Biological material applicable for therapy of osteoarthrosis, ligamentous injury and for treating joint pathologies
SUBSTANCE: group of inventions refers to medicine. What is described is a biological material containing: a) a liquid carrier containing a viscous solution containing at least one natural and/or semisynthetic polysaccharide and having a dynamic viscosity measured at 20°C and at shear rate D=350 s-1, within the range of 100 to 250 centipoise and/or kinematic viscosity within the range of 99 to 248 centistokes (measured in the same environment); b) a autologous or heterologous mesenchymal cell culture and/or c) platelet rich blood product.
EFFECT: material in form of viscous liquid is particularly applicable for the therapy of osteoarthritis, ligament injuries and administered intra-articularly, intradermally or applied in situ without change of the properties of the mesenchymal stem cells and/or its platelets.
11 cl, 5 ex
The scope to which the invention relates
The present invention relates to a biological material in the form of a viscous liquid suitable for the treatment of osteoarthritis, damage to tendons, ligaments, to treat disorders of the joints and connective tissues in General, and damaged skin.
Articular cartilage is particularly suitable for compression resistance, it has no blood supply, no lymphatic drainage, and it is completely devoid of nerve endings. This implies that he is unable to autoregeneration to compensate for superficial lesions, while in the process will not be involved Podhradie layer.
Thus, if the loss of cartilage shallow, regenerative reactions will not. On the contrary, if the damage is deep and penetrates into Podhradie bone, it starts autoregeneration the process by which stem cells in the bone marrow begin the process of differentiation of chondrocytes, which may lead to partial repair of damaged cartilage.
Symptoms such as pain and swelling of the joint (such as, for example, the knee joint), can result from damage to the cartilage and due to its progressive degeneration may develop osteoarthritis.
This type of lesion can often be from a professional who sportsmens (because they are more prone to injury) or in elderly patients due to joint injuries and postural defects or due to wear of the cartilage, associated with the age of the individual.
Currently, when cartilage lesions of the knee joint-surgical methods of treatment of this type of lesions, including physical therapy and medication, does not provide the complete healing of the cartilage defect, which meanwhile has been achieved with good percentage of success after performing the most innovative intra-articular surgical implant operations.
Basic techniques of surgical repair of cartilage, known in the prior art, are:
1. transplantation of autologous chondrocytes through at least two different surgical procedures that are performed sequentially: first, less invasive, provides for the collection (via arthroscopy) normal cartilage tissue of the patient from other undamaged areas of the joint or of the non-articular cartilage. Taken in this way the sample sent to the laboratory for cell multiplication in vitro. After multiplication of the chondrocytes should the actual surgical procedure consisting of transplantation directly into the affected area, derived chondrocytes (transported in saline solutions), which can be fixed in situ autologous periosteal tissue. This method is very expensive because it required the duty to regulate two surgeries and the process of growing chondrocytes in vitro. Thus, it relates to double hospitalization of the patient, therefore, the patient twice subjected to anesthesia and double-pharmacological therapy.
2. The second simple method consists in performing perforations on the surface of the joint to achieve Podhradie tissue damaged area and, thus, provide educational opportunities mesenchymal blood clot that can reach the surface defect of the cartilage, where cells can partially differentiate into chondrocytes. However, the newly formed cartilage was mainly fibrous and not hyaline, like the original cartilage, and thus, it does not have the same physical and mechanical characteristics as the native tissue of the joint.
3. For the treatment of bone and cartilage lesions known to the introduction of surgical implants or polymer frames containing chondrocytes and/or mesenchymal stem cells. In this case, the material that makes up the frame, can be a semi-synthetic polysaccharide, such as, for example, a derivative of hyaluronic acid , or may consist of collagen matrices. Even this procedure was especially expensive and required a double hospitalization of the patient and dual operation, as described previously.
Another very common type of injury and/or inflammation connector the s tissue is a lesion of the ligaments or tendons, and, in particular, lesions of the Achilles tendon, especially among professional athletes, which in General is treated (in its most severe forms) even surgically because of the need for partial or total reconstruction of the traumatized tissue. To date surgical techniques used to repair ligaments, were based on tissue grafts and synthetic prostheses, which, however, have had limited effectiveness over time. Meanwhile, recent scientific publications have proven the ability of stem cells to restore tissue damaged tendons and ligaments: mesenchymal cells collected from the same cells, introduced in travmirovannomu Achilles tendon, were in fact transformed into tenacity (typical cells of the tendon). Thus, the tendon was restored by increasing collagen production, which makes ligaments flexible and stable.
In recent years, maxillofacial, and bone surgery , and also (and primarily) in surgery of the connective tissue (and, in particular, the reconstruction/regeneration of tendons/ligaments, and skin) are increasingly used platelet-rich blood products, because this type of material enriched trophic factors, such as AGF (concentrate of Autologous Growth Factor), and,in particular, PDGF-AB (originating from platelets growth factors AB) and TGFβ (tumor growth factor beta) and so on [3, 4].
These blood products are actually used for the stimulation of reparative processes in the damaged skin due to trophic venous ulcers, mainly in patients with diabetes mellitus.
Stimulation is typically triggered by various methods, such as:
a) mechanical stimulation,
b) local application of growth factors
c) local application of tissue engineering products.
Mechanical stimulation is abrasion of the bottom and edges of the lesions dry sterile gauze or a scalpel to bleeding. Local application of growth factors from platelet concentrate, dissolved in the plasma, which allows the release of PDGF (with phytogenic and angiogenic effect), TGF-B (to stimulate fibroblast), EGF (epidermal growth factor) (for stimulation of the cells of the epidermis and mesenchyme) and IGF (insulin-like growth factor) (as a promoter of cell duplication). We experimentally demonstrate an increase in vascularization of the tissue, although these blood products are difficult to manipulate and their effect in situ has a very short duration.
The products of tissue engineering are more recent developments and presents in the form of a heterologous fibres the blast cells and keratinocytes on a biocompatible substrate or in the form of autologous fibroblasts on the substrate hyaluronic acid.
This involves the use of surgical procedures for taking cells from a patient with the purpose of their cultivation in vitro before they are loaded on a substrate.
With regard to the previously described prior art and in relation to intra-articular or vnutricerepnogo the introduction of cellular components and treatment using platelet products damaged tendons/ligaments, or skin (and cellular components, and platelet-enriched blood product is introduced through a special needle), there is a need for "media", which is quite fluid, but also is able to simultaneously provide:
- good physical/mechanical consistency to enable the above introduction preservation of viability, morphology of cell membranes and, at the same time, capacity for proliferation and differentiation of cells in the environment of the media, but which, in addition,
- provides the ability to maintain the above cells in the lesion, without further fixation, requiring subsequent suturing and medical treatment.
Due to similar reasons, it is necessary to ensure the "carrier"that can preserve the integrity of the platelet-derived blood products, which will be used to ensure all biochemical and enzyme is s properties of proteins (i.e., the above trophic factors)contained in it, and which, above all, provides the possibility of maintaining the introduced active ingredients in the lesion.
Summary of the invention
Currently, the applicant has found that it is possible to overcome the above disadvantages of the prior art by means of biological material in accordance with the present invention.
In particular, the biological material in accordance with the present invention includes:
a) a liquid carrier comprising a viscous solution containing at least one natural and/or semisynthetic polysaccharide, and having a dynamic viscosity, measured at 20 ° C and at shear rate D=350-1in the range from 100 to 250 centipoise and/or a kinematic viscosity in the range from 99 to 248 CST (measured in the same conditions);
b) culture or prepared for immediate use drug mesenchymal stem cells, and/or
c) platelet-rich blood product.
This type of material is suitable for the treatment of osteoarthritis, damage to cartilage, tendon injuries (in particular, damage to the Achilles tendon, ligaments, and, in General, the pathology of joints and connective tissues in General, and damaged skin.
In General, the infusion is her invention, furthermore relates to pharmaceutical compositions containing biological material according to the present invention, particularly suitable for intra-articular, vnutricerepnogo introduction, but also for direct application on the affected area.
A detailed description of the invention
In relation to the present invention, the term "viscous solution is used in this description to indicate a homogeneous mixture of two or more components present in which is dissolved substance, i.e. natural and/or semisynthetic polysaccharide, completely dissolved in the solvent, usually water, where the term "water" is used to indicate water for injectable drugs, saline, etc.
This type of solution should not be confused with the so-called gel or hydrogel, i.e. a semi-solid product, the components of which do not dissolve in the solvent, but remain suspended in it, and it generally made of a material which is obtained by creating a three-dimensional relationships (so-called cross-links) covalent chemical type, hydrogen bonds or bond van der Waals forces between the various components of the gel and/or solvent.
Media in liquid form (a) in a biological material in accordance with the present invention is preferably in ski solution containing natural and/or semisynthetic polysaccharide.
In accordance with another preferred embodiment of the present invention, the carrier (a) in liquid form is a viscous solution essentially consisting of a polysaccharide of natural and/or synthetic origin and is water.
In relation to the present invention, the expression "essentially consisting of" is used to indicate that a possible third component is present in concentrations in the range from 0.9 up to 0.001% of the total mass of viscous solution.
The polysaccharide of natural origin, preferably selected from hyaluronic acid (HA), cellulose, 'gellan, chitin, chitosan, pectin or pectic acid, agarose, alginic acid, alginates, starch, polymannans, polyglycerol, molecular weight, and the type of molecules is to ensure/to guarantee the formation of a viscous solution (not gel)with dynamic or kinematic viscosity within the above ranges.
Polysaccharide semi-synthetic origin, preferably selected from derivatives of hyaluronic acid, already known to the person skilled in the art, such as, for example, a complex benzyl ester of hyaluronic acid, is described in European patent EP 216453, it oktilovom, octadecyl the th, dodecyloxy and hexadecylamine amide (EP1095064) and esters of cellulose, such as carboxymethylcellulose (CMC) and derivatives of collagen. In any case, these natural and semi-synthetic polysaccharides should be of such molecular weight that their viscosity was in the range mentioned above, in addition to what they have to show molecular/physical and chemical characteristics, leading to the formation of a viscous solution, and not a gel.
Only this type of viscosity allows a formulation subject
• intra-articular injections or patches of lesions of tendons and/or ligaments,
• vnutriaortalina introduction in the case of skin lesions,
able to ensure the highest viability of the contained cells and also to maintain the integrity of all biochemical and enzymatic properties may present trophic factors contained in platelet-rich blood products.
In accordance with a particularly preferred form of the invention, are:
• Hyaluronic acid or its pharmaceutically acceptable salt, preferably the sodium salt, with an average molecular weight in the range from 450 to 730 kDa (average molecular mass (MW) HA); the concentration should be between 5 to 15 mg/ml, suppose timeline l0 mg/ml
• Hyaluronic acid or its pharmaceutically acceptable salt, preferably the sodium salt, with an average molecular weight in the range from 1000 to 1800 kDa, measured after sterilization (high molecular weight (MW) HA); the concentration should be in the range from 2 to 12 mg/ml, preferably from 6 to 8 mg/ml
• Actilume of hyaluronic acid, preferably with an average molecular weight (MW), therefore, hyaluronic acid having an average molecular weight within the above range from 450 to 730 kDa; the concentration of the amide must be from 1 to 10 mg/ml, preferably from 2 to 3 mg/ml
• Hexadecylamine of hyaluronic acid, preferably with an average molecular weight (MW), therefore, hyaluronic acid having an average molecular weight within the above range from 450 to 730 kDa; the concentration of the amide should be from 0.2 to l,5 mg/ml, preferably from 0.5 to l mg/ml.
• 'gellan; the concentration should be from 2 to 8 mg/ml, preferably 4 mg/ml
• CMC; the concentration should be between 15 to 40 mg/ml, preferably 25 mg/ml
Mesenchymal stem cells can be autologous and heterologous type, and they preferably are of mesenchymal stem cells derived from costner the brain, peripheral blood, umbilical cord or adipose tissue.
For the scope of the present invention, the expression "platelet-rich blood products" is used to indicate all of platelet-rich blood products, e.g. platelet-rich plasma (PRP), i.e. the supernatant obtained after centrifugation of venous blood, platelet concentrate (PC), i.e. the heavier the liquid phase obtained after centrifugation of platelet-rich plasma, and, finally, platelet gel, i.e. platelet concentrate, which, due to the actions precipitating agents (such as, for example, thrombin), is transformed into a gel .
Depending on the intended application and the type of lesion can select the type of platelet-rich blood product. In fact, these three products are enriched above trophic factors.
Biological material in accordance with the present invention contains components (a) and (b), or (a) and (c), or all three components (a), (b) and (c).
In addition, preferably, the addition of autologous component (c) to a biological material, comprising (a) and (b): the above platelet-rich product of blood obtained from the same patient, and this product can even be obtained shortly before the patient will undergo specified to enter the intra-articular injection or vnutriaortalina the introduction, or before the above material will be applied directly to areas of destruction.
Therefore, pharmaceutical compositions in accordance with the present invention can be used in orthopedics (mainly through their preparation immediately before use) in the treatment of cartilage and bone defects (including local application in dentistry to promote engraftment of the implant) and can directly inetservices in the affected area are damaged tendons and/or ligaments, or can be used in dermatology and in the form of injectable compositions for vnutricerepnogo injection or local application to local treatment of skin lesions, which are difficult to heal/recover.
Obtain a viscous solution containing HA average molecular weight
Stage 1: hydration
Some amount of HA sodium salt of the polysaccharide (MW 500-730 kDa), equal to 100 mg is weighed to obtain a viscous solution with a final concentration of 10 mg/ml Powder hydratious 50% of the desired final volume (5 ml) using a 0.9% solution of sodium chloride, phosphate buffer or water for an injectable drug to obtain the desired final concentration.
Stage 2: solubilization
The product obtained as described in stage subjected to stirring by the magnetic stirrer at ambient temperature for at least 1 hour
The remaining volume (5 ml) was subsequently added to achieve the set target concentration and left under stirring for at least 2 h to dissolve the powders.
Thus obtained solution is subjected to sterilization by autoclaving or UV-irradiation and then carry out the measurement of dynamic viscosity by using a rheometer HAAKE RS150. Rheometer at 20 ° C at shear rate D=350-1.
The obtained value of the dynamic viscosity amounted to 155 SP, and thus, the product will have a kinematic viscosity of 153.6 cSt.
Obtain a viscous solution containing high molecular weight HA
The method is performed as in example 1, starting with HA powders with high molecular weight for two viscous solutions with a final concentration of 6 mg/ml and 8 mg/ml in water grade "Water for injection".
The obtained solutions are sterilized and then carry out the measurement of dynamic viscosity by using a rheometer HAAKE RS150. Rheometer at 20 ° C at shear rate D=350-1.
The values of dynamic viscosity, respectively: 158 SP and 246 SP.
Obtain a viscous solution containing'gellan
The method is performed as in example 1, starting from powders'gellan, to obtain a viscous solution with a final concentration of 4 mg/ml in saline solution.
Thus obtained solution is sterilized and then carry out the measurement of dynamic viscosity by using a rheometer HAAKE RS150. Rheometer at 20 ° C at shear rate D=350-1.
The obtained value of the dynamic viscosity was 110 SP.
Obtain a viscous solution containing CMC
The method is performed as in example 1, starting from powders CMC, to obtain a viscous solution with a final concentration of 25 mg/ml in phosphate buffer.
Thus obtained solution is sterilized and then carry out the measurement of dynamic viscosity by using a rheometer HAAKE RS150. Rheometer at 20 ° C at shear rate D=350-1.
The obtained value of the dynamic viscosity was 220 SP.
Obtain a viscous solution containing actilume or hexadecylamine HA with an average molecular weight (MW)
The method is performed as in example 1, starting from powders octylamine (or hexadecylamine HA with an average molecularmass, to obtain two viscous solutions with a final concentration of 2 mg/m 3 mg/m (or 0.5 mg/m and l mg/m for hexadecylamine) in 0.9% sodium chloride solution.
After sterilization carry out the measurement of the dynamic viscosity of the thus obtained solutions using the rheometer HAAKE RS150. Rheomeer, at 20ºC, at the shear rate of D=350-1.
The values of dynamic viscosity, respectively: 143 SP and 220 SP for octylamine, and 160 SP and 230 SP for hexadecylamine HA.
1. EP 0863776.
2."Fattori di crescita autologhi nella chirurgia ossea ricostruttiva dopo infezione" (Autologous growth factors in reconstructive operations on the bones after infection) Carlo R. Romanόn et al., Unita operativa Chirurgia delle Complicanze Osteoarticolari Settiche (C.O.S., Istituto Ortopedico Gaetano Pini).
3. "Different preparation methods to obtain components as a source of growth factors for local applications (Different ways of obtaining components as a source of growth factors for local use) R. Zimmermann et al., Transfusion 2001; 41:1217-1224.
4. "Platelet-rich plasma preparation using three devices: Implications for platelet growth factor release (Obtaining platelet-rich plasma using three devices: Participation in the release of platelet-derived growth factor) P.A.M. Everts et al., Growth Factors, September 2006; 24(3):165-171.
5. US 6841170.
1. Biological material, suitable for intra-articular, vnutricerepnogo introduction or directly applied on the affected area, including:
a) a liquid carrier comprising a viscous solution containing at least one natural and/or semisynthetic polysaccharide, and having a dynamic viscosity, measured at 20°C and at a shear rate D=350-1in the range from 0.1 to 0.25 PA·s (from 100 to 50 CP) and/or a kinematic viscosity in the range from 0.99×10 -4to 2.48×10-4m2/s (from 99 to 248 CST), measured under the same conditions;
b) culture or prepared for immediate use drug mesenchymal stem cells, and/or
c) platelet-rich product of the blood,
where specified a viscous solution of the component (a) selected from the group consisting of:
I) an aqueous solution of hyaluronic acid or its pharmaceutically acceptable salt, preferably sodium salt, with an average molecular weight in the range from 450 to 750 kDa at a concentration in the range from 5 to 15 mg/ml;
II) an aqueous solution of hyaluronic acid or its pharmaceutically acceptable salt, preferably sodium salt, with an average molecular weight in the range from 1000 to 1800 kDa, measured after sterilization, at a concentration in the range from 2 to 12 mg/ml;
III) an aqueous solution of octylamine hyaluronic acid having an average molecular weight in the range from 450 to 730 kDa at a concentration in the range from 1 to 10 mg/ml;
IV) an aqueous solution of hexadecylamine hyaluronic acid having an average molecular weight in the range from 450 to 730 kDa at a concentration in the range from 0.2 to 1.5 mg/ml;
mesenchymal stem cells of the component (b) are autologous type or heterologous and selected from the class consisting of mesenchymal stem cells from bone marrow, tengkulak stem cells in the peripheral blood, mesenchymal stem cells of the periosteum, mesenchymal stem cells of the umbilical cord or cells of adipose tissue,
platelet-rich blood product component (c) selected among platelet-rich plasma, platelet concentrate and platelet gel.
2. Biological material according to claim 1, where the aqueous solution is selected from (I), then the concentration of hyaluronic acid is 10 mg/ml
3. Biological material according to claim 1, where the aqueous solution is selected from (II), then the concentration of hyaluronic acid is from 6 to 8 mg/ml
4. Biological material according to claim 1, where the aqueous solution is selected from (III), then the concentration of octylamine hyaluronic acid is in the range from 2 to 3 mg/ml
5. Biological material according to claim 1, where the aqueous solution is selected from (IV), then the concentration of hexadecylamine hyaluronic acid is in the range from 0.5 to 1 mg/ml
6. Biological material according to claim 1 for the treatment of osteoarthritis, damage to cartilage, tendon injuries, ligament, joint pathology, skin lesions or trophic ulcers of the skin.
7. Biological material according to claim 6, where the damage to the tendon is an injury of the Achilles tendon.
8. Biological material according to claim 1, selected from the class consisting of:
biological material from the containing a series of component (a) and (b), biological material containing the component (a) and (c), biological material, containing all three components (a), (b) and (C).
9. A pharmaceutical composition comprising a biological material according to claim 1, suitable for intra-articular, vnutricerepnogo introduction or directly applied on the affected area.
10. The pharmaceutical composition according to claim 9, where platelet-rich blood product and/or mesenchymal stem cells are autologous.
11. The pharmaceutical composition according to any one of PP and 10 for the treatment of cartilage and bone defects, damaged tendons, damaged ligaments or damaged skin.
SUBSTANCE: method involves a preclinical electroneuromyography (ENMG) of the neuromuscular apparatus of injured and intact lower extremities to measure a muscle response amplitude - an M-response. The findings are recorded. Starting from the second postoperative day, in the course of the drug-induced neuroprotective treatment and therapeutic exercises, the following therapy is additionally performed for 10-15 days. If the injured M-response amplitude is below 4.0 mV, while the respective intact value is more than 4.0 mV, the anti-inflammatory physical treatment covering the injured extremity is performed. If the injured M-response amplitude is more than 4.0 mV, while the respective intact value is below 4.0 mV, the stimulating passive physical treatment covering the intact extremity is performed. If the M-response amplitude of the injured and intact extremities is below 4.0 mV, the anti-inflammatory physical treatment covering the injured extremity and the stimulating passive physical treatment covering the intact extremity are performed. Three and six months following the surgical management, the repeated ENMG of the neuromuscular apparatus of the lower extremities to measure the M-response amplitude. If observing the preserving M-response amplitude below 4.0 mV on at least one lower extremity three months following the surgical management, the repeated complex of the drug-induced neuroprotective treatment and the stimulating passive physical treatment covering the neuromuscular apparatus of the hip with the M-response amplitude below 4.0 mV are performed. If observing the preserving M-response amplitude below 4.0 mV on at least one lower extremity six months following the surgical management, the repeated complex of the drug-induced neuroprotective treatment and the stimulating passive physical functional treatment covering the neuromuscular apparatus of the hip with the M-response amplitude below 4.0 mV are performed by walking electrical stimulation of the hip and shin.
EFFECT: method reduces the length of treatment and increases its effectiveness with decreasing a percentage of neurological complications by performing the individual complex exposure on the neuromuscular apparatus of the lower extremities taking into account the ENMG findings of the neuromuscular apparatus of the lower extremities.
2 cl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.
EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.
11 cl, 1 dwg, 18 tbl, 88 ex
SUBSTANCE: what is described is a method for the cartilaginous, osseous, muscular tissue regeneration stimulation involving the setting of a long bone fracture and introduction of the prepared agent into the intramedullary canal and the surrounding muscular tissue; that is combined with the tissue regeneration stimulation by introducing a mixture of aqueous solutions of recombinant beta interferon (IFN-β) in the concentration of 1∙105 units/ml and polyethylene glycol with a molecular weight of 6,000 (PEG 6000) in the concentration of 0.03∙10-9 mole/ml in the relation of 1:4 respectively; that is followed by a retrograde intramedullary osteosynthesis of the long bone fracture.
EFFECT: agent enables providing higher clinical effectiveness in the long bone fractures, reducing injuries, simplifying preparation technology of the agent for the tissue regeneration stimulation within the fracture, and reducing a rate of pyoinflammatory complications.
SUBSTANCE: invention relates to novel inhibitors of human poly(ADP-riboso)polymerase-1 based on uracyl derivatives of general formula (I), (II), (III) and (IV). Inhibitors of poly(ADP-riboso)polymerase-enzymes take part in DNA reparation. In general formula and R1=H, Cl, Br, I, methyl, ethyl, propyl or isopropyl; R2, R3, R4, R5=H, methyl, ethyl, propyl or phenyl; R6=(CH2)n, where n=1-4; X=OR2 or NR2R3, R2, R3=H, methyl, ethyl, propyl, phenyl, 3-hydroxypropyl.
EFFECT: obtaining novel inhibitors of human poly(ADP-riboso)polymerase-1.
1 tbl, 19 ex
SUBSTANCE: invention refers to medicine, namely traumatology, orthopaedics, and can be used for supporting treatment in large joint replacement. That is ensured by determining a volume of involved joint contracture six months before the operation. That is followed by X-ray and magnetic resonant examination of the involved and collateral joints to specify their state. Besides, a quality of the bone tissue is assessed by osteodensitometry. If observing changes in the bone tissue quality, the complex of the drug therapy is added with the preparations Bivalos and Calcemin. A pain syndrome intensity is assessed by the visual analogue scale three months before the operation. That is followed by the complex therapy aiming at optimising the state of extremity joints with added local injection therapy (LIT). That is ensured by preliminary exposing the biologically active periarticular zones in the proximal and distal direction from the involved joint to the focused infrared laser light. A mixture containing solutions of the therapeutic preparations: chondroprotectors, Contrykal, Lidocaine, vitamin B12 is injected into the same zones. Besides, Arthrofoon is administered for the whole preoperative period. If the pain syndrome intensity is less than 4 points, Arthrofoon is administered in a dose of 4 tablets a day. If the intensity value is more than 4 points, the preparation is administered in a dose of 8 tablets a day in a complex with a short course of a non-steroidal anti-inflammatory preparations and a chondroprotector. The replacement operation is immediately followed by fixing a collateral joint with an orthesis for the period of 3 months. The complex of the postoperative supporting therapy started three weeks after the operation is added with a single intravenous introduction of the preparation Aklasta, the preparation Arthrofoon in a dose of 4 tablets a day for three months, alpha calcidole and Calcemin continuously. A pectoral girdle of the extremities is reinforced by means of an individually specified set of therapeutic exercises and electric walking myostimulation. The LIT of the collateral joint is performed three months after the operation. If observing a degenerative process in the adjacent joints, the LIT is performed alternatively in these regions. Vasodilators, chondroprotectors, and the preparation Milgamma are administered with underlying LIT. If observing psychoemotional changes in the patient, the preparation Tenoten is additionally administered. A postoperative medication regimen, including the LIT is repeated 3-4 times every 6 months.
EFFECT: method provides optimising the effect of the surgical management and preventing developing complications both in the operated joint, and in the adjacent and symmetrical joints after the replacement, preventing developing instability of the endoprosthesis components, preventing developing or aggravating degenerative process in the symmetrical and adjacent joints that reduces a risk of the recurrent operations.
SUBSTANCE: invention refers to medicine, namely to therapy, and can be used for treating arthritis in a mammal, involving administering N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulphanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulphonyl)benzene sulphonamide (ABT 263).
EFFECT: invention provides treating arthritis by specific lymphocytic immune suppression in a patient caused by administering the above compound.
3 dwg, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to treating arthropathies, such as arthrosis and inflammatory loss of cartilage, tendon disorders and/or degenerative spine diseases. What is presented is a pharmaceutical composition for the above application, containing a corticosteroid and a cytokine antagonist - a natural or recombinant protein of interleukin IL-1Ra antagonist, particularly orthokine or anakinra, and optionally a growth factor; the composition is injectable into an injured nerve root, or into an injured intervertebral disk, or into their local context, or for intraarticular injection. There are presented: a kit comprising the pharmaceutical composition with the above cytokine antagonist and optionally the growth factor, and the pharmaceutical composition with the corticosteroid; using the above cytokine antagonist and optionally the growth factor for preparing the pharmaceutical composition to be used in combination therapy together with the corticosteroid for the above application; using the corticosteroid for preparing the pharmaceutical composition to be used in combination therapy with the above cytokine antagonist and optionally the growth factor for treating the above arthropathies, tendon disorders and/or degenerative spine diseases.
EFFECT: clinical success of treatment manifested by apparent joint detumescence, pain reduction by 60-100%, functional improvement of the joint, with the effect persisting 8 months later and more after the treatment.
39 cl, 1 tbl
SUBSTANCE: invention relates to a peptide represented by the formula (I) X1-Leu-X2-Leu-X3, where X1 is Glu or Asp, X2 is His, Lys or Arg, X3 is Asp or Glu, at that Glu, Asp, Leu, His, Lys and Arg, or its pharmaceutically acceptable salt and its compositions for treatment or prevention of cartilage damage and/or arthritis.
EFFECT: proposed peptide can affect the regeneration of cartilage tissue, inhibition of expression of the enzyme causing cartilage tissue matrix degradation, or inhibition of chondrosteosis.
7 cl, 2 tbl, 11 dwg, 15 ex
SUBSTANCE: invention relates to a method of prevention and to a method of control of inflammation and/or relief of inflammatory conditions in companion animals, including the introduction of a diet, which contains 50-250 ppm of lipoic acid, 500-2000 IU/kg of vitamin E, 40-200 ppm of vitamin C, 50-300 of carnitine and 1-10% counted per dry substance of vegetable mixture. The invention relates to the application of the said diet for obtaining a food product for pets for the prevention of inflammation and/or relief of inflammatory conditions.
EFFECT: invention relates to a composition, containing the said components.
10 cl, 3 tbl, 1 ex
SUBSTANCE: group of inventions refers to agents for preventing and treating arthropathies containing a mixture of peptides H-Ala-Glu-Asp-OH, Lys-Glu-Asp and H-Lys-Glu-OH and a mixture of chondroitin and/or its salts, and/or glucosamines and/or its salts; methods for using them. The group of inventions provides a positive variation of clinical-biochemical dynamics. What is also provided is normalising the morphological structure of joint tissues, including a cytoarchitectonic characteristic of cartilaginous tissue with decreasing apoptotic chondrocyte count, especially at the final stages.
EFFECT: provided favourable effect on the metabolic processes in chondrocytes, activated synthetic processes and normalised biopolymer composition of the cartilage matrix An evident analgesic effect is manifested.
20 cl, 5 ex, 5 tbl
SUBSTANCE: group of inventions refers to medicine and concerns methods for creation a tooth of a required size, and repair of the lost teeth in the oral cavity by transplantation of the created tooth into the dental loss. Particularly, the method for the tooth creation of a required length in one direction involves the stages: placing the first cell aggregate and the second cell aggregate in a tight contact inside a supporting carrier, wherein the first cell aggregate and the second cell aggregate respectively consists of mesenchymal or epithelial cells; culturing the first and second cell aggregate inside the supporting carrier; the tooth size is corrected by a contact length of the first cell aggregate and the second cell aggregate in the same pre-set direction. A method for determining the contact length of the first and second cell aggregate for the tooth preparation of the required size involves preparing a number of structural types containing structures of various contact length of the first and second cell aggregate in the same pre-set direction; culturing each of a number of structural types inside the supporting carrier; measuring the tooth length prepared at the previous stage in one direction; correlating the given length and contact length providing the basis for calculating the required contact length of the first cell aggregate and the second cell aggregate.
EFFECT: group of inventions enables creating the tooth of the required size that enables preparing a single tooth that can be used as it is in the form of a transplant.
23 cl, 1 tbl, 6 ex, 13 dwg
SUBSTANCE: presented are engineered multilayered vascular tubes, comprising at least one layer of differentiated adult fibroblasts, at least one layer of differentiated adult smooth muscle cells. Further, any layer comprises differentiated adult endothelial cells. The said tubes have the following features: a ratio of endothelial cells to smooth muscle cells makes approximately 1:99 to approximately 45:55; the tube is deformable; an internal diameter of the tube is approximately 6 mm or smaller; the length of the tube is up to approximately 30 cm; the thickness of the tube is substantially uniform along the tube section. It is also provided that the vascular tube is free of any pre-formed frame. What is also described is a method of forming the above tubes.
EFFECT: engineering the therapeutically acceptable alternative vascular tubes withstanding physiological pressure, for transplantation into a patient's body and for use in testing cardiovascular drugs and devices.
29 cl, 4 ex, 3 dwg, 2 tbl
SUBSTANCE: invention refers to a medical prosthesis to be implanted into the human body, particularly to a biological nasal bridge implant used in nasal bridge reparative surgery. The nasal bridge implant is made according to the method which involves sampling, sterilisation and cutting to the required size of the animal material in the form of cattle or swine tendons; cell recovery from the animal material; shaping of the animal material for establishing the required form of the nasal bridge; cross-linking of the animal material; antigen recovery of the animal material, alkaline treatment and introduction of the active substances promoting adhesion of a growth factor and stem cells; packaging of the implant into the container with a sterilisation solution.
EFFECT: preparing the biological nasal bridge implant.
16 cl, 2 dwg, 1 ex
SUBSTANCE: method is proposed to extract stem cells, including whirling of heparinised bone marrow with hydroxyethyl starch at the ratio of source ingredients of 1:2 with speed of 700g for 15 min. in the closed system of three haematological containers connected to each other with tubes with subsequent removal of fat admixtures and plasma into the container No.1, transfer of the mononuclear fraction of bone marrow, a part of supernatant and erythrocytes adjoining the interface of two media into the container No.2. Sludged erythrocytes and bone fragments remain in the main container, whirling of the produced sample with the speed of 900g for 15 min. in the container No.2 to produce cell material for intravascular introduction, at the same time after the specified whirling a part of supernatant is removed into the container No.1 without unsealing of the system.
EFFECT: production of paracrine effect of bone marrow mononuclear cells and provision of safety.
1 tbl, 2 ex
SUBSTANCE: method is proposed to produce epithelioid cells of buffalo cow light foetus by means of long-term no-reseeding cultivation having high sensitivity to the virus of infectious rhinotracheitis of cattle, parainfluenza-3, viral diarrhea-disease of mucous membranes and adenoviral infection.
EFFECT: possibility to use in diagnostics of virus infections.
SUBSTANCE: invention refers to medicine and veterinary science; it is used in transplantology, traumatology, surgery and oncology, and may be used to fill bone defects. What is described is a bioimplant which represents a donor bone deimmunised with chlorine-containing oxidants, a surface of which is covered with a multifunctional bioactive nanostructured coating (MBNC) of M-Ca-P-C-O-N or M-Ca-CON, wherein M is a metal specified in a group consisting of Si, Ti, Zr, Hf, Nb, Ta, and colonised by recipient's mesenchymal stem cells (MSC).
EFFECT: MBNC-coated bioimplant is in line with the anatomical and morphological characteristics of the replaced bone, provides cell adhesion, no transplant rejection, accelerated formation of connective tissue and callus.
8 dwg, 1 ex
SUBSTANCE: invention refers to medicine and veterinary science, namely to reconstructive surgery it aims at the applications in transplantation, traumatology, surgery, and oncology. What is described is a method for producing bioengineered constructs for bone defect replacement, which is based on a bone anatomically compatible with the replaced one which is deimmunised in 5-10% solution prepared of a dry mixture of sodium chlorite, sodium perchlorate, sodium chloride in a ratio of 7:2:1 and distilled water; it is coated with heterogeneous implantable gel and colonised with multipotent mesenchymal stromal cells recovered from the recipient's bone marrow using immunomagnetic separation technique.
EFFECT: method provides sizeable bone defect replacement, high strength, fast fixation and repair of the construct in the implantation region, causes no reject phenomena.
1 tbl, 4 dwg
SUBSTANCE: what is described is a composition for fistula treatment in an individual, including stromal stem cells of fatty tissue where at least approximately 50 % of stromal stem cells of fatty tissue making a composition, express CD9, CD10, CD13, CD29, CD44, CD49A, CD51, CD54, CD55, CD58, CD59, CD90 and CD105 markers and where the contents of the stromal stem cells of fatty tissue in the composition makes at least approximately 3×106 cells/ml.
EFFECT: invention extends the range of products for fistula treatment.
8 cl, 7 dwg, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to chemistry of high-molecular compounds, namely to preparing film and spongy chitosan and collagen materials effective in human skin cell culture and wound grafting. A method for preparing the composite chitosan and collagen resorbable matrixes for human skin cell culture involves preparation of solutions polysaccharide chitosan and protein collagen, mixing them in preset proportions and formation of film and spongy matrixes of mixed polymer solutions. For this purpose, chitosan and collagen solutions in the concentration 1.0-4.0 wt % in a general solvent (aqueous 2 % acetic acid) are prepared, mixed in preset proportions, and the film and spongy matrix materials are formed from the prepared solutions. An amount of collagen in polymer mixtures makes 2.5-10 wt % (of chitosan). Further, films and sponges are heated to temperatures within 50-100°C for 1.0-5.0 h in an atmospheric environment.
EFFECT: use of the declared method allows preparing the film and spongy resorbable composite materials of natural polymers effective in human skin cell culture.
2 cl, 6 ex, 2 tbl
SUBSTANCE: invention refers to medicine, namely to cardiovascular surgery. A biological material for cardiovascular surgery is made of a preserved carp swim bladder.
EFFECT: reduced calcification with maintained physical-mechanical properties.
SUBSTANCE: what is described is a method for applying a chitosan coating on a pericardial surface of a biological heart valve prosthesis by direct chitosan application from a non-immunogenic solvent absolutely biocompatible with a human body and possessing antimicrobial properties, - high-pressure carbonated water, onto the pericardium of the biological heart valve prosthesis pre-processed with 0.625% glutaric aldehyde. The method for chitosan coating from high-pressure carbonated water enables providing higher effectiveness and prolonged functioning of the biological heart valve prosthesis ensured by avoiding formation of deposited calcium on the surface, providing better elasticity, enhancing antimicrobial properties enabled by the chitosan coating on the surface.
EFFECT: making the non-immunogenic calcification resistant biological heart valve prostheses possessing the antimicrobial properties.
12 cl, 1 dwg, 4 tbl, 12 ex