Family of peptides possessing analgesic activity

FIELD: chemical-pharmaceutical industry, medicine, peptides.

SUBSTANCE: invention relates to preparing and using peptides of the formula (I) possessing analgesic activity: A-B-Tyr-Pro(D-Pro, dHPro, D-dHPro, DL-dHPro, Hyp)-C-X wherein A means -O, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C means 0, -Ala, -Asp, -Glu, -Phe, -Gly, -His, -He, -Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; X means -OH, -OCH3, -NH2. Proposed peptides can be used for design of new medicinal preparations. Peptides possess the enhanced activity as compared with pentalgin, analgin and morphine and have no toxic properties.

EFFECT: improved and valuable medicinal properties of peptides.

5 tbl, 4 ex


The present invention relates to the use of peptides of General formula A-B-Tyr-Pro(DPro, dHPro, DdHPro, DLdHPro, Hyp)-B-X, below, as analgesics analgesic drugs.

There are various painkillers, which by their chemical nature and mechanism of action are divided into narcotic (morphine and related structures) and analgesics (salicylic acid derivatives, pyrazolone, aniline and other). All of these analgesics have these or other deficiencies, which drastically reduce the possibilities of their application in medicine [Medmaravis. Medicines, Kharkov: in "Torching",1997, edition 13, s-145].

Known in mammals, endogenous ligands peptide, responsible for the physiological analgesic effects of the enkephalins and endorphins. In recent years, discovered and actively studied another class of endogenous peptides - dynorphin, in particular dermorphin [Emelyanova YEAR, Nezavibatko V.N., Usenko A.B., Andreeva L.A. Heptapeptide possessing analgesic activity, combined with thermoregulatory and/or vasomotor activity and/or influence on the behavioural response of the test, and how to change physiological activity of dermorphin [Patent No. 2134121, issued August 10, 1999], with the properties of the CN is agennix analgesics.

However, the use of these peptide sequences to create medicines failed. This is because in the body along with the educational system of endogenous analgesics exists and rapid destruction. Therefore, attempts to create new drugs peptide did not succeed.

To address these shortcomings, a new group of peptide sequences of the General formula

A-B-Tyr-Pro(DPro, dHPro, DdHPro, DLdHPro, Hyp)-X.

Synthesized dipeptides of the formula Tyr-Pro, Tyr-Pro-och3, Tyr-Pro-NH2the tripeptides Tyr-Pro-Ser-och3, Tyr-Pro-Ser-NH2, Tyr-Hyp-Ser-och3, Tyr-Hyp-Ser-NH2, Tyr-DPro-Ser-och3, Tyr-DPro-Ser-NH2, Tyr-DLdHPro-Ser-och3, Tyr-dHPro-Ser-NH2, Tyr-Pro-Lys-NH2, Tyr-Pro-Ala-NH2tetrapeptide: Tyr-Pro-Gly-Pro-NH2, Tyr-Tyr-Pro-Ser-NH2Ala-Tyr-DPro-Ser-NH2, DAla-Tyr-DPro-Ser-NH2Glu-Tyr-DPro-Ser-NH2, Met-Tyr-DPro-Ser-NH2that meets the above General formula, possessing analgesic activity.

The above amino acid sequence having analgesic activity, have a common pattern, namely the presence in the structure of the peptide sequence Tyr-Pro(DPro, dHPro, DdHPro, DLdHPro, Hyp) in 1,2 or 2,3-positions of the above peptides. First discovered pattern to affect the Central nervous with the system of the peptides of General formula


A - Oh, -Ala, -Asp, -Glu, -Phe -,- Gly, -His, -LEU, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

B - Oh, -Ala, -Asp, -Glu, -Phe -,- Gly, -His, -LEU, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

In - Oh, -Ala, -Asp, -Glu, -Phe -,- Gly, -His, -LEU, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

X - OH, -OCH3, -NH2.

This pattern is confirmed by the synthesis and analgesic tests conducted on animals, a variety of peptides that meet the General formula of amino acid sequence. Based on these studies, we can conclude that peptides corresponding to General formulacan be used to create new drugs with analgesic activity.

The invention relates to the field of physiology and pharmacology to create new drugs and may find application in medicine.

The technical result achieved by the present invention, is the creation of new peptides that meet the General formula (I), the identification of their useful analgesic properties and targeted development on their basis of drugs.

This technical result is achieved that can be directed to synthesize different peptide sequences that meet the General formula (I) according to the General scheme. Conduct targeted screening anesthetic properties with nasirovna peptides according to the standard program.

Some of the peptides of General formula (I) shown in table 1 and include:

All the peptides of this family possessed analgesic activity. Below are examples that prove it.

The synthesis of the peptides of formula (I) was carried out by methods of peptide chemistry, both in solution and solid-phase method for the synthesis using L and D amino acids, and L, D and DL degidro-amino acids (3,4-degidro-amino acid in the formula (I), in the tables and the examples marked with what psalom dHPro).

Example 1. Synthesis of Tripeptide HCl·H-Tyr-3,4-DLdHPro-Ser-OCH3.

For example, the synthesis of Tripeptide shows a General approach for the synthesis of peptides of formula (I) in solution.

Table 2 provides peptides of formula (I)synthesized by the methods of peptide chemistry in solution.

Table 2

Synthesis of Tripeptide HCl·H-Tyr-3,4-DLdHPro-Ser-och3carried out by condensation of the dipeptide DiBoc-Tyr-3,4-DLdHPro and HCl·H-Ser-och3using the methods of peptide chemistry in solution. Fragments synthesized using tetrabutylammonium salts (TBA) and the method of activated esters. Evaporation of the solutions was carried out on a vacuum evaporator at 40°C. control of the synthesis and the identity of the compounds was performed using thin-layer chromatography on plates with silica gel firm Silufol Czechoslovak) when spraying ninhydrin solution in the solvent system:

1 - acetone:benzene:acetic acid(2:1:1);

2 - chloroform:methanol:ammonia(8:1,75:0,25).

All solvents were absoluteradio accordingly. Melting points are not corrected. Column chromatography was performed using a media Silica gel L-40/100m and Silasorb 600 [LC] company Chemapol (Czechoslovak). Check the homogeneity of the peptide was performed using high performance liquid chromatography (HPLC). All solvents accordingly was absoluteradio.


Boc - tert-butyloxycarbonyl group;

DCGC - dicyclohexylcarbodiimide;

OSu - operations ether;

TBA is tetrabutylammonium;

The tea is triethylamine;

dHPro - 3,4 degidro-Proline;

HPLC - high performance liquid chromatography;

TLC - thin layer chromatography.

I. receiving the dipeptide DiBoc-Tyr-3,4-DLdH Pro.

1. To 3,4-DLdHPro 315 mg (2.78 mmol) was added 5.56 ml (2.78 mmol) of 13% TBA, evaporated 1 times with ethanol, 1 times with ISO-propanol, 1 times with benzene, cooled to 0°C.

2. To a chilled solution of TBA 3,4-DLdHPro in 20 ml of abs. ethyl acetate while cooling was added in dry form DiBoc-Tyr-OSu 1.330 g (2.78 mmol), stirred 1 hour at room temperature on a magnetic stirrer, the reaction course was monitored by TLC in the chromatographic system (1).

Upon completion of the reaction the solvent was evaporated, added water, acidified NaHSO4(5-fold excess, to pH 3, extracted 5 times with 50 ml ethyl acetate. The combined ethyl acetate fraction was washed with water, 10% solution of KHSO4, water, dried over MgSO4was evaporated, and the planting of ether-hexane (twice). The precipitated powder was dried in vacuum.

Yield 1.32 g (2.76 mmol) of 99.3%

Rf=0.382 (1)

II. DiBoc-Tyr-3,4-DLdHPro-Ser-OCH3

DiBoc-Tyr-3,4-DLdHPro of 1.32 g (2.76 mmol) was dissolved in 20 ml of acetonitrile, was added an excess (1.3) N-hydroxysuccinimide 412.8 mg (3.59 mmol), cooled to 0°was added in excess (1.3) DCGK 810.88 mg (3.59 mmol). Was stirred on a magnetic stirrer for 1 hour, cooled to 0°With added excess (1.3) HCl·H-Ser-och3558.22 mg (3.59 mmol) and excess (1.3) the tea 0.5 ml (3.59 mmol), stirred for 1 hour under cooling and two days at room temperature. The reaction mixture was filtered, evaporated, was added 100 ml of ethyl acetate, was extracted with water, 10% solution of KHSO4, water, 5% solution of NaHCO3, water, feast upon. a solution of NaCI. The ethyl acetate solution was dried over MgSO4, was filtered and was evaporated. Was perioadele twice from acetone-hexane. The precipitate was dried in vacuum.

Yield 1.38 g (2.38 mmol) is 86.56%

Rf=0.238 (1); 0.812 (2)

III. HCl·H-Tyr-3.4-DLdHPro-Ser-OCH3.

To 1.38 g (2.38 mmol) DiBoc-Tyr-3,4-DLdHPro-Ser-OCH3added 7.14 ml of 1N. HCl/CH3COOH and 2% anisole (0.14 ml anisole). Kept for 45 minutes at room temperature, upriv the Lee, was perioadele from methanol-ether.

Output: 860 mg (1.93 mmol) of 81%

Rf=0.512 (2).

Results HPLC: Column Bond SB-AQ C18. of 4.6*150 mm; flow rate 1 ml/min; eluent 5% Meon-50 mM buff, pH 2.8), linear gradient, temperature 30°C, a pressure of 9.0 MPa, time out 7,73 minutes

Example 2.

Table 3 shows examples of the synthesis of peptides automatic solid-phase method.

Table 3

The peptides listed in table 3 were synthesized by automated solid-phase method for Fmoc-scheme on the Rink polymer (4-(2,4-acid-fluorenylmethyl-aminomethyl)-phenoxy-polystyrene, 0.5 mmol of amino groups per 1 g of polymer) using DEPCDI/HOBt activation of amino acids. The peptides were tsalala from the polymer and was unblocked with a mixture of TFA:m-crezole (95:5). Purification of peptides was performed using reversed-phase HPLC (column Jupiter Cis (10×250 mm) in the following gradient of acetonitrile: 5 min at 2%, then a linear gradient from 2 to 60% for 50 min in 0.1% triptoreline b the sphere at a flow rate of 4 ml/min The peptides were characterized by mass spectrometry (MALDI).

Example 3.

Comparative biological testing of the dipeptide Tyr-Pro, Tyr-Pro-och3, Tyr-Pro-NH2, tripeptides Tyr-Pro-Ser-och3, Tyr-Pro-Ser-NH2, Tyr-Hyp-Ser-och3, Tyr-Hyp-Ser-NH2, Tyr-DPro-Ser-och3, Tyr-DPro-Ser-NH2, Tyr-DLdHPro-Ser-och3, Tyr-dHPro-Ser-NH2, Tyr-Pro-Lys-NH2, Tyr-Pro-Ala-NH2, tetrapeptides: Tyr-Pro-Gly-Pro-NH2, Tyr-Tyr-Pro-Ser-NH2Ala-Tyr-DPro-Ser-NH2, DAla-Tyr-DPro-Ser-NH2Glu-Tyr-DPro-Ser-NH2, Met-Tyr-DPro-Ser-NH2in the test "otdergivanija tail" to identify analgesic activity with Hexapeptide Tyr-DPro-Ser-Pro-Gly-Pro, heptapeptides Tyr-DAla-Phe-Gly-Tyr-Pro-Ser-NH2- dermorphin and known analgesics - Pentalgin, aspirin and morphine.

Test "otdergivanija tail - tail flick (D Amor. 1941). The animal was placed in an individual plastic camera, the tail was immersed for 5 cm in a container of water with a temperature of 55±1°C. the Reflex otdergivanija tail is closed at the level of the spinal cord. In test fixed latent period of deliverance from a painful stimulus is the time period (s)during which the animal pulled the tail out of the water completely. The maximum time presenting a painful stimulus to 30 seconds. The original pain sensitivity was defined as the arithmetic average of the rates recorded at 60, 40 and 20 minutes of donyelle. The latent period of deliverance from a painful stimulus was fixed in 20, 40 and 60, and 120 minutes after injection. Analgesic activity was assessed by the change in the latent period of reaction according to the formula A=PLop-LPRefwhere PLop- the latent period of redemption after the introduction of substances, PLRef- the arithmetic mean latent periods of deliverance before the introduction of the substance.

The analyzed peptides at a dose of 1 mg/kg was administered intraperitoneally in an aqueous solution males nonlinear albino rats weighing 200-300 g of the Control animals were injected intraperitoneally distilled water. The results are shown in table 4.

td align="left">  
Table 4
20 min40 min60 min90 min120 minThe area under the curve
The dipeptides in the dose of 1 mg/kg
Tyr-Pro-NH21,3 8,4*4,7*3,8*0,8438
The tripeptides in a dose of 1 mg/kg
Tyr-Pro-Lys-NH23,4*/td> 3,1*8,0*1,4-0,2369
Tetrapeptide dose of 1 mg/kg
Hexapeptide Tyr-DPro-Ser-Pro-Gly-Pro
at a dose of 1 mg/kg10,3*1,71,10,5-0,1290
Heptapeptide Tyr-DAla-Phe-Gly-Tyr-Pro-Ser-NH2-dermorphin
at a dose of 1 mg/kg3,41,90,70,30,1100
in the dose of 10 mg/kg2,43,56,27,88733
Pentalgin at a dose of 750 mg/kga 3.97,97,57,57,5802
Analgin dose of 2500 mg/kg-0,100,10,20,116
at a dose of 1 mg/kg1,40,70,90,90,589
in the dose of 10 mg/kg7,57,57,57,57,5750
Control0,50,40 0,2-0,418
* - p<0,05 - significant differences from the control group

Table 4 shows that intraperitoneal administration of the dipeptide of the formula (I) Tyr-Pro, Tyr-Pro-och3, Tyr-Pro-NH2causes a significant increase in the latent period of reaction otdergivanija tail in response to painful stimulation through 40 minutes after injection. The effect is maintained for 90 minutes.

Intraperitoneal administration of the tripeptides of formula (I) Tyr-Pro-Ser-och3, Tyr-Pro-Ser-NH2, Tyr-Hyp-Ser-och3, Tyr-Hyp-Ser-NH2, Tyr-DPro-Ser-och3, Tyr-DPro-Ser-NH2, Tyr-DLdHPro-Ser-OCH3, Tyr-dHPro-Ser-NH2, Tyr-Pro-Lys-NH2, Tyr-Pro-Ala-NH2also led to an increase in the latent period of reaction otdergivanija tail. Introduction Tyr-Pro-Ser-NH2, Tyr-DPro-Ser-NH2or Tyr-Pro-Ala-NH2induced significant prolongation of the reaction time at 90 minutes after injection. Tyr-Pro-Ser-och3and Tyr-Pro-Lys-NH2caused analgesic effect within hours. The effect of Tyr-DLdHPro-Ser-och3, Tyr-dHPro-Ser-NH2developed on 40 minutes after injection and lasted up to 60 minutes at Tyr-DLdHPro-Ser-och3and up to 90 minutes at Tyr-dHPro-Ser-NH2, Tyr-DPro-Ser-och3caused analgesic response at 20 and 40 minutes after injection. Analgesic effect Tyr-Hyp-Ser-och3, Tyr-Nur-Ser-NH2it was weak. Thus, it was stopped that the amidation of C-terminal amino acid residue leads to lengthening and strengthening effect of tripeptides of the General formula (I). Modification of the Pro residue also alter the analgesic activity.

Intraperitoneal administration of tetrapeptides formula (I) Tyr-Pro-Gly-Pro-NH2, Tyr-Tyr-Pro-Ser-NH2Ala-Tyr-DPro-Ser-NH2, DAla-Tyr-DPro-Ser-NH2Glu-Tyr-DPro-Ser-NH2, Met-Tyr-DPro-Ser-NH2changed the latent period of reaction otdergivanija tail. The highest analgesic activity possessed Glu-Tyr-DPro-Ser-NH2. The increase in latent period of reaction was observed within 90 minutes of observation. Tyr-Pro-Gly-Pro-NH2and Tyr-Tyr-Pro-Ser-NH2extended latent period otdergivanija tail PA within 60 minutes of observation. The effect of Ala-Tyr-DPro-Ser-NH2and DAla-Tyr-DPro-Ser-NH2started 40 minutes after injection and lasted from Ala-Tyr-DPro-Ser-NH2up to 60 minutes, a DAla-Tyr-DPro-Ser-NH2- up to 90 minutes. Met-Tyr-DPro-Ser-NH2was not significantly changed the latent period of reaction otdergivanija tail. Thus, changing amino acid residues around the sequence Tyr-Pro affects analgesic activity.

Example 4.

The biological tests of the dipeptide Tyr-Pro, Tyr-Pro-och3, Tyr-Pro-NH2, tripeptides Tyr-Pro-Ser-och3, Tyr-Pro-Ser-NH2, Tyr-Hyp-Ser-och3, Tyr-Hyp-Ser-NH2, Tyr-DPro-Ser-och3, Tyr-DPro-Ser-NH2Tyr-DLdHPro-Ser-och3, Tyr-dHPro-Ser-NH2, Tyr-Pro-Lys-NH2, Tyr-Pro-Ala-NH2, tetrapeptide Tyr-Pro-Gly-Pro-NH2, Tyr-Tyr-Pro-Ser-NH2Ala-Tyr-DPro-Ser-NH2, DAla-Tyr-DPro-Ser-NH2Glu-Ty-DPro-Ser-NH 2, Met-Tyr-DPro-Ser-NH2in the test of writhing induced by acetic acid.

Test of writhing induced by acetic acid (Chernov et. al., 1967). The studies were conducted in males nonlinear white mice weighing 20-30 g Animals were randomly divided into two groups of 10 mice. The analyzed peptides at a dose of 1 mg/kg was administered intraperitoneally 20 minutes before intraperitoneal injection of 0.6% acetic acid solution. Control animals were injected intraperitoneally distilled water for 20 minutes before intraperitoneal injection of 0.6% acetic acid solution. Animals were placed in individual boxes. Registered number of writhing within 30 minutes after intraperitoneal injection of 0.6% acetic acid solution (10 ml per 1 kg of body weight). The number of writhing in the control group was taken as 100%. The results are shown in table 5.

Table 5
The number of writhing%
The tripeptides
* - p<0.05 - significant differences from the control group.

Table 5 shows that intraperitoneal injection of dip is ptid formula (I) Tyr-Pro-och 3, tripeptides of formula (I) Tyr-Pro-Ser-och3, Tyr-Pro-Ser-NH2, Tyr-Hvp-Ser-och3, Tyr-Hyp-Ser-NH2, Tyr-DPro-Ser-och3, Tyr-DPro-Ser-NH2, Tyr-DLdHPro-Ser-och3, Tyr-dHPro-Ser-NH2, Tyr-Pro-Lys-NH2, Tyr-Pro-Ala-NH2tetrapeptides formula (I) Tyr-Pro-Gly-Pro-NH2Ala-Tyr-DPro-Ser-NH2, DAla-Tyr-DPro-Ser-NH2Glu-Tyr-DPro-Ser-NH2, Met-Tyr-DPro-Ser-NH2causes a significant decrease in the number of cramps after injection of acetic acid compared with the control group.

Thus, dipeptide, tripeptides, tetrapeptides formula (I) have expressed analiticheskim effect in the test of writhing induced by acetic acid.

The peptides of General formula

A-B-Tyr-Pro(DPro, dHPro, DdHPro, DLdHPro, Hyp)-B-X,

where a, -Ala, -Asp, -Glu, -Phe -,- Gly, -His, -He, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

B - Oh, -Ala, -Asp, -Glu, -Phe -,- Gly, -His, -He, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

In - Oh, - Ala, -Asp, -Glu, -Phe -,- Gly, -His, -He, -Lys, -Leu, -Met-Pro-Arg-Ser, -Thr, -Val-Trp-Tyr;

X - OH, -och3, -NH2,

possessing analgesic activity (O - denotes the absence of amino acids).


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FIELD: medicine.

SUBSTANCE: method involves applying composition based on receptor antagonist P substance and magnesium salt.

EFFECT: reduced hematoencephalic barrier permeability; reduced risk of vasogenic brain edema; prevented water accumulation in brain; smoothing consequences caused by reduced cognitive abilities.

23 cl, 2 dwg, 3 tbl

FIELD: medicine, ophthalmology, pediatrics.

SUBSTANCE: method involves apparatus treatment for 10 days with preliminary intramuscular administration of neuropeptide cortexin in the dose 5-10 mg, 10 injections. During apparatus treatment nootropic agent semax is administrated by intranasal route as instillations in the dose 1-2 drops, 2-3 times per 24 h for 10 days. Method provides improving eye memory, increasing rate in delivery and processing the eye information and the prolonged memory concentration necessary for effective apparatus method of treatment. Invention can be used in treatment of amblyopia in children with delayed intellectual development.

EFFECT: improved treatment method.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves introducing solutions into articulation to inhibit cartilage destruction. The solutions contain: (a) therapeutically effective amount of anabolic chondroprotective agent selected from a group composed of interleukine antagonists stimulating anabolic processes in cartilage, members of superfamily transforming growth β-factor including TGF-β agonists and agonists of morphogenous bone proteins stimulating anabolic processes in cartilage, insulin-like fibroblast growth factors stimulating anabolic processes in cartilage; (b) therapeutically effective amount of a cartilage catabolism inhibitor selected from a group composed of antagonists of interleukine-1-receptors, antagonists of TGF-α-receptors, specific cyclo-oxygenase-2 inhibitors, nitrogen oxide synthase inhibitors, nuclear kB factor inhibitors, matrix metalloproteinase inhibitors, cell adhesion molecules including integrin agonists and integrin antagonists, anti-chemotaxis agents, intracellular signal transmission inhibitors including protein kinase C inhibitors and tyrosine protein kinase inhibitors, intracellular (protein-tyrosine)-phosphatases and SH2-domain inhibitors inhibiting cartilage catabolism. The solution is locally supplied.

EFFECT: stimulated integration and modulation of anti-inflammatory synoviocyte and chondrocyte responses.

54 cl, 9 dwg, 30 tbl

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, phthisiology, anesthesiology.

SUBSTANCE: during the day of operation one should perform autohemotransfusion, then introduce epocrine intravenously by drops at the dosage of 50-200 U/kg patient's body weight; next day after interference one should inject epocrine subcutaneously at the dosage of 25-100 U/kg; at hematocrit level being below 35% 48 h after operation it is necessary to repeat subcutaneous injection of the above-mentioned preparation at the dosage not exceeding 50 U/kg. The present innovation favors hemopoiesis stimulation in postoperational period, that, in its turn, accelerates postoperational rehabilitation in patients of this group and enables, also, to avoid allotransfusions being dangerous because of immunoconflicting reactions.

EFFECT: higher efficiency of compensation.

1 ex, 1 tbl

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: in the suggested composition one should apply heptapeptide of Met-Glu-His-Phe-Pro-Gly-Pro sequence (heptapeptide A) for treating ischemic insult due to introducing 2 drops of compositions into each nasal canal 5-6 times daily for 10 d at disease of average severity degree, and in case of severe degree - per 3 drops of the present composition into each nasal canal 7 times daily for 10 d. The present innovation provides increased efficiency at decreased concentration of heptapeptide without any side effects.

EFFECT: higher efficiency of therapy.

2 cl, 6 dwg, 8 ex, 5 tbl