Inhibitors of glycogen synthase kinase-3 (gsk-3) in glaucoma treatment

FIELD: medicine, ophthalmology, medicinal biochemistry.

SUBSTANCE: invention relates to manufacturing ophthalmic composition used for reducing intraocular pressure. Invention proposes using inhibitors of glycogen synthase kinase-3. Proposed composition provides reducing intraocular pressure by increasing intraocular liquid efflux and to prevent loss of retina ganglion cells.

EFFECT: valuable medicinal properties of inhibitors.

19 cl, 6 ex

 

The present invention relates to inhibitors of kinase-3 glikogensintetazy used to reduce and regulate normal or elevated intraocular pressure (IOP) and glaucoma treatment.

Background of invention

Pathological condition called glaucoma, is characterized by a permanent reduction of visual function due to irreversible damage of the optic nerve. Glaucoma several morphologically and functionally different types usually are characterized by elevated IOP, which, as expected, etiological associated with pathological development of this disease. Ocular hypertension is a condition in which increased intraocular pressure, but is not noticeable reduction in visual function, and these patients belong to the risk group with a high probability of vision loss associated with glaucoma. Some patients with glaucoma narrowing of the field of view is relatively low intraocular pressure. These patients with so-called normotensive or hypertensive glaucoma favorable effect can also give agents, reducing and regulating IOP. If glaucoma or intraocular hypertension is detected at an early stage and immediately subjected to treatment with drugs, the effect of the EIT reducing elevated intraocular pressure, the decline in visual function or progressive deterioration can be mostly suspended. Drug therapy, which, as has been confirmed, is effective to reduce intraocular pressure, involves the use of agents that reduce the level of watery moisture, and agents, contributing to the outflow of fluid from the eye. Such therapeutic agents mainly introduce one or two ways, topically (directly in the eye) or oral.

Some individuals in the treatment of some known methods of therapy of glaucoma is not observed satisfactory answer. There is therefore a need for other therapeutic agents topical application, which regulate IOP.

Brief description of the invention

The present invention relates to inhibitors of GSK-3, which can be used for the treatment of glaucomatous neuropathy of the optic nerve and/or for the reduction and regulation of IOP associated with normotensive glaucoma and intraocular hypertension, and/or for the treatment of glaucoma in warm-blooded animals, including humans. These connections are made in the form of pharmaceutical compositions suitable for local injection into the eye.

Description of the preferred embodiments of the invention

Increased intraocular pressure (IOP) hour is about is a sign of glaucoma. Unregulated, constant and prolonged increase of IOP can lead to progressive damage of the retina and reduced visual function. Therefore, to reduce the likelihood of development or progression of glaucomatous retinopathy treatment of patients with glaucoma often aimed at reducing IOP. It was shown that even in patients with glaucoma, which is not detected elevated IOP, there is a beneficial effect in the treatment agents that reduce or control IOP. Unfortunately, some individuals in the treatment of glaucoma some existing methods are not satisfactory answer.

Wnt proteins constitute a large family of structurally related ligands that activate the transmission of Wnt signal. A collection of "twisted" (frizzle) proteins includes key components that are involved in this way and serve as a membrane-associated receptor for Wnt. "Tortuous" proteins are a family of seven transmembrane proteins that have an N-terminal extracellular rich in cysteine domain and cytoplasmic carboxylate tail. The binding of Wnt with "tortuous" proteins initiates a cascade of events, one of which leads to inhibition (GSK-3), which prevents phosphorylation β-catenin. Phosphorylation β-catenin, prevadid its decomposition. Activation of the Wnt pathway leads to increased intracellular concentrations of non-complex β-catenin that can activate transcription of a gene dependent on the complex "β-catenin - T-cell factor/factor stimulation of lymphoid cells (TCF/Lef)".

Proteins related "tortuous" proteins (FRP)are a family of secreted proteins with cysteine rich regions that are homologous to regions of the family "tortuous" proteins, but lacking the transmembrane segments available to these "twisted" proteins. Secreted FRP act as antagonists transmission Wnt signal by binding of extracellular Wnt and prevent its interaction with "tortuous" proteins or through the formation of nonfunctional complexes with "tortuous" receptor. Bafico et al. (1999).

Recently it was discovered that a protein related "tortuous" protein (FRP)are differentially expressed in several cell lines glaucomatous trabecular network. Perfusion FRP-1 through perfoirmance anterior segments of human eyes, supported in culture leads to the reduction of the flow velocity and a corresponding decrease in levels of protein β-catenin in the ciliary body and trabecular network (TC). The reduction of the flow velocity in cultured models of the front segments leads to increased resistance to outflow (Uwe is icenew intraocular pressure) in the intact eye. These results indicate that there is an active transmission Wnt signal in the TS and in the ciliary body, and suggest that this path is at least partially responsible for maintaining the level of the fluid from the vehicle and thereby for the regulation of IOP.

Since the intracellular level β-catenin at least partially regulated by its phosphorylation under the action of GSK-3, inhibition of GSK-3 leads to increased levels of non-soluble complex β-catenin, regardless of the levels of FRP. Inhibitors of GSK-3 "escape" from FRP-mediated suppression of transmission Wnt signal induced elevated levels of FRP, and prevent an increase in resistance to outflow, which is the result of an increase in the level of production of FRP in individuals with glaucoma.

Increased expression of FRP was also detected in the retina of donors with retinitis pigmentosa (RP). PR is a number of degenerative diseases that affect the photoreceptors and lead to blindness. Because FRP stimulates apoptosis of neurons in vitro, it is assumed that the presence of elevated levels of FRP indicates that FRP-mediated disturbance transfer Wnt signal causes retinal degeneration. Although glaucoma is associated with selective loss of ganglion cells of the retina, but not cells, photoreceptors, one is to, glaucoma toxicity caused by increased expression of FRP or other mechanism, operated by the GSK-3-mediated way, can lead to loss of ganglion cells of the retina in glaucoma. Therefore, inhibitors of GSK-3 must prevent the loss of retinal ganglion, as well as to contribute to the reduction of intraocular pressure by increasing outflow of aqueous humor.

Without pretending to a particular theory, the authors present invention indicate that inhibition of GSK-3 will lead to the reduction and regulation of normal or elevated intraocular pressure (IOP) and will have a positive effect on the neuropathy of the optic nerve associated with glaucoma. Compounds that act as inhibitors of GSK-3, is well known in the art and are used for various purposes, mainly for the treatment of disorders or conditions associated with diabetes, dementia, such as Alzheimer's disease and manic-depressive psychosis. In U.S. patent No. 6057117 described the use of selective inhibitors of GSK-3 for the treatment of diseases associated with the activity of GSK-3, including diabetes. In WO 00/38675 described method of treating conditions associated with a need for inhibition of GSK-3, such as diabetes; conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as the disease is of lzgamer, manic-depressive psychosis; mood disorders, such as schizophrenia; neurotraumatic disorders, such as acute shock, hair loss and cancer. In WO 00/21927 describes some pyrrole-2,5-dinavia derivatives, which are inhibitors of GSK-3 and used for the treatment of diabetes, dementia, such as Alzheimer's disease, manic-depressive psychosis. In WO 01/56567 described derivatives of 2,4-diaminetetra and their use as inhibitors of GSK-3, in WO 01/49709 described peptide inhibitors of GSK-3, in WO 01/47533 describes the development of modulatory strategies for the treatment of various diseases. In WO 01/41768 described using geminiengine or its derivatives for the inhibition of cyclin-dependent kinases, GSK-3-beta and casein kinase 1 for the treatment of neurodegenerative disorders such as Alzheimer's disease, diabetes, inflammatory diseases and cancer. In WO 01/37819 described using indirubin derivatives to obtain drugs, inhibiting GSK-3-beta.

It was reported (Leost et al., 2000)that some analogues pullano are inhibitors of GSK-3. It is expected that these compounds may be used for research and possibly for the treatment of neurodegenerative and proliferative disorders.

It was reported that 3-aniline-4-arylmaleimides are strong and selective inhibitors of GSK-3 (Smith et al., 2001).

Geniality is an inhibitor of GSK-3. It has been suggested that it may be used to treat neurodegenerative disorders (Thunnissen et al. 2000).

It was reported that inhibitors of protein kinase C, GF1092 and Ro 31-8220, are inhibitors of GSK-3 (Tavare et al., 1999).

Indirubin inhibit GSK-3 (Garnier et al., 2001). Described the possible use of these indirubin for the treatment of neurodegenerative disorders.

Inhibitors of GSK-3, SB-415286 and SB216763 protect both Central and peripheral grown in culture neurons from death induced by low activity phosphatidylinositol path (Cross et al., 2000).

So far not described the use of these compounds for the reduction and regulation of normal or elevated intraocular pressure (IOP) and glaucoma treatment.

The present invention relates to the treatment of glaucoma through inhibition of GSK-3. It is believed that the methods of the present invention can be used any GSK-3-inhibitory connection. The authors of the present invention believe that may be, in particular, used any of the compounds described in WO 00/38675; WO 00/21927; Coglan et al. 2000, Leost et al. 2001; Smith et al., 2001; Garnier et al., 2001; Cross et al., 2001; Thunnissen et al., 2000; Tavare et al. 1999 (discussed above, each of which is incorporated into this description by reference).

In one of predpochtitelnei embodiment of the invention, the compound for use in the methods of the present invention are selected from compounds defined in the works: WO 00/21927, EP 470490, WO 93/18766, WO 93/18765, EP 397060, WO 98/11103, WO 98/11102, WO 98/04552, WO 98/04551, DE 4243321, DE 4005970, DE 3914764, WO 96/04906, WO 95/07910, DE 4217964, US 5856517, US 5891901, WO 99/42100, EP 328026, EP 384349, EP 540956, DE 4005969 or EP 508792.

The preferred compounds are the compounds of formula

where R1and R2independently mean

R3=H, C1-6alkyl, (UN)substituted phenyl, With1-6alkyl-NR6R7With1-7-cycloalkyl,1-6alkyl-OR6With1-6alkyl-S(O)2R5With1-6alkyl-C(O)NR6R7;

R4=H, or one or more alternates With1-6alkyl, (UN)substituted phenyl, -OR6, -SR6, halogen, (UN)substituted phenoxy, -CN, -NO2With1-6alkyl-NR6R7, -NR6R7With1-7-cycloalkyl, (UN)substituted heterocyclyl, S(O)2R5With1-6alkyl-S(O)2R5With1-6alkyl-C(O)NR6R7; and

R5, R6, R7=H, C1-6alkyl, (UN)substituted phenyl.

Preferably

R1=A, b; R2=,;

R3=H, C1-6alkyl, C1-6alkyl-NR6R7With1-6alkyl-OR6With1-6alkyl-S(O)2R5With1-6alkyl-C(O)NR6R7;

Rsup> 4=H, or one or more substituents: With1-6alkyl, (UN)substituted phenyl, -OR6, halogen, (UN)substituted phenoxy,

-NO2With1-6alkyl-NR6R7, -NR6R7, (UN)substituted heterocyclyl, S(O)2R5With1-6alkyl-S(O)2R5With1-6alkyl-C(O)NR6R7; and

R5, R6, R7=H, C1-3alkyl.

The most preferred compounds for use in the methods of the present invention are

3-(1-[3-aminopropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione and

3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.

In other embodiments of the invention, the compounds used in the methods of the present invention, are selected from analogs of indirubin defined in WO 01/37819. Basically, the preferred compounds are indirubin, 5-iodine-indirubin-3'-monoxime, 5-(hydroxyethylsulphonic)indirubin, indirubin-3'-monoxime, 5-(methyl)sulfonamide of indirubin and 5-(dimethyl)-sulfonamide of indirubin.

Other embodiments of the invention include compounds selected from 2,4-diaminetetra analogues defined in WO 01/37819. The preferred compounds are

(4-amino-2-phenylimidazol-5-yl)cyclopropylmethanol,

(4-amino-2-phenylimidazol-5-yl)-(4-forfinal)methanon,

(4-amino-2-phenyl shall mintezol-5-yl)phenylmethanone,

(4-amino-2-phenylimidazol-5-yl)pyridine-3-ylmethanol,

1-(4-amino-2-phenylimidazol-5-yl)propan-1-he,

(4-amino-2-phenylimidazol-5-yl)-(3,4-differenl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(3-forfinal)methanon,

(4-amino-2-phenylimidazol-5-yl)naphthalene-2-ylmethanol,

(4-amino-2-phenylimidazol-5-yl)biphenyl-4-ylmethanone,

(4-amino-2-phenylimidazol-5-yl)-(3-benzyloxyphenyl)methanon,

[4-amino-2-(4-brompheniramine)thiazol-5-yl]cyclopropylmethanol,

(4-amino-2-phenylimidazol-5-yl)-(3,4-dichlorophenyl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(3-methylbenzo[b]thiophene-2-yl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(2-methoxyphenyl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(3-methoxyphenyl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(4-methoxyphenyl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(4-chloro-3-were)methanon,

(4-amino-2-propylimidazol-5-yl)pyridine-3-yl-methanon,

(4-amino-2-phenylimidazol-5-yl)pyridin-2-yl-methanon,

(4-amino-2-phenylimidazol-5-yl)pyridin-4-yl-methanon,

(4-amino-2-phenylimidazol-5-yl)thiophene-2-yl-methanon,

(4-amino-2-phenylimidazol-5-yl)thiophene-3-yl-methanon,

(4-amino-2-phenylimidazol-5-yl)-(2,6-differenl)methanon,

(4-amino-2-phenylimidazol-5-yl)-(2,6-dichlorophenyl)methanon,

1-(4-amino-2-phenylimidazol-5-yl)Etalon,

[4-amino-2-(pyridine-3-ylamino)thiazol-5-yl]meta is he,

[4-amino-2-(pyridine-3-ylamino)thiazol-5-yl]phenylmethanone,

[4-amino-2-(3-methoxypropylamine)thiazol-5-yl)]pyridine-3-ylmethanol,

ethyl ester of 3-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid,

[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxy-phenyl)methanon,

[4-amino-2-(4-chlorpheniramine)thiazol-5-yl]-(3-benzyloxyphenyl)-methanon and

(4-amino-2-ethylaminoethanol-5-yl)phenylmethanone.

In another embodiment of the invention, the methods of the present invention can be used compounds selected from a derivative or analogue 1,2,4-triazolinone acid defined in WO 01/09106. Preferred derivatives of 1,2,4-triazolinone acids are

3-amino-5-aniline-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-(3,4-methylenedioxybenzyl)-1,2,4-triazole,

3-amino-5-aniline-2-(3-TRANS-(2-ferracioli)-1,2,4-triazole,

3-amino-5-aniline-1-(3-TRANS-(2-ferracioli)-1,2,4-triazole,

phenylamide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

cyclohexylamin 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

cyclohexylamin 3-amino-5-aniline-1,2,4-triazole-1-carboxylic acid,

3-amino-5-(5-chloro-2-methylaniline)-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-(4-chlorbenzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-naphtol)-1,2,4-triazole,

3-amino-5-aniline-2-(3-bromobenzoyl)-1,2,4-triazole,

3 am is but-5-aniline-2-(4-phenylbenzyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-trifloromethyl)-1,2,4-triazole,

3-amino-5-aniline-2-((3-benzoyl)benzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-biphenylyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-titilate)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-phenylthiazol-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-phenoxybenzoyl)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-cyclohexylcarbonyl-1,2,4-triazole,

3-amino-5-aniline-2-phenylacetyl-1,2,4-triazole,

3-amino-5-aniline-2-(3-nicotinyl)-1,2,4-triazole,

3-amino-5-aniline-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-acetylbenzoic)-1,2,4-triazole,

3-amino-5-aniline-2-(3-indolylacetic)-1,2,4-triazole,

3-amino-5-aniline-2-(4-pertenecer)-1,2,4-triazole,

3-amino-5-aniline-2-(3-bromobenzoyl)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(3-benzoylphenyl)-1,2,4-triazole,

3-amino-5-aniline-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(3-benzoylbutyric)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoic)-1,2,4-triazole,

4-biphenylamine 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-phenoxyphenyl)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-bromo-2-were)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(1-naphthyl)amide 3-amino-5-a is ilino-1,2,4-triazole-2-carboxylic acid,

(3-methoxyphenyl)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-chlorophenyl)amide 3-amino-5-(4-methoxyaniline)-1,2,4-triazole-2-carboxylic acid and

3,5-diamino-2-benzoyl-1,2,4-triazole.

In some embodiments of the invention can be used geniality or its derivative or analog, are described in WO 01/41768. The preferred compounds are

geniality (4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-he),

4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-he

4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-he.

In other embodiments, the methods of the present invention involve the use of analogues Paullina, including 9-Mitropoulos, 9-pompolo, 9-globulin and 9-bromo-12-methoxycarbonylmethylene.

Compounds of the present invention can be included in the ophthalmic compositions of various types for introduction into the eye (e.g., locally, inside the camera eye or via an implant). These compounds are preferably introduced into the composition in ophthalmic compositions local use for their delivery in the eye. These compounds can be combined with ophthalmically acceptable preservatives, surfactants, agents, polysoude and viscosity, agents that increase the permeability, buffers, sodium chloride, or water to obtain aqueous, sterile ophthalmic suspension or sterile aqueous ophthalmic solution. Ophthalmic preparations in the form of solutions can be obtained by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. In addition, the ophthalmic solution may include ophthalmically acceptable surfactant to improve the dissolution of this compound. In addition, the ophthalmic solution may contain an agent that increases the viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hypromellose, methylcellulose, polyvinylpyrrolidone or the like, to increase the residence time of the specified drug in the conjunctival SAC. Can also be used gelling agents, which include, but are not limited to, 'gellan and xanthan gum. To obtain sterile ophthalmic preparations in the form of ointment active ingredient combined with a preservative in an appropriate medium such as mineral oil, liquid lanolin, or white vaseline oil. Sterile ophthalmic preparations in the form of a gel can be obtained by suspension of the compounds in the hydrophilic base is received in the merger, N. the example, with carbopol-974 or the like in accordance with known methods of preparation is similar to ophthalmic drugs, and these drugs can be included preservatives and agents, giving toychest.

These connections are preferably prepared in the form of ophthalmic suspensions or solutions for local use, having a pH from about 4 to 8. The particular scheme of doses for each individual can be installed at the discretion of the attending physician. In these preparations, these compounds typically contain from 0.01 to 5 wt.%, preferably in quantities of from 0.05 to 2 wt.%, and most preferably in an amount of from 0.1 to 1.0 wt.%. Dosage form may be a solution, suspension or microemulsion. For example, the local application on the eye surface must instill 1-2 drops of these drugs 1-4 times per day in accordance with the doctor.

These compounds can also be used in combination with other agents used to treat glaucoma, and such agents include, but are not limited to, the β-blockers, prostaglandin inhibitors carbonamides, α2agonists, mitotic means and neuroprotectant.

In the following examples are representative of the methods used by the authors in some TSA is tah the present invention. It should be noted that, although these methods are examples of preferred embodiments of the invention, however, any expert on the basis of the descriptions of these options can be made in the invention, various modifications, not beyond being and scope of the present invention.

Example 1

Inhibition of GSK-3

Inhibition of GSK-3 can be analyzed by methods described in WO 00/38675. Compounds were evaluated for their ability to inhibit the phosphorylation of the biotinylated peptide derived from the peptide sequence of the site of phosphorylation of glycogen synthase. As the peptide substrate used Biot-KYRRAAVPPSPSLSRHSSPHQ(SP)EDEEE, where (SP) is preposterously serine, andSrepresent the three consensus site for phosphorylation of GSK-3-specific phosphorylation. GSK-3-kinase (final concentration 10 nm) in MOPS buffer, pH 7.0, containing tween-20, 0.01 percent; glycerin, 5%; 2-mercaptoethanol, 7.5 mm, magnesium acetate, 10 mm peptide substrate, 8 μm, [γ-33P]-ATP, 10 μm, and inhibitor were incubated at room temperature for 1 hour. The reaction was stopped by addition of an aqueous solution (50) mm EDTA containing streptavidin coated beads SPA. After centrifugation radioactivity was counted in a beta scintillation counter.

The use of the 2

Inhibition of FRP-induced reduction in speed and outflow levels β-catenin in perfoirmance front segments

Anterior segments of human eyes perfesional modified by way of Dulbecco medium Needle (DMEM) at a constant pressure of 11 mm Hg speed of the outflow for each eye was measured by weighing his tank during certain periods of time. After a period of stabilization eyes were subjected to perfusion or the media, or FRP-1 (10 μg/ml) and monitored the speed of outflow within 2-5 days. Perfusion FRP-1 resulted in decreased aqueous outflow in the eye. Then add the inhibitor and the anterior segment was subjected to perfusion within 2-4 days. The rate of outflow was measured by weighing the reservoir eyes during certain periods of time.

Example 3

IngredientsAmount (wt.%)
Connection example 10.01 to 2%**
The hypromellose0,5%
Dibasic sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
Disodium-EDTA (dimitriades)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01
The sodium hydroxide/hydrochloric acidto bring the pH to 7.3 to 7.4
Purified waterDostal to 100%

Example 4

IngredientsAmount (wt.%)
Connection example 10.01 to 2%
The methylcellulose4,0%
Dibasic sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
Disodium-EDTA (dimitriades)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidto bring the pH to 7.3 to 7.4
Purified waterDostal to 100%

Example 5

IngredientsAmount (wt.%)
Connection example 10.01 to 2%
Guar gumof 0.4 to 6.0%
Dibasic sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
Disodium-EDTA (dimitriades)0,01%
Polysorbate 800,5%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidto bring the pH to 7.3 to 7.4
Purified waterDostal to 100%

Example 6

IngredientsAmount (wt.%)
Connection example 10.01 to 2%
White petroleum jelly, mineral oil and lanolinConsistency ointment
Dibasic sodium phosphate (anhydrous)0,2%
Sodium chloride0,5%
Disodium-EDTA (dimitriades)0,01%
Polysorbate 800,05%
The benzalkonium chloride0,01%
The sodium hydroxide/hydrochloric acidto bring the pH to 7.3 to 7.4

All compositions and/or methods described and claimed in this application can be developed without additional experimentation, only in accordance with the present invention. Although the compositions and methods of the present invention have been described in preferred embodiments of its implementation, however, it is obvious that described herein compositions and/or methods and in the steps or in placentas the stages of this method can be amended, not beyond beings, volume and ideas of the present invention. More specifically, it should be noted that the described agents can be replaced by some chemically and structurally related agents, giving similar results. For every person it is obvious that such substitutions or modifications do not need to go beyond being, volume and ideas of the present invention defined in the attached claims.

Links

The following works, which are illustrated procedures, or other specific aspects, in addition to those already described in this application are entered into the present description by reference.

Patents

DE 3914764

DE 4005969

DE 4005970

DE 4217964

DE 4243321

EP 328026

EP 384349

EP 397060

EP 470490

EP 508792

EP 540956

U.S. patent No. 5856517

U.S. patent No. 5891901

U.S. patent No. 6057117

WO 93/18765

WO 93/18766

WO 95/07910

WO 96/04906

WO 98/04551

WO 98/04552

WO 98/11102

WO 98/11103

WO 99/42100

WO 00/21927

WO 00/38675

WO 01/09106

WO 01/37819

WO 01/41768

WO 01/47533

WO 01/49709

WO 01/56567

Other links

Bafico et al., J. Biol. Chem., 274(23): 16180-16187 (1999)

Leost et al., EUR. J. BIOCHEM., 267: 5983-5994 (2001)

Smith et al., Bioorganic & Med. Chem. Letters, 11: 635-639 (2001)

Thunnissen et al., CHEM. & BIO., 7: 51-63 (2000)

Tavare et al., FEBS LETTERS 460: 433-436 (1999)

Cross et al., J. Neurochem., 77: 94-102 (2001)

Coglan et al., Chem. & Bio., 7(10): 793-803 (2000)

Garnier et al., J. BIOL. CHEM., 276(1): 251-260 (2001)

1. When is the change kinase inhibitor-3, glycogen synthase (GSK-3) for the preparation of ophthalmic composition for reducing intraocular pressure (IOP) in patients in need thereof.

2. The use according to claim 1, where the specified inhibitor of GSK-3 is a compound of the formula

where R1and R2independently represent:

R3=H, C1-6alkyl, (UN)substituted phenyl, C1-6alkyl-NR6R7C1-7-cycloalkyl, C1-6alkyl-OR6With1-6alkyl-S(O)2R5C1-6alkyl-C(O)NR6R7;

R4=H, or one or more substituents C1-6alkyl, (UN)substituted phenyl, -OR6, -SR6, halogen, (UN)substituted phenoxy, -CN, -NO2With1-6alkyl-NR6R7, -NR6R7With1-7-cycloalkyl, (UN)substituted heterocyclyl, S(O)2R5C1-6alkyl-C(O)2R5C1-6alkyl-C(O)NR6R7; and

R5, R6, R7=H, C1-6alkyl, (UN)substituted phenyl.

3. The use according to claim 2, where

R1=A, B; R2=B, C;

R3=H1-6alkyl, C1-6alkyl-NR6R7With1-6alkyl-OR6With1-6alkyl-S(O)2R5C1-6alkyl-C(O)NR6R7;

R4=H, or one or more alternates With1-6alkyl, (UN)substituted phenyl, -OR6, halogen, (UN)substituted phenoxy, -NO2With1-6alkyl-NR6R7, -R 6R7, (UN)substituted heterocyclyl, C(O)2R5With1-6alkyl-S(O)2R5C1-6alkyl-C(O)NR6R7; and

R5, R6, R7=H, C1-3alkyl.

4. The use according to claim 3, where the specified inhibitor of GSK-3 is 3-(1-[3-aminopropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione or 3-(1-[3-hydroxypropyl]-3-indolyl)-4-(2-chlorophenyl)pyrrole-2,5-dione.

5. The use according to claim 1, where the specified inhibitor of GSK-3 is a compound selected from the group consisting of analogs of indirubin, analogues of 2,4-diaminetetra, derivatives or analogs of 1,2,4-triazolinone acid, geminiengine or its derivatives or analogs, and analogs Paullina.

6. The use according to claim 5, where the specified inhibitor of GSK-3 is the analogue of indirubin.

7. The use according to claim 6, where the specified analogue of indirubin selected from the group consisting of indirubin, 5-iodine-indirubin-3'-monoxime, 5-(hydroxyethylsulphonic)indirubin, indirubin-3'-monoxime, 5-(methyl)sulfonamida of indirubin and 5-(dimethyl)sulfonamida of indirubin.

8. The use according to claim 5, where the specified inhibitor of GSK-3 is similar 2,4-diaminetetra.

9. The use of claim 8, where the specified analogue 2,4-diaminetetra selected from the group consisting of

(4-amino-2-phenylimidazol-5-yl)cyclopropylmethanol,

(4-amino-2-phenylimidazol-5-yl)-(4-forfinal)methanone,

(4-amino-2-phenylimidazol-5-yl)pyridine-3-ylmethanone,

1-(4-amino-2-phenylimidazol-5-yl)propan-1-it,

(4-amino-2-phenylimidazol-5-yl)-(3,4-differenl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(3-forfinal)methanone,

(4-amino-2-phenylimidazol-5-yl)naphthalene-2-ylmethanone,

(4-amino-2-phenylimidazol-5-yl)biphenyl-4-ylmethanone,

(4-amino-2-phenylimidazol-5-yl)-(3-benzyloxyphenyl)methanone,

[4-amino-2-(4-brompheniramine)thiazol-5-yl)]cyclopropylmethanol,

(4-amino-2-phenylimidazol-5-yl)-(3,4-dichlorophenyl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(3-methylbenzo[b]thiophene-2-yl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(2-methoxyphenyl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(3-methoxyphenyl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(4-methoxyphenyl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(4-chloro-3-were)methanone,

(4-amino-2-propylimidazol-5-yl)pyridine-3-yl-methanone,

(4-amino-2-phenylimidazol-5-yl)pyridin-2-yl-methanone,

(4-amino-2-phenylimidazol-5-yl)pyridin-4-yl-methanone,

(4-amino-2-phenylimidazol-5-yl)thiophene-2-yl-methanone,

(4-amino-2-phenylimidazol-5-yl)thiophene-3-yl-methanone,

(4-amino-2-phenylimidazol--yl)-(2,6-differenl)methanone,

(4-amino-2-phenylimidazol-5-yl)-(2,6-dichlorophenyl)methanone,

1-(4-amino-2-phenylimidazol-5-yl)ethanone,

[4-amino-2-(pyridine-3-ylamino)thiazol-5-yl]methanone,

[4-amino-2-(pyridine-3-ylamino)thiazol-5-yl]phenylmethanone,

[4-amino-2-(3-methoxypropylamine)thiazol-5-yl]pyridine-3-ylmethanone, ethyl ester 3-[4-amino-5-(pyridine-3-carbonyl)thiazol-2-ylamino]butyric acid,

[4-amino-2-(3,4-dichlorophenylamino)thiazol-5-yl]-(3-benzyloxyphenyl)-methanone,

[4-amino-2-(4-chlorpheniramine)thiazol-5-yl]-(3-benzyloxyphenyl)-methanone, and

(4-amino-2-ethylaminoethanol-5-yl)phenylmethanone.

10. The use according to claim 5, where the specified inhibitor of GSK-3 is a derivative or analogue of 1,2,4-triazolinone acid.

11. The use of claim 10, where the specified derivative or the specified analog 1,2,4-triazolinone acid selected from the group consisting of:

3-amino-5-aniline-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-(3,4-methylenedioxybenzyl)-1,2,4-triazole,

3-amino-5-aniline-2-(3-TRANS-(2-ferracioli)-1,2,4-triazole,

3-amino-5-aniline-1-(3-TRANS-(2-ferracioli)-1,2,4-triazole, phenylamide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid, cyclohexylamine 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid, cyclohexylamine 3-amino-5-aniline-1,2,4-triazole-1-carboxylic acid,

3-amino-5-5-chloro-2-methylaniline)-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-(4-chlorbenzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-naphtol)-1,2,4-triazole,

3-amino-5-aniline-2-(3-bromobenzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-phenylbenzyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-trifloromethyl)-1,2,4-triazole,

3-amino-5-aniline-2-((3-benzoyl)benzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-biphenylyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-titilate)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-phenylthiazol-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(2-naphthylacetyl)-1,2,4-triazole,

3-amino-5-aniline-2-(2-phenoxybenzoyl)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-benzoyl-1,2,4-triazole,

3-amino-5-aniline-2-cyclohexylcarbonyl-1,2,4-triazole,

3-amino-5-aniline-2-phenylacetyl-1,2,4-triazole,

3-amino-5-aniline-2-(3-nicotinyl)-1,2,4-triazole,

3-amino-5-aniline-2-(3,5-dichlorobenzoyl)-1,2,4-triazole,

3-amino-5-aniline-2-(4-acetylbenzoic)-1,2,4-triazole,

3-amino-5-aniline-2-(3-indolylacetic)-1,2,4-triazole,

3-amino-5-aniline-2-(4-pertenecer)-1,2,4-triazole,

3-amino-5-aniline-2-(3-bromobenzoyl)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(3-benzoylphenyl)-1,2,4-triazole,

3-amino-5-aniline-2-(cyclopent-2-enyl)acetyl-1,2,4-triazole,

3-amino-5-(3-Chloroaniline is)-2-(3-benzoylbutyric)-1,2,4-triazole,

3-amino-5-(3-chloroanilino)-2-(3,3-diphenylpropanoic)-1,2,4-triazole,

4-biphenylamine 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-phenoxyphenyl)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-bromo-2-were)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(1-naphthyl)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(3-methoxyphenyl)amide 3-amino-5-aniline-1,2,4-triazole-2-carboxylic acid,

(4-chlorophenyl)amide 3-amino-5-(4-methoxyaniline)-1,2,4-triazole-2-carboxylic acid, and

3,5-diamino-2-benzoyl-1,2,4-triazole.

12. The use according to claim 5, where the specified inhibitor of GSK-3 is a derivative or analogue geminiengine.

13. The application indicated in paragraph 12, where the specified derivative or the specified analog geminiengine selected from the group consisting of:

geminiengine (4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-it),

4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-2-bromo-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-it, and

4-(2-amino-4-oxo-2-imidazolin-5-ilidene)-3-bromo-4,5,6,7-tetrahydropyrrolo(2,3-C)azepine-8-it.

14. The use according to claim 5, where the specified inhibitor of GSK-3 is similar Paullina.

15. The application 14, where the specified analog Paullina selected from the group consisting of 9-nitropyrene, 9-Pampulha, 9-Harpa is Llona and 9-bromo-12-methoxycarbonylmethylene.

16. The use according to claim 1, where the specified introduction is a local application, the introduction into the chamber of the eye or the introduction by the implant.

17. The use according to claim 1 where the concentration of the indicated inhibitor of GSK-3 in a specified composition ranges from 0.01 to 2%.

18. The use according to claim 1, where the specified patient suffering from glaucoma or ocular hypertension.

19. Use p where specified glaucoma is glaucoma with normal intraocular pressure.



 

Same patents:

FIELD: medicine.

SUBSTANCE: method involves introducing Mytomycin C metabolite into eyes where compensated and subcompensated intraocular pressure being achieved as a result of maximum hypotensive therapy application. The preparation is introduced 4 weeks in advance before operation in initial and advanced glaucoma stages and 2-3 weeks in advance in cases gone too far. The dose to be introduced is equal to 0.1 ml with concentration equal to 0.15 mg/ml. Additional Mytomycin C injection of the same volume and concentration of 0.2 mg/ml is introduced after having finished the reparative operation.

EFFECT: enhanced effectiveness of treatment; prolonged intraocular pressure stabilization.

1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves administration of the preparation "Ginkor-Fort" in the dose 1 tablet, 2 times per a day for 2 weeks and after one month break the preparation "Diovenor" is administrated in the dose 1 tablet, once per a day for 2 weeks at the constant instillation of the preparation "Ksalatan" in the dose 1 drop, once time before night. Such schedule of the method provides the stable normalization of intraocular pressure based on improvement of venous orbital and cerebral circulation. Invention is designated for medicinal treatment of glaucoma discirculatory variant.

EFFECT: improved method of treatment.

2 tbl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with medicinal treatment of ischemic variant of primary glaucoma in case of stable normalization of intraocular pressure (IOP) in patients with myopic refraction. For this purpose, it is necessary to carry out electromagnetic impact successively onto cerebral orbital, temporal and occipital areas, carotid sinuses of cervical autonomic plexus, and, also, one should additionally inject gliatilin per 1.0 in combination with instillations of 0.5%-betaxolol solution per 2 drops twice daily into ocular conjunctival cavity. Therapy should last for 10 d at repeating the course once or twice annually. The method provides stable normalization of IOP, improves cerebral and orbital hemodynamics and stabilization of visual functions.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with introducing medicinal preparation onto scleral bottom and episclerally at the end of operation. As medicinal preparation one should apply 50%-glycerol solution, onto scleral bottom and episclerally introduced per 1 drop of solution. Exposure of glycerol solution corresponds to 1-2 min. The innovation enables to decrease the quantity of complications in post-operational period.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves per os introducing lipoic acid concurrently with beta-carotene at a dose of 0.05 and 10 mg 3 times a day during 1 month, respectively.

EFFECT: enhanced effectiveness of treatment; improved antioxidation activity in eye tissues; improved vision function.

3 dwg, 1 tbl

FIELD: biotechnology, medicine, veterinary, in particular inhibition of vegetative and spore cell (Bacillus anthracis) vitality and malignant anthrax prophylaxis.

SUBSTANCE: invention relates to agent of bactericide action in relates to vegetative spore cells Bacillus anthracis. Agent contains bacteriolytic complex produced by Lysobacter sp.XL1. In method for malignant anthrax prophylaxis bacteriolytic complex produced by abovementioned bacterium strain is used as active ingredient. Said method includes subdermal injection in one dose not later than 3 hours after contamination, or application of dressing (drape) impregnated with active ingredient on place of possible exciter penetration, or treatment of possible contamination focus with aerosol.

EFFECT: bactericide agent without side effects and decreased prophylaxis time.

6 cl, 8 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: method involves excluding provoking factors influence, administering diet, carrying out substitution therapy with enzymes, inhibiting pain syndrome, applying infusion therapy, introducing anabolic steroids, phosphodiesterase inhibitors, anti-diarrhea drugs and antioxidants like Freedox and Emoxipin. Perfluorane is introduced daily at a dose of 2 ml/kg, Freedox at a dose of 3-9 mg/kg and Emoxipin at a dose of 3 mg/kg once a day not less than 3 days long but not longer than 7 days.

EFFECT: provided combined oxygenation normalization, metabolic cell control and phospholipid composition of cell membranes; accelerated pain syndrome alleviation.

Liquid detergent // 2294756

FIELD: medicine, in particular cleaning of medicine articles before sterilization.

SUBSTANCE: claimed liquid detergent contains: subtilisin, alpha-amylase, lipase, benzyl alcohol, methylchloroisothiosolinone, methylisopusolinone, mixture of ethoxylated C9-C15-alcohols, alkylpolyglycoside, boric acid, 2,2',2''-nitrylotriethanolamine, calcium chloride, 1,2-propylene glycol, and water in specific component ratio (mass %).

EFFECT: increased effectiveness of cleaning of medicine articles before sterilization.

2 ex

FIELD: medicine, surgery.

SUBSTANCE: on the 2nd d after operation it is necessary to carry out infrared spectrometry (IRS) of blood plasma. Predisposition to the development of peritoneal adhesive disease (PAD) should be detected by the value of the average coefficient of infrared radiation transmission in the range at wave length being about 3500 - 3200 cm-1. At its value being below 64.4 one should introduce Wobenzym for 14 d and Filtrum for 7 d. Physiotherapeutic impact should be fulfilled due to conducting UHF for the stomach for about 8-10 d. Then one should introduce Cuprenil for 2 wk, carry out electrophoresis as "polymineral filter cloths" based upon iodine-bromine natural underground water for the stomach for 10 d. Since the 10th d after laparotomy during 1 mo it is necessary to introduce Bifiform and Hylak Forte. The innovation enables to detect early predisposition to the development of adhesive disease by the onset of prophylactic procedures.

EFFECT: higher efficiency of prophylaxis.

6 cl, 2 ex

FIELD: medicine, biology, pharmaceutical industry.

SUBSTANCE: invention relates to agents improving quality of semen. Invention proposes an agent improving quality of semen that comprises recombinant interferon-α, hyaluronidase, Trilon B 0.02% buffered solution with pH value 5.5-7.0 and glycerol in the following content of components per 1.0 g of the agent: recombinant interferon-α, 10000-200000 IU, hyaluronidase, 2-64 arbitrary units (AU), Trilon B 0.02% buffered solution with pH value 5.5-7.0, 0.25-0.5 g, and glycerol, the balance. Proposed agent can comprise additionally polyethylene glycol 4000-6000 Da in the amount 0.005-0.02 g, polyglucin in the amount 0.005-0.02 g, 3,7-bis-(dimethylamino)phenothiazonium chloride in the amount 0.0000015-0.02 g, organic preparation from cattle prostate in the amount 0.005-0.05 g, dry immunoglobulin preparation or dry immunoglobulin preparation for enteral using in the amount 0.02-0.3 g. The agent provides the directed improving semen quality in case of pathology in male urogenital tract, namely, enhancing the semen anti-viral activity caused by interferon-α.

EFFECT: improved and valuable biological property of agent.

17 cl, 24 ex

FIELD: medicine, namely, cardiology, possible use for treatment of diseases of peripheral vessels of extremities complicated due to osteochondrosis.

SUBSTANCE: in accordance to method, drugs are injected by means of laser photophoresis with use of low intensity laser radiation. Laser radiation with wave length 0,89-0,63 micrometers is used, and frequency between 8 and 90 Hz. In first day, biologically active zones of skin cover in area of back along the spinal column on both sides of spinous processes of vertebra and along the drive of blood vessels of legs, photo-sensitizing extracts of plants are applied with following laser irradiation with total time of effect ranging from 15 to 17 minutes. Then skin of aforementioned portions of back is processed with solution of botulinic toxin of A type, diluted in 10 ml of physiological solution, their following laser irradiation during 3 minutes for each zone, after that spinal column is subjected to effect of traction load. In second day biologically active zones of skin cover in area of back along the spinal column on both sides of spinous processes of vertebra and along the drive of blood vessels of legs photo-sensitizing extracts of plants are applied with following laser irradiation with total time of effect ranging from 15 to 17 minutes. Then, skin of aforementioned portions of back is processed with a solution of proteoclastic drug with their following laser irradiation during 3 minutes for each zone, after that spinal column is subjected to traction load effect. Then, starting from third and ending at 10-11 treatment days, procedures are performed same as in second day of treatment.

EFFECT: restoration of structure of degenerately altered muscles, ligaments, subcutaneous fat, structures of connective tissue and vessels.

6 ex

FIELD: medicine.

SUBSTANCE: method involves applying IAG-laser treatment to exudates fixation region. Then, drug mixture is additionally introduced into lymphatic orbit region. The mixture has Lidocaine 20-40 mg, Dalargin 1-2 mg, Mexidol 50-100 mg, Lidase 16-32 units, Hemase 3000-5000 IU. The drug mixture is introduced into the lymphatic orbit region daily by carrying out pterygopalatine block on the same side with the injured eye with 3-5 blocks in a course.

EFFECT: accelerated postoperative rehabilitation; accelerated exudates destruction; arrested inflammatory process with drug mixture.

3 cl

FIELD: medicine.

SUBSTANCE: method involves administering Wobenzyme combined with brachytherapy with radiomodification and transpupillary thermotherapy or combined with isolated transpupillary thermotherapy. When combined with brachytherapy with radiomodification, Wobenzyme is given 2 days before brachytherapy at a dose of 3 pills 3 times a day with the exception of 8 h before fixation and removal of β-applicator. Next to it, Wobenzyme is given at a dose of 4-6 pills 3 times a day during 3 months. Then, the dose is reduced by 2 pills every month at the fourth, fifth and sixth months. Adjuvant transpupillary thermotherapy is carried out 6 months later after brachytherapy. Wobenzyme is given at a dose of 2-3 pills 3 times a day 2 days before transpupillary thermotherapy. Then, the dose is 4-6 pills 3 times a day during 2 months with following dose reduction by 3 pills every month to prophylactic dose of 1 pill a day. When carrying out isolated transpupillary thermotherapy, Wobenzyme is given in the same mode that it was the case when carrying out adjuvant transpupillary thermotherapy after brachytherapy. To prevent metastasis occurrence, Wobenzyme administration is continued at a dose of 1 pill 7 days every month during the first year and at a dose of 1 pill 3 days every month during the second observation year.

EFFECT: accelerated resorption processes; reduced risk of radiation treatment complications.

FIELD: veterinary science.

SUBSTANCE: the suggested preparation for preventing and treating respiratory and gastrointestinal infectious diseases of bacterial and viral etiology in farm animals contains tetracycline (oxytetracycline) (8-10%-solution) at the quantity of about 10-15 vol.%, polyethylene glycol (15-20%-solution) - about 10-15 vol.%, polyvinyl pyrrolidone (15-20%-solution) - about 10-20 vol.%, ethylene diamine tetraacetate (0.01-0.02%-Versen's solution) - about 10-15 vol.%, and, also, trypsin (0.01-0.25%-solution) - the rest. As for the method for preventing and treating the above-mentioned diseases, it deals with a single intramuscular injection of the present preparation for farm animals (predominantly, for piglets) at the dosage of about 0.5-1.0 ml/animal. The suggested preparation is of immunostimulating properties and provides efficient therapy of respiratory and gastrointestinal diseases of bacterial and viral etiology.

EFFECT: higher efficiency of prophylaxis and therapy.

2 cl, 6 tbl

FIELD: medicine, urology.

SUBSTANCE: the present innovation deals with prostatic studying, neurological trials, measuring skin electroconductivity and temperature of paraspical areas in dermatomes Th12, L1, L2. At detecting vertebral and myofascial syndromes, segmental asymmetries of skin temperature and electroresistance it is necessary to carry out, at first, segmental regional pharmacotherapy, and then - manual therapy. Thus, beforehand it is necessary to detect myofascial trigger points due to manual inspection to conduct infiltration in them due to puncturing followed by introducing a solution that contains actovegin and dissolved lidocaine. Injection lasts till achieving maximal tissue resistance identified by decreased resistance to solution injection after the period of its increase, 1-3 injections should be conducted. While fulfilling manual therapy the technique of manipulation should be preferred for the course consisted of about 5-10 seances. The innovation enables to affect defected vertebral and spinal segments simultaneously and "central" mechanisms of the lesion, as well.

EFFECT: higher efficiency of therapy.

2 ex, 6 tbl

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the agent comprising the following components: lidazum (16-32 U), proserinum 0.05% solution, 0.00025-0.0005 g; methylprednisolone succinate sodium, 0.02-0.04 g; lidocaine 10% solution, 0.05-0.1 g, and glucose 40% solution, 3-4 ml. Also, invention relates to a method for administration of agent and a method for treatment of inflammatory diseases. Invention provides expanding assortment of medicinal agents and improving the regional transport of medicinal preparations.

EFFECT: improved and valuable properties of agent.

6 cl, 5 ex

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