (12 rats each), which received distilled water (v / f, 1 time per day, 5 ml / kg, group 1) for 28 days, AT RI (v / f, 2.5 ml / kg, group 2), AT RI + AT NOS (w / w, 5 ml / kg, group 3). Plasma glucose levels were determined using a glucose analyzer (Beckman, Fullerton, California, USA) before drug administration and on the 4th, 8th, 12th, 16th, 20th, 24th, 28th day of drug administration. On day 28, rats were given glucose orally (1 g / kg) and a glucose tolerance test was performed.

The introduction of AT RI led to a significant (p <0.05) decrease in blood glucose in rat plasma, however, the use of the claimed drug AT RI + AT NOS was more effective (p <0.001 vs control) (Figure 3).

Figure 4 shows the effect of the test drugs on day 28 of administration on the area under the concentration-time curves (AUC) in the glucose tolerance test in rats with spontaneous non-insulin-dependent diabetes mellitus.

Thus, the introduction of AT RI led to an increase in glucose tolerance (an unreliable decrease of 44% of the area under the concentration-time curve relative to the control). At the same time, the decrease in this indicator, caused by the introduction of the claimed drug AT RI + AT NOS, was 62% and was significant (p <0.05 relative to the control).

Example 3

For experimental study of the claimed technical solution, 250 mg tablets were used in the form of a pharmaceutical composition containing aqueous-alcoholic solutions of activated-potentiated forms (ultra-low doses - SMD) of antibodies to the C-terminal fragment of the beta subunit of the insulin receptor (AT RI) and to endothelial NO synthase (AT NOS) deposited on isomalt in the form of a water-alcohol mixture of homeopathic dilutions C 12, C30, C200 (ATRI + ATNOS complex preparation).

An open, incomparable study of the efficacy and safety of using AT RI + AT NOS in patients with type I diabetes mellitus (DM) included patients with a diagnosis of mild to moderate type I diabetes without signs of severe macro- and microvascular pathology. After obtaining the patient’s voluntary informed consent to participate in the clinical trial, an initial examination was conducted to determine if the patient met the inclusion / exclusion criteria. Prior to the use of the drug, a “wash-out period” was carried out for 2 weeks, during which the condition of the patients was assessed (collection of complaints, determination of fasting glycemia, glycated hemoglobin, daily glycemic profile, lipid profile, treatment efficacy and safety were noted). The study is 12-week, the main stages of the examination were carried out at the weeks of "washing", then after 6 and 12 weeks. In 4 patients, at the week of “washing” and at the end of the study, daily monitoring of glycemia level is carried out using the CGMS system for daily monitoring of glycemia. The system of daily monitoring of glycemia (CGMS) allows you to control the level of glycemia for three days. The results of the study show how glucose levels change over 3 days, depending on insulin therapy and lifestyle. These data help highlight periods of high or low glucose depending on diet, medication, or physical activity. The system graphically shows the minimum glycemia values of 2.2 mmol / L, the maximum up to 22.2 mmol / L, as well as the daily average glycemia.

Patients with type I diabetes, moderate and mild in the stage of decompensation before inclusion and during the study received standard insulin therapy in the form of:

1. Long-acting insulin (Protafan, Lantus) in average doses from 12 to 26 units / day.

2. Short-acting insulin (Apidra, Novorapid, Actropid) in average doses:

- morning from 8 to 10 units / day;

- lunch from 8 to 12 units / day;

- dinner from 8 to 13 units / day.

After confirming the patient’s ability to participate in the study, the patient was included in the study and received, in addition to standard therapy of type I diabetes, the complex preparation AT RI + AT NOS, depending on the severity and compensation of type I diabetes in various dosages:

1. Four patients - 1 tablet 4 times a day at 8:00, 12:00, 18:00, 22:00.

2. Two patients - 1 tablet 2 times a day at 8:00, 18:00.

At weeks 3 and 8, the glycemic profile (eight-point) was additionally monitored, telephone “visits” were conducted. Clinical status was monitored weekly. In total, the patient was observed for 14 weeks.

The study included 6 patients, of which 5 patients completed the study. Evaluation of glycemia was performed according to the daily eight-point test initially, after 3, 6 and 12 weeks of treatment. The level of glycated hemoglobin was determined initially and after 12 weeks of therapy.

All patients included in the study with type I diabetes, 6 weeks after taking the study drug, noted a tendency to decrease in daily glycemia. In patients with type I diabetes, an eight-day daily profile showed a decrease in glycemia, an average of 20%. After 12 weeks of therapy, glycated hemoglobin decreased on average by 10-15% compared with the initial value.

When analyzing the results of glycemic monitoring using the CGMS system in all patients included in the study, 3 months after therapy with AT RI + AT NOS, a decrease in average daily glycemia and a decrease in the fluctuation of the minimum and maximum glycemia by 15-20% of the initial value were revealed.

I would like to note that one patient with type I diabetes mellitus in the stage of decompensation showed a marked decrease in daily glycemia by 48% (1 week - 8.0 mmol / l, 12 weeks - 4.8 mmol / l), in connection with which correction of insulin therapy was made (reduction of the daily dose of short-acting insulin by 8 units / day). The dynamics of the average values of blood glucose and glycated hemoglobin are presented in Fig. 5.

During the study, no adverse events and serious adverse events were recorded, which may indicate the safety of the drug.

Example 4

For experimental studies of the effectiveness of the claimed technical solution, 250 mg tablets were used in the form of a pharmaceutical composition containing aqueous-alcoholic solutions of activated-potentiated forms (ultra-low doses - SMD) of antibodies to the C-terminal fragment of the insulin receptor beta subunit (AT RI) and endothelial NO synthase (AT NOS) deposited on isomalt in the form of a water-alcohol mixture of homeopathic dilutions C12, C30, C200 (AT RI + AT NOS).

An open, incomparable study of the efficacy and safety of the use of the AT RI + AT NOS drug in patients with type II diabetes mellitus (DM) included patients with a diagnosis of mild to moderate type II diabetes without signs of severe macro- and microvascular pathology, receiving moderate therapeutic doses of Metformin . After obtaining the patient’s voluntary informed consent to participate in the clinical trial, an initial examination was conducted to determine if the patient met the inclusion / exclusion criteria. When confirming the possibility of taking part in the study, the patient received, in addition to the standard therapy for type II diabetes, the complex preparation AT RI + AT NOS, 1 tablet 4 times a day. Prior to the use of the drug, a “wash-out period” was carried out for 2 weeks, during which the condition of patients was assessed (complaints collection, fasting glycemia, glycated hemoglobin, daily glycemic profile, lipid profile, determination of insulin resistance index (HOMA-IR)), efficacy was noted and treatment safety. The study is 12-week, the main stages of the examination were carried out at the weeks of "washing", then after 6 and 12 weeks. In 4 patients, at the week of “washing” and at the end of the study, daily glycemic level monitoring is performed using the daily glycemic monitoring system (CGMS). At weeks 3 and 8, the glycemic profile (eight-point) was additionally monitored, telephone “visits” were conducted. Clinical status was monitored weekly. In total, the patient was observed for 14 weeks.

Eleven patients were included in the group of patients with type II diabetes at the stage of decompensation. One patient dropped out of the study of his own free will. Two patients completed the study after 12 weeks, the remaining patients continued treatment.

In patients with type II diabetes, an eight-day daily profile showed a decrease in glycemia by an average of 20% by the 6th week. At the 12th week, a decrease in glycated hemoglobin was noted on average by 15-19% of the initial one.

OAK values (red blood cells, hemoglobin, white blood cells, platelets, white blood cell count, ESR), lipid profile, ECG, liver tests (ALT, ACT, bilirubin and its fractions) for 12 weeks in all patients remained within normal limits. The insulin resistance, determined by the HOMA-IR test, decreased on average by 17 -19% from the original.

When assessing the safety profile over 12 weeks, no serious adverse events were detected. From the side of the functional activity of the liver, deviations were also not revealed.

The dynamics of the average values of blood glucose and glycated hemoglobin are presented in Fig.6.

Example 5

Patient X., 74 years old. Suffers from type II diabetes. For a number of years he receives maninil (the active substance is glibenclamide, manufacturer Berlin - Chemie) no 5 mg 2 times a day. Despite sugar-lowering therapy, a deep necrotic ulcer formed up to the calcaneus 3 years ago on the right foot. He was hospitalized twice in a surgical hospital, but the treatment did not lead to significant improvement. Then, the claimed drug in the form of a tablet weighing 250 mg was added to therapy based on a pharmaceutical composition containing aqueous-alcoholic solutions of activated-potentiated forms (ultra-low doses - SMD) of antibodies to the C-terminal fragment of the beta subunit of the insulin receptor (AT RI) and to endothelial NO synthase (AT NOS), applied to isomalt in the form of a water-alcohol mixture of homeopathic dilutions C 12, C 30, C 200 (AT RI + AT NOS), which the patient received against the background of manniline, the dose of which was 4 weeks later reduced to 1 tablet (5 mg) n night. During treatment, blood glucose levels returned to normal: from 8-10 mmol / L to 5-6 mmol / L. Within a month, the ulcer on the foot underwent reverse development, cleared of necrosis, and epithelization occurred. On examination, there is no ulcer; on the calcaneus there is intense white peeling, round, 3.5 cm in diameter.

Claims (20)

1. A pharmaceutical composition for reducing insulin resistance and for the treatment of diabetes mellitus, comprising an activated-potentiated form of antibodies to an insulin receptor, characterized in that it further includes an activated-potentiated form of antibodies to endothelial NO synthase as a reinforcing component. 2. The pharmaceutical composition according to claim 1, characterized in that it contains an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that the activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and the activated-potentiated form of antibodies to endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous -alcohol solution, the activity of which is due to the process of repeated dilution of the matrix solution of the corresponding antibodies in an aqueous or aqueous-alcohol solvent in combination with external mechanical stress - m shaking gently for each dilution. 4. The pharmaceutical composition according to claim 1 or 2, characterized in that it is made in solid dosage form and contains an effective amount of an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO- neutral carrier granule synthase and pharmaceutically acceptable additives. 5. The pharmaceutical composition according to claim 1 or 2, characterized in that aqueous or aqueous-alcoholic solutions of activated-potentiated forms of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase are obtained by repeated serial dilution in combination with external mechanical action - multiple shaking of each dilution from matrix solutions of affinity-purified antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and to endothelial NO synthase with a concentration of 0.5 ÷ 5.0 mg / ml. 6. The pharmaceutical composition according to claim 1 or 2, characterized in that each of the components is used in the form of a mixture of various, mainly hundred, dilutions prepared by homeopathic technology. 7. The pharmaceutical composition according to claim 4, characterized in that the pharmaceutically acceptable additives include isomalt, crospovidone and magnesium stearate. 8. A method of reducing insulin resistance, comprising introducing into the body an activated-potentiated form of an antibody to an insulin receptor, characterized in that it additionally simultaneously and concomitantly injects an enhancing component in the form of an activated-potentiated form of an antibody to endothelial NO synthase. 9. A method of treating diabetes mellitus, comprising administering to the body an activated-potentiated form of an antibody to an insulin receptor, characterized in that an additional reinforcing component in the form of an activated-potentiated form of an antibody to endothelial NO synthase is additionally simultaneously and simultaneously administered. 10. The treatment method according to claim 9, characterized in that for the treatment of type I diabetes mellitus, an activated-potentiated form of antibodies to the insulin receptor is administered simultaneously and combined with an activated-potentiated form of antibodies to endothelial NO synthase. 11. The treatment method according to claim 9, characterized in that for the treatment of type II diabetes mellitus, an activated-potentiated form of antibodies to the insulin receptor is administered simultaneously and combined with an activated-potentiated form of antibodies to endothelial NO synthase. 12. The method according to claim 8 or 9, characterized in that the activated-potentiated form of antibodies to the insulin receptor and the activated-potentiated form of antibodies to endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution, the activity of which is due to the process multiple dilutions of the matrix solution of the corresponding antibodies in an aqueous or hydroalcoholic solvent in combination with an external mechanical action - multiple shaking of each dilution. 13. The method according to claim 8 or 9, characterized in that the pharmaceutical composition is administered in the form of a single drug - a single dosage form containing an activated-potentiated form of antibodies to the β-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase. 14. The method according to p. 13, characterized in that the pharmaceutical composition is administered in the form of a single drug - a single dosage form containing an activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor β and an activated-potentiated form of antibodies to endothelial NO synthase. 15. The method according to claim 8 or 9, characterized in that the pharmaceutical composition is administered in the form of a single drug - a single dosage form containing an activated-potentiated form of antibodies to the α-subunit of the insulin receptor and an activated-potentiated form of antibodies to endothelial NO synthase. 16. The method according to claim 8 or 9, characterized in that the pharmaceutical composition is introduced into the body in the form of a single drug - one dosage form containing an activated-potentiated form of antibodies to the α-subunit of the insulin receptor and an activated-potentiated form of antibodies to β the subunit of the insulin receptor in combination with an activated-potentiated form of antibodies to endothelial NO synthase. 17. A method of treating diabetes mellitus with insulin and / or hypoglycemic drugs, characterized in that the pharmaceutical composition is additionally introduced into the body, containing an activated-potentiated form of antibodies to an insulin receptor, mainly to the C-terminal fragment of the insulin receptor β-subunit, and an activated-potentiated form of antibodies to endothelial NO synthase. 18. The method according to 17, characterized in that the activated-potentiated form of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor and the activated-potentiated form of antibodies to endothelial NO synthase are used in the form of an activated potentiated aqueous or aqueous-alcoholic solution of each a component whose activity is due to the process of repeated dilution in an aqueous or aqueous-alcoholic solvent in combination with an external mechanical action - multiple shaking of each dilution. 19. The treatment method according to 17 or 18, characterized in that the pharmaceutical composition is used in the form of a single drug - one dosage form containing a mixture of different dilutions of antibodies to the C-terminal fragment of the β-subunit of the insulin receptor β-subunit in combination with a mixture various dilutions of antibodies to endothelial NO synthase prepared according to homeopathic technology. 20. A method of lowering glucose levels, comprising introducing into the body an activated-potentiated form of an antibody to an insulin receptor, characterized in that it additionally simultaneously and simultaneously administered a reinforcing component in the form of an activated-potentiated form of an antibody to endothelial NO synthase.

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