Colostrinin and its application

 

Application colostrinin as drugs in the treatment of chronic disorders of the Central nervous system, immune system, neurological, mental disorders, dementia, neurodegenerative diseases, Alzheimer's disease, motoneuron diseases, for the treatment of psychosis or neurosis, as a dietary Supplement. Farmcampsite contains colostrinin, dietary Supplement, nonapeptide. The invention allows to realize the specified destination. 12 s and 12 C. p. F.-ly, 6 PL. , 1 Il.

The present invention relates to colostrinin and its use as medicine.

Colostrum is a thick, yellowish fluid produced by the breast glands of mammals in the first few days after birth. After four or five days after birth, it is replaced by Mature milk. Compared with Mature milk produced breast, colostrum contains less sugar. However, colostrum is rich in lipids, proteins, mineral salts, vitamins and immunoglobulin. It also contains various free wandering cells, such as granular and stromal cells, neutrophils, monocytes/macrophages and lymphocytes, and includes faktoriya connection. In 1974, Janusz and others (FEBS Lett., 49, 276-279) was isolated from Ovine colostrum polypeptide enriched in Proline (Proline-rich polypeptide, PRP). The content of this article is not associated with the existing link. It was found that colostrum other mammals also contains similar PRP. Then PRP was named colostrinin and experimentally identified as a new class of cytokines.

Janusz and others in the "Proline-Rich Polypeptid (PRP)-Immunomodulatory Peptide from Ovin Colostrum" (Archivum Immunologiae et Therapiae Experimentalis, 1993, 41, 275-279) indicate that PRP from sheep colostrum has immunotropic activity in mice. However, in this document there is no indication that PRP may have some therapeutic effect on any other animal. Note that if the composition is a therapeutic activity against mice does not mean that it will have the same therapeutic effect on any other animal.

In the present invention discovered that colostrinin has a number of before unknown therapeutic properties. Found that mostly it has immunotropic and psychotropic action.

One of the objects of this invention is colostrinin for use as medicines. Calotren colostrinin especially useful as a drug for the treatment of the person.

Another object of this invention is the use of colostrinin for the manufacture of drugs for treatment of disorders of the Central nervous system or disorders of the immune system.

Primarily the object of this invention is colostrinin for use in the treatment of disorders of the Central nervous system, especially chronic disorders of the Central nervous system. These Central nervous system disorders that can be treated with colostrinin include neurological disorders and mental disorders.

As examples of neurological disorders that can be successfully treated with colostrinin include dementia, and disorders that cause dementia, such as neurodegenerative disorders. Neurodegenerative disorders include, for example, senile dementia and motoneurone disease; example motoneurone disease that can be treated with colostrinin is Parkinson's disease. It was found that colostrinin especially effective in the treatment of neurodegenerative disease known as Alzheimer's disease.

Examples of mental disorders that can be treated with the help of violations especially emotional disorders in psychiatric patients in a state of depression was found that the use of colostrinin gives the patient a sense of well being and helps to stabilize mood. Colostrinin can also be used as an aid in withdrawal symptoms in cases of drug addiction after a period of detoxification and for people that are dependent on stimulants.

Another object of the invention is colostrinin for use in the treatment of disorders of the immune system, especially in the treatment of chronic disorders. Found that colostrinin can be used in the treatment of diseases requiring immunomodulation. In particular colostrinin useful in the treatment of such disorders in non-rodent animals, including humans. Colostrinin useful in the treatment of various immunological and infectious diseases. For example, colostrinin can be used in the treatment of chronic diseases of bacterial or viral etiology and treatment of acquired immunological deficiency, which develops, for example, after chemotherapy or radiotherapy of tumors. The invention is particularly useful in the treatment of chronic is ironicheskim disorder is a disorder, which persists for a long period of time, usually at least during the week, usually at least a month and often, at least for 3 or 6 months.

The present invention relates also to the use of colostrinin to improve the development of the immune system in newborns. A further feature of the present invention is the use of colostrinin for the correction of immunodeficiency in children. This application colostrinin especially useful for infants and children who did not receive colostrum. This applies, for example, for infants and children who do not receive breast feeding, artificial feeding, which receive such babies and children, contains no colostrinin.

Another object of the invention is the use of colostrinin as dietary supplements. Especially useful colostrinin as dietary supplements for infants and young children with the purpose of correcting the insufficient development of their immune system. As mentioned above, this deficit in development of the immune system may occur in infants and children who did not receive breast-feeding after birth. Colostrinin can also be used as dietic is a chronic disease. Another object of the invention is a dietary Supplement containing oral composition colostrinin in combination with a pharmacologically acceptable carrier. Dietary Supplement can be performed in liquid or solid form; it can also be in the form of tablets.

In accordance with the present invention, colostrinin may be administered prophylactically to prevent disorders of the Central nervous system and the immune system.

Used in the present invention colostrinin can be as sheep and NeoVision colostrinin. Neowiki colostrinin can be isolated from colostrum, for example, humans, cows, horses, goats, pigs, yaks, llamas and donkeys. Usually it is contained in the colostrum of these animals in the first 1-4 days after birth.

Used herein, the term "colostrinin" means a polypeptide obtained in its natural form from mammalian colostrum. Colostrinin, sometimes known as "colostrinin", has the following properties: (I) a molecular weight of 16,000 up to 26,000 daltons; (II) it is a dimer or trimer of subunits, each of which has a molecular weight of from 5,000 to 10,000 daltons, mainly 6000 daltons; (III) it contains a Proline, and the number of PR is alaysia its subunits are non-polar.

The molecular weight can be determined by electrophoresis in the presence of sodium dodecyl sulfate; the presence of a dimer or trimer can be shown by using the same method. Electrophoresis in restored or unrestored condition shows that the relations between the subunits are non-covalent. The presence of Proline can be installed using conventional amino acid analysis. Polarnet can be demonstrated by chromatography in non-polar terms.

Used in the present invention colostrinin can be sheep or NeoVision colostrinin. Sheep colostrinin has a molecular weight of about 18,000 daltons, consists of three ecovalence linked subunits having a molecular weight of about 6000 daltons each, and contains about 22 wt.% Proline. Amino acid composition consists of the following number of residues per subunit: lysine, 2 - histidine - 1, arginine - 0, aspartic acid, 2 - threonine - 4, serine - 3, glutamic acid - 6, Proline - 11, glycine, 2 - alanine - 0, valine - 5, methionine, 2 - isoleucine - 2, leucine - 6, tyrosine - 1, phenylalanine - 3 and cysteine - 0.

As mentioned above, natural colostrinin derived from mammalian colostrum. From colostrum mammals colostrinin you can select the Phnom farm animals, using column chromatography, and other biochemical methods, and it can be obtained using genetic engineering.

Mainly colostrinin get from colostrum mammals, using the following stages: (I) removal of lipids, for example, by centrifugation; (II) the removal of proteins, such as casein, for example, a decrease in pH; (III) the Department colostrinin associated with immunoglobulin, for example, by: (a) processing of serum, obtained after removal of lipids and proteins, using ion-exchange chromatography and (b) elution salt phosphate buffer and collect fractions containing colostrinin associated with immunoglobulin, for example, sheep IgG2; (IV) the Department colostrinin from the immunoglobulin, for example, gel chromatography and
(V) further purification of colostrinin, mainly through:
(a) desalting the fraction with molecular weight below 30,000 daltons and
(b) injection of antibodies against immunoglobulins and subsequent removal of this class of proteins with obtaining the target product.

The above applies to natural colostrinin mammals, but the term colostrinin includes here and its analogs and fragments having essentially the same biological activity as Colo is Sovana, also includes biologically active polypeptides essentially the same composition as the natural colostrinin obtained synthetically.

Another object of the invention is also a method of treatment of disorders of the Central nervous system and the immune system using colostrinin. Disorders that can be successfully treated described in the present invention by the method described above. Mainly colostrinin appoint the patient for a first period in the amount of about 1 to 2 therapeutic doses daily, followed by a second period during which colostrinin not accept. The first period is usually about 2 to 4 weeks, preferably for about 3 weeks; and the second period is usually about 2 to 5 weeks, mostly about 4 weeks. Typically, this cycle is repeated once, but it is advisable to do it more than once.

Used in the present invention, therapeutic dose is usually from 25 to 1000 μg colostrinin, preferably from 50 to 100 mcg.

Colostrinin may be administered in any pharmaceutical form. For example, it can be oral, rectal or parenteral purpose. It is more preferable to assign to the Noah cavity, through the digestive tract or through any mucous surface. Oral formulations may be suitable for swallowing, but it is preferable to perform them in a format suitable for dissolving in the saliva, followed by absorption through the mucous membrane of the oral nasal cavity. Oral formulations can be made in the form of tablets for oral administration, cakes (i.e. sweetened tablets, suitable for long-term presence in the mouth and resorption), sticky gel to be rubbed into the gums. Colostrinin can be shaped in the form of adhesive tape or pads to attach to the gums. Colostrinin can be made in a pharmaceutical form suitable for penetration through the mucous membranes of the urinary organs.

Obviously, colostrinin may be administered in the form of whole colostrum, but this is undesirable because the whole colostrum has an unpleasant taste and hard to store.

Suitable for use in the present invention colostrinin can be obtained from any mammal, including humans or animals, such as cows, horses, goats, pigs, yaks, sheep, llama and donkey, camels, etc.

Tests were conducted by colostrinin sheep and humans. Sheep colostomy is x animals in vivo and in vitro was found that colostrinin has immunotropic effect that follows from its ability to modulate the development, differentiation and maturation of thymocytes to active T-cells and the ability to stimulate or inhibit the immune response and to induce the expression of different surface markers in thymocytes. Intraperitoneal injection to mice colostrinin inhibits the development of hemolytic anemia in mice NZB, inhibits the growth of sarcoma 180 and protects mice exposed to gamma radiation from radiation sickness.

Toxicological studies on mice as in oral and parenteral application showed low toxicity - LD50 is about 1.25 g/kg of body weight. Colostrinin also has the ability to stimulate the growth, maturation and differentiation of immunologically active cells both in humans and in animals. In cultures of peripheral blood lymphocytes person (including culture of lymphocytes isolated from umbilical cord blood) colostrinin stimulates the production of cytokines, especially interferon-gamma (IFN-), tumor necrosis factor (TNF-), interleukins (such as IL-6 and IL-10) and various growth factors. The number is x analogues sheep colostrinin, with its biochemical properties, are present in human colostrum and colostrum of all mammals, especially large farm animals such as cows, horses, goats, pigs, yaks, sheep, llama and donkey, camels, etc., in the first 1-4 days after birth. Colostrinin enters the body of newborn animals sucking and swallowing of maternal colostrum. Due to low molecular weight colostrinin able to act on the mucous membrane of the oral nasal cavity through cellular receptors and even in the simple diffusion. Studies have shown that, as the mucosa and epithelium of the upper section of the digestive tract contain receptors some immunomodulators, colostrinin can be applied in the form of tablets and sublingual tablets for sucking tablets and capsules for swallowing, in the form of adhesive gels and adhesive patches to attach to the gums. Colostrinin can also be entered through the mucous membrane of the urinary organs.

Research to explain the biological activity induced by colostrinin, showed the presence of similar biological activity colostrinin person collected in women camping in obtaining colostrinin from colostrum farm animals, especially from sheep colostrum. It was found that colostrum secreted by the Breasts of the woman in the first 1-7 days after birth, contains polypeptide colostrinin, the amount of which depends on lactation and is optimal between 2-3 days, when its content is about 300 mg per liter of colostrum. This number colostrinin person coincides with the content in sheep colostrum. It was also shown that many biological properties colostrinin person similar, for example, the properties of his sheep equivalent. Also found that colostrinin derived from human colostrum, stimulates the lymphocytes present in the colostrum, and cord blood lymphocytes to release cytokines, including mainly interferon (IFN-), tumor necrosis factor TNF-, interleukins (IL-10 and IL-6) and other cytokines. These cytokines are involved in humoral and cellular immune response.

These biological properties colostrinin, both human and animal origin were determined by a known method described in the patent Poland (PL 170592 B1) and the European patent EP-B-0609225, pt: Immunology Testing.

Studies on human volunteers showed that after the appointment of the tablet is within about 3 weeks, no adverse outcomes were observed; on the other hand, this leads to a state of hyporeactivity to the induction of interferon IFN-and especially tumor necrosis factor TNF-. After stopping colostrinin state hyporeactivity returns to normal. The results are a consequence of the involvement of cytokines produced by Th-1 and Th-2 lymphocytes and cells-helper.

In addition, clinical studies have shown that colostrinin has immune modulating action and the action on the Central nervous system that can be used for prevention and therapy of the following diseases, for example, to prevent the emergence, development and remission of Alzheimer's disease, senile dementia of a different nature and for the treatment of chronic immunological and infectious diseases.

Instead colostrinin you can use the nonapeptide, denoted as NP, and having the following composition and amino acid sequence: Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro. NP can be obtained by enzymatic cleavage colostrinin with chymotrypsin, followed by separation through column chromatography, or by chemical is otherwise the same biological effect, as colostrinin, and particularly useful in the treatment of chronic disorders of the immune and Central nervous system described above, particularly Alzheimer's disease. NP can be used to treat any of the above diseases. It can also be used as dietary supplements. It can be recycled in the preparative form in the same way as colostrinin. NP useful for treatment of mammals, especially humans.

For better understanding, the following are examples, not limiting the present invention.

Example 1
In sheep colostrinin with a molecular weight of 18,000 daltons, built from three ecovalence related subunits with a molecular weight of 6000 daltons, each subunit had the following amino acid composition (table 1).

Colostrinin was obtained from sheep colostrum taken after birth, within 24 hours after the start of lactation. To remove fat and part of the casein material was centrifuged at 35000 g. Received the Ig fraction was passed through a column of DEAE-cellulose to separate immunoglobulin IgG2 associated in a complex with a polypeptide colostrinin, suirvey from the column colostrinin was separated from IgG2 using column chromatography on Sephadex G-which was applied on the column with Separate, conjugated with antibodies against sheep IgG2. The resulting preparation was absoluely using Sephadex G-25 and liofilizovane, and then kept at a temperature of +4oWith or -20oC.

Received colostrinin branded ColostrininTM(ColostrininTM).

Electrophoresis in polyacrylamide gel in the presence of sodium dodecyl sulfate (LTOs) gives an intense band corresponding to a molecular weight of 5800 daltons, and two weak bands corresponding to the molecular weight 12400 Dalton and 18200 Dalton.

Example 2
The nonapeptide NP having the following composition and amino acid sequence: Val-Glu-Sr-Tyr-Val-Pro-Leu-Phe-Pro, was obtained from colostrinin obtained in example 1.

50 mg colostrinin enzymatic digested with 10 units of proteolytic activity of the enzyme chymotrypsin for 20 hours at a temperature of 30oC. separation from the product of the cleavage is performed using one cycle chromatography on a column of Sephadex G-10. The resulting product lyophilizer and stored at a temperature of +4oWith or -20oC. Selected nonapeptide separated by determining the N-terminal amino acids.

Example 3
A single dose in the form of tablets for sucking is following the go designed for the treatment of early or late stages of dementia, including Alzheimer's disease, and the various stages of senile dementia, chronic bacterial and viral infections, requiring non-specific immune stimulation, and immune disorders, and acquired immune deficiency caused by various agents. In addition, they are used for emotional disorders, especially in States of depression in psychiatric patients, to improve overall health and stabilize mood and as an aid in withdrawal symptoms in cases of drug addiction after a period of detoxification and for people that are dependent on stimulants. Colostrinin can also be used to compensate for a lack of nutrition in infants and young children associated with artificial feeding.

Example 4
The composition of the drug in the form of a gel for application to mucosal membranes are presented in table 3.

To 1 ml of gel media used 0.0003 g polypeptide colostrinin (ColostriniTMand 0.0015 g of albumin. Thus obtained dosage unit form is intended primarily for the treatment of bacterial and viral infections of the mouth area and respiratory tract.

Example 5
Drug for VL is built in accordance with example 1.

Stabilizer: albumin human, free from impurities.

Media: sterile, pyrogen free and no (increasing body temperature) water.

1 ml ampoule uses 0.0003 g polypeptide CoiostrininTM, 0.0015 g of albumin and, as an antibacterial agent, about 0.001% merthiolate, i.e., sodium salt ethylmercurithiosalicylate acid. Received dosage unit form is primarily intended for treatment of bacterial and viral infections.

Example 6
Preparation for intramuscular, subcutaneous or intravenous injection
Active ingredient: NP, obtained in accordance with example II.

Stabilizer: albumin human, free from impurities.

Media: sterile, pyrogen free and no water.

1 ml ampoule uses 0.0003 g NP, 0.0015 g of albumin and, as an antibacterial agent, about 0.001% merthiolate, i.e., sodium salt ethylmercurithiosalicylate acid. Received dosage unit form is primarily intended for treatment of bacterial and viral infections.

Example 7
The induction of cytokines by polypeptide ColostrininTMin vitro in blood collected from healthy volunteers and patients who took treatment of drugs in the form set forth in example III, Khujand is in the ratio of 1: 10 in culture medium RPMI 1640. Incubation is carried out in the same culture medium without inductors (negative control) or in the presence of 1-100 μg/ml of the polypeptide ColostrininTMor in the presence of 2 μg/ml blood phytohemagglutinin (PHA) and 2 µg/ml of blood lipopolysaccharide (LPS) at a temperature of 37oC in an atmosphere of 5% carbon dioxide for 20 h Samples with a mixture of PHA and LPS represent a positive control, because they can stimulate a number of cytokines. The results obtained are presented in tables 4 and 5. They show that ColostrininTMat concentrations of 1-100 μg/ml stimulates the production of cytokines in a dose-dependent manner. In relation to negative control (no inductors) these results are statistically significant (p<0,0001). Patients with Alzheimer's disease have impaired ability to IFN production and, to a lesser extent, TNF.

Induction of cytokines under the effect of ColostrininTM(series a of 1993) from sheep in cultures of lymphocytes present in the whole blood of healthy volunteers or patients with Alzheimer's disease are presented in table 4.

A group of healthy volunteers (22 people) was heterogeneous in age (from 20 to 64 years). The group of patients with Alzheimer's disease (50 people) also src="https://img.russianpatents.com/chr/177.gif">SD) of the differences between the results of the control tests without inductors (no) and test results with ColostrininTMwere statistically significant (p<0,001).TM(series a of 1993) from sheep in experiments using whole blood of healthy volunteers and patients with various diseases is presented in table 5.

Example 8
Umbilical cord blood was obtained from the Department of obstetrics and gynecology at the Wroclaw regional hospital. The induction of cytokines under the effect of ColostrininTMin vitro in lymphocytes from umbilical cord blood collected after 4-6 h after birth, was carried out as follows.

Lymphocytes were isolated in the gradient Ficoll-Pak containing 5.7 g component Ficoll-400 and 9.0 g of diatrizoate sodium in 100 ml. of Selected cells suspended in culture medium RPMI-1640 at a density of 2106lymphocytes in 1 ml of culture medium. To a suspension of lymphocytes was added ColostrininTMat a concentration of 1-20 mg/ml or phytohemagglutinin at a concentration of 10 μg/ml of Culture were incubated 20 h at a temperature of 37oC. Then determined the levels of cytokines in the culture fluids of biological methods. Kini (IFN and TNF) like a classical inducer of IFN-- phytohemagglutinin.

Induction of cytokines under the effect of ColostrininTM(series a of 1996) the culture of cells isolated from umbilical cord blood (PBL), is presented in table 6.

Because cord blood is enriched in immature stem cells, which are able to reproduce hematopoietic cells and a variety of immunologically active cells, the results show that CoiostrininTMsignificantly speeds up the maturation of stem cells. The obtained results show the possibility of using CoiostrininTMfor the treatment of immunnodefitsitov of different types and to stimulate hematopoietic system, for example, after injuries, infections, chemotherapy and radiotherapy. When biomedical research substances of natural origin such activity is very rare.

Example 9
A method of treatment of disorders of the Central nervous system was studied in the group of patients-volunteers with Alzheimer's disease at the mild or moderate stage. A single dose was used in between meals in the form of tablets for sucking containing 0.00015 grams CoiostrininTMspecified in examples 1 and 3. First used one tablet daily for 3 weeks, then the treatment in the treatment of pre CoiostrininTMthere is a state of hyporeactivity or tolerance. This is a result of the inability to synthesize IFN and tumor necrosis factor TNF-. This phenomenon can quantify the effect of the active agent.

After you stop taking these medicines state of tolerance disappears spontaneously. The temporary state of tolerance to ColostrininTMis a result of the involvement of cytokines produced by Th1 - and Th2 dysbalance-lymphocytes and cells assistants, such as monocytes, macrophages, dendritic cells, endothelial cells and their products. As a result, patients with Alzheimer's disease improves contact and mood.

The drawing illustrates the appearance of the spontaneous disappearance of the state of hyporeactivity (partial tolerance) to the induction of IFN-γ (TNF-), the patient (J. M.) with Alzheimer's, which received ColostrininTMin tablets of 100 mg each day for three weeks. Then followed a 3-week break in treatment (during a break in tolerance induction was returning to normal). Every week he took blood samples for research stimulation INFcolostrinin (C is the result of the determination described in the previous sections.

The results of determination of the levels induced INF-showed that hyporeactivity appears in the first week of admission ColostrininTM(100 mg/tablet every other day) and reaches its maximum in the third week of admission. The state of tolerance induction INFspontaneously disappears during the 3-week break in treatment (i.e., at the sixth week from the start of treatment). Moreover, this diagram shows that the "specific" hyporeactivity against sheep CoiostrininTM(Avcal) is still at the sixth week, while hyporeactivity to PHA completely disappears.

Example 10
A method of treatment of disorders of the Central nervous system was studied in the group of patients-volunteers with early stages of Alzheimer's disease. Single doses were taken in between meals in the form of tablets for sucking containing 0.00015 grams NP obtained in example 2. First, take one tablet daily for 3 weeks, then stop treatment for 3 weeks and I repeat again, taking 2 tablets daily for 3 weeks. It was found that the treatment of NP induces a state of hyporeactivity or tolerance. This is the result of nesposoben the NGOs to measure the effect of the active agent.

After discontinuation of these drugs, the state of tolerance spontaneously disappears.

The temporary state of tolerance to NP is a result of the involvement of cytokines produced by Th1 - and Th2 dysbalance-lymphocytes and cells assistants, such as monocytes, macrophages, dendritic cells, endothelial cells and their products. As a result, patients with Alzheimer's disease improves contact and mood.


Claims

1. Application colostrinin for the manufacture of a medicinal product for the treatment of chronic disorders of the Central nervous system.

2. Application colostrinin for the manufacture of a medicinal product for the treatment of neurological disorders and/or mental disorders.

3. Application colostrinin for the manufacture of a medicinal product for the treatment of dementia and/or neurodegenerative diseases.

4. Application colostrinin for the manufacture of a medicine for the treatment of Alzheimer's disease.

5. Application colostrinin for the manufacture of a medicinal product for the treatment of motoneuron disease.

6. Application colostrinin for the manufacture of a medicinal product for the treatment of psychosis and inhibiting the development of Alzheimer's disease in humans.

8. The use according to any one of paragraphs.1-7, where the specified colostrinin is NeoVision colostrinin.

9. The use according to any one of paragraphs.1-8, where the specified drug is presented in the form of oral dosage forms in combination with a physiologically acceptable carrier.

10. The use according to any one of paragraphs.1-9, where specified colostrinin represented in the currently selected form.

11. Pharmaceutical composition comprising an oral dosage form containing a pre-selected number colostrinin in combination with a physiologically acceptable carrier.

12. The pharmaceutical composition according to p. 11, where colostrinin is NeoVision colostrinin.

13. The pharmaceutical composition according to paragraphs.11 or 12 in a form suitable for absorption through the mucous membrane of the oral/nasal cavity, and/or in a form suitable for absorption in the digestive tract.

14. The pharmaceutical composition according to paragraphs.11, 12 or 13 in the form of a tablet, pellet, gel, cloth or patch.

15. The pharmaceutical composition according to any one of paragraphs.11-14, ranging from 25 to 1000 μg colostrinin.

16. The pharmaceutical composition according to any one of paragraphs.11-15, comprising from 50 to 100 µg colostrinin.

17. Pharmaceutical is colostrinin in a highlighted form as dietary supplements.

19. Application under item 18 as a dietary Supplement for infants, small children, adults affected by chemotherapy and/or suffering from malnutrition or weight loss as a result of chronic disease.

20. Use PP.18 or 19, where the dietary Supplement is presented in solid or liquid form.

21. Dietary Supplement that includes oral dosage form containing colostrinin in a dedicated form, in combination with a physiologically acceptable carrier.

22. Nonapeptide with composition and amino acid sequence Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro, as the active ingredient for the manufacture of a medicinal product for the treatment of chronic disorders of the Central nervous system.

23. Nonapeptide on p. 22 as the active ingredient for the manufacture of a medicine for the treatment of Alzheimer's disease.

24. Pharmaceutical composition comprising an oral dosage form containing nonapeptide with composition and amino acid sequence Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro, in combination with a physiologically acceptable carrier.

 

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