Using pharmaceutical composition comprising epidermal growth factor (egf) for prevention of diabetic limb amputation

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising epidermal growth factor (EGF) used in treatment of wounds on skin and soft tissues of lower limb in diabetic patient. Method of treatment involves topical infiltration of EGF-containing solution into different points and by contours of tissue damaged zone to provide administration of the solution into wound in the total volume 4-20 ml and irrigation of all deep surface of wound base and edges with the indicated composition. Invention provides prevention of diabetic limb amputation, stimulation of cellular proliferation in patients with foot ulcer being especially in geriatrics.

EFFECT: valuable medicinal properties of pharmaceutical composition.

19 cl, 1 tbl, 9 ex

 

The technical field

This invention relates to the use of a pharmaceutical composition that contains an epidermal growth factor (EGF), preferably in an injectable form, and which is injected through infiltrations inside and near the contours of the skin chronic ischemic ulcer wounds (i.e. by injections of ulcerative wounds to prevent diabetic amputation of a limb. The composition can be applied on the surfaces of newly formed after ablation by surgery or damaged as a result of immediate reperfusion oksigenirovannym blood after prolonged ischemia. This prevents repeated surgical interventions, thereby contributing to the conservation of the limbs.

Prior art

Every organ and tissue of the body prone to the occurrence of irreversible damage after partial or complete, acute or chronic suppression of arterial blood supply. Tissue damage may also occur as a result of chronic disturbance of venous outflow (T. D. Lucas y I. L. Szweda. Cardiac reperfusion injury: aging, lipid peroxidation and mitochondrial dysfunction. Proc. Natl. Acad. Sci. USA 1998, 95 (2): 510-514). All these disorders are largely often found in patients suffering from diabetes. In these individuum the local circulation of the extremities may deteriorate due to macro - and microvascular disorders. In addition, affected patterns of peripheral nerves, which also contributes to poor blood circulation. Associated with diabetes damage offline or sensitive innervation systems give rise to the disorder of the protective mechanisms of the skin of the extremities, such as sweating and sebum production. Local insensitivity makes the foot prone to local manifestation of injuries that can lead to the formation of trudnoozhidaemyh wounds.

A number of risk factors associated with note in diabetic patients, "the difficulty of healing", i.e., high and long glicemia, glycosylation of hemoglobin and many other circulating and tissue proteins, i.e. collagen, etc. (Kurose I, Argenbright LW, Wolf R, Lianxi L, Granger DN. Ischemia/reperfusion-induced microvascular dysfunction: role of oxidants and lipid mediators. Am. J. Physiol. 1997, 272: H2976-H2982). In the result of the above violations of the healing process, which is further complicated by circulatory disorders, many diabetic patients undergo amputation. In patients with inflammatory or degenerative arteriopathy limbs often manifests little or no perfusion below the knee). This prolonged hypoxic script calls other skin, micro-vascular, nerve and joint complications, while the first leads to in which the emergence of untreatable ischemic ulcers. In addition, nerves, vessels and other skin structures can be subjected to severe damage and often they die. This further increases the predisposition to the formation of a non-treatment of ulcers. (McCallon SK, Knight CA, Valiulus JP, Cunningham MW, McCulloch JM, Farinas LP. Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds. Ostomy Wound Manage 2000, 46:28-32).

In the present description, the applicants describe some of the solutions currently used in clinical practice to facilitate the flow of this disease.

The common treatment methods used at present in this field, the correction of metabolic balance reduces the risk factors of diabetic complications. In addition, the unloading of the affected limb can be targeted impact, facilitate healing of ulcers of the leg. The introduction of antibiotics and frequent surgical debridement of dead and fistulous tissues are part of the current status of treatment in this area. These procedures can be performed regardless of the perfusion infected foot. However, in the case of severe and trudnootdelema treatment of progressive ulcers amputation is inevitable. In the case of either chronic conditions or in a state of recovery in this area use and other additional therapeutic intervention, to the which are now showing some advantages.

Hemorheological therapy:the rationale of this therapy is based on the well known hemorheological disorders found in the blood of diabetic patients, which at the same time can increase the risk of infection.

Vasoactive therapy:this intervention was used to facilitate the violation of perfusion due to macro - and microangiopathy. It was found that some prostanoids useful at the level of the affected tissue.

The use of any of the aforementioned therapeutic intervention, however, requires prior examination of a number of functional systems, such as cardiovascular, renal, hepatic, etc. that may be affected in patients with diabetes, especially the first and the second system. In some conditions, were used and other therapies to prevent or correct platelet aggregation, as well as thrombolytic tools.

Surgical methods the main revascularization is always dangerous for any ischemic condition in a patient, regardless of whether diabetic or not. In addition, they are expensive and not suitable for many patients. Therefore, the indication for surgical intervention is very limited. In addition, endovascular surgery is difficult, expensive and it has limited the use of the cost for arterial sites, such as areas ═ Powszechny region and parts of the femoral artery in the popliteal fossa. Most often these areas are calcified due to accidental damage.

Lumbar sympathectomy is currently used exclusively in diabetes. The availability of earlier autonomic neuropathy prevents its implementation.

Recently introduced the hope to solve the problem of treatment of wounds diabetic foot connected with human recombinant growth factor produced from platelets, commercially known as Becaplermin or Regranex, which is approved by Food and Drug Administration (FDA) of the USA. The above remedy is particularly indicated in the case of neuropathic ulcers of the foot. The most recent published data indicate only 50% the efficiency of a drug in a controlled and randomination clinical study in the U.S. (T. Jeffery Wieman, Janice M. Smiell, Yachin Su. Efficacy and safety of topical gel formulation of recombinant human platelet derived growth factor - BB (Becaplermin) in patients with chronic neuropathic diabetic ulcers. Diabetes Care 1998, 21: 822-827). Interestingly, wounds, treat drug - Becaplermin in the above PDGF-BB study were small and superficial, and that they in no case may not be comparable in size or severity with wounds that were treated according to the claimed invention. With another hundred the ons, a clinical trial was carried out on neuropathic ulcers of the foot with normal arterial blood supply. In our case, treated and shivlani severe ischemic ulcers related to stages IV and V according to the classification by Wagner. Most of the wounds, which were controlled, were ischemic. All the wounds that have been processed, has an area of more than 20 cm2and a depth of 10 to 40 mm In a clinical trial PDGF-BB were involved only wounds with an area of about 2.7 ± of 3.45 cm2and 0.5 ± 0,49 cm deep. A critical aspect to be judged with the help of therapy PDGF-BB is a high rate of relapse. She was about 30% in three months.

Another new invention related to a large acute skin wounds, such as burns or chronic wounds such as venous ulcers, was the creation of bioisosteric equivalents of human skin. However, controlled clinical trial for ischemic diabetic foot ulcers have failed and it seems unlikely that any of the equivalents of human skin could regulate or reverse the course of the disease, based on ischemic process (Editorial. New Skin for Old. Developments in Biological Skin Substitutes. Arch Dermatol 1998; 134: 344-348).

In General, there is no conservative Le is to be placed, which proved effective in the healing of this type of wounds, and it is untreatable physiological behavior of the RAS is associated with local ischemia. Prevention of relapse can lead to even more complex symptomatology (complications).

Detailed description of the invention

The aim of the invention is the use of injectable pharmaceutical compositions containing epidermal growth factor (EGF), which helps to improve tissue survival and adaptation to hypoxia; composition allows you to adjust the healing of ischemic skin and chronic ulcers of the skin and adjacent soft tissue irreversibly. Composition adjusts the healing of ischemic ulcers or atypical wounds or wounds exposed to and damaged by the process of reperfusion arterial blood in the skin and adjacent neighboring tissues. In this context, ischemic wound is defined as a wound on the skin and soft tissues of the lower limb, resulting from human peripheral perfusion due to long-term damage to large and small vessels in a patient with diabetes. Wounds resulting from reperfusion, mainly formed after amputation or deep debridement, when to re-initiate saturated with oxygen blood flow after prolonged the periods of local hemodynamic perfusion. Alternatively, these processes may occur after surgical revascularization procedures in patients with diabetes.

The use of EGF in these lesions weakens the progressive degradation of the tissue, particularly on the shins and feet, associated with disruption of blood flow and accumulation of toxins in the tissues.

It was found that the composition initiates and stably supports the healing process of chronic ischemic wounds, the treatment of which at the present level was unsuccessful. Using the above composition, amputations can be avoided in cases where there are no other medical alternatives that are suitable for healing of ischemic and chronic wounds. It turned out that the composition is as well useful to reduce damage associated with surgical reperfusion, correcting complete healing of ischemic ulcers in/infected/neuropathic feet. The process of cell inhibition on the edges of the wound and subsequent blanching of tissue openly broken by the above treatment. This eliminates the need for additional and growing serious surgical treatment of wounds and partial amputations. Composition by usually chitosamine and curative effect enhances the healing of ischemic/infected/neuropathic ulcers diabetic foot.

p> The composition is administered by local infiltration within the wound edges and the base damage and the composition may contain a polypeptide derived from a natural source or chemical or biological by using recombinant technology or chemical synthesis. The insertion procedure is similar to the anesthetic blockade, including the introduction of needles into various points inside and on the contours of the affected area so that all the deep surface of the base and the edges of the wound was copiously irrigated specified composition. The composition is applied in 4 to 20 infiltration points so that the distance between each of those points provided was not more than 1.5, see the Number of points, subject to coating composition, it is obvious for skilled professionals in this field. Above wounds with large size typically requires more infiltration points. For qualified specialist in this field is obvious pair of generally accepted effects during injection: local swelling and local resistance to the composition. Deep surgical treatment of the wound edges and the base is usually carried out in accordance with the experience of a qualified specialist in this field. In General, deep surgical treatment of wounds and minor amputation significantly obrashautsya after progress in treatment. If during the period of treatment the wound edges become atonic, these dead areas can be surgically removed and later infiltration should be in the subepithelial space. Infiltration is usually conducted on alternating days of the week, so each week to spend three infiltration session. The number of infiltration points in each session depends on the size of the wound, usually their number is in the range of 4-20. Infectious/ischemic wounds related to stages IV and V according to the classification by Wagner, the appearance of granulation tissue occurs after the sixth infiltration session. In the case of less severe wounds, you can see some response after the first week of treatment, then after three infiltration sessions. Alternatively, in the case of very severe ischemia associated with complete absence of pulsation in the arteries and anemia below 9 g/l, used the treatment according to the scheme of daily processing. In these patients, evidence of early signs of granulation appear approximately at the ninth session of infiltration. In all cases, the total amount to be injecting approximately 1 milliliter, so that the ulcer has received the total amount of the composition 4-20 ml, Preferably using hypodermal needles 271/2. The composition may contain an EGF polypeptide, in which scientists from a natural source, by chemical synthesis or using methods of recombinant DNA. The use described herein, pharmaceutical compositions containing EGF, allows you to fully regenerate tissue and chronic ischemic damage, taking into account the fact that this method is minimally invasive. In addition, the composition has reduced the number of minor amputations or major amputations. In other cases, the use of the invention described here allowed (I) to remove ischemic capsules without the need for surgery. This is probably due to the emergence of a new reconstructed granulation tissue from the deep zones, which rises and displaces necrotic tissue. (II) the growth inside the new skin februaryjune tissue resulting from successive infiltrations, before resorting to amputation, for example, toes, forming granulation environment, replacing the previous necrotic tissue. This helps to limit and stop septic complications, improves wound healing and reduces the damage induced by reperfusion.

The pharmaceutical composition may include the following components:

The epidermal growth factor (EGF):Chitosamine tool that adjusts the activation of defence mechanisms of the cells in the conduct of his ulcer. EGF promotes adaptation and preservation survival of cells to stress conditions. EGF triggers apoptosis in aged fibroblasts, such as fibroblasts damaged and/or aged, and acts as a survival factor in relation to the other, which ultimately saved. EGF exerts a selective effect within the microenvironment, which records the adapted cells to proliferate. Due to inherent EGF cytotaxonomy action damage caused by ischemia/reperfusion, are prevented. The composition contains 10-1000 micrograms/ml of sterile filler. EGF can be of natural origin, synthetic, or recombinant. EGF can be in liquid form, suspended in water, in solution with a buffer in the form of a freeze-dried, subjected to silica powder, etc. EGF may be in the form of a powder of finely granulate, and can be applied through the device, injectibles high pressure. EGF can be used in the form of his DNA inside the appropriate genetic constructs, suitable for transient expression in transfected human cells.

Polyethylenimine (PEI): Represents the protonated molecule that carries a high positive charge, which enhances the interaction of EGF with his recipe for the rum, prolong the half-life of EGF in the extracellular matrix and prevents its intracellular degradation, thereby enhancing its biological impact. The specified component may be present in the composition at a molar ratio of EGF:PEI from 1:1 up to 1:10.

Sodium phosphate buffer: a Chemical stabilizer. Its pH is about 6.5 and the molar concentration in the range of 5-100 mm. The optimal range of concentration in the composition is 10-20 mm.

D(+)-Raffinose: a Stabilizing means for a process of freeze-drying. You can use the concentration of 5-50 mg/ml, whereas the optimal range is 8-20 mg/ml

L-Glycine:Isotonic agent. You can use the concentration of 5-50 mg/ml, whereas the optimal range is 10-20 mg/ml

Fibronectin:Contributes to the stability of EGF with its biological functioning. It stimulates the interaction between EGF and its cellular receptors. The range of concentrations when using it is 10-20 mcg/ml

Levan:Is a protective agent for EGF, when EGF is in solution. It acts as a screening agent for EGF. Facilitates the biodistribution EGF within the extracellular space. The composition of this tool is in the concentration range of 1-20 mg/ml

Pharmaceutical composition which I also can contain EGF in combination the following active components:

Rutin:Phlebotonics and phlebotomine. It can be present in the composition at concentrations of 20-1000 μg/ml can be used in the form of a hydrate of the free routine or in the form of liofilizovannyh salt routine, such as sulfate.

Lidocaine:Trophic tool. Lidocaine reduces the secretion of Pro-inflammatory cytokines, which play the role of adhesion molecules inside the cavities of the vessels. Lidocaine used drugs in the form of hydrochloride and he may be present at concentrations in the range of 5-40 mg/ml

Adenosine triphosphate (ATP):He acts as vasodilator and has Pro-metabolic actions. Its concentration in the composition ranges from 0.05 to 20 mg/ml when used in the form of sodium salt or free acid.

The GTP-independent (GTP): Strengthens local vasodilatation. It is present in the composition in the form of sodium salt. Its concentration in the composition ranges from 1 to 100 mg/ml

Nicotinic acid amide (Nicotinamide): Makes useful anabolic substrates for cells. Its concentration ranges from 1 to 130 mg/ml

L-Arginine: Contributes to the regulation of vascular tone. Used in the composition in the form of crystals cleaners containing hydrochloride salt. Its concentration varies in the range of 1-100 ng/ml

Heparin: Chitosamine Pro-mitogenic sredstava in the composition in the form of sodium salt at a concentration in the range from 1 to 10 mcg/ml (0.1 to 1 S).

Composition r-EGF was prepared using generally accepted in the field of tools and techniques, for example, was carried out by mixing the ingredients to obtain solutions, sterilization and lyophilization, as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Pensylvania, 20th Edition, 2000, or similar pharmaceutical guidelines.

Examples:

Patients in the amount of 9 people received treatment a pharmaceutical composition. All patients had in common the following features of the disease:

1. All patients suffered from diabetes mellitus type II with disease duration of 10-25 years, most were treated with oral hypoglycemic drugs.

2. The dynamics of the difficult process of healing was recorded for all patients. Some patients were previously subjected to the contralateral amputations.

3. All outstanding treatment of the wounds were consistent with chronic diabetic ulcers of the extremities, which were klasifikovany as ischemic/infectious/neuropathic diabetic foot or as mixed forms. All wounds on his condition corresponded to stages IV or V according to the classification by Wagner.

4. All wounds should be treated by the claimed composition could be considered as wounds, untreatable or tradepolicies healing; some had a duration of one month and more.

5. All wounds occupies and area of about or greater than 20 cm 2; in most cases the depth of the ulcer is covered the periosteum, exposing the bone. Among patients was patient with concomitant ischemic heel bone.

6. All patients under treatment, was in a condition in which there was a high probability of requiring amputation.

7. All patients were subjected to control after discharge from the hospital and not one of them had until relapse. It was not observed any adverse reactions or local ischemic symptoms. It has not been registered no late adverse reactions to the end of the control.

The treatment was based on the deep infiltration of tissues near your damage by penetration through at least five different and equally-spaced points of the base of the wound and its contours. The needle should always be oriented towards the Central zone of the base of the wound, the edges of the wound and/or tunnels, if they exist. At each injection point per 1 ml solution. There are no adverse reactions during and after treatment, in addition to the usual local damage to the skin. The composition is always contained EGF as the main active component, although in some cases, the composition contained and some of the above active ingredients. All patients subjected Leche is tion, were prevented procedures minor amputation (toes, feet) or amputation (lower or upper limb). The total number of infiltration sessions for each patient are listed in each example.

Example 1:

The patient ACDF, age 49, female. The patient with ischemic/infectious diabetic foot, with experience of diabetes type II 16 years previously underwent sympathectomy and namyslowski amputation of the right limb two and a half years ago. The first finger of the left foot surgically removed as indicated ulcer, wet, atonic and trudnootdelema healing damage, despite minor debridement to remove ischemic capsules, restore the edges and base of the wound. Later, 5 days after surgery amputation rod becomes ischemic with cyanotic and atonic edges. Begin the infiltration of the song, waiting for spontaneous regeneration of epithelial ulcers. Since the fourth infiltration, there has been a sharp change in appearance of the wound, starting and productive education granulation tissue, bleeding, and after a few days the wound is covered again epithelium. The patient had received a total of 9 sessions infiltration (3 per week and, therefore, three weeks of treatment). After the reg is erali epithelium on the damaged surface, the patient was discharged from the hospital. It shows satisfactory development of re-examination.

Example 2:

The patient ERC, age 66 years, female. The patient experience of diabetes type II 12 years, bearing ischemic infectious foot and decreased distal pulses. Was carried out small transplacentally amputation, when it formed a large tunnel in the downward direction. After amputation the base of the zone amputation became cyanotic, ischemic, atonic and with a great touch of yellow component. Infiltration begin in anticipation of the start of production of granulation tissue and spontaneous secondary targeted healing. After 11 sessions infiltration of the affected wound foot fully healed thanks to the production of granulation tissue and re-covered with epithelium, including the tunnel. The healing was included and lateral tunnel about 4 cm in depth. This patient was first seen manifestations of reconstruction of the scar.

Example 3:

The patient ECS, age 63 years, a woman. The patient suffering from diabetes mellitus type II, who was diagnosed with it at the age of 41 years. Upon admission to the hospital, which reads: the presence of ischemic infectious foot and previously held the contralateral padmasambava amputation. The patient was hospitalized for held what I amputation of the first toe due to severe ischemia. After surgery implanted ischemic capsule base nearest the toe, which is moved back and down. At this point, the damage zone looked atonic and there was no progress in healing. The fingers and the surrounding soft tissue is removed, exposing the deep edge of the wound such as long tunnel 6 see Ischemic symptoms and signs of necrosis repeated again on day 3 after surgery. Three days later the contours of the wound become cyanotic and ischemic. Begin infiltration song, waiting for the secondary purposeful reaction of healing. Complete healing was achieved after 11 sessions infiltration when the patient is fully formed again kapitalizirovana wound with a well-keratinized epithelium. Patient discharged from hospital. Also watched the reconstruction of the scar.

Example 4:

The patient RNP, age 69 years, male. The patient experience of diabetes type II 12 years, when stated: decreased distal pulses and the presence of ischemic/infectious foot. The patient undergoes transmediterranea amputation due to ulcerative lesions, trudnootdelema healing with the help of modern therapy. At the site of surgical intervention occurred ischemic b is Yashka and the healing process, as it was found, was not developed in the direction of improvement. The patient complained of spontaneous pain in the affected layer. Cyanosis spread near the contours of the post-operative area and had a slight bleeding during readjustments of the wound area. Coronary plaques removed surgically and on the 4th day after the operation start of infiltration therapy. Signs of improvement tissue observed on the 6th day of the infiltration therapy, manifested in the disappearance of spontaneous pain and the appearance of red granulation tissue. After 12 infiltration sessions, which corresponds to 4 weeks of treatment, the patient is fully formed again kapitalizirovana wound. Patient discharged from hospital and he develop normally, with no recurrence during the 12-month follow-UPS.

Example 5:

The patient ISV, age 74 years, female. The patient suffering from diabetes for 30 years. The patient has ischemic/infectious foot. At the time of admission has previously held transplacentally amputation and fixed chronology difficulty healing. She was hospitalized due to necrotic lesions of the 5th toe. Perform surgery in the next few days appear coronary plaques. He who receives an additional reorganization of the wound cavity and the outer vast region of open wounds with exposed periosteum at the bottom and the outer side of the foot. The edge becomes ischemic within the next 48 hours and, therefore, proceed to infiltration therapy, trying to reach secondary spontaneous purposeful healing, including the edge. After the 6th infiltration appears useful granulation tissue with vascular network. The damage zone respond positively to treatment and after 11 infiltration sessions the damaged surface is completely covered with regenerated epithelium. The patient had a satisfactory condition after discharge from the hospital.

Example 6:

The patient RDR, 44 years old, male. Suffer from diabetes type II diabetes for 12 years. The patient has ischemic/infectious diabetic foot and ischemic injuries to two fingers of the foot moves transmitterallows amputation. The patient lacks the distal pulsations and demonstrates the clinical data are insufficient peripheral perfusion. He had a history of violations of the healing process on the contralateral tibial region. After the amputation on the skin contours of a wound appeared cyanotic lesions. Begin infiltration with the intention to produce a sufficient amount of granulation tissue as autograft for the owner or to heal and reconstruct according to the second intention. On the 4th of infiltration appear first shoots of granulate is authorized fabric and there is a resuscitation of the wound edges, also be normochromatic and gipertroficskie. The autograft was not needed. In the implementation of 15 sessions infiltration (5 weeks) no need for the implementation of autotransplantation. After discharge from hospital the patient had a successful development.

Example 7:

The patient RGR, age 49, female. A diabetic for about 10 years, with painful movement, accompanied by intermittent claudication (syndrome Charcot) at a distance of 100 meters and a background of difficult wounds. She had several trudnootdelema the treatment of ulcers on paratively area of both legs. The damage to be repaired, was ischemic ulcer on the lower third of the left tibia on its lateral outer side with a diameter of approximately 6.4 cm and a depth of 0.5 cm Ulcer progressed within two months without healing. The first approach to treatment was conservative surgical treatment of the base and edges of the wound, and then the next day began the treatment of the wound infiltration. The damage zone began to pelletize after the third infiltration, which was accompanied by compression of the edges and proliferation simple neo-epithelium, which, ultimately, became stratified and keratinized layer. There were 12 infiltration sessions (4 weeks of treatment). After discharge from the hospital the condition of the patient is and was satisfactory.

Example 8:

The patient GPJ, age 57 years. The patient diagnosed with diabetes mellitus type II 12 years ago. He has ischemic/infectious diabetic foot, without symptom tibial pulses. He takes transmitterallows amputation due to ischemia and necrosis 4 toes of the right foot. Seven days after amputation, the healing process is stopped and the wound edges become cyanotic and are lifeless with no sign of wound healing. Begin infiltration as an alternative to other surgical procedures. After 9 sessions (3 weeks), the patient was fully regenerated epithelium on the damaged surface. After discharge from the hospital he developed successfully without complications.

Example 9:

The patient DLF, age 51 years, male. Patient with history of type II diabetes and asthma approximately 20 years ago. The patient was hospitalized with a penetrating plantar ulcer with severe ischemia and necrosis of the surrounding tissue. Left foot is almost completely died. After surgery the heel bone ends exposed periosteum. Begin infiltration as an alternative treatment with the intention of preventing immediate amputation. The only possibility was the emergence of productive and vascularized granulation tissue, suitable for a host of skin Tran is plantat. Conducted a total of 15 sessions infiltration, covering the heel bone. After the 5th infiltration begins to emerge granulation tissue. After 15 sessions infiltration (5 weeks) graft was implanted. The patient was successfully developed. Currently, he is able to walk on her own.

Table 1.
Composition and active ingredients enter each patient.
The patient ID.Track
ACDFEGF (50 μg/ml) + Rutin (50 mg/ml)
ERCEGF (125 μg/ml sodium buffer solution, pH 6.5+20 mg D (+)-raffinose and 10 mg L-glycine/ml buffer)
ECSEGF (125 μg/ml) + Lidocaine (10 mg/ml)
RNPEGF (10 μg/ml) + ATP (2.5 mg/ml)
ISVEGF (100 μg/ml) + GTP (5 mg/ml)
RDREGF (30 μg/ml) + NAD (25 mg/ml)
RGREGF (25 μg/ml) + L-arginine (10 ng/ml)
GPJEGF(100 μg/ml) + Heparin (Of 0.75 u/ml)
DLFEGF (100 μg/ml sodium buffer solution, pH 6.5+10 mg D(+)-raffinose, 100 μg of fibronectin and 15 mg L-glycine

1. The use of epidermal growth factor (EGF) for the treatment of wounds on the skin and soft tissues of the lower extremity in a patient with diabetes by local infiltration of the pharmaceutical composition in the form of a solution EGF at different points inside and along the edges of a zone of tissue damage so to wound received total composition 4-20 ml, and all the deep surface of the base and the edges of the wounds were irrigated specified composition.

2. The use of epidermal growth factor according to claim 1, where the specified wound in the lower limbs is located on the foot, lower or upper leg, or on both parts.

3. The use of epidermal growth factor according to claim 1, where said treatment makes amputation or incremental re-amputation unnecessary.

4. The use of epidermal growth factor according to claim 1, where the specified EGF is human EGF.

5. The use of epidermal growth factor according to any one of predshestvuyuschih points where the solution EGF restored before using water or aqueous buffer of EGF-containing freeze-dried powder, or powder of finely granulate.

6. The use of epidermal growth factor according to claim 5, where the solution is water, optionally buffered.

7. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition contains EGF in the range from 10 to 1000 micrograms of EGF per ml.

8. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition additionally contains at least one representative from the group consisting of fibronectin, O-raffinose, Levan and the floor is etilenimina (PEI) in an amount of from 10 micrograms to 500 micrograms per milliliter.

9. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition further comprises at least one natural isoflavonoid in the amount of from 20 to 1000 micrograms per milliliter.

10. The use of epidermal growth factor according to claim 9, where the specified natural isoflavonoids is rutin.

11. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition additionally contains lidocaine in an amount of 5 to 40 milligrams per milliliter.

12. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition additionally contains adenosine triphosphate (ATP) or its salt in an amount of from 0.05 to 20 milligrams per milliliter.

13. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition further comprises a GTP-independent (GTP) or its salt in an amount of from 1 to 100 milligrams per milliliter.

14. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition further comprises nicotinamide in an amount of from 1 to 130 milligrams per milliliter (mg/ml).

15. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition further comprises L-argine is in an amount of from 1 to 100 nanograms per milliliter.

16. The use of epidermal growth factor according to claim 1, where the specified EGF-containing pharmaceutical composition further comprises a salt of heparin in an amount of from 1 to 10 micrograms per milliliter.

17. The use of epidermal growth factor according to claim 1, where said treatment local infiltration is carried out every day, every other day, once every three days, two or three times a week.

18. The use of epidermal growth factor according to claim 1, where said treatment local infiltration exercise three or more times, preferably from 4 to 20 times.

19. The use of epidermal growth factor according to claim 1, where said treatment local infiltration is carried out each time on three or more areas of the lesion, preferably from 4 to 20 sites distributed around the circumference of the damaged area.



 

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10 cl, 1 tbl, 411 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel analogs of fatty acids of the general formula (I): R1-[Xi-CH2]n-COOR2 wherein R1 represents (C6-C24)-alkene with one or more double bond, and/or (C6-C24)-alkyne; R2 represents hydrogen atom or (C1-C4)-alkyl; n represents a whole number from 1 to 12; I represents an uneven number and shows position relatively to COOR2; Xi is chosen independently of one another from the group comprising oxygen (O), sulfur (S) and selenium (se) atom and -CH2 under condition that at least one among Xi is not -CH2 and under condition that if R1 represents alkyne then a carbon-carbon triple bond is located between (ω-1)-carbon atom and (ω-2)-carbon atom, or between (ω-2)-carbon atom and (ω-3)-carbon atom, or between (ω-3)-carbon atom and (ω-4)-carbon atom, and to their salts and complexes. The claimed compounds can be used in treatment and/or prophylaxis of X syndrome, obesity, hypertension, hepatic fatty dystrophy, diabetes mellitus, hyperglycemia, hyperinsulinemia and stenosis. Also, invention relates to methods for preparing novel analogs of fatty acids. Also, invention relates to a nutrient composition comprising indicated analogs of fatty acids and to a method for reducing the total body mass or amount of lipid tissue in humans or animals. Invention provides the development of novel fatty acid analogs-base compositions or methods for suppression of stenosis, restenosis or associated disorders as result of proliferation and mobilization of vessel smooth muscle cells after, for example, traumatic damages of vessels during surgery operation in vessels.

EFFECT: improved preparing method, valuable medicinal properties of analogs.

12 cl, 2 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present insulin solution for peroral intake should be applied for treating patients with diabetes mellitus. The suggested insulin solution consists of water and insulin, additionally, it contains sodium chloride at the following ratio of components, weight%: insulin 0.005-0.02, sodium chloride 0.5-1.0, water - up to 100.0. The innovation provides decreased glucose level in blood of animals in case of peroral intake of the solution up to 40% at insulin dosages being about 10 U/kg animal body weight.

EFFECT: higher efficiency.

12 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel lactam compounds of the formula (I) or their pharmaceutically acceptable salts wherein A means phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl; R2, R3 and R4 can be similar or different and mean independently of one another hydrogen atom (H), halogen atom, -OH, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -NH2, -NO2, -CF3, phenyl that can comprise substitute(s), benzyloxy-group that can comprise substitute(s), pnehylvinyl, and one among R2, R3 and R4 means -CF3-O- and others mean H; B means phenyl that can comprises substitute(s), monocyclic aliphatic (C3-C8)-ring, dihydropyrane ring; -X- and -Y- xan be similar or different and they mean independently -O-, -NH-, -NR5-, -S-; Z means -CH2-, -NH-; W means -NR1-, -CR8R9- wherein R1 means H; R8 and R9 are similar or different and mean H; wherein R5 represents a linear alkyl group that can comprise substitute(s), (C1-C8)-linear or branched alkoxycarbonyl group, acyl group chosen from formyl group, acyl group comprising (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl group that can comprise substitute(s), carbamoyl group comprising (C1-C6)-alkyl group at nitrogen atom that can comprise substitutes, sulfonyl group comprising (C1-C6)-alkyl group at sulfur atom that can comprise substitute(s); each among a, b and c represents position of carbon atom under condition that: (i) substitute(s) is chosen from the group comprising halogen atom, -OH, (C1-C6)-alkyl, mercapto-group, (C1-C6)-alkoxy-group, -NO2, -COOH, -CF3, phenyl, -NH2, (C1-C8)-linear or branched alkoxycarbonyl group, (C1-C8)-linear or branched acyl group, (C1-C8)-linear or branched acyloxy-group; (ii) when B represents benzene ring, each among -X- and -Y- represents -NH-, -Z- represents -CH2- and -W- represents -NH- then R2, R3 and R4 can not mean phenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group, 2-hydroxyphenyl group, 3,4-dimethoxyphenyl group or 3-methoxy-4-hydroxyphenyl group. Compounds of the formula (I) show the enhanced capacity for transport of sugar and can be used in pharmaceutical compositions for prophylaxis and/or treatment of diabetes mellitus and diabetic nephropathy.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 21 tbl, 54 ex

FIELD: chemistry of heterocyclic organic compounds, medicine.

SUBSTANCE: invention relates to a novel heterocyclic derivative of the formula (I'): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents-CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R5 represents (C2-C8)-alkenyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; R20 represents phenyl substituted with unsubstituted (C1-C6)-alkyl, (C1-C6)-alkyl substituted with fluorine atom, (C1-C4)-alkoxy-group, phenyl-(C1-C4)-alkoxy-group, hydroxyl group, halogen atom, nitro-group, unsubstituted amino-group or amino-group substituted with (C1-C4)-alkyl; n means a whole number from 1 to 4, or to its pharmaceutically acceptable salt. Also, invention relates to heterocyclic derivative of the formula (I): , wherein R1 represents hydrogen atom or (C1-C6)-alkyl; R2 represents -CO-C(R4)=C(R4)-R5 wherein R4 represents hydrogen atom; R represents (C4-C8)-alkyl or (C2-C8)-alkenyl or -CO-C≡C-R6 wherein R6 represents (C1-C8)-alkyl; R3 represents hydrogen atom or (C1-C4)-alkyl; X represents oxygen atom or sulfur atom; n means a whole number from 1 to 4, or its pharmaceutically acceptable salt. Compounds of the formulas (I') and (I) are effective as a hypoglycemic agent, hypolipidemic agent, agent improving resistance to insulin, therapeutic agent in treatment of diabetes mellitus, therapeutic agent in treatment of diabetes mellitus complications, agents enhancing tolerance to glucose, anti-arteriosclerotic agent, agents against obesity or agent for X syndrome.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 2 tbl, 56 ex

FIELD: medicine.

SUBSTANCE: method involves first introducing chemical compound of local anesthetic activity into paraneural space of sympathetic trunk and retroperitoneal space under ultrasonic control. Next, chemical compound causing superficial injury of sympathetic nerve is introduced.

EFFECT: avoided negative consequences of total sympathectomy and radiation loading.

2 dwg

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with obtaining compositions being of bactericidal, antiphlogistic, regenerating, antioxidant and antimicrobial properties at no allergic action. Wound-healing preparation (variant 1) contains: stearic acid 4.5-6.0; purified lanolin and its derivatives 3.0-6.0; vegetable oil 3.0-5.0; Vaseline 1.5-2.5; glycerol 4.0-8.0; castor oil 8.0-12.0; zinc stearate 1.0-2.5; 70%- alcoholic extract of phytospecies 2.5-3.5; extract of common John's wort grass 3.5-8.5; dog rose oil or sea buckthorn oil 2.6-6.0; Na-salts of fatty acids of wool fat 0.3-0.6; triethanolamine 0.7-1.1; anesthesin 2.0-3.0; 10%-butyric solution of propolis 0.3-1.0; boric acid 0.4-0.6; purified water - the rest. Wound-healing preparation (variant 2) contains: stearic acid 4.5-6.0; purified lanolin and its derivatives 3.0-6.0; vegetable oil 3.0-5.0; Vaseline 1.5-2.5; glycerol 4.0-8.0; castor oil 8.0-12.0; zinc stearate 1.0-2.5; 70%-alcoholic extract of phytospecies 2.5-3.5; extract of common John's wort 3.5-8.5; dog rose oil or sea buckthorn oil 2.6-6.0; Na-salts of fatty acids of wool fat 0.3-0.6; triethanolamine 0.7-1.1; anesthesin 2.0-3.0; levomycetin or gentamycine 2.0-3.0; 10%-butyric solution of propolis 0.3-1.0; boric acid 0.4-0.6; purified water - the rest. Additional introduction of the extract of common John's wort has increased antioxidant properties; 10%-butyric propolis - antioxidant and bactericidal properties, and levomycetin and gentamycine - has widened the range of antimicrobial action. Application of the preparation suggested in patients with burns and wounds revealed positive therapeutic effect without any cicatricial neoplasms and allergic action. No contraindications had been established.

EFFECT: higher efficiency of application.

4 cl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with compositions of ingredients that have curative indication due to external application at patient's body. The suggested ointment contains vegetable oil, wax as fatty product, rivanol, tannin, glycerol as antiseptic at the following ratio of components, weight%: wax 13-15; rivanol solution 1.2-1.3; tannin 3-5; glycerol 15-20; vegetable oil - the rest. The innovation provides increased efficiency of healing action at no side complications.

EFFECT: higher efficiency of therapy.

4 ex, 1 tbl

FIELD: dermatology, cosmetology, in particular treatment of skin cicatrice treatment.

SUBSTANCE: claimed method includes application of collagenase preparation in therapeutically effective dose which is administered intradermally directly into pathological region by multiple injections in depth of 2-5 mm on distance of approximately 1 cm. Cure includes 10-20 sessions, wherein sessions are carried out one time per 7-10 days.

EFFECT: simplified method of increased effectiveness.

3 ex, 2 cl

FIELD: medicine, in particular treatment of endophagus chemical burns.

SUBSTANCE: claimed method includes application of pharmaceutical compositions in form of two regencur-based gel-like compositions perorally or through catheter, wherein for one week in second/third steps of burn process development method includes application of composition containing (g per 100 g): metronidazole 0.75; prednisolone 0.05; lidocaine hydrochloride 0.1; sodium saccharinate 0.24; natural-identical food flavoring 0.5; regencur 4.0; glycerol 8.0; and balance: water. Then in fourth step of burn process development for two weeks composition is used that contains (g per 100 g): metronidazole 0.75; methyluracil 2.0; lidase 128 U; sodium saccharinate 0.24; natural-identical food flavoring (strawberry) 0.5; regencur 4.0; glycerol 8.0; and balance: water.

EFFECT: formation of more smooth cicatrix; shorter time of endophagus mucous epithelialization.

5 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: invention relates to surgery methods of treatment. Method involves insertion of gel into wound representing a photosensitizing agent comprising 0.5-1.5% of chlorin E6 glucamine salt followed by carrying out treatment of wound by laser in continuous regimen at wavelength 660 nm, energy density supplied to wound 30-40 J/cm2 and power density 0.8-1.0 Wt/cm2. Method provides simplifying, acceleration and enhancing effectiveness of treatment based on using the optimal density of radiation powder. Invention can be used in treatment of spacious suppurative diseases of soft tissues.

EFFECT: improved method of treatment.

3 ex

FIELD: veterinary.

SUBSTANCE: claimed ointment contains (mass %): fir oil 5.0-10; xeroform 3.0-6.0; and balance: ointment base.

EFFECT: nontoxic and hypoallergic ointment of with high effectiveness and prolonged storage time.

7 ex

FIELD: pharmaceutical industry, in particular production of ointment having antiinflammation and antimicrobial activity.

SUBSTANCE: method for ointment production includes extraction of ground dogwood stones with chloroform during certain time followed by solvent removing and isolation of lipophilic fraction. Then dried solvent cake from dogwood stones is extracted with boiled purified water, solvent is removed and hydrophilic fraction is isolated. Further emulsifier, petrolatum and lipophilic fraction taken in specific ratio are fused at certain temperature; mixture is cooled and blended with water purified and heated up to certain temperature; obtained mixture is blended with solution comprising purified hydrophilic fraction, glycerol and water taken in specific ratio.

EFFECT: ointment of increased antiinflammation and antimicrobial activity.

2 tbl, 6 ex

FIELD: pharmaceutical industry, in particular production of ointment having antiinflammation and antimicrobial activity.

SUBSTANCE: method for ointment production includes grinding of plant raw materials namely solid coconut husk up to certain particle size; extraction with chloroform during certain time followed by solvent removing and isolation of lipophilic fraction. Further emulsifier, lipophilic fraction and coconut oil are fused under specific conditions; mixture is cooled to certain temperature and blended with celandine juice heated up to certain temperature.

EFFECT: ointment of increased antiinflammation and antimicrobial activity.

3 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical composition preferably in ointment form for treatment of skin lesions containing as active ingredient dexpanthenol and target additives such as fatty additives, namely solid, soft and liquid additives, emulsifier and water. As emulsifier cetostearyl alcohol is used. Composition of present invention has storage time not less than 2 years.

EFFECT: composition of improved quality and prolonged storage time.

8 cl, 2 tbl, 6 ex

FIELD: chemical engineering.

SUBSTANCE: method involves pretreating bone tissue of stock-farm animals, comminuting it, precipitating the end product and drying it by lyophilizing. The bone tissue is degreased with alcohol-ether mixture. Demineralization 0.5 and HCl is carried out after grinding during 20 h. Non-resolvable matrix is subjected to proteolysis in HCl of pH=2.0 in pepsin presence at 37°C during 18 h. Then it is centrifuged at 40000g. The end product is precipitated from supernatant with ammonium sulfate to 25% saturation and centrifuged at 6000g. The precipitate is lyophilized against distilled water and chromatographically purified using CM-Sephadex at pH=4.8 and dried with lyophilization.

EFFECT: low cost collagen production; high purity cosmetic preparation production.

2 dwg

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