Compositions and methods for treatment of aorta fibrosis

FIELD: biotechnologies.

SUBSTANCE: invention relates to compositions containing vasoactive intestinal peptide (VIP) or its fragments, and to application of such compositions in treatment of aorta fibrosis.

EFFECT: group of inventions is effective in treatment and prophylaxis of aorta fibrosis.

10 cl, 4 dwg, 2 ex

 

The scope of the invention

The present invention relates to compositions and methods for therapeutic or prophylactic treatment of fibrosis of the aorta. In particular the present invention relates to compositions containing VIP (vasoactive putting peptide) or certain active fragments of VIP and their use in the treatment of fibrosis of the aorta.

Prior art

Any discussion of prior art in the description in no way should be seen as a recognition of the fact that this prior art is widely known or forms part of common knowledge in this technical field.

The number of cases of conditions such as stroke and dementia, more closely related to systolic blood pressure than diastolic blood pressure. I believe that the increase in systolic blood pressure occur as a result of reduced production of internal vasodilating endothelial relaxing factor (EDRF) or nitric oxide (NO), which leads to increased vascular tone or narrowing of blood vessels. This explains the increase in systolic blood pressure, but does not explain the fall in diastolic blood pressure and extended pulse amplitude, which is associated with increased risk for cardiovascular system. Only structure the e changes in the main blood vessel, the aorta, which reduce compliance and thus reduce the ability of the aorta to relax and absorb the wave systolic blood pressure, and also to experience elastic traction during cardiac filling or diastole, can explain this phenomenon. Loss of elastic fibers and their replacement by collagen, as well as the destruction of the smooth muscle fibers by increasing the amount of collagen and fibrous tissue leads to decreased elasticity and extensibility. These changes in the aortic wall causing rigidity, which in turn leads to a reflective wave in response to the pressure wave of the cardiac systole. The effect of reflecting waves increases and then increases systolic blood pressure. Increased rigidity prevents elastic recoil during cardiac filling, reduces the ability of the vascular system to maintain blood pressure during diastole and leads to reduced diastolic blood pressure. The difference between systolic and diastolic pressure is called the pulse pressure. Increased pulse pressure (>90 mm RT.CT.) indicates a high absolute risk of cardiovascular pathologies like stroke.

Current agents that reduce blood pressure, aimed at improving vasoconstrictor factor systolic pressure and reduce Sisto as is practical, and diastolic pressure in the close degree. The inability of these agents to affect structural correction in the aorta means that in patients with elevated pulse pressure treatment is limited to reducing diastolic pressure. As a result, the systolic blood pressure is often higher than the recommended level. Thus, pulse pressure remains elevated despite treatment, or the treatment may reduce the pressure, and these patients remain at increased risk for cardiovascular pathologies, such as stroke.

Thus, there is a need for remedies that will prevent and/or completely change the structural changes of the aorta.

The present invention is to overcome or avoid at least one of the disadvantages of the prior art or to provide a suitable alternative.

Summary of the invention

The present invention relates to a VIP and/or fragments of VIP and their use for the treatment of fibrosis of the aorta. The compositions of the present invention have the ability to prevent or reverse established fibrosis in the aorta and, thus, they can be used for therapeutic or preventive treatment.

In accordance with the first aspect the invention proposed composition for the prophylactic or therapeutic treatment of fibrosis of the aortic containing a pharmaceutically effective amount of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16.

Preferably the compositions of the present invention are administered together with a pharmaceutically acceptable carrier, which may be any known in the art or developed in the future and suitable for the specified use. In addition to the media, the pharmaceutical composition according to the invention may include other ingredients including, for example, dyes, preservatives, buffers and antioxidants. Preferably they can be administered together with one or more other active agent used in the treatment of fibrosis of the aorta or heart disease. They can be preferably prepared for the introduction of oral, intravenous, intramuscular or subcutaneous route. Other routes of administration, such as plasters, medicated powders for inhalation through the nose, nasal sprays, etc., will be clear to experts in the given field of technology.

Pharmaceutically effective amount of VIP or active fragment VIP will vary depending on the patient and/or the severity of the condition, the cat is PoE treat. These variables can be defined by experts in the art using standard experimental studies. A suitable dosage in the initial phase can be determined from the dose injected animal model described here, or with reference to PCT/AU2005/000835 and PCT/AU2006/001869. The composition of the invention can be applied to prevent or slow the progression of fibrosis of the aorta, as well as for reducing or preventing the development of fibrosis.

In accordance with the second aspect of the invention, a method of prophylactic or therapeutic treatment of fibrosis of the aorta in a patient, wherein the patient with fibrosis of the aortic or the risk of its development, introducing a composition containing a pharmaceutically effective amount of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16.

In relation to preventive treatment should be understood that such treatment will help patients, especially those who are at risk of fibrosis of the aorta. Examples of patients at risk under this category are those patients who suffer from ACC is chinovnik States, such as atherosclerosis, hypertension, chronic renal insufficiency, chronic intoxication with vitamin D, vasculitis, diabetes mellitus, hypothyroidism, hyperlipidemia, isolated systolic hypertension, stroke, heart failure, myocardial infarction, the last stage of renal failure and aortic aneurysm.

Preferably prophylactic treatment is used to prevent or slow the development of fibrosis in a patient. The treatment can also be used to prevent or slow the progression of established fibrosis, aortic, or, alternatively, reduce the extent of established fibrosis.

Preferably the method further includes introducing one or more than one active agent, suitable for the treatment of fibrosis of the aorta.

To a person skilled in the art it is obvious that the method of application of the compositions according to the invention may be changed to achieve optimal effect. It may be important to take into account the nature of the disease or condition and its severity, and any associated risk or predisposing factors.

Preferably VIP or one or more than one functional fragment VIP introduce a method selected from intravenous, intramuscular, subcutaneous injection, oral, sublingual or intranasal in which edenia.

Preferably VIP or one or more than one functional fragment VIP impose a dosage form selected from tablets, capsules, powders, liquid compositions with delayed or prolonged release, patches, medicinal powders for inhalation through the nose, nasal sprays, etc.,

In accordance with a third aspect of the present invention is proposed vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16, for use in the prophylactic or therapeutic treatment of fibrosis of the aorta.

Preferably the application is intended to prevent or slow the progression of established fibrosis of the aorta. An alternative application is intended to prevent or slow down the progression of fibrosis in patients at risk. Also preferably, the application is intended to reduce the extent of established fibrosis.

Preferably the application additionally includes the introduction of one or more than one active agent suitable for the treatment of fibrosis of the aorta.

In accordance with the fourth aspect of the invention proposed the use of vasoactive putting PE the Chida (VIP) (SEQ ID NO: 1) or one or more than one functional fragment VIP, selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, in the manufacture of medicaments for prophylactic or therapeutic treatment of fibrosis of the aorta.

The term "prevention" as used in the context of the present invention encompasses, inter alia, the treatment used to prevent or slow the development of fibrosis of the aorta at risk. A high percentage of patients, which can be scheduled preventive treatment, may have signs of fibrosis aortic or cardiac disease.

In accordance with the fifth aspect of the invention, a method for reducing the formation of collagen or increased destruction of collagen in the aorta of the patient, wherein the patient is administered pharmaceutically effective amount of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16.

If in the context it is explicitly stated otherwise in the description and the claims the word "contain", "containing" and such be interpreted in a broad sense, as the inverse of the exclusive or exhaustive sense; that is, in the sense of "including, but not limited to it."

A brief description of graphic materials

Fig.1: Fibrosis of the aorta in rats 4 weeks after injection of control solvent or peptide at a concentration of 5 pmol/kg/min

In Fig.2: shows the effect of four weeks of treatment VIP and various VIP fragments at a concentration of 5 pmol/kg/min in rats SHR to fibrosis within the aortic wall. *p<0,005, **p<0,0005 compared to controls.

In Fig.3: shows the effect of four weeks of treatment in various parts of the VIP at a concentration of 5 pmol/kg/min in SHR on fibrosis in the wall of the aorta. *p<of 0.025, **p<0,01, ***p<0.005 and****p<0,001 compared with the control infusion.

In Fig.4: shows the effect of four weeks of treatment in various parts of the VIP at a concentration of 5 pmol/kg/min in SHR on fibrosis in the wall of the aorta.

Description of the preferred embodiments

Presently discovered that the molecule VIP entirely valid for the purposes of prevention, reduction or reversal of fibrosis of the aorta. In addition, from the viewpoint of the conventional in the art of opinions, suddenly discovered that fragments of VIP, lost amino acids and motifs, which are considered to be important for their functioning, however, are effective therapeutic agents that reversiruyut or delay the manifestation of fibrosis aortic or prevent the manifestation of fibrosis in a patient, which is the risk of developing heart disease. Especially effective VIP fragments can be selected from VIP (16-24), VIP (16-28), VIP (6-10), VIP (6-12), VIP (6-16), VIP (6-20), VIP (6-24) and VIP (6-28), but they are not limited to.

The use of pharmaceutical compositions according to the invention in the treatment of fibrosis of the aorta represents a new class of therapeutic agents for these conditions. Currently there is no treatment of fibrosis of the aorta. Not wishing to be bound to any particular mechanism of action, suggest that the pharmaceutical compositions according to the invention can be designed virtually all of the currently known promoters of fibrosis of the aorta.

On the basis of these studies, but not wishing to be bound by theory, admitted that VIP or VIP fragments act as master regulators to prevent the development of fibrosis and that the depletion of VIP can free synthesis of a large number profibrotic mediators, thereby causing damage to the aorta. It is believed that the VIP fragments of the present invention can act in much the same way as native VIP, but more suitable for therapeutic applications due to the small size and, consequently, improve the stability and the ease of obtaining.

It should be understood that the present invention also covers some analogues of VIP fragments, which are based on stable replacement of one or more than one aminoxy the lots in the VIP fragments of amino acids, which do not alter the biological activity of fragments of VIP. Such substitutions are well known to experts in the art and do not require more than a simple method of trial and error, using well-known methods. Therefore, assume that used in the context of the present invention, the term "fragment VIP" covers such analogs.

All sequences related to VIP and the fragments are of human origin, but due to the very high level of conservative amino acids, VIP and its fragments, isolated from other mammalian species are also considered and covered by the present invention. The present invention also encompasses pharmaceutical compositions that include VIP and/or active fragments of VIP. Such compositions may include any type of dosage forms such as tablets, capsules, powders, liquid compositions, forms with delayed or prolonged release, plasters, medicated powders for inhalation through the nose, nasal sprays, etc., the Composition may optionally include other ingredients, such as dyes, preservatives, buffers and antioxidants. The physical form and the content of the considered pharmaceutical compositions corresponds to the traditional drugs that may be manufactured by experts in the field of formats whitesky compositions based on well-established principles and compositions described, for example, in Remington: The Science and Practice of Pharmacy, 19thEdition, 1995; British Pharmacopoeia 2000 and similar textbooks and manuals compositions. The compositions of the present invention can also include other active agents useful in the treatment of fibrosis of the aorta.

The method and frequency of administration of compositions of the present invention will depend on the requirements of the treatment and the nature of the input molecules. Thus, drugs can be made accordingly for intravenous, intramuscular or subcutaneous injection. VIP and/or fragments of VIP can also be suitable for administration through mucous membranes, such as oral, sublingual, nasal, etc., These parameters are easily set the specialists in this field of technology.

It is shown that the pharmaceutical compositions of the present invention are effective for preventing or slowing the progression of fibrosis of the aorta, as well as to reduce the degree (reversal) of established fibrosis and, thus, important for therapeutic applications. Compositions of the present invention, therefore, suitable for prophylactic and therapeutic treatment of fibrosis of the aorta. This result is important in relation to limits and severity of conditions that can be treated by the compositions of the present invention.

The compositions of the present invention can be is to use prophylactically in patients at risk of developing fibrosis of the aorta. Examples of patients at risk are those who see related conditions such as atherosclerosis, hypertension, chronic renal insufficiency, chronic intoxication with vitamin D, vasculitis, diabetes mellitus, hypothyroidism, hyperlipidemia, isolated systolic hypertension, stroke, myocardial infarction, end-stage renal failure, aortic aneurysm, etc.,

By storing the content of a VIP in the aorta in patients with fibrosis of the aortic or having a risk of its development in the application of the compositions of the present invention can be achieved considerable therapeutic advantages, including the reduction of fibrosis, lower level of education or activity profibrotic mediators, slow the progression of fibrosis, reduction in collagen formation or increased degradation of collagen in the aorta.

Hereinafter the invention will be described in more detail with reference to not limit the invention to the examples.

Experimental part

All the basic methods are described in detail in PCT/AU2005/000835, included here by reference.

Example 1 - Amino acid sequence of VIP and VIP fragments.

SEQ ID NO: 1: VIP(1-28) - His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn

SEQ ID NO: 2: VIP(4-12) - Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg

SEQ ID NO: 3: VIP (4-16) - Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-ArgLys-GIn

SEQ ID NO: 4: VIP (4-10) - Ala-Val-Phe-Thr-Asp-Asn-Tyr SEQ ID NO; 5: VIP (4-20) - Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys

SEQ ID NO: 6: VIP (4-24) - Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn

SEQ ID NO: 7: VIP (10-28) - Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn

SEQ ID NO: 8: VIP (16-20) - GIn-Met-Ala-Val-Lys

SEQ ID NO: 9: VIP (16-24) - GIn-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn

SEQ ID NO: 10: VIP (16-28) - GIn-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn

SEQ ID NO: 11: VIP (6-10) - Phe-Thr-Asp-Asn-Tyr

SEQ ID NO: 12: VIP (6-12) - Phe-Thr-Asp-Asn-Tyr-Thc-Arg

SEQ ID NO: 13: VIP (6-16) - Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-GIn

SEQ ID NO: 14: VIP (6-20) - Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys

SEQ ID NO: 15: VIP (6-24) - Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn

SEQ ID NO: 16: VIP (6-28) - Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-lle-Leu-Asn

Example 2 - the Effect of introducing a fragment VIP fibrosis aortic aneurysm in a rat model of fibrosis.

Used two animal models of fibrosis of the aorta (the animals were obtained from the Australian Animal Resources, Perth, Western Australia, Australia)

1) Male rats of the SHR, which is 2.2% salt diet,

2) Males KpbicWKY, which is 4.4% salt diet.

In each model rats randomized by VIP(1-28), VIP(4-12), VIP(4-16), VIP (4-10), VIP (4-20), VIP (4-24), VIP (10-28), VIP (16-20), VIP (16-24), VIP (16-28), VIP (6-10), VIP (6-12), VIP (6-16), VIP (6-20), VIP (6-24), and VIP (6-28). All the peptides obtained or synthesized using Auspep, Australia. Fragments of VIP was dissolved in the solution Hartman for further research introduction.

Since the age of 12 weeks, rats acclimatized to the tail cuff to measure the rhenium blood pressure and taught them within 2 weeks. Then they were subjected to rapid application of osmotic minipump (Alzet), which is designed to deliver only the diluent (solution Hartman, (Baxter Health Care Corporartion)-(control) or VIP, VIP fragments in a dose of 5 pmol/kg/min intravenously.

The infusion was continued for 4 weeks, during which rats were weighed and measured their blood pressure twice a week. At the end of the four week period of infusion rats were subjected to anesthesia, and the aorta was removed.

After fixation in buffered formalin aorta was dipped in wax, cut and stained with hematoxylin and eosin or trichrome Masson (Lomb Scientific).

For the quantitative assessment of fibrosis aortic twenty fields of each aorta aziraphale, and the amount of fibrosis in each was determined as the percentage of surface area using the software Image-Pro Plus V5.0. And then determined the average value for each rat and, consequently, for each infusion group.

In Fig.1-4 shows a decrease in fibrosis of the aorta, which occurred as a result of infusion for 4 weeks VIP and various fragments of VIP SHR rats, which is 2.2% salt diet.

The importance of the present invention to health will be immediately obvious to a person skilled in the art after reading this description of the invention. The pharmaceutical preparations according to the invention, which is s act to prevent progression, underlying damage (fibrosis), or even reverse fibrosis, have the ability to prevent the escalation of moderate disease severe, and, therefore, significantly reduce the burden of medical care. Total size of certain fragments of VIP and their activity makes them ideally suitable as targets for drug development.

You should take into account that discusses other embodiments and variations of the compositions, methods, and applications of the invention in accordance with the concept and scope of the described invention, and that they are included in the scope of the invention.

1. A method of prophylactic or therapeutic treatment of fibrosis aorta of the subject, including the introduction of the subject composition containing a pharmaceutically effective amount of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16.

2. The method according to p. 1 wherein the treatment prevents or slows the development of fibrosis in the subject.

3. The method according to p. 2, where the treatment prevents or slows the progression of established fibrosis aortic or reduces the degree of established fibrosis.

4. The method according to p. 1, further comprising centuries the definition of one or more than one other active agent, useful in the treatment of fibrosis of the aorta.

5. The method according to p. 1, in which VIP or one or more than one functional fragment VIP introduce a method selected from intravenous, intramuscular or subcutaneous injection, oral, sublingual, or intranasal.

6. The method according to p. 1, in which VIP or one or more than one functional fragment VIP is administered in the dosage form selected from tablets, capsules, powders, liquid compositions, forms with delayed or prolonged release, patches, medicinal powders for inhalation through the nose, nasal sprays and the like.

7. Vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16, for use in the prophylactic or therapeutic treatment of fibrosis of the aorta.

8. The use of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16, in the manufacture of drugs for the prophylactic or therapeutic treatment of fibrosis of the aorta.

9. The method according to p. 1, where the treatment is s reduces the formation of collagen or enhances the breakdown of collagen in the aorta.

10. Composition for prophylactic or therapeutic treatment of fibrosis of the aorta containing a pharmaceutically effective amount of vasoactive putting peptide (VIP) (SEQ ID NO: 1) or one or more than one functional VIP fragment selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15 or SEQ ID NO: 16.



 

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13 cl, 13 dwg, 17 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I) , where ring A is cycloalkane ring with number of members from 3 to 7, benzene ring or monocyclic 5-member or 6-member aromatic heterocyclic ring, containing 1 heteromember of ring, selected from the group, containing N and S, and benzene and heterocyclic rings can optionally have one or two similar or different substituents, selected from the group, containing halogen, HO-, R1-O-, H2N-C(O)- and NC-; Y is selected from the group, containing S, C(R12)=C(R13) and C(R15)=N; Z is selected from the group, containing C(R16); R1, R30, R33, R35, R54 and R55 independently on each other group R1, R30, R33, R35, R54 and R55 are selected from the group, containing (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(C1-C4)-alkyl-, and all of them can optionally have one or more similar or different substituents R70; R3 and R5 represent hydrogen; R4 and R6 are selected independently on each other, from the group, containing hydrogen and , (C1-C4)-alkyl; R12, R13, R15 and R16 are selected independently on each other, from the group, containing hydrogen, halogen and O2N-; R20 is selected from the group, containing hydrogen and (C1-C4)-alkyl; one of the groups R21 and R22 is group of formula II: R24-R23-, and the other of groups R21 and R22 is selected from the group, containing hydrogen, halogen, R30, HO-, R30-O-, R30-S(O)m-, H2N-, R30-NH-, R30-N(R30)-, R30-C(O)- and NC-; R23 is chain, containing from 1 to 5 chain members of which 0 or 1 chain member is heteromember of chain, selected from the group, containing N(R25), O, S, with other chain members being similar or different groups C(R26)(R26), where two adjacent groups can be bound to each other by double bond; R24 is selected from the group, containing hydrogen, R31, R31-O-, R31-NH-, R31-N(R31)-, R31-C(O)-NH-, HO-C(O)- and monocyclic, bicyclic or tricyclic ring with number of members from 5 to 10, which is saturated or non-saturated and contains 0, 1, 2 or 3 similar or different ring heteromembers, selected from the group, containing N, N(R32), O, S, and ring can optionally have on ring carbon atoms one or 2-3 similar or different substituents, selected from the group, containing halogen, R33, R33-O-, R33-S(O)m-, R33-C(O)-NH-, R33-S(O)2-NH-, R33-C(O)-, HO-C(O)-, H2N-C(O)-, R33-NH-C(O)-, R33-N(R33)-S(O)2-, NC-, oxo, phenyl and Het; on condition that total number of C, N, O and S atoms, present in two groups R23 and R24, constitutes not less than 5; R25 is selected from the group, containing hydrogen and (C1-C4)-alkyl; R26, independently on each other group R26, is selected from the group, containing hydrogen, fluorine, (C1-C4)-alkyl and HO-, or two groups R26, together with included into them chain members, form monocyclic ring with number of members 4, which is saturated and contains 1 ring heteromember, selected from the group, containing O; R31 is selected from the group, containing (C1-C6)-alkyl, which can optionally have one substituent R70; R32 is selected independently on each other, from the group, containing hydrogen, R35 and phenyl; R50 is selected from the group, containing R51-O- and R52-N(R53)-; R51 is selected from the group, containing hydrogen and R54; R52 is selected from the group, containing hydrogen; R53 is selected from the group, containing hydrogen; R70 is selected from the group, containing HO-, R71-O-, H2N-, R71-NH-, R71-N(R71)-, R71-C(O)-NH-, HO-C(O)-, H2N-C(O)- and phenyl; R71, independently on each other group R71, is selected from the group, containing (C1-C4)-alkyl; Het, independently on each other group Het, is monocyclic heterocyclic ring with number of members 5, which contains 1 or 2 similar or different ring heteromembers, selected from the group, containing N and S, and ring is saturated or non-saturated and optionally substituted with one or more similar or different substituents, selected from the group, containing (C1-C4)-alkyl; m, independently on each other number m, is integer number, selected from the group, containing 0, 1 and 2; phenyl, independently on each other phenyl group, can optionally have one or more similar or different substituents, selected from the group, containing halogen and (C1-C4)-alkyl.

EFFECT: invention also relates to method of obtaining compound of formula (I) and its application for manufacturing pharmaceutical for inhibiting receptor Edg-2.

17 cl, 14 tbl, 362 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely to a formulation for oral transmucosal administration which contains a lipid-lowering active substance specified in statins, fibrates or ezetimibe; an aqueous-alcohol solution consisting of water and 30° to 70° ethanol, wherein the above active substance is found in a stable and completely dissolved state with the pH value of the formulation falling within the range of 5.0 to 8.0. The invention also refers to a method for preparing the above formulation and using it for treating hyperlipidemia.

EFFECT: invention provides better efficacy for lower doses of the active substances (statins, fibrates and ezetimibe); their immediate bioavailability for hepatocytes and considerably reduced production of harmful metabolites that stands for eliminating the main side effects of these agents.

11 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biochemistry and is intended for treatment or prevention of undesirable immune response. Claimed is novel soluble polypeptide CD83 (sCD83), containing SEQ ID NO:7, in which amino acid residues 12, 20, 92 and 114 represent cysteine, amino acid in position 85 represents serine and one or several of amino acids 1, 2, 3, 4 and 130 can be absent. Also claimed is nucleic acid, coding said sCD83, and application of said polypeptide in methods of treatment or prevention of transplant rejection or autoimmune diseases, such as type I diabetes, multiple sclerosis, Crohn's disease and ulcerative colitis.

EFFECT: invention makes it possible to increase stability and biological activity of sCD83 preparations.

15 cl, 39 dwg, 9 tbl, 10 ex

FIELD: metallurgy.

SUBSTANCE: invention relates to casein succinylate of iron (III) wherein iron content varies from 4.5 wt % to 7 wt %, water solubility exceeds 92% while phosphorus-to-nitrogen ratio exceeds 5 wt %.

EFFECT: additionally, invention relates to production of iron (III) and to pharmaceutical composition containing casein succinylate of iron (III).

17 cl, 4 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: group relates to peptides or polypeptides inducing the anti-alpha-synuclein antibody production in vivo for producing medicaments for preventing and/or treating synucleinopathies.

EFFECT: producing the peptides or polypeptides, which induce the antibodies responsible for the removal of the alpha-synuclein involved in the production of alpha-synuclein aggregates, the Lewy bodies, or for the dissolution of alpha-synuclein aggregates, the Lewy bodies in the individual suffering from synucleinopathies.

22 cl, 3 ex, 5 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to biotechnology, and concerns a DLK1-Fc fused protein and using it for the metastases inhibition, a polynucleotide coding such a protein, an expression vector containing the polynucleotide, a host cell producing the above fused protein, a method for producing the fused protein by culturing the above host cell, a composition containing the above fused protein, and a method for the metastases inhibition. The characterised fused protein contains a DLK1 extracellular soluble domain consisting of the amino acid sequence SEQ ID NO:4 and Fc domain of a human antibody.

EFFECT: group of inventions can be used for preparing a therapeutic agent for reduction of cancer cell migration and the metastases inhibition.

11 cl, 36 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, namely to a biologically active complex for organogenesis. The biologically active complex for organogenesis, is characterised by the fact, that a three-dimensional multi-component structure is organised by a three dimensional layer-by-layer replication of a native tissue of a human or animal structure, for the regeneration of which it is applied, for this purpose biopsy of the recipient's tissue is carried out, and in case of the absence of the tissue section with a need of its substitution an amino-acid composition of a protein component is determined by confocal microscopy, scanning and transmission electronic microscopy, a supramolecular structure is identified by a protein analyser, the composition of glycoseaminoglycanes and lipids is determined by the method of atomic-absorption analysis, then all basic protein components of the complex are synthesised by an autosynthesiser of proteins, glycoseaminoglycanes and lipids are selected qualitatively and quantitatively in ratios, maximally close to the ones obtained in biopsy analysis, then all the components are applied on a polymer substrate layer-by-layer, with the formation due to aggregation of the structure, similar to the recipient's own tissue, stem allogenic or autologous cells, covered by the following layer of proteins, lipids and glycoseaminoglycanes, are placed on each layer, the obtained complex is incubated and transplanted, closing the defect of the recipient's tissue.

EFFECT: complex described above makes it possible to reduce the period of rehabilitation due to the absence of a tissue, cellular and immune response of the recipient and, accordingly, fibrous changes in the area of the complex implantation.

10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, namely to leukolectins, and can be used in medicine. What is prepared is the polypeptide leukolectin characterised by SEQ ID NO:1-8. The recombinant preparation is ensured by using a nucleic acid coding it and integrated into an expression vector which is used to transform a host cell. Testing absence-presence or determining an amount of the polypeptide leukolectin are ensured by using an antibody or an antigen-binding fragment of a variable region of the above antibody which is specifically bound to the polypeptide leukolectin. The polypeptide leukolectin or the nucleic acid coding it are used as ingredients of a pharmaceutical composition in therapy of pathological disorders of skin and mucous membranes.

EFFECT: invention enables treating or preventing autoimmune disorders of skin, inflammatory diseases of skin or mucous membrane, or injured skin in an animal effectively.

16 cl, 19 dwg, 3 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical antiangiogenic composition for treating eye diseases contains an active substance that is a fragment of one of recombinant polypeptides: endostatin fragment with an amino acid sequence from 1 to 49 or tumstatin fragment with an amino acid sequence from 69 to 95 or pigment epithelium-derived factor (PEDF) fragment with an amino acid sequence from 44 to 77 having stabilising ProGlyPro cluster on C-terminal, and a pharmaceutically acceptable carrier. The active substance and pharmaceutically acceptable carrier are found in the following proportions, wt %: active substance - 3.9×10-7 to 53×10-7 and pharmaceutically acceptable carrier - up to 100 wt %.

EFFECT: using this composition provides the antiangiogenic effect mediated by various biological targets at different stages of angiogenesis.

1 dwg, 3 tbl, 11 ex

FIELD: food industry.

SUBSTANCE: inventions group relates to food industry. The nutritive composition for improvement of the immune system with a mammal, preferably, with the human includes the following components: (a) at least 18 en% of protein material; (b) at least 12 wt % of leucine of the total quantity of protein material; (c) lipid fraction including at least one ω-3 polyunsaturated fatty acid chosen from the group consisting of eicosapentaenoic acid, docosahexaenoic acid, eicosatetraenoic acid and docosapentaenoic acid; (d) immunomodulator.

EFFECT: inventions group ensures intensification of protective immune response to an exogenous pathogene or autologous trigger such as neoplastic cells as well as improved humoral immunity or their combination.

17 cl, 4 dwg, 6 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and can be used for treatment of Crohn's disease, ulcerous colitis and type 1 diabetes mellitus. For this purpose applied is APL peptide or its analogues, obtained from a human heat shock protein with a size of 60 kDa (hps60) in order to obtain a pharmaceutical composition. Also claimed are the pharmaceutical composition and the application of a medication for induction of apoptosis of pathogenic clones of T-cells in patients with inflammatory intestinal disease or type 1 diabetes.

EFFECT: group of inventions possesses an immunomodulating action and makes it possible to regulate mechanisms of the peripheral tolerance in gastrointestinal tract.

10 cl, 6 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: method involves retrobulbar administration of dexamethasone, intramuscular administration of cerebrolysin and proserine, intravenous administration of nootropil. The preparations are introduced for 10 days. Administration further is followed by a percutaneous transcranial pulse magnetic stimulation and an electric stimulation of the optic nerve once a day for 10 days. The magnetic stimulation is performed at the magnetic field strength 2 T, modulation frequency 1 Hz. The exposure covers four points in the projection of the optical nerve sequentially: eyes, temporal region, postaural region, inion - for 5 minutes on each point. The electric stimulation represents the exposure to negative train pulses a frequency of which is equal to a patient's pulse rate at an electrical characteristic not less than 10-15 mC per one session.

EFFECT: method prolongs the remission of optical neuritis in the patients suffering multiple sclerosis.

2 ex, 1 tbl

FIELD: medicine, pediatrics.

SUBSTANCE: the present innovation deals with treating motor-autonomic disorders in children associated with affected function of central nervous system. For this purpose one should puncture perineural areas in the region of the main nervous trunks with alfetin dissolved in cerebrolysine. Additionally, one should puncture in projection area of cervical and lumbar spinal thickenings and areas that correspond to segmentary innervation of organs with affected function and, also, in scalp areas depending upon the character of patient's disorders. The method suggested provides improved autonomic-trophic impact of nervous system.

EFFECT: higher efficiency of therapy.

2 ex

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