Combination drug containing corticosteroid and exosomes

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical compositions for the combined therapy of arthropathies, except for rheumatoid arthritis, degenerative disk diseases, joint pains and/or autoimmune disease (particularly alopecia, neurodermitis). There are presented: a pharmaceutical composition for the above application containing a glucocorticoid, exosomes prepared of autologous blood and a cytokine antagonist ortokin or anakinra; a method for producing it involving the pharmaceutical composition containing the exosomes prepared of autologous blood and the cytokine antagonist ortokin or anakinra, and the pharmaceutical composition containing the glucocorticoid and the cytokine antagonist ortokin or anakinra, and versions of using the above substances for producing the pharmaceutical composition for the combined therapy.

EFFECT: technical effect consists in achieving the synergetic effect both on the exposure rate and remote outcomes of the specified diseases with reducing side effects of the glucocorticoid (cortisone).

33 cl, 1 dwg

 

The technical field TO WHICH the INVENTION RELATES

The present invention relates to pharmaceutical compositions intended for combination therapy containing a corticosteroid and exosomes. Combination therapy allows for the treatment of diseases such as osteoarthritis, arthritis and/or degenerative diseases of the spine, the treatment of which should preferably be local.

PRIOR art

In Germany, under the osteoarthritis can understand the wear and tear of the joints” to the degree above normal for age. He is accompanied by a loss of cartilage in the corresponding joint, causing pain and loss of function. The reasons are considered excessive load, congenital or traumatic disorders, such as displacement of a joint or bone deformity as a result of such bone diseases as osteoporosis. Also the reason can be a different disease, such as joint inflammation, or other conditions presenting with effusion caused by excessive load.

Overall, osteoarthritis changes may be subjected to any joints. In Germany the disease most often develops in the knee joints. Osteoarthritis is one of the main reasons of visiting the General practitioner. From osteoarthritis affects approximately 10% of the population of transated. If we also add osteoarthritis diseases of the small vertebral joints and degenerative diseases of the intervertebral discs, the total value will amount to about 15-20% of the population. The risk of developing osteoarthritis increases with age. This disease affects almost two-thirds of the population older than 65 years; however, not all individuals suffer from its symptoms.

At present, there are several methods of treating osteoarthritis. Known methods include both conservative (e.g., drug) therapy, and surgical operations up to a total joint replacement prosthesis. In order to avoid such extensive and irreversible interventions and to prolong the total replacement of a joint, as a rule, preferably with effective drugs.

However, many medical methods also have their drawbacks. On the one hand, this is due to the presence of side effects in the drugs themselves, but also partially limited.

For the treatment of osteoarthritis and rheumatoid arthritis often used the drug cortisone (also applied topically) and related corticosteroids. They systematically apply in the case of RA, and topically, by injection into the affected joint, in the case of osteoarthritis. However, it was found�about, the positive effects of the introduction of corticosteroids in osteoarthritis and in rheumatoid arthritis is significantly reduced after the first week. It has been clinically proven by studies using random sampling, and clinical practice. In the case of RA it was checked by continuous administration of cortisone to maintain a high systemic level of the drug, however this method is questionable because of the increased side effects and reduced therapeutic effect with repeated administration.

Exosomes are small vesicles coated with a lipid membrane in the intercellular space, for example, of the human body. They are created and secreted by cells by separation from the cellular plasma membrane. Normal data exosomes also contain proteins, borrowed from the parent cell. Methods of preparation and introduction of actcom described for example in patent application WO 2006/007529 A2. Exosomes are formed in vitro when activated, a prophylactically or therapeutically effective proteins, such as, for example, IL-1Ra, in the laboratory by incubation of the blood sample in a suitable vessel, such as, for example, a syringe. As a result, for example, ortokin contains exosomes. The formation of actcom can be increased by adding additives, stimulating the formation of actcom Concentration of actcom can be increased, for example, by centrifugation with high centrifugal force. The use of actcom in the treatment of rheumatoid arthritis is known in itself.

Also medicine that can be used in the treatment of osteoarthritis, is a protein of IL-1Ra, which is naturally produced in the body, or isoform, or a fragment thereof, which have similar activity. Interleukin-1 receptor antagonist (IL-1Ra) binds to the same receptors on the cell surface, and interleukin-1 (IL-1), but it does not activate the signaling cascade, normally caused by the binding of IL-1Ra. Binding to IL-1 receptor IL-1Ra inhibits the binding of IL-1, thus preventing the transmission of its signals, and consequently, the inflammatory effect of IL-1 on target cells.

In the prior art the treatment of patients autologous serum, enriched with IL-1Ra. IL-1Ra used in this way, also called orthokine. In contrast, recombinant fragment of IL-1Ra, anakinra, showed no results in the treatment of osteoarthritis compared to placebo treatment. Anakinra is isoforms of human interleukin-1 receptor antagonist, reduced to amino acids 26-177 and blocked at the ends of L-methionine, is the length of the sequence of 153 amino acids. Cooking is, for example, strains of Escherichia coli with and�using recombinant methods.

In light of the prior art the problem to be solved was the provision of medical treatment of osteoarthritis with greater efficiency and, in particular, showing a good efficiency over a long period of time. When this treatment is, preferably, should have a good efficiency, it is preferable efficiency over a long period of time, in arthritis, especially in rheumatoid arthritis.

Summary of the INVENTION

It has surprisingly been found that the efficiency, particularly efficiency over a long period of time, and the speed effects of corticosteroids, such as cortisone, osteoarthritis, arthritis and degenerative diseases of the spine can be significantly or synergistically increased by the additional introduction of actcom. Especially strongly this effect is manifested when the introduction of a therapeutic agent is exposed to treatment the joint. One of the surprising discoveries is, for example, that the use of corticosteroids in combination with ectosomal obtained, for example, in the syringe orthokine from a blood sample (e.g., a corticosteroid together with orthokine), in terms of speed manifestations of drug effect in osteoarthritis exceeds therapy without the use of the drug actcom. Quick to�tion of the medicinal effect is also observed in the case when exosomes are used as a complementary drug in the treatment of osteoarthritis (e.g., in the form of a corticosteroid together with the connection anakinra).

The combination of corticosteroids and aqsacom shows unexpectedly high effect in the treatment of rheumatoid arthritis with respect to both speed effects, and long-term results. Especially noticeable the effect was due to an unexpectedly powerful effect of the drug (due to various pathophysiological approaches) combined with a particularly favourable profile of side effects for the patient. The favorable profile of side effects is particularly important since prolonged administration of corticosteroids causes significant side effects such as metabolic disorders, osteoporosis and many others. However, the combination of actcom with corticosteroids, such as cortisone may reduce the negative side effects of corticosteroids (cortisone), which increases the effectiveness of treatment.

In spite of the evidence that for many patients it was shown that the combination of actcom with corticosteroids were given therapeutic effect that exceeds the sum of those of corticosteroids and aqsacom in a separate introduction, especially if not every agent of the two was therapeutically effective when administered separately.

Thus, the first�m aspect of this invention is to provide pharmaceutical compositions comprising a corticosteroid in conjunction with ectosomal in the presence or in the absence of a cytokine antagonist and/or growth factor.

The phrase “the absence of a cytokine antagonist” in the context of this invention means that the composition does not include a single cytokine antagonist. The same applies to the growth factor, subject to appropriate amendments.

Pharmaceutical composition according to the first aspect in each case includes a corticosteroid and exosomes. Further, there is a possibility of the presence or absence of a cytokine antagonist; it is also possible the presence or absence of growth factor.

The treatment may also be performed in two different pharmaceutical compositions, simultaneously or sequentially. In this regard, the invention in the second and third aspects provides a pharmaceutical composition comprising exosomes in the presence or in the absence of the antagonist of a cytokine and/or growth factor, designed for use in combination therapy together with a corticosteroid; the invention also provides a pharmaceutical composition comprising a corticosteroid in the presence or in the absence of a cytokine antagonist and/or growth factor, designed for use in combination therapy together with ectosomal.

In a fourth aspect the invention provides Pharma�quarter composition comprising a cytokine antagonist and/or growth factor, designed for use in combination therapy in combination with corticosteroid and ectosomal.

In a fifth aspect according to the invention provided with a kit containing (i) a pharmaceutical composition comprising exosomes in the presence or in the absence of a cytokine antagonist and/or growth factor, and (ii) a pharmaceutical composition comprising a corticosteroid in the presence or in the absence of a cytokine antagonist and/or growth factor.

Furthermore, the invention in the sixth aspect is directed to the use of actcom in the presence or in the absence of a cytokine antagonist and/or growth factor for the manufacture of pharmaceutical compositions intended for use in combination therapy in combination with a corticosteroid; and in the seventh aspect to the use of corticosteroid in the presence or in the absence of a cytokine antagonist and/or growth factor to obtain pharmaceutical compositions intended for use in combination therapy in combination with ectosomal.

Above in connection with aspects of the second, third, fourth, sixth and seventh combination therapy is preferably combined therapy in combination with an antagonist of a cytokine and/or growth factor, especially in cases where an antagonist of a cytokine �/or growth factor missing directly in the pharmaceutical composition.

In the eighth aspect, the present invention relates to a method of manufacturing a pharmaceutical composition comprising a corticosteroid and exosomes, comprising the following stages: providing a blood sample containing exosomes; preferably, the concentration of eksasol; and mixing with a corticosteroid.

Additional embodiments of the invention are mentioned in the following detailed description and the claims.

Description of the INVENTION

The invention is based on the unexpected discovery that the effectiveness of treatment with corticosteroids articular and spinal diseases such as osteoarthritis, arthritis and degenerative spine diseases, and autoimmune diseases, such as atopic dermatitis or alopecia baldness, can be greatly enhanced by the additional introduction of actcom. Thus, the present invention is directed to a comprehensive treatment of such diseases with corticosteroids in combination with ectosomal. The treatment may be carried out in the presence or in the absence of a cytokine antagonist and/or growth factor. The presence of a cytokine antagonist and/or growth factor, preferably.

Various drugs can be administered sequentially or simultaneously in the same dosage form or in different dosage forms. Pharmaceutical�e composition according to the invention comprising only one of the two agents (exosomes and a corticosteroid), and a set according to the invention can be introduced simultaneously; it is also possible sequential administration of actcom and corticosteroid. However, simultaneous administration is preferable, especially when using a single dosage form. Thus, according to the invention two pharmaceutical compositions of the kit may be mixed in the required proportions, and then can be administered to the patient in a dosage form. In the case of sequential introduction of actcom and corticosteroid certain drugs are preferably administered within a temporal interval of one week, preferably within 5 days, 3 days, one day or within 12 hours.

According to the invention in pharmaceutical compositions, including exosomes and/or a corticosteroid antagonist of a cytokine and/or growth factor can be present or absent. The presence of a cytokine antagonist and/or growth factor, preferably. This caused a clear enhancement of drug effects of corticosteroids in diseases of joints and spine, especially over a long period of time if additionally introduces a cytokine antagonist, such as ortokin (natural IL-1Ra) and anakinra (recombinant IL-1Ra);this is especially true with the direct introduction of therapeutic agents in a subject to treatment of the joint. Similar, unexpectedly good results from the combining of data from agents was observed in the treatment of autoimmune diseases; in this case, a particularly useful anti-inflammatory effect. Also, with the additional introduction of a cytokine antagonist significantly increases the efficiency of combined therapy with corticosteroids and ectosomal diseases of joints and spine such as osteoarthritis, arthritis and degenerative diseases of the spine. In the treatment of recombinant IL-1Ra anakinra, surprisingly, the medicinal effect is manifested only when combining this protein with corticosteroid. When using natural IL-1Ra orthokine especially noticeable efficiency increase is observed in inflammatory diseases. This fact is presumably due to the fact that cytokine antagonist has an anabolic effect and can neutralize or even reverse the existing negative catabolic effect of corticosteroid in the affected joints. Thus, in the treatment of, for example, osteoarthritis corticosteroids can regardless of cytokine antagonists, in accordance with another variant or additionally, may be combined with anabolic growth factors to achieve a similar effect. Overall, the cytokine antagonist may be replaced by a growth factor or �interrupted with a growth factor.

Pharmaceutical composition comprising a cytokine antagonist and/or growth factor, designed for use in combination therapy together with a corticosteroid and ectosomal according to the invention (according to the fourth aspect of the present invention), is intended for simultaneous administration and sequential administration of a cytokine antagonist and/or growth factor, aqsacom and corticosteroids. Preferably a one-time introduction, especially in the case of a single dosage form. For example, the cytokine antagonist and/or growth factor may be mixed in suitable proportions with corticosteroid and ectosomal, and then can be injected into a patient as a single dosage form. Alternatively, in case of simultaneous application, the cytokine antagonist and/or growth factor, exosomes and the corticosteroid can be administered sequentially, in any order; or one of these agents can be administered at a different time than the other two. In the case of sequential application of individual agents are preferably administered within a temporal interval of one week, preferably within 5 days, 3 days, 1 day or 12 hours.

In the case of other pharmaceutical compositions according to the invention, in the case of a set according to the invention, and when used according to Fig�the plants (first, second, third, fifth, sixth and seventh aspects of this invention) it is possible the presence or absence of a cytokine antagonist in the pharmaceutical composition. The presence of a cytokine antagonist preferably. Moreover, the combination therapy according to the invention preferred combination therapy together with a cytokine antagonist, in particular in those cases where an antagonist of a cytokine no (see above) in the pharmaceutical composition.

An antagonist of a cytokine used in accordance with the invention, may be any substance or any mixture of substances, reducing or inhibiting at least one, preferably all biological processes associated with one or more cytokines to the patient's body. The antagonistic effect can be invoked directly by the antagonist, or indirectly, e.g., by activating or inhibiting further signaling pathways also affect the biological activity of the cytokine. Preferably, the inhibition of the biological activity of the cytokine by preventing its interaction with one or more receptors to which it can contact. This effect may be achieved, for example, competitive binding of the antagonist with the corresponding(s) receptor(s), or by binding of the antagonist directly with citoc�nom. Preferably, the cytokine antagonist inhibited the effect of the cytokine IL-1.

The cytokine can be, for example, protein, peptide, nucleic acid, lipid or organic compound. The cytokine antagonist may also consist of a mixture of two or more antagonists of cytokine. In particular, the cytokine antagonist may be a natural peptide or protein, or recombinante obtained a peptide or protein. Moreover, the cytokine antagonist may be or include an antibody or antigen-binding fragment of the antibody; in particular, it can be an antibody or antibody fragment capable of binding with the appropriate cytokine or cytokine receptor. Examples of suitable cytokine antagonists are antagonists of interleukin, in particular, antagonists of IL-1 such as IL-1Ra; antagonists of tumor necrosis factor (TNF), in particular, an antagonist of TNF-α, such as an antibody against TNF-α; interferon antagonists and antagonists of the chemokine. In particular, preferred is a natural or recombinant protein of IL-1Ra, preferably IL-1Ra person. IL-1Ra preferably comprises or consists of the amino acid sequence of the isoform or homolog of IL-1Ra of human rights, according to SEQ ID NO: 1, 2, 3, 4 or 5; isoform equine IL-1Ra according to SEQ ID NO: 6 or 7; or isoforms of IL-1Ra dogs, according to SEQ ID NO: 8.

Also, according to every�the acquisition, fragments or derivatives of IL-1Ra can be used as a cytokine antagonist, provided that they can perform the required function, i.e. reducing or inhibiting one or more biological functions of IL-1. Fragments of IL-1Ra should preferably include at least 20 amino acids, and preferably at least 40, 60, 80 or at least 100 amino acids from the natural sequence of IL-1Ra. Preferred fragments are naturally secreted fragments of IL-1Ra. In one embodiment, the IL-1Ra contains amino acids 26-177 of IL-1Ra person, preferably amino acids 26-177 sequence according to SEQ ID NO:1. Derivatives of IL-1Ra is preferably homologous to the natural IL-1Ra and preferably have a homology or identity with the natural IL-1Ra level is at least 60%, more preferably at least 70%, 75%, 80%, 85%, 90%, 95%, and most preferably at least 98% in the area of at least 20 contiguous amino acids, preferably at least 40, 60, 80 or at least 100 contiguous amino acids; and more preferably along the entire length IL-1Ra. Especially preferred is the use of IL-1Ra, isolated from biological samples such as blood, also called ortokin, or a fragment of IL-1Ra-containing amino acids 26-177 from IL-1Ra) also called Anak�NRA. Getting orthokine described, among others, in patent applications WO 00/46249 A1 and WO 03/080122 A1. Anakinra and other antagonists of IL-1, which can be used in the present invention, are described, among others, in patent application EP 0343684 A1.

In the case of IL-1Ra from natural biological samples such as blood, for example, ortokin, the resulting solution of IL-1Ra predpochtitelno contains growth factors. Thus, according to the invention, the cytokine antagonist can also be present in combination with one or more growth factors, or be substituted by one or more growth factors. The growth factor according to the invention has an anabolic effect. Examples of suitable growth factors are TGF-β, IGF, BMP, HGF and VEGF. In addition, the composition may include analogs, derivatives and fragments of these growth factors, provided that they can perform the desired function, particularly the function of growth factor.

Corticosteroid used according to the invention, can be as the natural corticosteroid, and artificially produced. In particular, it can be a glucocorticoid, mineralcorticoid or androgen, where glucocorticoids are preferred. Can also be used a mixture of two or more corticosteroids. Examples of glucocorticoids are cortisone, hydrocortisone, prednisone, prednisolone, clopra�Nol, deflazacort, fluocortin, triamcinolone, dexamethasone, methylprednisolone, fluprednisolone, clocortolone, clobetasol, alclometasone, flumethasone, flupredniden, flurandrenolide, betamethasone, beclomethasone, fluokortolon, mometasone, fluticasone, halobetasol, fluocinolone, diflorasone, desoximetasone, fluocinonide, amcinonide, halcinonide, diflucortolone, clobetasol, paramethasone. Examples of mineralcorticoids are aldosterone, deoxycorticosterone, fludrocortisone; examples of androgens are dehydroepiandrosterone (DHEA) and estrogens. A corticosteroid may be used in the form of a free compound or as a salt, ester or prodrug. In the preferred embodiments as corticosteroid use triamcinolone, cortisone, hydrocortisone, prednisolone or prednisone.

According to the invention, exosomes in medicinal preparations containing exosomes, or in sets preferably be obtained by using the method containing the following steps: providing a blood sample containing exosomes; preferably, the concentration of actcom. Concentration is preferably carried out by centrifugation at at least 100,000 g, since such a high centrifugal force is especially suitable for concentration of actcom. This stage is preferable to spend at least 30mins, in particular, at least 60 minutes, as in this case, increasing the concentration maximum.

Stage providing a blood sample preferably should include the following stages: providing a blood sample taken from a patient; optional - add additives that increase the formation of eksasol; and incubation of the blood sample in the receptacle suitable for receiving actcom. Incubation tends to separate blood into its individual components. Vessels suitable for the preparation of actcom are, for example, syringes, test tubes, vacuum tubes, titration microplates, the container (bag) for blood components. As surfaces for contacting the blood sample in the blood vessels that are suitable for receiving actcom, it is preferable to use glass, plastics (such as polystyrene, polyvinyl chloride, polyethylene or polypropylene), corundum or quartz, and preferably, it consisted of one of these materials. Preferred additives that increase the surface area and added to produce actcom are beads, gels, fibers, fine powders, granules or particles of glass, plastic, corundum or quartz. As an additive that stimulates the formation of actcom, it is preferable to use IL-1Ra. Additive that stimulates the formation of actcom, preferably of dobavlyaty the number of 1-20 µg per milliliter of blood.

A necessary criterion applied to pharmaceutical compositions used in combination therapy together with ectosomal, according to the invention, it is preferable to obtain actcom from a blood sample. preferably, the exosomes to the patient was autologous or logicznymi. The following describes the preparation of actcom according to the present document. Above the stage centrifugation at at least 100,000 g (preferably at least 30 minutes, in particular at least 60 minutes), preferably in the treatment of diseases in which appropriate high concentration of eksasol; preferably for the treatment of rheumatoid arthritis. It should be particularly noted that the stage of centrifugation, usually carried out in cases where combination therapy involves exosomes obtained from a blood sample of the patient.

The above detailed description of the receiving actcom with the appropriate amendments can be applied to a method of manufacturing a pharmaceutical composition containing a corticosteroid and exosomes according to the invention, comprising the following stages: providing a blood sample containing exosomes; preferably, the concentration of actcom and mix with corticosteroid. Mixing can be performed by any of methods�s, known to the average expert in this field of technology.

The preferred embodiment of the pharmaceutical compositions according to the invention and/or kit according to the invention is intended for use in the treatment of lesions of the joints, such as osteoarthritis, arthritis, inflammation of the joints, inflammatory loss of cartilage, degenerative diseases of the spine, joint pain, and autoimmune diseases. Osteoarthritis is exposed to treatment may be caused by excessive workload, congenital or traumatic disorders, or may appear as a result of another disease, such as inflammation. Preferably be treated in a similar way such osteoarthritis as osteoarthritis in the active phase or inflammatory osteoarthritis. Pharmaceutical compositions according to the invention can be used for the treatment of osteoarthritis or arthritis of any joints, e.g. knee joint, hip joint, elbow joint, shoulder joint, vertebral joints, finger joints, cubital joint, the joints of the toes, the temporomandibular joint and the wrist joint. Arthritis exposed to treatment can be infectious-allergic arthritis, such as bacterial arthritis or infectious arthritis, such as rheumatoid arthritis, psoriatic arthritis or �tarifesi arthritis. Alternative pharmaceutical composition according to the invention and/or the kit according to the invention can be designed for use in diseases other than one or more of the above diseases (e.g., rheumatoid arthritis). Examples of degenerative diseases of the spine, subject to the treatment, there may be a herniated disc. Autoimmune diseases include, among others autoimmune diseases of the joints, such as ankylosing spondylitis, rheumatoid arthritis and systemic red lupus, and other autoimmune diseases, such as, including, neurodermatitis and focal alopecia.

Pharmaceutical compositions according to the invention and/or the kit according to the invention is preferably suitable for topical administration. Their topical administration preferably. Thus, the preferred embodiments are intended for injection, and more specifically, injections in the body region, in particular in the affected joint, the affected nerve root or into the affected intervertebral disc, or topically; for intra-articular injections; for local application. Pharmaceutical composition, therefore, is intended, in particular, for intra-articular and/or periarticular injection. Alternative pharmaceutical compositions according to the invention can be prepared DL� local administration, in particular, in the form of cream or gel; or for systemic administration, in particular oral, in the form of tablets, capsules or lozenges. Method of administration, among other things, depends on the disease being treated. The local osteoarthritis or degenerative diseases of the spine preferably topical administration according to the invention. In the preferred embodiments of the pharmaceutical compositions according to the invention and/or the kit according to the invention are exclusively designed or suitable for administration other than the system.

Pharmaceutical compositions according to the invention, it is appropriate to prepare for various forms of administration by methods well known to the average expert in the art. For example, a pharmaceutical composition suitable for injection, preferably has the form of a solution or dispersion; or it may also have a dry form, e.g. powder or lyophilizate intended for cultivation in a suitable solvent, such as water, prior to injection. Pharmaceutical compositions according to the invention contain exosomes and/or a corticosteroid in therapeutically effective amounts. Pharmaceutical compositions containing a corticosteroid, the corticosteroid is preferably contained in a concentration of 1-80 mg/dose, preferably 5-40 mg/dose. In pharmaceutical compositions, with�ergasia antagonist of a cytokine the cytokine antagonist is preferably contained in a concentration of 0.5-150 mg/dose, but it may be in much lower concentrations, such as 1 ng or more, for example, 1-1000 ng/dose. Low concentrations in doses can be used, especially in combination with growth factors and/or compounds with natural IL-1Ra, such as, for example, compounds with orthokine. Higher concentrations at doses preferably used, for example, when recombinante cooked cytokine antagonists, such as anakinra. Moreover, the pharmaceutical compositions according to the invention may also contain one or more carriers and/or one or more auxiliary substances.

The pharmaceutical compositions according to the invention can also be used to treat patients who have already undergone any treatment of the respective diseases, i.e., for example, osteoarthritis, arthritis and/or degenerative diseases of the spine; especially, if the treatment was not successful or symptoms of the disease are at least partially returned after initially successful treatment. In preferred embodiments these other methods of treatment are therapy ectosomal, but without corticosteroid therapy; or therapy with a corticosteroid, especially with the glucocorticoid, as described above, but without actcom.

Patients according to the invention could�t be people or animals, suffering from one of the illnesses described in this document. Thus, pharmaceutical compositions according to the invention may be suitable for the treatment of human and/or animal, such as, for example, dog, cat, horse, pig, goat or camel, or similar.

BRIEF DESCRIPTION of FIGURES

Fig.1A-1C show pictures of the feet of a patient with atopic dermatitis whose case is described below as case IX (Example 4).

Fig.1A shows dermatological changes on both feet immediately after treatment with ectosomal and triamcinolone.

Fig.1B shows the state of the right foot one week after treatment.

Fig.1C shows the state of the left foot a week after treatment.

EXAMPLES

The following describes the study of various cases of patients with complicated osteoarthritis. These patients were treated with a combined therapy comprising a cytokine antagonist (e.g., recombinant IL-1Ra or IL-1Ra, obtained from an autologous blood sample) and a corticosteroid.

Abbreviations:

ol - right

Le - left

BL - bilateral

VNV - internal rotation

VEVEY - external rotation

VAP - visual analog pain (0 to 10)

WOMACK - questionnaire patient in relation to osteoarthritis

CRP - C-reactive protein, a marker of inflammation, obnaruzhiv�in my blood

Hip - hip

Therapy orthokine and cortisone in osteoarthritis

Number of patients: N = 129

The average time between inspections: 3 months

The average reduction in pain: 71% (i.e., reduction in pain with 100% before treatment to 29% after treatment)

Amazingly quick manifestation of drug effect

1. Local application anakinra with cortisone and ectosomal

Case I: T., 56 years, female

Diagnosis: clinical radiology showed medial and retropatellar gonarthrosis Le, IV degree. Apparently was a planned total knee replacement.

Therapy: 3 injections of actcom in combination with anakinra and 10 mg of triamcinolone in the left knee (twice a week) in order to avoid surgery.

Treatment outcome: At the time of the 3rd injection reduced pain by 100%, a clear improvement of the function.

Surgery cancelled, the patient had no pain for 5 months after the end of therapy.

2. Local application anakinra with cortisone and orthokine

Case II: L, 57 years, male

Diagnosis: severe pain in the left shoulder for 6 months (GSA 8); later a prominent sleep disturbance. The patient barely slept the last 6 months, in this regard, there was poor health. Numerous cortisone injections in his left shoulder brought no results. A consultation with a surgeon. The decree�but the ability to avoid surgery. Radiological and clinical characteristics of partial rupture of the capsule of the shoulder joint and the subacromial Konstrukcija with the full rigidity of the left shoulder. The unpleasant sensation of the left hand with the weakening of the left palm and forearm, level 4.

Therapy: dorsal and lateral injection in the left shoulder. The syringe was injected 2 ml orthokine with 10 mg anakinra and 10 mg of triamcinolone. Therapy was conducted for 4 consecutive days.

Result of treatment: on the 2nd day of treatment the patient noted a powerful reduction in pain, with reduced pain 90%. VAP fell from 8 to 1, the shoulder became normal move. The patient was able to sleep at night for the first time in 6 months. This has led to a definite improvement in health. Therapy lasted up to 4 days. Until now there had been a steady marked improvement, as on day 2; inspection 6 months after therapy showed consistently good condition. Surgery was cancelled, mobility was restored, the patient again without problems can raise the suitcases and books over the shoulder.

Case III: F., 45 years, female

Diagnosis: complete immobility of the shoulder por approximately 8 months. All prior therapy were unsuccessful, it was planned surgical intervention. The patient would go through a different conservative treatment. Sleep at night was impossible for several weeks. On�inuasha shoulder pain on the left however, the main GSA right shoulder 9, with short-term strongest attacks to 10; this has led to a strong decline in overall health.

Therapy: Treatment of the right shoulder by a combination of introduced separately, different syringes, 2 ml orthokine and a mixture of 150 g anakinra and 5 mg of triamcinolone for 6 consecutive days.

Result of treatment: reduce pain by 85% since 5 days. Sleeping at night became possible after the 2nd procedure, which led to significant improvements in overall health. GSA at the first examination after the treatment, after 8 months, still showed a very good unmodified result; surgery was cancelled.

3. Exosomes, inkubirovaniya with IL-1Ra and triamcinolonum/prednisolone

Case IV: C., 25 years old, male

Diagnosis: severe juvenile rheumatoid arthritis since about 15 years.

Treatment with 25 mg Enbrel 2 times a week, 10 mg of methotrexate, 5 mg decortin and naproxen 2×1 a day. Massive synovitis and pain both hips, both shoulders. Abduction of both shoulders 60 degrees before treatment. According to laboratory tests the value of CRP: 5,35 (normal value: 0.5 mg); leukocytosis.

Therapy: Blood to obtain actcom was taken 6-ml syringe (syringe orthokine). Then incubation 24 h at 37 degrees, and before filling with the blood in the syringe were added 1 mg anakinra (IL-1Ra) and 2 mg prednisolo�and. After a few consecutive tsentrifugirovanie (up to 100,000 g), the mixture was introduced in the hips and shoulders of the patient.

Result of treatment: 3 days starts to decrease swelling of the joints. Clinical and chemical test after 9 days: decrease pain by 80%, TBC normal, no swelling. The value of CRP to 1.93. Also improvements in other affected joints, local injections which were not carried out. The General level of well-being significantly increased. During the inspection after 3 months the situation remains stable. GSA 9 before treatment, after the first week of treatment - VAP 3. The patient is very satisfied, can continue its work.

4. Injection actcom and more triamcinolone injection

Case V: M., 64 years, female

Severe, resistant to treatment of rheumatoid arthritis, despite basic therapy: prednisolone 15 mg daily, lantaren 20 mg weekly Humira every 2 weeks. Radiation senatobia wrists showed minimal effect, periarticular injection of triamcinolone in doses of 10 to 40 mg showed only a weak (20% reduction in pain after one week) effect on pain, and indicators of inflammation. At the time of granting ectosomal therapy - CRP 120 mg/l, although the above-described basic therapy, severe pain in the hands and both shoulders. Produced by the injection of eksasol (after incubation with IL-1Ra) and an additive in a total of 20 mg Tr�aminalon in PFS-5 BC and in both shoulders. Then clinically strong improvement (reduction in pain 80% after one week), which started after two days and continued for the next 3 months. Analysis of CRP after 3 months showed a CRP of 42.6 mg/l, basic therapy was not changed, so the effect can be explained by a combination of actcom with triamcinolonum. Large doses only of triamcinolone, as described above, have not yielded comparable effects.

Case VI: M, age 25, male

Known psoriatic arthritis; basic therapy of 5 mg of prednisone and 10 mg of methotrexate; the main problem is the availability, despite basic therapy, obvious swelling of the left knee with synovitis and swelling of 2 cm compared with the opposite side. Also, despite background therapy, there is swelling in the wrists. Periarticular injection of doses of 20-40 mg cortisone in the knee and wrist showed only a weak effect for a few days, with a decrease in pain by 10-30%. Proposed actsoma therapy. DRR immediately after the injection of 5.6 mg/l After treatment (exosomes obtained after incubation of IL-1Ra according to the description) the introduction of actcom in left knee (exosomes + triamcinolone 10 mg) and SFCs 2+3 bilateral (exosomes with 2 mg of triamcinolone in each joint, respectively). Uncomplicated for few days there was a clear reduction in pain 90%; CRP after 3 months 3.0 mg/l; swelling of the knees was completely gone after a week, there is no difference between�do left and right; it was possible to completely cancel 5 mg of prednisone, as the effect of periarticular injections actcom and triamcinolone was prolonged.

Case VII: R., 32 years, male

Complete baldness is known for a few years, all attempts ineffectual treatment, including systemic and local injection of cortisone in high systemic and local doses (10-80 mg of prednisolone); proposed therapy ectosomal. Preparation of actcom methods described above; a single intramuscular injection of actcom together with 10 mg of triamcinolone. Follow-up normally after three months growth of hair about half covered from hair to the lesion area.

Case VIII: G., 47 years, male

Osteoarthritis of the knee joint PR with defects of cartilage, with the help of arthroscopy confirmed the extent of 2-4 according to the Outerbridge. The patient wishes to delay surgery and joint replacement. Used intra-articular injections of triamcinolone in doses of 10-40 mg, to no avail. Conducted injection of 1 ml of actcom prepared by the above methods, after incubation with IL-1Ra. A single intra-articular injection of 2 ml of eksasol; after 4 weeks the patient is dissatisfied with clinical effect in relation to pain and function. The decision to make intra-articular injection in his right knee in combination with 10 mg of triamcinolone. Neolog�for military. After 1 week reduction in pain by 95%, complete recovery of function, the patient for the first time in a few years could play tennis.

Case IX: J., 27-year-old male

Heavy dermatologically confirmed neurodermatitis with strong changes, especially in the hands and feet. No known dermatological therapies have not shown sustained improvement, or rather, there has been only a short-term improvement within 1 week after topical application of corticosteroids and systemic intramuscular injection of prednisolone and triamcinolone in doses of 80 mg. Preparation of actcom carried out according to the method described above, intramuscular; no satisfactory skin changes and impact on the disease in 3 weeks. Then attempt intramuscular injection of 2 ml of actcom in combination with 20 mg of triamcinolone. Within 2 weeks - a clear improvement, persisting for more than 6 months. This was followed by a weak decrease, however, this still is an improvement compared to the initial situation. Fig.1A shows dermatological changes of both feet after treatment; Fig.1B and 1C - a week after treatment for right and left feet, respectively.

Case X: B., 69 years, female

Severe arthritis spondylitis with iridocyclitis of the left eye. The patient as baseline therapy was given prednisolone and methotrexate � various dosages. The RBU of 20.3 mg/l; apparent swelling of the left hip, + 2 cm compared with another; the left SFC and the first interphalangeal joint of the 1st finger is clearly swollen, painful; right shoulder swollen, painful, discharge reduced by 30 degrees compared to the norm. Sequential injections of actcom in the affected joints according to known technology did not bring pain reduction and DRR; sequential injection of triamcinolone in a total dose of 40 mg all affected joints, some improvement by 20% for 1 week. Through 4 weeks, followed by injections of actcom and triamcinolone, total dose 20 mg; then improvement to shoulder 80% of the fingers - 50% with a reduction of the swelling of the joint SFC thumb from 8.2 cm to 6.6 cm Clear effect on the knee not yet discovered. DRR within 1 week of reduced 20.3 mg/l to 2.9 mg/L.

The LIST of SEQUENCES

<110> Orthogen AG

<120> a Combination drug that includes a corticosteroid and exosomes

<130> 52 761 K

<160> 8

<170> PatentIn version 3.3

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Ser Phe Thr Phe Tyr Arg Arg Asp Met Gly Leu Thr Ser Ser Phe Glu

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Ser Ala Ala Tyr Pro Gly Trp Phe Leu Cys Thr Val Pro Glu Ala Asp

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Ser Gly Asp Glu Ile Arg Phe Gln Leu Glu Ala Val Asn Ile Thr Asp

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Asn Ser Gly Pro Thr Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp

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Phe Leu Cys Thr Ala Gln Glu Ala Asp Arg Pro Val Ser Leu Thr Asn

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Tyr Met Arg Asn Asn Gln Leu Val Ala Gly Tyr Leu Gln Glu Ser Asn

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Thr Lys Leu Gln Glu Lys Ile Asp Val Val Pro Ile Glu Pro Asp Ala

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Thr Lys Leu Glu Glu Lys Leu Asp Val Val Pro Val Glu Pro His Ala

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Val Phe Leu Gly Ile Gly His Gly Lys Leu Cys Leu Ala Cys Val Lys

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Leu Ser Lys Asn Lys Gln Asp Asp Lys Arg Phe Thr Phe Ile Leu Ser

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Phe Leu Cys Thr Ala Leu Glu Ala Asp Arg Pro Val Ser Leu Thr Asn

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1. Pharmaceutical composition for treatment of joint diseases such as osteoarthritis, arthritis, with the exception of rheumatoid arthritis, inflammation of the joints and inflammatory loss of cartilage, degenerative diseases of the spine, joint pain and/or autoimmune disease containing the glucocorticoid exosomes derived from autologous blood, and cytokine antagonist ortokin or anakinra.

2. Pharmaceutical composition according to claim 1, in which the glucocorticoid is selected from the group including cortisone, hydrocortisone, prednisone, prednisolone, clopidol, deflazacort, fluocortin, triamcinolone, dexamethasone, methylprednisolone, fluprednisolone, clocortolone, clobetasol, alclometasone, flumethasone, flupredniden, flurandrenolide, betamethasone, beclomethasone, fluokortolon, mometasone, fluticasone, halobetasol, fluocinolone, diflorasone, desoximetasone, fluocinonide, amcinonide, halcinonide, diflucortolone, clobetasol, paramethasone;
their salts, esters and �of alacarta.

3. Pharmaceutical composition according to claim 1, wherein the glucocorticoid is in a concentration of 1-80 mg/dose of a pharmaceutical composition containing a glucocorticoid.

4. Pharmaceutical composition according to claim 1, wherein the exosomes prepared by the method comprising the following steps: providing a blood sample containing exosomes; and preferably, the concentration of actcom.

5. Pharmaceutical composition according to claim 1, wherein the osteoarthritis is osteoarthritis in the active phase or inflammatory osteoarthritis.

6. Pharmaceutical composition according to claim 1, wherein the arthritis is arthritis caused by infection, such as bacterial arthritis, psoriatic arthritis or gouty arthritis.

7. Pharmaceutical composition according to claim 1, wherein the degenerative disease of the spine is a herniated disc.

8. Pharmaceutical composition according to claim 1, wherein the autoimmune disease is atopic dermatitis or alopecia baldness.

9. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is suitable for local administration.

10. Pharmaceutical composition according to claim 9, where topical administration is selected from the group consisting of injection in the affected area of the body, particularly in the affected joint, the affected nerve root or diseased intervertebral disc, or in its local environment; intra-articular and�jaczie; and local application.

11. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition also contains a carrier and/or auxiliary substance.

12. Pharmaceutical composition according to claim 1, in which the cytokine antagonist is present in a concentration of 0.5-150 mg/dose of a pharmaceutical composition comprising a cytokine antagonist.

13. Pharmaceutical composition according to claim 1, in which there is the growth factor, the growth factor is selected from the group consisting of TGF-β, IGF, BMP, HGF and VEGF.

14. Kit for treatment of joint diseases such as osteoarthritis, arthritis, with the exception of rheumatoid arthritis, inflammation of the joints and inflammatory cartilage loss; degenerative diseases of the spine, joint pain and/or autoimmune disease, comprising (i) a pharmaceutical composition comprising exosomes derived from autologous blood, cytokine antagonist ortokin or anakinra, and (ii) a pharmaceutical composition comprising a glucocorticoid and cytokine antagonist ortokin or anakinra.

15. The kit according to claim 14, where the pharmaceutical(s) composition(s) suitable(s) for simultaneous or sequential introduction of actcom and glucocorticoid.

16. The kit according to claim 14, wherein the glucocorticoid is selected from the group including cortisone, hydrocortisone, prednisone, prednisolone, clopidol, deflazacort, flucort�n, triamcinolone, dexamethasone, methylprednisolone, fluprednisolone, clocortolone, clobetasol, alclometasone, flumethasone, flupredniden, flurandrenolide, betamethasone, beclomethasone, fluokortolon, mometasone, fluticasone, halobetasol, fluocinolone, diflorasone, desoximetasone, fluocinonide, amcinonide, halcinonide, diflucortolone, clobetasol, paramethasone;
their salts, esters and prodrugs.

17. The kit according to claim 14, where the glucocorticoid is in a concentration of 1-80 mg/dose of a pharmaceutical composition containing a glucocorticoid.

18. The kit according to claim 14, where exosomes prepared by the method comprising the following steps: providing a blood sample containing exosomes; and preferably, the concentration of actcom.

19. The kit according to claim 14, where the osteoarthritis is osteoarthritis in the active phase or inflammatory osteoarthritis.

20. The kit according to claim 14, where the arthritis is arthritis caused by infection, such as bacterial arthritis, psoriatic arthritis or gouty arthritis.

21. The kit according to claim 14, where a degenerative disease of the spine is a herniated disc.

22. The kit according to claim 14, where the autoimmune disease is atopic dermatitis or alopecia baldness.

23. The kit according to claim 14, where the pharmaceutical(s) composition(s) suitable(s) for local administration.

24. The kit according to claim 23, where the local introduction �ybiraut from the group consisting of introducing into the affected area of the body, particularly in the affected joint, the affected nerve root or diseased intervertebral disc, or in its local environment; intra-articular injections; and topical application.

25. The kit according to claim 14, where the pharmaceutical(s) composition(s) contains(contain) the carrier and/or excipient.

26. The kit according to claim 14, in which the cytokine antagonist is present in a concentration of 0.5-150 mg/dose of a pharmaceutical composition comprising a cytokine antagonist.

27. The kit according to claim 14, in which there is a growth factor; a growth factor selected from the group consisting of TGF-β, IGF, BMP, HGF and VEGF.

28. The use of actcom obtained from autologous blood, for the preparation of pharmaceutical compositions for use in combination therapy together with a glucocorticoid in the presence of a cytokine antagonist orthokine or anakinra for the treatment of joint diseases such as osteoarthritis, arthritis, with the exception of rheumatoid arthritis, inflammation of the joints and inflammatory loss of cartilage, degenerative diseases of the spine, joint pain and/or autoimmune disease.

29. The use according to claim 28, where the pharmaceutical composition is intended for simultaneous or sequential introduction of actcom and glaciochemical.

30. The use of glucocorticoid DL� the preparation of pharmaceutical compositions for use in combination therapy together with ectosomal, obtained from autologous blood, in the presence of a cytokine antagonist orthokine or anakinra for the treatment of joint diseases such as osteoarthritis, arthritis, with the exception of rheumatoid arthritis, inflammation of the joints and inflammatory loss of cartilage, degenerative diseases of the spine, joint pain and/or autoimmune disease.

31. The use according to claim 30, where the pharmaceutical composition is intended for simultaneous or sequential introduction of actcom and glucocorticoid.

32. The use of a cytokine antagonist orthokine or anakinra for the preparation of pharmaceutical compositions for use in combination therapy together with glucocorticoid and ectosomal obtained from autologous blood for the treatment of joint diseases such as osteoarthritis, arthritis, with the exception of rheumatoid arthritis, inflammation of the joints and inflammatory loss of cartilage, degenerative diseases of the spine, joint pain and/or autoimmune disease.

33. The method for preparing the pharmaceutical composition according to claim 1, comprising the following stages: provision of autologous blood sample containing exosomes; the concentration of actcom and mix with orthokine or anakinroj and mix with glucocorticoid.



 

Same patents:

FIELD: medicine.

SUBSTANCE: group of inventions relates to the strain of Bifidobacterium longum NCIMB 41675, a composition, containing thereof, and a food product, containing the said strain or composition. The claimed strain possesses an ability to induce the production of cytokins and control IL-10:IL-12 ratio is suitable for application in immunomodulation, treatment of an autoimmune disease.

EFFECT: claimed strain, composition and food product possess probiotic properties.

25 cl, 16 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of biotechnology, namely to internalisation of therapeutic molecules into cell, and can be applied in medicine. Obtained is composition for delivering molecules of nucleic acids into cells, containing at least one peptide with at least 92% identity to GAAEAAARVYDLGLRRLRQRRRLRRERVRA (SEQ ID NO: 2); IREIMEKFGKQPVSLPARRLKLRGRKRRQR (SEQ ID NO: 3); or YLKVVRKHHRVIAGQFFGHHHTDSFRMLYD (SEQ ID NO: 4), bound to one or several molecules of nucleic acids.

EFFECT: invention makes it possible to increase efficiency of delivery of molecules of nucleic acids into mammalian cell due to peptide, capable of internalisation into mammalian cell with efficiency, constituting at least 200% of efficiency of internalisation of peptide TAT, which has amino acid sequence GRKKRRQRRRPPQ (SEQ ID NO: 1).

8 cl, 16 dwg, 1 tbl, 8 ex

Crystals // 2556206

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes crystals of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulphonyl)acetamide ("compound A"), as a form I of the compound A crystal, which shows diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees in its power X-ray diffraction spectrum, as a form II of the compound A crystal, which shows diffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in its power X-ray diffraction spectrum, as a form III of the compound A crystal, which shows diffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees in its power X-ray diffraction spectrum. There are also described methods for producing the forms I, II and III of the compound A crystal, based pharmaceutical composition and PGI2 receptor agonist agent, an accelerating agent for angiogenic therapy, gene engineering or autoimmune bone marrow transplantation, and an accelerating agent for angiogenesis for peripheral artery recovery or angiogenic therapy on the basis thereof; there are also described a preventive or therapeutic agent for a wide range of diseases and conditions.

EFFECT: preparing the new therapeutic agent for the wide range of diseases and conditions.

11 cl, 6 dwg, 6 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented invention refers to immunology. What is presented is a monoclonal anti-IFNAR1 antibodies with L234F, L235E and P331S Fc mutations of human IgG1 possessing a lower affinity to Fcgamma RI, Fcgamma RIIIA and c1q receptors as compared to a non-modified antibody. There are described the recovered nucleic acid providing expression of the above antibody containing a nucleotide sequence coding the antibody, and a pharmaceutical composition based on the above antibody.

EFFECT: using the invention provides the antibody possessing the lower affinity to Fcgamma RI, Fcgamma RIIIA and c1q receptors that provides reducing the undesired effector functions in treating chronic inflammation and autoimmune conditions.

9 cl, 34 dwg, 7 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates for composition for treatment or prevention of disorders, associated with reduced level of defensins. Composition contains from 0.005 to 1000 mg of Lactobacillus johnsonii Lal (NCC533, No CNCM 1-1225) per a daily dose, with at least 90% of L. johnsonii Lal (NCC533, No CNCM 1-1225) being transferred into state in which they become non-replicating at temperature110-140°C for 5-30 s.

EFFECT: invention provides enhancement of expression of defensin hBD1 mRNA.

5 cl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

FIELD: medicine.

SUBSTANCE: invention refers to biochemistry, particularly to affinity-matured CRIg versions. Declared is the CRIg versions, which is an alternative complement pathway inhibitor at least twice stronger than human CRIg with a native sequence, and optionally possesses C3b-bindingaffinity at least twice as much. There are also declared a chimeric molecule and a pharmaceutical composition, both containing the above CRIg version. The CRIg version can be used for preparing a therapeutic agent for treating a complement-associated disease or condition.

EFFECT: invention enables improving the therapeutic effectiveness of CRIg polypeptides.

17 cl, 17 dwg, 4 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to biotechnology, namely to novel IL-17-inhibiting polypeptides, corresponding to fused proteins, to compositions and their application for medicinal purposes. Polypeptide contains amino acid sequence, which is selected from group, consisting of GVTLFVALYD YKAFWPGDLS FHKGEKFQIL RTSDGDWWEA RSLTTGETGY IPSNYVAPVD SIQ (SEQ ID NO: 39), GVTLFVALYD YKAFWPGDIS FHKGEKFQIL RTSDGEWWVA RSLTTGEEGY IPSNYVAPVD SIQ (SEQ ID NO: 57) or GVTLFVALYD YKAFWPGDIS FHKGEKFQIL RTSDGEWWIA RSLTTGEEGY IPSNYVAPVD SIQ (SEQ ID NO: 107); amino acid sequence, which has, at least, 80%, preferably, at least, 90%, more preferably, at least, 95% identity of amino acid sequence with SEQ ID NO: 39, SEQ ID NO:57 or SEQ ID NO: 107; fragment or functional derivative of SEQ ID NO: 39, SEQ ID NO: 57 or SEQ ID NO: 107, obtained due to substitution, addition and/or removal of not more than 5 amino acids.

EFFECT: invention makes it possible to bind IL-17 with high specificity and affinity.

33 cl, 17 dwg, 3 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to immunology. What is disclosed is using a peptide with an amino acid sequence GLAGGSAQSQRAPDRVL for selecting CεmX-specific antibodies and antigen-binding fragments of these antibodies. What is presented is the CεmX-specific antibody, as well as a method providing selecting the antibodies specifically binding the peptide according to the invention, and a method of treating IgE-mediated diseases involving administering the antibody into an individual according to the invention.

EFFECT: it has been disclosed that the monoclonal antibodies specifically binding the CεmX segment GLAGGSAQSQRAPDRVL can effectively bind to mIgE in human B-cells and are applicable for targeting to these B cells for treating IgE-mediated diseases.

14 cl, 5 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition, containing compound of formula or for prevention or treatment of diseases, associated with oxidative stress, selected from group, consisting of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibres) or Kearns-Sayre syndrome, arrhythmia, cardioplegia or myocardium infarction. in formula (1) na stands for 1 or 2, Aa represents 5-membered heteroaryl or heterocycle, each of which has 2 heteroatoms, selected from N, O and S, Rla represents R5a-Xa-Ba-X′a-, Ba represents direct bond, Xa and X′a independently on each other represent direct bond or -OC(O)-, R5a represents hydrogen or 6-9-membered monocyclic or condensed cyclic heterocycle or heteroaryl, each of which has from 1 to 3 heteroatoms, selected from N, O and S, and is optionally substituted with oxo or C1-C6-alkyl, R2a represents -(CR8aR9a)pa-Ya-R7a, pa stands for number from 0 or 1, Ya represents direct bond or -O-, R7a represents hydrogen or phenyl, R3a, R8a, R9a, R10a represent hydrogen, R4a represents -(CH2)pa-Da-R10a-, Da represents C5-cycloalkyl or 6-membered heterocycle, which has 1 heteroatom, selected from N, S and O. Radical values for formula (2) are give in invention formula.

EFFECT: obtaining compositions for prevention or treatment of diseases, associated with oxidative stress.

19 dwg, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to rheumatology, and can be used in treating patients suffering from rheumatoid arthritis. The method involves prescribing methotrexat 15 mg a week per os, folic acid 5 mg a week per os, movalis 15 mg a day per os. If the patient has the second degree of activity of rheumatoid arthritis, IL-1β of 1.3±0.3 pg/ml and more, IL-6 of 1.5±0.3 pg/ml and more, TNF-α of 1.78±0.35 pg/ml and more, IL-4 of 3.7±0.34 pg/ml and less, leptine of 6.4±0.42 pg/ml and more, glycosaminoglycans of 0.310±0.032 g/l, 7 daily procedures of intravenous laser exposure are prescribed. The KL-VLOK radiation head with a wavelength of 635 nm, disposable light guide tip power of 1.5 mW, exposure time of 15 minutes is alternated every second day with the KL-VLOK-365 laser head for UV blood exposure with a wavelength of 365 nm, light guide tip power of 1.0 mW and exposure time of 5 minutes. If observing the third degree of activity, IL-1β of 2.01±0.18 pg/ml and more, IL-6 of 3.01±0.38 pg/ml and more, TNF-α of 3.3±0.25 pg/ml and more, IL-4 of 1.3±0.24 pg/ml and less, leptine of 8.8±0.72 pg/ml and more, glycosaminoglycans of 1.3±0.54 g/l, 10 daily procedures are performed. The KL-VLOK radiation head with a wavelength of 635 nm, disposable light guide tip power of 1.5-2.0 mW, exposure time of 15 minutes is alternated every second day with the KL-VLOK-365 laser head for UV blood exposure with a wavelength of 365 nm, light guide tip power of 1.0 mW and exposure time of 5 minutes.

EFFECT: method enables reducing a rate of aggravations, an intensity of clinical manifestations, drug load on the patient, prolonging remissions ensured by a normalising effect on cytokine dynamics - reduced pro-inflammatory and increased anti-inflammatory cytokines.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula

,

or its pharmaceutically acceptable salt. In claimed formula each symbol has values, determined in formula of invention. Versions of formula [I] compound and particular compounds are also objects of invention. In addition, invention relates to pharmaceutical composition, ITK inhibitor and means for treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection and other diseases and methods of treating said diseases.

EFFECT: claimed compounds inhibit induced T-cellular kinase (ITK).

32 cl, 86 tbl, 387 ex

Treatment // 2554801

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and concerns using a human Annexin-1 antibody (Anx-A1), which has the sequence SEQ ID NO: 23 for treating a disease caused by abnormal T-cell activation. The group of inventions also concerns a method of treating a disease caused by abnormal T-cell activation, involving administering a therapeutic amount of the above antibody into an individual in need thereof; using the above antibody for producing a therapeutic agent for treating a disease caused by abnormal T-cell activation.

EFFECT: group of inventions provides treating the disease caused by abnormal T-cell activation.

9 cl, 11 ex, 22 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.

EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.

47 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: as medications administered are: methotrexate 15 mg per week intake, folic acid 5 mg per week intake, movalis 15 mg per day intake. Laser therapy is administered in differential way depending on degree of disease activity and level of glucosaminoglycanes (GAG). In case of second stage of rheumatoid arthritis - index DAS28 3.2-5.1, level of glucosaminoglycanes 0.510±0.032 g/l, 7 daily procedures of intravenous laser irradiation are carried out. Radiating head KL-VLOK with wavelength 635 nm, power at the end of disposable light guide 1.5 mW, exposure time 15 minutes and laser head KL-VLOK-365 with wavelength 365 nm, power at the end of light guide 1.0 mW, exposure time 5 minutes, are alternated. In case of third degree of activity index DAS28 is higher than 5.1, GAG level is equal or is higher than 0.618±0.069 g/l, 10 procedures are carried out Radiating head KL-VLOK with wavelength 635 nm, power at outlet of disposable light guide 1.5-2.0 mW, exposure time 15 minutes and laser head KL-VLOK-365 nm, power at outlet of disposable light guide 1.0 mW, time of exposure 5 minutes.

EFFECT: method makes it possible to reduce frequency of exacerbations, reduce expression of clinical manifestations, reduce drug load on patient, provides earlier arrest of disease symptoms due to differentiated approach in case of administration of intravenous laser irradiation of blood and its normalising action on GAG indices and reduction of disease activity degree.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition in the form of a tablet with an erodible matrix, which contains one or more fumaric acid ethers, as well as a rate-controlling agent, representing hydroxypropylcellulose and a binding agent, representing lactose, with the decomposition of the said degradable matrix providing the controlled release of the said fumaric acid ether (ethers).

EFFECT: provision of the controlled release of fumaric acid ether (ethers).

19 cl, 43 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the novel and unexpected application of sulphated hyaluronic acid as a cytokine activity regulator for the prevention and/or treatment of asthma and degenerative joint osteoarthritis, associated with the activation of IL-1, IL-2, IL-6, IL-7, IL-8 and IL-12, the said sulphated hyaluronic acid has a molecular weight from 10000 to 50000 Da, from 150000 to 250000 Da and from 500000 to 750000 Da and where sulphated hyaluronic acid has a sulphation degree equal to 3.

EFFECT: invention provides the extension of an arsenal of means for the prevention and/or treatment of asthma and degenerative joint osteoarthritis.

3 cl, 25 ex, 4 tbl, 12 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to application of medication "Osteomed" for treating arthritis and arthrosis.

EFFECT: said application makes it possible to accelerate treatment of arthritis and arthrosis, increased efficiency of such treatment with simultaneous elimination of risk of hypercalcemic condition development.

2 dwg

FIELD: medicine.

SUBSTANCE: Alloplant dispersed biomaterial dissolved in normal saline is introduced in an amount of 10-20 ml per one injection into a space between paraspinal muscles and the neural spine or the intertransverse ligament. Each injection of the biomaterial is immediately followed by introducing normal saline in an amount of 20-100 ml to generate eccentric discomfort or pain and to produce a supplementary pressure making the biomaterial advancing along hydraulically extended intertissue, perineural and paravascular spaces to an involvement region. Thereafter, the patient is placed pronated for 12-24 hours to ensure the gravity distribution of the solution to the anterior spine. The treatment involves a therapeutic course of 3-5 one- or two-side injections of the biomaterial followed by introducing normal saline after each injection of the biomaterial every 8-12 days.

EFFECT: invention enables restoring the involved intervertebral disks with performing no traumatic operation relieving a disk radicular conflict.

2 cl, 2 ex

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