Tetrapeptide and preparation, possessing cerebroprotective and antiamnestic activities (versions)

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology, namely to novel tetrapeptides, representing Acetyl-(D-Lys)-Lys-Arg-Arg-amide; Acetyl-Lys-(D-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-Lys-Arg-(D-Arg)-amide; Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide; Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide; Acetyl-(D-Lys)-(D-Lys)-(D-Arg)-(D-Arg)-amide; Acetyl-(D-Arg)-(D-Arg)-(D-Lys)-(D-Lys)-amide, which possess cerebroprotective and antiamnestic activity.

EFFECT: claimed peptides produce stimulating impact on cholinergic processes in brain, are of low toxicity and are promising for application in medical practice as active component of medications.

11 cl, 5 tbl, 5 ex

 

The invention relates to the field of biotechnology, namely to new peptides of the General formula: Acetyl-A1-A2In1In2-amide, where A1- lysine, D - lysine or D - arginine;2- lysine, D - lysine, N - methyl-lysine or D - arginine;1- arginine, D - arginine, N - methyl-arginine, or D - lysine;2- arginine, D - arginine, or D - lysine, and drugs on the basis of these peptides with cerebroprotective and antiamnesic activity. The invention can be used in medicine, veterinary medicine, cosmetics, food and dairy industry and related industries.

In modern conditions of acute disorders of cerebral circulation (cerebral vascular accident) are among the diseases among the leading causes of morbidity and mortality of patients, which results in a large value of this problem in the medical and socio-economic aspects [EN 2386439, 2010; Gusev, E. I. and other Therapy of ischemic stroke // Consilium Medicum. in 2003, 5, No. 8, - n-21-29; O. Agyeman et al. Time to admission in acute ischemic stroke and transient ischemic attack // Stroke. - 2006. - Vol.37 - p.963-966; C. J. Murray, A. D. Lopez. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factor sin 1990 and projected to 2020 // Harvard University Press. - 2000. No. 3, p.105]. Annually in the world, stroke is transmitted by about 6 million people die from this disease 4.7 million. Disability due to vascular Zab the diseases brain takes the leading place among all diseases, however after stroke working only 20% of patients. In Russia, stroke ranks second in the total mortality of the population, second only to cardiovascular disease. According to the who in Russia, the incidence of acute vascular diseases of the brain (OSSM) is 400 persons per 100 thousand population. Thus there is an increase in the prevalence of stroke among persons of working age; the frequency of stroke in healthy individuals aged 25-65 years at the present time is 2.5-3 for the urban population and rural and 1.9 per 1,000. Thus, the solution to the problem of prevention and treatment OSSM, in particular the creation of new highly effective and safe means possessing cerebroprotective and anti-ischemic properties, an issue of emergency medical and social significance.

Currently, for the treatment of patients with signs of circulatory failure of the brain used drugs such as diazepam, phenazepam, piracetam, acid, pyritinol, pantogram, sodium oxybutyrate and other stimulating redox processes, increase glucose utilization, improves regional blood flow in the brain [Mashkovsky M. D. Medicines. The textbook of pharmacotherapy for physicians. In 2 hours - Vilnius, 1993, - the .1, - S. 101-110]. Drugs such as diazepam, phenazepam, have strong negative side effects - causes myorelaxation, reduced muscle tone, overall sedative effect, daytime sleepiness, memory impairment, and with long - term use addiction, drug addiction. The most famous cerebroprotective means is piracetam used in the form of a 20% solution [Mashkovsky M. D. Medicines. - M.: 2002. - T. 1, - n-111], which has a positive effect on metabolism, blood flow and bioenergetic processes of the brain, however, has an antioxidant effect and has negative side effects of severe coronary insufficiency and the occurrence of dyspeptic phenomena, can cause sleep disorders, increased convulsive readiness, nonspecific General excitation. In this regard, recommends the use of a combination of drugs based on it, improves cerebral blood flow and cerebral energy metabolism, for example fezam (piracetam and Cinnarizine), thiotriazoline and piracetam [RU2386439, 2010; RU2248203, 2005]. The disadvantage of these drugs is that they only stimulate the synthesis of neurotrophic factors, and do not possess neurotrophic activity [Korsching S. The neurotrophic factor concept: a reexamination // Neuroscience. - 1993. - Vol.13, N 7. - p.2739]. In addition, this drug is not without side effects and contraindications.

Along with the chemical-pharmaceutical preparations for the treatment of this group of diseases is widely used biological substances, in particular drugs based on natural proteins and peptides. Thus, the known biologically active protein-polypeptide complex with a molecular mass constituent of protein-polypeptide components in the range from 5 to 200 kDa, with content weight fraction in the range from 10 to 120 kDa at least 80%, with a total protein concentration of 0.8-4.2 mg/ml at a concentration of 0.01-2.0 mg/ml, obtained from bystrozamorozhennogo embryonic brain agricultural ungulates [RU2445106, 2012].

Widely known drug Cerebrolysin representing protein-free hydrolyzate of the brain, consisting of amino acids, low molecular weight peptides and trace elements, the raw material for which is the brain of pigs [Mashkovsky M. D. Medicines. The textbook of pharmacotherapy for physicians. In 2 hours - Vilnius, 1993, - h 2, - S. 84-88]. Neuroprotective and trophic action of the drug is due to specific peptides and amino acids molecular weight not higher than 10,000 daltons, of which the dominant and determining the properties of the drug are alanine, leucine and lysine. The drug is intended for intramuscular, intravenous and has a low concentration of biologically active the components, therefore injected into the patient's body in large doses for a long time. The disadvantage of this drug is significant duration of treatment, low activity and specificity of the drug due to weak neuroprotective effect, extremely low regenerative, including reparative, the potential for nerve tissue. Drug use does not allow to achieve a significant recovery of the anatomical structure and functional activity of neurons in the brain and spinal cord after injury [Krivitsky, N., Gelfand Century B., Popova E. N. Destructive and reparative processes in focal lesions of the brain. - M.: Medicine, 1980. - 214 S.; PL So N. Stimulation of regenerative processes in the injured spinal cord. - M.: Nauka, 1971. - 255 S.; Kryzhanovsky, N., Karaban, I. N., Makeeva C. Century. and other Compensatory and reparative processes in Parkinson's disease. - Kiev: Academy of medical Sciences of Ukraine, 1995. - 186 S.]

Known low molecular weight proteins (15-30 KD), synthesized cellular elements of the Central nervous system: a growth factor for neurons derived from brain-derived neurotrophic factor, neurotrophins -3, -4, -5, basic and acidic fibroblast growth factors, epidermal growth factor, astrocytic factor S-100; protein, lipoprotein [Ernfors P., Ivanez C. F., Ebendal T. Molecular cloning and neurotrophic activities of a protein with strctural similarities to nerve growth factor; developmental and topographical expression in the brain // Proc. Natl. Acad. Sci. USA. - 1990. - Vol.87, No. 9. - p.5454-5458; Elde, R., Y. Cao, A. Cintra Prominent expression of acidic fibroblast growth factor in motor and sensor neurons // Neuron. - 1991. - Vol.7, N 8. - p.349-364]. Adding small doses of these substances in culture neurons provides vital functions of the cells, the formation and growth of neurites through the stimulation of the biosynthesis of RNA, DNA, protein. However, it is found experimentally that the efficiency of their application is limited to neuro - protective action, and neurotrophic effects manifest themselves at a later date.

The most promising direction of development of new drugs with cerebroprotective step is the synthesis of analogues of endogenous peptide substances such as neuropeptides, which are the means of the integral of the modulating functions of the Central nervous system, reparative processes, memory, motor activity, feelings of pain and pleasure, etc. and can act as neurohormones, neurotransmitters or neuromodulators [Jakubke H.-D., Escaut X. Amino acids, peptides, proteins: Lane. with it. - M.: Mir, 1985. - 456 S.; Tepperman J., Tepperman X. Physiology of metabolism and endocrine system: Lane. from English. - M.: Mir, 1989. - 656 S.; Bakharev C. D. Clinical neurophysiology regulatory peptides. - Sverdlovsk: Publishing house of the Ural. University, 1989. - 136 C.].

Known Semax (methionyl-glutamyl-histidyl-fenilalanil-shed-glycyl-Proline) - drug belonging to the class of regulatory peptides and providing nootropic, stimulating, neuroprotective, antioxidant and antihypoxic effect, which is a modified fragment of the protein of adrenocorticotropic hormone (ACTH), containing seven amino acid residues [ru.wikipedia.org/wiki/]; known tetrapeptide L-alanyl-L-glutamyl-L-asparagi-L-Proline General formula L-Ala-L-Glu-L-Asp-L-Pro [RU2155063, 2000], stimulating the functional activity of neurons of the Central and peripheral nervous system due to the normalization of metabolic processes, stimulation indices of the antioxidant defense system, improvement of electrophysiological characteristics. The disadvantages of these compounds is not high enough cerebroprotective and antiamnesic activity.

Closest to the claimed invention on the structure and the achieved effect is previously obtained by the authors tetrapeptides drug NP-4 acetyl-Lys-Lys-Arg-Arg-amide, homologous in primary sequence fragment adrenergic corticotropes hormone (ACTH) [EN 2356573, 2009].

Tetrapeptide has combined anti-ischemic and hypoxic activities and promising for the treatment of OSM, but its activity, as shown by the experiments, is not high enough.

Technical the task, faced by the authors, was the creation of new peptide compounds and broadening the range of medicines that combine high cerebroprotective and antiamnesic activity with minimal negative effects on the body.

1. The technical problem was solved in the study of peptides included in the composition of the natural hormones that regulate the activity of higher organisms. The basis for the creation of new cerebroprotective was the type structure Lys-Lys-Arg-Arg homology in primary sequence fragment of adrenocorticotropic hormone (ACTH) and characterized by the presence of four positive charges. The result of this research group was created conformationally restricted peptides containing N-methylated and D-amino acid residues with concomitant cerebroprotective and antiamnesic activity, which included the following compounds in this group: ACE-tyl-(D-Lys)-Lys-Arg-Arg-amide; Acetyl-Lys-(D-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-Lys-Arg-(D-Arg)-amide; Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide; Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide; Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide; Acetyl-(D-Arg) (D-Arg) (D-Lys)-(D-Lys)-amide.

This means having cerebroprotective and antiamnesic activity, contains as active principle at least one tetrapeptide, selected from the group of kotarou include: Acetyl-(D-Lys)-Lys-Arg-Arg-amide; Acetyl-Lys-(D-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-Lys-Arg-(D-Arg)-amide; Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide; Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide; Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide; Acetyl-(D-Arg) (D-Arg) (D-Lys)-(D-Lys)-amide.

Peptides receive the standard techniques of peptide synthesis on solid phase or in solution, in which the first amino acid is attached to an insoluble polymer, capacity polypeptide chain is made sequentially or at the stage of condensation are protected fragments, removal of excess reagents is carried out by filtration, followed by washing peptidyl-polymer [J. M. Steward and J. D. Young, "Solid Phase Peptide Synthesis", W. H. Freeman Co., San Francisco, 1969]. The synthesis can be carried out using Boc/Bzl or Fmoc/tBu technology or any other system of orthogonal protective groups. Upon completion of the target sequence spend cleavage of the peptide from the polymer, accompanied, as a rule, the permanent removal of protective groups. Purification of the final product are usually, chromatographic methods, for example using reverse-phase or ion-exchange high-performance liquid chromatography. The compounds obtained data are characterized by analytical RP HPLC, amino acid and mass spectral analyses. The structure and codes of the peptides obtained during the execution of the conducted research is Avani, shown in table 1.

Table 1
The structure of the synthesized peptides
N p/pCipherStructure of peptide
1KK-1Acetyl-(D-Lys)-Lys-Arg-Arg-amide
2QC-2Acetyl-Lys-(D-Lys)-Arg-Arg-amide
3QC-3Acetyl-Lys-Lys-(D-Arg)-Arg-amide
4QC-4Acetyl-Lys-Lys-Arg-(D-Arg)-amide
5KK-5Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide
6QC-6Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide
7QC-7Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide
8QC-8Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide
9KK-9Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide
10QC-10Acetyl-(D-Arg) (D-Arg) (D-Lys)-(D-Lys)-amide

Studies have shown that all compounds obtained by incorporating in the structure of the N-methylated and D-amino acid residues have increased resistance against proteases of the blood serum in comparison with the known analogues.

The study of the cytotoxicity of the compounds obtained in the model system in vitro showed that all the compounds are non-toxic and do not affect the viability of mouse thymocytes in a wide range of concentrations from 0.01 to 100 µg/ml

To assess cerebroprotective actions peptides investigated in a model of acute cerebral ischemia in rats (bilateral carotid occlusion, anesthesia - propofol). Peptides QC-1, QC-2, QC-3 QC-4 QC-9 QC-10 showed high cerebroprotective activity at a dose of 20 mg/kg by intra. On the effectiveness of QC-10 on the 1st day of cerebral ischemia, in contrast to peptide was significantly more effective activity of piracetam. Peptides QC-2, QC-4 QC-9 showed the same result, reducing the mortality from 1 day up to 16.7%, which is statistically significantly greater than control groups pathology and piracetam. The leader was peptide QC-3, the treatment of which within the first 3 days in the s rats survived. No mortality during this period, the peptide QC-3 significantly exceeds Mexidol, piracetam, Semax and NP-4. On the 4th day and thereafter, mortality was 16.7%. Mortality in the group treated with NP-4 was 50%.

Antiamnesic effect of the peptides was evaluated on the model anterograde amnesia (scopolamine) in the conditional test of passive avoidance response. In the groups treated with the peptides QC-1, QC-2, QC-5 QC-8 QC-10 in a dose of 20 μg/kg intranasally, training was 100% versus 90% in the group of intact control. In the groups receiving similar dose of peptides ck-3, ck-7, and QC-9, this figure was 80% versus 30%, 50% and 56% in the groups treated with the peptide, piracetam and NP-4, respectively.

The nature and advantages of the claimed group of inventions are illustrated by the following examples.

Example 1. Synthesis of peptides

Peptide synthesis solid-phase method using Boc/Bzl strategy was carried out on the peptide synthesizer ABI 430A (Applied Biosystems, USA). For the temporary protection of the α-AMINOPHENYL used tert-butyloxycarbonyl group. For blocking of side radicals of arginine and lysine used mesitylenesulfonyl and 2-chlorobenzenesulfonyl groups, respectively. As insoluble matrix was used 4-methyl-benzylaminopurine (1% copolymer of styrene and divinylbenzene) with an initial capacity of 0.8 m is ol/year Capacity polypeptide chains were in situ. The release was performed undiluted triperoxonane acid (TFA) twice for 1 minute. Neutralization in the first condensation was carried out by adding 3x-fold excess of diisopropylethylamine (DIPEA) directly into the reaction mixture at the stage of joining amino acid residue; re-condensation was carried out after an additional washing peptidyl-polymer 10% solution of DIPEA in dimethylformamide (DMF). The joining of amino acid residues was performed 1-hydroxybenzotriazole esters, using multiples of 3 excess reagents.

After joining of the amino acid residues corresponding to the sequence of the synthesized peptides was performed acetylation of N-terminal amino group using 40 equivalents of acetic anhydride in DMF. The permanent removal of protective groups and cleavage of the peptides from the insoluble matrix was performed anhydrous liquid hydrogen fluoride in the presence of scavengers. In the vessel with the peptidyl-resin was transferred 9.5 ml of hydrogen fluoride and 0.3 ml of m - cresol and 0.2 ml ethicial and stirred at 0°C for 1 hour. Then hydrogen fluoride was evaporated and the peptide were planted ether of triperoxonane acid.

Selected crude products were subjected to the purification method prepreparation reversed-phase the HPLC column Waters Prep Nova-Pak HR C-18, 6µ, 60Å,19×300mm in a gradient of acetonitrile 5-75% for 30 minutes. Detection at 220 nm. The fraction corresponding to the main product peak was collected and liofilizirovanny.

Received target compounds were characterized by the data of mass spectrometry, amino acid and HPLC analyses. The conditions of HPLC analysis: analytical chromatograph Gilson, France, column DeltaPak C-18, 5µm, 100A°, a 3.9×150 mm; gradient (1-20)% acetonitrile in 0.1% TFA over 25 minutes.

Conditions of amino acid analysis: amino acid analyzer LKB 4151 Alpha Plus, Sweden; hydrolysis:

- 4M methansulfonate containing 0.2% tryptamine, 110°C, 22 h;

- 12N hydrochloric acid, and propionic acid (1:1), 110°C, 22 hours. Conditions mass spectral analysis: mass spectrometer Voyager-DE BioSpec-trometry Workstation, Per Sepetive Biosystems, USA.

All synthesized peptides had amino acid composition and molecular mass, corresponding to theoretical values. The purity of the compounds according to the analytical RP-HPLC was not less than 95%.

The structure of the peptides, the molecular weight and the time of exit in the analytical conditions OF HPLC are shown in table 2.

Table 2
Structure and physico-chemical characterization of peptides
Cipher Structure of peptideMolecular weightTime, min
Theory.Exp.
KK-1Acetyl-(D-Lys)-Lys-Arg-Arg-amide627.80628.448.83
QC-2Acetyl-Lys-(D-Lys)-Arg-Arg-amide627.80628.447.36
QC-3Acetyl-Lys-Lys-(D-Arg)-Arg-amide627.80628.448.92
QC-4Acetyl-Lys-Lys-Arg-(D-Arg)-amide627.80628.448.36
KK-5Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide627.80628.457.44
QC-6Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide627.80628.457.14
QC-7Acetyl-Lys-(NMe-Lys)-Ar-Arg-amide 641.80642.468.60
QC-8Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide641.80642.469.51
KK-9Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide627.80628.457.12
QC-10Acetyl-(D-Arg) (D-Arg) (D-Lys)-(D-Lys)-amide627.80628.447.49

Example 2. Investigation of the stability of peptides in relation to serum proteases

Lyophilized peptides were dissolved in DMSO at a concentration of 10 mg/ml (in terms of the content of the peptide). Used polerowanie serum from 6-8 healthy donors.

To 1 ml of culture medium RPMI-1640 containing 25% human serum, warmed to +37±1°C for 15 minutes, was added 5 μl of the peptide solution, thoroughly mixed and placed in a thermostat at 37°C. After a certain period of time selected 100 μl of the reaction mixture were added 20 μl of 15% aqueous trichloroacetic acid and intensively mixed. Then added 5 μl of 0.5 M NaOH, the sample was cooled to 0 to +4°C and centrifuging the Ali at 16000 g for 3 minutes to precipitate precipitiously proteins. Samples of the reaction mixture were collected at the following time intervals: 0, 0.25, 1, 2, 4, 24 hours. In between sampling the reaction mixture was kept in a thermostat at 37°C. Samples were analyzed by reverse phase HPLC. Conditions chromatographic analysis: analytical chromatograph Gilson, France, column DeltaPak C-18, 5µm, 100A°, a 3.9×150 mm; gradient (1-25)% acetonitrile in 0.1% TFA over 25 minutes. The results are presented in percentage as the ratio of the number of surviving peptide to the amount introduced into the reaction environment. The amount of peptide was calculated as the area under the curve of the corresponding peak, obtained by HPLC analysis of the sample.

The results of the study are presented in table 3.

Table 3
PeptideThe time of incubation, h
00.2512424
NP-410023±910±7---
KK-1 10085=1278±1962±1645±1115±14
QC-410098±396±492±585±425±2
QC-710092±1083±775±1456±178±6
KK-910098±396±497±595±1085±13
QC-1010099±498±598±696±1482±12

According to the information provided peptides containing D-amino acids, are more stable against proteases of human serum than peptide NP-4. Maximum stability was observed in connection with all amino acid residues in the D-configuration (QC-9 QC-0).

Example 3. The study of the cytotoxicity of the peptides

The toxicity of the synthesized peptides was evaluated in the in vitro system in relation to the mouse thymocytes. The thymocytes were isolated, washed twice culture medium RPMI 1640 and resuspendable in the same medium containing 2% fetal calf serum. The cell suspension was placed in a cell 96-well tablet (1×106cells on the cell), then added the analyzed peptides, dissolved in culture medium, so that the final concentration of the peptides was 0.01, 0.1, 1, 10 and 100 μg/ml After incubation in CO2incubator for 4 hours at 37°C. cell viability was assessed by staining with eosin b In the control cells was added only cultural environment.

The results of the experiment showed that the peptides QC-1, QC-2, QC-3 QC-4 QC-5 QC-6, CC-7, CC-8, CC-9 CC-10 in the concentration range from 0.01 to 100 µg/ml cytotoxic activity against mouse thymocytes do not possess.

Example 4. The study cerebroprotective actions peptides

The experiment was performed on 92 outbred albino male rats weighing 180-220 g contained in standard vivarium conditions. Cerebroprotective activity was evaluated on the model of irreversible bilateral carotid occlusion [Manual on experimental (preclinical) study of new FA is metologicheskikh substances / edited Ed. by R. U. Khabriev. - 2nd ed., Rev. and supplementary): JSC "Publishing house "Medicine", 2005. - 832 S.].

The common carotid artery was ligated under protopopovym anesthesia (Diprivan, "Fresenius Kabi, Austria, 60 mg/kg intraperitoneally), tightening the ligature at the beginning of their animals anaesthesia. Within 3-5 min after recovery from anesthesia, rats were injected drugs comparison: 3-hydroxy-6-methyl-2-ethylpyridine succinate (Mexidol, NBC "pharmasoft", Russia) at a dose of 100 mg/kg, 2-oxo-1-pyrrolidin-ndimethylacetamide (piracetam, "Darnitsa", Ukraine) at a dose of 400 mg/kg intravenously into the tail vein, heptapeptide Semax (Innovative SPC "Pathogen", Russia) - intranasal dose of 20 mg/kg, tetrapeptide NP-4 is administered in doses of 2 and 20 µg/kg Peptides QC-1, QC-2, QC-3 QC-4 QC-9 QC-10 was administered intranasally at a dose of 20 µg/kg to the Animals of the control group pathology was injected in a vein of isotonic NaCl solution. Introduction preparations continued for 4 days 1 time per day. Recorded mortality, evaluating the statistical significance of intergroup differences using angular transformation Fischer. Observation of the animals was continued for 10 days.

The results of the experiment are presented in table 4.

Table 4
Comparative influence of drugs n the mortality of rats in a model of acute disorders of cerebral circulation (irreversible bilateral carotid occlusion)
Group, the drug, dose, number of animalsThe period of observation, h
24487296 and later
Control pathology (GER), n=107/70%7/70%8/80%9/90%
BRP+Mexidol 100 mg/kg, n=104/40%5/50%5/50%6/60%
BRP+piracetam 400 mg/kg, n=106/60%7/70%7/70%7/70%
BRP+Semax 20 µg/kg/h, n=62/33,3%2/33,3%2/33,3%∗2/33,3%∗
BRP+NP-4, 2 µg/kg/h, n=107/70%7/70%7/70%7/70%
BRP+NP-4, 20 µg/kg/h, n=103/30%∗4/40%4/40%∗/td> 5/50%∗
BRP+KK-1 20 µg/kg/h, n=62/33,3%2/33,3%2/33,3%∗2/33,3%∗
BRP+KK-2 20 µg/kg/h, n=61/16,7%∗^1/16,7%∗^1/16,7%∗^1/16,7%∗#^
BRP+QC-3 20 ág/kg/h, n=60/0%∗#^&$0/0%∗#^&$0/0%∗#^&$1/16,7%∗#^
BRP+QC-4 20 µg/kg/h, n=61/16,7%∗^1/16,7%∗^1/16,7%∗^1/16,7%∗#^
BRP+QC-9 20 µg/kg/h, n=61/16,7%∗^1/16,7%∗^1/16,7%∗^1/16,7%∗#^
BRP+QC-10 20 µg/kg/h, n=61/16,7%∗^2/33,3%∗2/33,3%∗2/33,3%∗
Notes:
1. BRP - bilateral Karoti the Naya occlusion;
2. /- intravenous, and/n - intranasal;
3. The numerator is the absolute number of animals, in the denominator - %.
4. Statistically significant differences (p<0,05): ∗ - group index control pathology,#- with a group index of Mexidol, ^ - indicator group pyracetam,&- indicator group, Semax,$with group index NP-4 (20 µg/kg).

As can be seen from the data presented in table 4, in control group pathology already for the 1st day killed 70% of the animals, on the 3rd day mortality was 80%, ranging from 4 hours to 90%, still further constant that corresponds to the data of literature [Strigol S. Y. Modulation of the pharmacological effects at different salt regimes / S. Y. Strigol. - X.: Avista-VLT, 2007. - 360 S.].

The effectiveness of the famous cerebroprotective of Mexidol and pyracetam in this model of stroke was low: Mexidol reduced mortality by 30%, piracetam 20% that did not reach a statistically significant level. The peptide was significantly more effective Mexidol and piracetam. Since 3 days it was significantly (from 80% to 33.3%) reduced mortality, but this result was not statistically significant differences with the effects of Mexidol and piracetam. Tetrapeptide NP-4 in a dose of 2 mg/kg proved to be as ineffective as piracetam. At a dose of 20 mg/kg NP-4 showed cerebroprotein the priori activity close to that of the peptide in the same dose, but statistically significantly reduced the mortality of animals from the 1st day. Final mortality under the influence of NP-4 in a dose of 20 mg/kg was 50%, which was significantly (40%) lower than in control group pathology, and unreliable (1.0-20%) lower than in the groups of Mexidol and pyracetam.

Peptides QC-1, QC-2, QC-3 QC-4 QC-9 QC-10 showed high cerebroprotective activity at a dose of 20 µg/kg Peptides QC-2, QC-4 QC-9 showed the same result, reducing mortality from 1 day up to 16.7%, which is statistically significantly higher than the control group pathology and the effects of piracetam and NP-4.

The most effective cerebroprotective was peptide QC-3, on the background of the application for the first three days of experimental cerebral vascular accident 100% of the animals remained alive. No mortality during this period, the peptide QC-3 at a dose of 20 mg/kg statistically significantly superior to all Comparators, including NP-4. On the 4th day died 1 animal out of 6 (16.7%). Thus, the lower end of lethality peptide QC-3 significantly more effective than piracetam and Mexidol.

Example 5. The study antiamnesic activity of the peptides

To identify neuroprotective (antiamnesic) actions peptides QC-1, QC-2, QC-3 QC-4 QC-5 QC-6, CC-7, CC-8, CC-9, CC-10 used the conditional test reaction passive house is Denmark (passive avoidance reaction) [Manual on experimental (preclinical) study of new pharmacological substances / edited Ed. by R. U. Khabriev. - 2nd ed., Rev. and supplementary): JSC "Publishing house "Medicine", 2005. - 832 S.].

Used 105 nonlinear white mice of both sexes weighing 18-24, Just a random selection was formed 15 groups of animals, each of which was composed of approximately equal numbers of females and males. The group of intact control learning intraperitoneally received 0.25 ml of 0.9% NaCl solution, the control group amnesia - only scopolamine dose of 1.5 mg/kg over 20-30 min before the formation of the passive avoidance reaction. In other groups 20-30 min after intraperitoneal administration of scopolamine mice intranasally injected solutions of the investigated peptides at a dose of 20 mg/kg and after 5 min was placed in the illuminated chamber of the device for the formation of the passive avoidance reaction. Comparators served 2-oxo-1-pyrrolidin-ndimethylacetamide (piracetam, "Darnitsa", Ukraine) in doses of 200 mg/kg and 400 mg/kg vnutribruchinno, heptapeptide Semax (Innovative SPC "Pathogen", Russia) - intranasal dose of 20 mcg/kg and tetrapeptide NP-4-intranasal dose of 20 mg/kg was Determined by a latent period of entry into the dark chamber where animals received electrobalance irritation. After 24 h were checking the reproducibility of the passive avoidance reaction in latincentro time of entry into the dark chamber. Under the criterion of skills believed mice that did not belong in a dark chamber for 3 minutes.

For statistical assessment of the inter-group differences in latent period of entry into the dark chamber used the student's t-test, the number of animals reached the criterion of training - corner of the Fisher transformation.

Quantitative research data antiamnesic properties are given in table 5.

Table 5
The effect of drugs on memory mice model anterograde amnesia in the test passive avoidance reaction
Group SubstanceDose, mg/kg, route of administrationnPassive avoidance reaction
PL sourcePL after 24 h,% of mice that reached the criterion of training
Control of trainability (intact)-1016,7±1,85168,4±N,9∗90∗
Control amnesia (scopolamine)-1422,6±6,0433,2±5,67#0#
Piracetam200 b/W6 15,8±5,5089,0±30,0#16,7∗#
400 V/b633,3±a 4.83to 124.4±26,0∗50,0∗#
Semax0.02 n/a1028,1±3,49128,3±14,0∗#30∗#
NP-40.02 n/a928,7±a 7.85a 126.7±17,9∗55,6∗#
KK-10.02 n/a533,8±4,79180,0±0,00∗^&$100∗^^&$
QC-20.02 n/a522,8±was 4.02180,0±0,00∗^&$100∗^^&$
QC-30.02 n/a523,2±to 4.41164, 8mm±14,6∗^80∗^&
QC-40.02 n/a529,4±6,51116,0±20,5∗#20∗#
KK-50.02 n/a5the 15.6±2,11180,0±0,00∗^&$100∗^^&$
QC-60.02 n/a522,6±5,75to 154.2±23,9∗60∗
QC-70.02 n/a527,6±3,64154,0±26,8∗80∗^&
QC-80.02 n/a515,0±4,21180,0±0,00∗^&$100∗^^&$
KK-90.02 n/a5of 31.8±12,6150,0±26,8∗80∗^&
QC-100.02 and/h/td> 513,0±1,34180,0±0,00∗^&$100∗^^&$
Notes:
1. PL - latent period of entry into the dark chamber;
2. in/b - intraperitoneally, and/n - intranasal;
3. Statistically significant differences (p<0,05): ∗ - group index control, amnesia,#with metric learning control (intact), ^ - group index of piracetam (200 mg/kg), ^^ - with a group index of piracetam (400 mg/kg),&- indicator group, Semax,$with group index NP-4.

As the data presented in table 5, all mice groups of intact control learning formed the passive avoidance reaction: the latent period of entrance into the dangerous dark chamber after 24 h increased, on average, 10 times, while the criterion of training has reached 90% of the animals. Scopolamine had a typical amnestic effect: the latent period of unreliable increased an average of only 1.5 times, no mouse has not reached the criterion of training.

Piracetam showed dose-dependent antiamnesic properties, increasing the latent period of entry into the dark chamber after 24 h on average 3.8-5.6 times and increasing the number of animals reached the criterion of training, up to 16.7% (200 mg/kg) and up to 50% (400 mg/kg, p<0.05 relative to control AMS is Ziya).

Semax has had a similar effect, similar to that of piracetam high dose (increase of the latent period in 4.6 times increase to 30% the number of mice that reached the criterion of training, p<0.05 for control of amnesia.

Antiamnesic effect of peptide NP-4 in a dose of 20 mg/kg was close to that of piracetam 400 mg/kg (increase of the latent period of the input in a dark chamber at 4.4 times and increase the number of animals reached the criterion of training, up 55.6%, p<0.05 for control of amnesia. The number of mice that reached the criterion of training, the effect of all control drugs were statistically significantly inferior indicator of intact control learning (p<0.05).

Peptides QC-1, QC-2, QC-5 QC-8 QC-10 in a dose of 20 µg/kg/h had a pronounced antiamnesic activity: the latent period of entry into the dark chamber after 24 h increased 5.5-13.8 times and amounted to 180 C, i.e. 100% of the animals reached the criterion of training. This is 10% higher than in the intact control group learning, and statistically significantly higher than in groups treated with piracetam and Semax (p<0.05).

On the background of peptides ck-3, ck-7, ck-9 latent period of entry into the dark chamber was increased 4.5-7.1 times; the number of mice that reached the criterion of training amounted to 80%, which is statistically significantly surpassed the effect of piracetam (200 mg/kg) and Semax (p<0.05), practically not inferior to display the indicator of intact control learning (90%).

In animals treated with the peptide KK-6, antiamnesic effect was slightly higher than that in groups of Semax, piracetam (400 mg/kg) and NP-4: latent period in a dark chamber increased 6.8 times the number of mice that reached the criterion of training, was 60% (p<0.05 relative to control amnesia).

The results of the study suggest that all studied peptides have a stimulating effect on cholinergic processes in the brain, because the mechanism used models of amnesia due to the anticholinergic action of scopolamine.

In these examples, the data show that the inventive tool has a strong cerebroprotective and antiamnesic effects on the body and is promising for use in medical practice.

1. Tetrapeptide General formula Acetyl-(D-Lys)-Lys-Arg-Arg-amide.

2. Tetrapeptide General formula Acetyl-Lys-(D-Lys)-Arg-Arg-amide.

3. Tetrapeptide General formula Acetyl-Lys-Lys-(D-Arg)-Arg-amide.

4. Tetrapeptide General formula Acetyl-Lys-Lys-Arg-(D-Arg)-amide.

5. Tetrapeptide General formula Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide.

6. Tetrapeptide General formula Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide.

7. Tetrapeptide General formula Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide.

8. Tetrapeptide General formula Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide.

9. Tetrapeptide General formula Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide.

10. Tetrapeptide General formula Acetyl-(D-Arg) (D-Arg) (D-Lys)-(-Lys)-amide

11. A means of having cerebroprotective and antiamnesic activity, containing as active principle at least one tetrapeptide selected from the group comprising: Acetyl-(D-Lys)-Lys-Arg-Arg-amide; Acetyl-Lys-(D-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-Lys-Arg-(D-Arg)-amide; Acetyl-(D-Lys)-Lys-(D-Arg)-Arg-amide; Acetyl-Lys-(D-Lys)-(D-Arg)-Arg-amide; Acetyl-Lys-(NMe-Lys)-Arg-Arg-amide; Acetyl-Lys-Lys-(NMe-Arg)-Arg-amide; Acetyl-(D-Lys)-(D-Lys)-(D-Arg) (D-Arg)-amide; Acetyl-(D-Arg)-(D-Arg) (D-Lys)-(D-Lys)-amide.



 

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FIELD: medicine.

SUBSTANCE: invention refers to medicine and veterinary science, and can be used as an effective agent for the targeted delivery of DNA complexes with molecular conjugates into certain mammalian organs and tissues. The declared invention considerably improves the efficiency of the DNA delivery into the tumour cells and substantially simplifies, reduces the prices and time of molecular conjugate synthesis by using a module-based approach, as well as by providing a possibility of rapid alternation of ligand components for varying a conjugate affinity to various tumour and normal body cells.

EFFECT: invention enables correcting the problem of tumour disease gene therapy, as the prepared module peptide conjugate is as shown by multiple real-time tests an effective agent for the targeted delivery, and most significantly, non-toxic, immunogenic and causes no side effects.

2 cl, 7 dwg, 10 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to novel biologically active derivatives of 1-(1-adamantyl)ethylamine (remantadine) representing adamantyl peptides having antiviral action. The invention may find application in medicine, pharmacology and virology as new medicinal products to treat Hepatitis C.

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3 cl, 6 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to conjugates for the delivery of medications, which bind receptors on the cell surface, containing hydrophilic linker spacers.

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38 cl, 19 dwg, 49 ex

FIELD: chemistry.

SUBSTANCE: disclosed is an agent which is one of the derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane, which exhibits antiviral activity on DNA viruses. The disclosed agent can be used in veterinary and healthcare.

EFFECT: higher antiviral activity towards DNA viruses.

6 dwg, 3 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition showing stress-protective action which contains peptide R1-Lys1-Arg2-Pro3-R2 [SEQ ID NO:1] or R1-Lys1-Arg2-Arg3-Pro4-R2 [SEQ ID NO:2] wherein R1=NH2 or CH3CO and R2=OH or NH2 and a method for prevention and/or treatment functional or stress-induced disorders caused by extreme factors.

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3 cl, 9 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: agent is an N- and C-substituted peptide selected from n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-glycyl lysyl-glycine (1), n-decyl ether (1-tetradecyl-1,4-diazoniabicyclo[2.2,2.]octan-4-yl)-acetyl-glutamyl-β-alanyl-arginyl-glycine (2) and n-decyl ether glutamyl-β-alanyl-lysyl-glycine (3).

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3 dwg, 2 tbl, 6 ex

FIELD: chemistry.

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Rgd-like peptides // 2396271

FIELD: chemistry.

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2 tbl, 1 ex

FIELD: chemistry; medicine.

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EFFECT: medications possess higher efficiency.

9 cl, 64 ex

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EFFECT: high specific activity of introduced peptide and decrease of side effect risk.

4 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to medicine, in particular to a composition, the application of the composition and a method of treating abuse with substances, causing painful addiction in a subject. The composition contains a carbamoyl compound, or its pharmaceutically acceptable salt, or an ester as an active ingredient and the method includes the introduction of a therapeutically effective quantity of the carbamoyl compound, or its pharmaceutically acceptable salt, or the ester.

EFFECT: composition is used for the treatment of abuse with substances, causing painful addiction in a subject, as well as to an improvement of behaviour associated with the abuse.

14 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: cerebroprotective and antineurotic agent containing an active ingredient presented by a dry extract of meadowsweet (Filipendula ulmaria (L.) Maxim.) prepared according to a certain procedure, and additive agents - lactose, microcrystalline cellulose, potato starch, magnesium stearate taken in certain proportions.

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2 cl, 5 tbl, 9 ex

FIELD: pharmacology.

SUBSTANCE: pharmaceutical composition possessing the sedative and spasmolytic action and containing valerian tea, motherwort tea, hawthorn tea, peppermint tea with a number of biologically active substances in each of the teas, and an antihistamine preparation of diphenhydramine hydrochloride; as ingredients of the biologically active substances, the composition contains flavonoids in a certain amount.

EFFECT: composition possesses the high sedative therapeutic effect, the improved therapeutic effect in treating psychoemotional disorders, including in women suffering from menopausal syndrome.

2 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: sedative and spasmolytic agent containing valerian tea, motherwort tea, hawthorn tea, peppermint tea with a complex of biologically active substances in each of the teas, and an antihistamine preparation of diphenhydramine hydrochloride. As ingredients of the biologically active substances, the composition contains carboxylic acid esters and menthol in a certain amount.

EFFECT: agent has no side effect, as dry mouth, and possesses the more pronounced therapeutic action in treating psychoemotional disorders.

2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to neurology, and concerns treating neurological complications of varicella in children. That is ensured by administering acyclovir, interferon and intravenous immunoglobulins. Acyclovir is administered in a dose of 10-15 mg/kg 3 times a day in a combination with viferon in rectal suppositories of 500,000-1,000,000 International Units 2 times a day for 10-14 days. Intravenous immunoglobulin G is administered in a dose of 0.4 mg/kg once a day for 3 days. If observing a severe condition in a combination with multiple CNS involvements, the antiviral therapy is added with administering Metypred 500-1000 mg once a day intravenously drop-by-drop and Elcar 50-70 mg/kg once a day for 5-7 days, then 50-70 mg/kg twice a day orally.

EFFECT: complex of the antiviral and specific causal treatment provides the higher clinical effectiveness and reducing the length of treatment of the neurological complications of varicella in children.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (1), which possess an affinity to the µ-opiod receptor and the ORL1-receptor. The invention also relates to the application of the said compounds for obtaining medications, which can be used in treatment of fear, stress and associated with stress syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as nootropic), withdrawal syndromes, alcohol and/or drug abuse and/or abuse of medications and/or alcohol, narcotic and medication addiction, etc. In general formula (1) (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' in each case stand for -H; Q stands for -R0, -C(=O)-R0, -C(=O)OR0, -C(=O)NHR0, -C(=O)N(R0)2 or-C(=NH)-R0; R0 in each case stands for -C1-8-aliphate, -C3-12-cycloaliphate, -aryl, -heteroaryl, -C1-8-aliphate-C3-12-cycloaliphate, -C1-8-aliphate-aryl, -C1-8-aliphate-heteroaryl, -C3-8-cycloaliphate-C1-8-aliphate, -C3-8-cycloaliphate-aryl or -C3-8-cycloaliphate-heteroaryl; R1 and R2 independently on each other stand for -C-1-8-aliphate; R3 stands for -C1-8-aliphate, -aryl, -heteroaryl or -C1-8-aliphate-C3-12-cycloaliphate; n stands for 0; X stands for -NRA-;RA stands for -C1-8-aliphate; RB stands for -C1-8-aliphate; on condition that R1, R2, RA and RB simultaneously do not stand for the non-substituted-C1-8-aliphate.

EFFECT: increased efficiency of the application of the compounds.

9 cl, 11 tbl, 164 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents an injectable form of 5α-androstane-3β,5,6β-triol containing a liquid injectable form, containing a solvent, or a solid injectable form containing at least one soluble additive with the above at least one soluble additive containing hydroxypropyl-β-cyclodextrine.

EFFECT: invention provides preparing the stable injectable form of 5α-androstane-3β,5,6β-triol.

10 cl, 7 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention refers to new phenoxymethyl compounds of formula (I) or its pharmaceutically acceptable salts, wherein: HET represents a heterocyclic ring having formula A29 or A31, wherein the far left part is connected to the group X of formula (I); X represents substituted phenyl or optionally substituted pyridinyl, wherein the substitutes are specified in C1-C4alkoxy and cyano; Z represents imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl or imidazo[1,2-b]pyridazin-6-yl each of which can be substituted, wherein the substitutes are specified in C1-C4alkyl and a halogen atom; and each R2 are independently specified in C1-C4 alkyl inhibiting at least one phosphodiesterase 10, as well as to pharmaceutical compositions containing these compounds, and methods of treating various CNS disorders.

EFFECT: preparing the new compounds.

23 cl, 2 tbl, 732 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and concerns using tetrapeptide Pro-Gly-Pro-Val as an agent for preventing or treating lipid storage disease; a method for preventing or treating lipid storage disease involving the intranasal administration of a therapeutic agent containing tetrapeptide Pro-Gly-Pro-Val in an effective amount; to a pharmaceutical composition for preventing or treating lipid storage disease, containing peptide Pro-Gly-Pro-Val with the anticholesteremic and triglyceridemic action as an active substance, and an auxiliary substance as a preserving agent.

EFFECT: group of inventions provides the more effective prevention and treatment of lipid storage disease as compared to natural tripeptide Pro-Gly-Pro.

6 cl, 4 ex, 5 tbl

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