Diagnostic technique and method of therapy of drug-induced dry eye syndrome

FIELD: medicine.

SUBSTANCE: invention aims at treating drug-induced dry eye syndrome (DI-DES). Treating DI-DES implies taking the past medical history, measuring tear production and eye xerosis values reduced and increased respectively in relation to the norm. Unpreserved ocular hypotensive medications are prescribed in the patient. Unpreserved artificial tears are also applied. The lachrymal fluid is analysed by a multicytokine technique. If the analysis shows increased concentrations of proinflammatory cytokines - interleukin-6, interleukin-8, interleukin-12, Th-1 - interleukin-2, interferon-gamma, and Th-2 - interleukin-4, by min 30% in relation to the patient's age norm, a chronic immune ocular inflammation is detected. That requires transpalpebral Blepharogel-1 phonophoresis and 1% hydrocortisone ointment phonophoresis on the sub-mastoidal region from both sides; the therapeutic course is 8-10 daily procedures.

EFFECT: optimal conditions for diagnosing and reasoned differentiated therapy of DI-DES that enables prescribing the pathogenetically reasoned therapy in due time and increasing the efficacy of the therapeutic exposure.

1 tbl, 2 ex

 

The alleged invention relates to medicine, namely to ophthalmology and can be used for the diagnosis and treatment pharmacological forms of the syndrome of "dry eye".

Under pharmacological form of the syndrome of "dry eye" (o-DES) is commonly understood as changes in the surface of the eye and lacrimal gland, developing on the background of the use of drugs that reduce the secretion of the mucous membranes and/or due to long-term installations of eye drops containing preservative that Deplete the lipid layer of the tear film and damaging the epithelial lining of the conjunctiva and cornea (Murube J. et al. The triple classification of dry eye for practical clinical use // Eur. J. Ophthal. - 2005. - Vol.15, No. 6. - P. 660-667). Diagnostics f-RESS is carried out by seeking the history of the disease, evaluation of installation experience, the value of lesoproduktsii, state proroguing the tear film and the rate of xerosis (The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007) // Ocul Surf. - 2007. - Vol.5. - P. 75-92.).

Treatment of this variant of f-RESS involves the transfer of a patient on anti-hypertensive anti-glaucoma drugs without preservative and slessareva (Astakhov S. Yu., Tkachenko N. In. First experience with the use of β - blockers without mothballs // Ophthalmic statements. - 2010. - Volume 3 No. 2. - p. 66-70; Brzheskij V. V. Principles of prescribing "artificial tears" to patients with �various forms of dry eye syndrome" // actual problems of ophthalmology. SPb. - 2007. pp. 235-237).

However, in some patients in the development of the f-RESS in addition to these mechanisms plays a crucial role in the immune inflammation of the ocular surface (Ermakova N. And. The role of lymphoid tissue associated with mucous in the appearance of lesions of the ocular surface // X all-Russian scientific-practical conference with international participation "Fedorov readings - 2012": Sat. proc. / Under the General editorship of B. E. malugin - M.: Publishing house "Ophthalmology". - 2012. - 207). As mentioned above, traditional diagnostic algorithm for f-RESS does not include detection of the presence of immune inflammation of the eye surface and the nature of changes of local immunity. As for the traditional therapeutic effects, the elimination of modifiable risk factor (transfer to asconservative drugs) and ketsumeishi in this category of patients are ineffective, because they don't interrupt the pathological range "closed" chronic immune inflammation of the ocular surface (Malvitte L., Montange T, Vejux, A., Baudouin C. et al. Measurement of inflammatory cytokines by multicytokine assay in tears of patients with glaucoma topically treated with chronic drugs // Br. J. Ophthalmol.- 2007.- Vol.91. - No. 1. - P. 29-32.). These facts determine the relevance of new approaches for the diagnosis of immune inflammation of the ocular surface in patients with f-RESS and ways of pathogenetically proved imunomodulatorului.

As a result, previously we conducted exploratory research it was found that during the development of immune inflammation in patients with f-RESS, there was an increase (not less than 30%) as a key Pro-inflammatory (interleukin - 6, interleukin - 8, interleukin -12) and Th-1 (interleukin - 2, interferon - gamma), Th-2 (Il - 4) cytokines. In our opinion revealed the facts give the possibility to perform diagnostics of immune inflammation in the f-RESS, and to determine the orientation of the immune modulating effects (steroid use).

The use of steroids for the treatment of dry eye syndrome (the ineffectiveness of lesozagotoviteley) previously offered Vladimir Brzheskij et al. (Brzheskij V. V., Somov E. E. Corneal conjunctival xerosis (diagnostics, clinic, treatment). - SPb.: "Lefty", 2003. - 157 C). The disadvantage of this treatment approach is the risk of developing ocular hypertension and cataracts with long-term (over 10 days) use of steroids (Reference Vidal. Drugs in Russia: a Handbook. - M.: Attraversare, 2012. - Pp. 1531-1532) on the other hand, the clinical efficacy of a short course of instillations or applications of steroids (in terms of relief of chronic immune inflammation of the eye surface) usually is not sufficient.

From our point of view, another promising direction justification�tion exposure at f-RESS can be therapeutic eyelid hygiene with the use of the drug Blafasel-1 (containing hyaluronic acid and Aloe Vera), because components of this drug have both anti-inflammatory and hydrating effect (Polunin G. S., Zabegailo A. O., I. A. Makarov Effectiveness of therapeutic eyelid hygiene when treating patients blepharoconjunctivitis form of dry eye syndrome // Vestnik of ophthalmology. - 2012. - No. 1. - P. 37-40.; Polunin G. S., etc. Physiotherapy in the treatment of diseases of the tear film // X all-Russian scientific-practical conference with international participation "Fedorov readings - 2012": Sat. proc. / Under the General editorship of B. E. malugin - M.: Publishing house "Ophthalmology". - 2012. - 213 p.)

The disadvantage of the traditional use of a drug Blafasel-1 (in the form of applications) is the slow development of effect (- 2-3 months, the rate of application 2 times a day) (Polunin G. S., etc., the Role of chronic blepharoconjunctivitis in the development of the syndrome of "dry eye" // Bulletin SB RAMS. - 2009. - №4 (138). - Page. 123 to 126). It should also be noted that the previously mentioned preparation was successfully used for the treatment blepharoconjunctivitis forms of the syndrome of "dry eye" (Polunin G. S., etc., the Role of chronic blepharoconjunctivitis in the development of the syndrome of "dry eye" // Bulletin SB RAMS. - 2009. - №4 (138). - Page. 123 To 126; Sakhnov S. N., Yanchenko S. V., Malyshev V. A., etc. New features pathognomonic therapy blepharoconjunctivitis forms of the syndrome of "dry�th eyes" // Ophthalmology. - 2011. - Vol. 8, No. 3. - P. 48-52). In the available literature we could not find data on the use of the drug Blafasel - 1 in the treatment of f-RESS.

Given the above data, for the closest analogue diagnostics f-RESS we have adopted the algorithm, including the identification of medical history, assessment of the installation experience, the definition of the reduction of the magnitude of lesoproduktsii, state proroguing the tear film and the rate of xerosis (Somov E. E., Rims V. A. lacrimal dysfunction Syndromes // Manual under the editorship of Professor Somov E. E. - 2011. - Publisher "The Man" In St. Petersburg. - Pp. 99-109).

The nearest equivalent therapeutic effects for f-RESS we have accepted the transfer of the patient to drugs without preservative and slessareva (Astakhov S. Yu., Tkachenko N. In. First experience with the use of β-blockers without preservative // Ophthalmic statements. - 2010. - Volume 3 No. 2. - p. 66-70; Brzheskij V. V. Principles of prescribing "artificial tears" to patients with various forms of dry eye syndrome" // actual problems of ophthalmology. SPb. - 2007. Pp. 235-237).

The shortcomings of the diagnostic and therapeutic approach in the f-RESS adopted for the closest analogue: 1) inability to diagnose the presence of immune inflammation of the eye surface; 2) the inability to determine the nature of changes of local immunity; 3) inability to identify indications for immuno�delatores and anti-inflammatory therapy; 4) lack of differentiated approaches to the treatment of f-SSG (under conditions of chronic inflammation of the eye surface or in its absence); 5) lack of clinical efficacy of traditional therapy f-RESS.

Tasks:

1. Providing differential diagnosis, f-RESS by detecting the presence of immune inflammation of the ocular surface.

2. Increase the effectiveness of therapy, individualization of treatment for patients f-RESS.

3. Shortening the medical-social rehabilitation of patients f-RESS.

The invention consists in that for the diagnosis and treatment of f-RESS in addition to revealing the history, definitions of reduction relative to the standard length of lesoproduktsii and increase the index of xerosis of the eye surface, put the patient on asconservative glaucoma antihypertensive medications and appointments bezkonkurencni of lesozagotoviteley spend multiloquence study of the lacrimal fluid, and subject to increased concentrations of proinflammatory (interleukin - 6, interleukin - 8, interleukin - 12), Th-1 (interleukin - 2, interferon - gamma) and Th-2 (Il - 4) cytokines by at least 30% relatively age of the patient is diagnosed by the presence of chronic immune inflammation of the eye surface, and appoint transpalpebral phonophoresis with Leverageit - 1 and fanfare� with 1% hydrocortisone ointment on submittedvalue region, on both sides, daily, course of 8-10 treatments.

As a result, previously we conducted exploratory research it was found that during the development of immune inflammation in patients with f-RESS, there was an increase (not less than 30%) as a key Pro-inflammatory (interleukin - 6, interleukin - 8, interleukin - 12) and Th-1 (interleukin - 2, interferon - gamma), Th-2 (Il - 4) cytokines. In our opinion revealed the facts give the possibility to perform diagnostics of immune inflammation in the f-RESS, and to determine the orientation of the immune modulating effects (steroid use).

The technical result of the invention is the provision of optimal conditions for diagnosis and rationale for differentiated therapy f-RESS. The above is achieved by detecting the presence of immune inflammation and the nature of the changes of local immunity at the f-RESS that enables us to assign pathogenetically substantiated therapy and increase the efficiency of therapeutic effects.

The method is as follows.

Patient pharmacological form of dry eye after collecting history determine the amount of the total lesoproduktsii (Schirmer test-1), the rate of conjunctival xerosis (Bijsterveld), quantitative levels of proinflammatory (interleukin - 6, interleukin - 8, interleukin� - 12), Th-1 (interleukin - 2, interferon - gamma) and Th-2 (Il - 4) cytokines in unstimulated tear fluid. Subject to the reduction Schirmer test - 1 less than 15 mm, the increase of xerosis more than 3 points, increased levels of the above cytokines by at least 30% relative to age norms diagnose the presence of chronic immune inflammation of the eye surface with activation of both proinflammatory and anti-inflammatory markers and involvement in the immune response of both cellular and humoral. In this case, the patient in addition to translating on misconstruancy glaucoma hypotensive drug (0,5% ophthalmic solution of timolol without a preservative - Timolol-POS 2 times daily), prescribed ketsumeishi hypotonic ophthalmic solution hyaluronic acid without a preservative (Hilo-Chest 4-6 times a day) and transpalpebral phonophoresis with Leverageit - 1 (intensity of 0.2 W/cm2mode pulse 4 m/s, the procedure time 6-8 minutes) and phonophoresis with 1% hydrocortisone ointment (Hydrocortisone-PIC) on submittedvalue area (intensity of 0.4 W/cm2mode pulse 4 m/s, the procedure time 6-8 minutes), both sides, daily for 8-10 procedures.

The method was tested in the clinic. The study included 90 patients (180 eyes) 61±5.2 years with with�habilitowany primary open-angle II "And" glaucoma with intraocular pressure (IOP), normalized installations beta-blockers (ophthalmic solution 0.5% timolol, containing not less than 0.1 mg benzalkonium hydrochloride in 1 ml; 2 installations per day; installation experience more than 1 year) and for the first time identified changes in the surface of the eye according to the type of the syndrome of "dry eye" (decrease in Schirmer test-1 less than 15 mm; the improvement in xerosis of 3 points or more).

All patients were sampled unstimulated tear fluid with the determination of IL-6, IL-8, IL-12, IL-2, IFN-gamma, IL-4. 52 patients (57,8%) reported increasing concentrations of the above markers by more than 30% relative to age norms and diagnosed chronic immune inflammation of the eye surface (by increasing both proinflammatory and anti-inflammatory cytokines). At the age norm for this age group, we took the data of previously conducted investigations: IL-6=73,6+to 12.3 PG/ml, IL-8=of 197.3+to 25.3 PG/ml, IL-12=37,3+7,7 ng/ml, IL-2=9,1+1,9 ng/ml, IL-4=9,5+2,4 PG/ml (Yanchenko S. V., Eremenko, A. I., etc. Multiloquence study of the lacrimal fluid of ophthalmological healthy elderly persons. // Kuban scientific medical journal. - 2009. - Volume 109, No. 4. - P. 165-167.).

The remaining 38 patients (42.2 per cent) of the increase of the studied markers in lacrimal fluid was not observed. All patients f-RESS without chronic immuno� inflammation of the eye surface was assigned to conventional therapeutic effect (put the patient on anti-hypertensive anti-glaucoma drugs without preservative and ketsumeishi), proved effective in all patients.

Sick f-RESS diagnosed with immune inflammation were divided into three groups using the method of simple randomization.

In study group included 18 patients (36 eyes) who in addition to traditional exposure (transfer of the patient to drugs without preservative and ketsumeishi) was assigned based treatment of immune inflammation in accordance with the developed method (translated into misconstruancy glaucoma hypotensive drug (0,5% ophthalmic solution of timolol without a preservative - Timolol-POS - 2 times a day), ketsumeishi hypotonic ophthalmic solution hyaluronic acid without a preservative (Hilo-Chest 4-6 times a day) and transpalpebral phonophoresis with Leverageit - 1 (intensity of 0.2 W/cm2mode pulse 4 m/s, the procedure time 6-8 minutes) and phonophoresis with 1% hydrocortisone ointment (Hydrocortisone-PIC) on submittedvalue area (intensity of 0.4 W/cm2, pulsed mode 4 m/s, the procedure time 6-8 minutes), both sides, daily for 8-10 procedures).

In the first control group consisted of 18 patients (36 eyes) who had been appointed only traditional treatment (patients on anti-glaucoma drugs without preservative and ketsumeishi).

The second control group included 16 patients (32 g�Aza), which in addition to traditional therapy were additionally prescribed steroids and Leveraging - 1 using conventional routes of administration: application of a 1% ophthalmic hydrocortisone ointment (hydrocortisone - PIC) 1 times a day (morning), therapeutic eyelid hygiene with Leverageit - 1 (2 times a day).

Given the potential increase in IOP during long-term use of steroids, the multiplicity of procedures in the basic and application of steroids in the control groups the observations were limited to 8-10. Throughout the study we conducted control IOP 4 times a day(8.00; 12.00; 16.00; 20:00), revealed no increase of IOP during the day above the target level.

The main criteria for the effectiveness of therapy are the reduction of the rate of xerosis and reduction of the quantitative indicators of the investigated cytokines. Additional criteria were the terms of relief of subjective symptoms of "dry eye" and the number of installations of classemates during the day, needed for relief of subjective symptoms dry eye.

Statistical processing of the results included calculation of the average value in the sample (M) and standard square deviation (s), assessment of the reliability of differences of average (student test).

The results of therapy f-RESS with the presence of chronic immune inflammation in the comparison groups are presented in table

The proposed method for the diagnosis of immune inflammation in the f-RESS allow for differentiated and pathogenetically reasonable approach to the treatment of different variants of the f-RESS.

Based on the data presented in the table: developed and introduced into clinical practice a method of diagnosing an immune inflammation of the eye surface in pharmacological form of the syndrome of "dry eye", which allows to detect the presence of immune inflammation of the ocular surface and conduct differential diagnosis, f-RESS.

The effectiveness of the proposed method were significantly higher efficiency closest analogue: on the background of therapy of immunological indicators are normalized, and the result is relief of immune inflammation of the ocular surface, which increases the effectiveness of treatment and reduces the time of medico-social rehabilitation of patients with f-RESS.

Example 1.

Patient V., 69 years, diagnosed with primary open-angle II "And" glaucoma, pharmaceutical form of the syndrome of "dry eye", primary cataracts, hypertensive angiopathy of the retina of both eyes. Hypotensive mode - S. Timololi maleati 0.5% 1 drop 2 times a day, the installation experience of 4.5 years.

Complaints: discomfort in the eyes, dryness, smarting in the eyes, feeling of "sand" for centuries.

Objective: acuity OD of 0.3 with sph+1.5 D=0,8; OS - with 0,4 sph+1.25 D=0,7. Front cut: "sluggish" conjunctival hyperemia, no meniscus tear, a functional test on the total volume of lesoproduktsii Schirmer - 1: OD=3 mm, OS=4 mm, the rate of xerosis of the conjunctiva and cornea OD=8 points, OS=8 points. Quantitative cytokine levels: IL=111,2 PG/ml, IL=257,7 PG/ml, reporting agent2=12,5 PG/ml, IL-12=49,0 PG/ml, INF-γ=110,1 PG/ml, IL=to 15.3 PG/ml.

Based on the foregoing, was diagnosed pharmacological form of the syndrome of "dry eye", with the presence of immune inflammation of the eye surface.

The patient was assigned antihypertensive drug without preservative Timolol-POS - 2 times a day, lesozagotovitelnaya drug therapy without preservatives Hilo - Chest 6-8 times a day, with subsequent independent determination required instillation, focusing on subjective discomfort, "sand" in the eyes. Also, the patient received daily phonophoresis transpalpebral with Leverageit - 1 and phonophoresis with 1% hydrocortisone ointment on submittedvalue area daily No. 8.

At 4 days of observation, the number of installations of the drug Hilo - Chest 3 times a day, the Schirmer test - 1: OD=9 mm, OS=8mm, after vital staining dye (2% solution disseminator green) indicator xerosis amounted OD=5 points, OS=6 points. After the course of therapy sub�active signs of dry eye are missing, eyes calm, determined by the tear meniscus at the edges of the eyelids (the ratio of height to width of 1:1), the number of installations of the drug Hilo - Chest 2 times a day, the Schirmer test-1: OD=11 mm, OS=10 mm, after vital staining dye (2% solution disseminator green), the average xerosis amounted OD=3 points, OS=2.5 points. After treatment, the quantitative levels of cytokines: IL=72,2 PG/ml, IL=196,9 PG/ml, reporting agent2=8.5 PG/ml, IL=36,9 PG/ml, INF-γ=80,1 PG/ml, IL=a 10.1 PG/ml.

Example 2. V. patient, 57 years of age, diagnosed with primary open-angle II And glaucoma, pharmaceutical form of the syndrome of "dry eye", focusclass. For 1.5 years gets S. Timololi maleati 0.5% 2 times a day.

Complaint: concerned with the sense of "foreign body" for centuries, periodically redness of the eye, reduced visual capacity by the end of the working day.

Objective: acuity OD of 0.7 with sph+0.75 Y=1,0; OS - 0,5 with sph+1,0 D=1,0. When examined from the anterior segment of the eye: decreased tear meniscus (the ratio of height to width of 1:1), biomicroscopy of the anterior segment of the eye, after vital staining dye (2% solution disseminator green) indicator xerosis - OU=5 points. A functional test that determines the amount of the total lesoproduktsii (Schirmer test - 1), was as follows: OD=3.5 mm, OS=4 mm. Quantitative cytokine levels in unstimulated tear fluid cytokines: IL=69,2 PG/ml, IL=189,1 PG/ml IL=30,7 PG/ml, Reporting agent2=8,1 PG/ml IFN-γ for 79.7 PG/ml, IL=9,2 ng/ml. based On the foregoing, was diagnosed with pharmacological form of the syndrome of "dry eye" without clinical signs of immune inflammation of the anterior surface of the eye. Was appointed as a hypotensive drug without preservative Timolol-POS - 2 times a day, lesozagotovitelnaya drug therapy without preservatives Hilo - Chest 6-8 times a day, with subsequent independent determination of the required installations, focusing on subjective feeling of grit in the eyes. In the absence of relief of complaints re-examination after 9 months to control the level of cytokines.

A method for the treatment pharmacological forms of dry eye syndrome, including identification of anamnesis, determination of the improvement relative to the standard length of lesoproduktsii and increase the index of xerosis of the eye surface, transfer the patient to asconservative glaucoma antihypertensive drugs and the appointment bezkonkurencni of lesozagotoviteley, characterized in that it further conduct multiloquence study of the lacrimal fluid and subject to increased concentrations of Pro - interleukin-6, interleukin-8, interleukin-12, Th-1 - interleukin-2, interferon-gamma, and Th-2 - interleukin-4, cytokines not less than 30% relatively age of the patient, identify chronic immune�e inflammation of the eye surface and spend transpalpebral phonophoresis with Leverageit-1 and phonophoresis with 1% hydrocortisone ointment on submittedvalue region on both sides, daily course of 8-10 treatments.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical compositions, in particular to pharmaceutical composition, recovering visual pigment in case of insufficiency of endogenic 11-cis-retinal, which contains effective quantity of retinal derivatives and pharmaceutically acceptable carrier, where retinal derivative is converted into retinal, capable of forming functional complex opsin/retinal, where retinal derivative represents ester of 9-cis-retinyl of formula

ester of 11-cis-retinyl of formula or their combination, where A in each case stands for CH2OR and R represents ester-forming carboxylate radical of monocarboxylic acid C1-C10 or polycarboxylic acid, selected from oxalic acid, succinic acid, malic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, citric acid, ketoglutaric acid, fumaric acid, malonic acid and oxalacetic acid, which is substituting group in ester, where 11-cis-retinal insufficiency is caused by mutation in genes, coding proteins RPE65 and LRAT.

EFFECT: invention relates to method of recovering photoreceptor function or attenuation of loss of photoreceptor function; and to application of said retinal derivative for drug manufacturing.

43 cl, 7 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves performing a vitrectomy with removing a posterior hyaloids of a vitreous body, and a laser retinal endocoagulation at wave length 532 nm, emitting power 120-200 mWt, pulse length 0.1-0.2 s, spot diameter 150-200 mcm. A chorioretinal venous anastomosis (CRVA) is induced by exposing the branches of the central vein of the retina to the third-order laser light at wave length 532 nm in a number of 4 coagulated, emitting power 500 mWt, pulse length 1 sec and spot diameter 50 mcm. The vitrectomy is preceded by the intramuscular injections of 12.5% etamylate 4ml and the intravenous administration of 0.5% tranexamic acid 1 g 25-30 minutes before. That is followed by the droplet intravenous administration of an infusion solution containing 0.1% perlinganit 10 ml in 0.9% normal saline 100 ml at an initial rate of 5 mcg/min. The area to be exposed to laser is specified at least in 3 diameters of the disk from the optic disk. The third-order laser applications are applied on the branches of the central vein of the retina in a number from 2 to 4 at wave length 532 nm, emitting power 300-400 mWt, exposure 0.5 s, spot diameter 500 mcm in two points in the proximal and distal direction from the CRVA induction point. Immediately before the CRVA induction, a salt-water infusion flow is increased until the central retinal artery starts pulsating. The surgical management is completed by plugging the vitreal cavity with 20% air-gas mixture SF6.

EFFECT: effective management of the clinical course of the retinal venous thrombosis by considerable reduction of postoperative haemophthalmias.

2 ex

FIELD: medicine.

SUBSTANCE: agent contains riboflavin riboflavin mononucleotide and dextran in the following proportions, wt %: riboflavin mononucleotide 1.0; dextran 20.0; normal saline - the rest.

EFFECT: forming the stable pre-corneal sustained-action colouring film, additional therapeutic activity of active substances and additives.

3 ex

FIELD: medicine.

SUBSTANCE: what is presented is a kit for corneal saturation with a photosensitiser. The kit comprises a porous coating impregnated with 0.1% riboflavin and fitting the size of the corneal surface. The kit also comprises a coating fixation instrument comprising a semispherical umbrella-shaped base of 10-11.5 mm in diameter, 7.5-8.0 mm in radius of curvature, and a holder handle.

EFFECT: using the kit simplifies and accelerates the procedure of corneal saturation with the photosensitiser and reduces the time for the corneal collagen cross-linking procedure.

2 cl, 2 dwg, 1 ex

FIELD: medicine, pharmaceutics.

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

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

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to biotechnology, specifically to VEGF-A specific binding proteins, and can be used in medicine for treating pathological angiogenesis in mammals. The antiangiogenic protein contains one ankyrin recurrent domain consisting of a N-terminal capping module of ankyrin recurrence, a recurrent module presented by an ankyrin recurrent motif of the sequence 1D23G4TPLHLAA56GH7EIVEVLLK8GADVNA (SEQ ID NO:5), wherein 1 represents an amino acid residue specified in A, N, R, V, Y, E, H, I, K, L, Q, S and T; 2 is specified in S, A, N, R, D, F, L, P, T and Y; 3 is specified in T, V, S, A, L and F; 4 is specified in W, F and H; 5 is specified in P, I, A, L, S, T, V and Y; 6 is specified in W, F, I, L, T and V; 7 is specified in L or P and 8 is specified in A, H, N and Y; a recurrent module presented by an ankyrin recurrent motif of the sequence 1D23G4TPLHLAA56GHLEIVEVLLK7GADVNA (SEQ ID NO:1), wherein 1, 2, 3, 4, 5, 6 and 7 independently represents an amino acid residue specified in the group of A, D, E, F, H, I, K, L, M, N, Q, R, S, T, V, W and Y, and a C-terminal capping module.

EFFECT: invention enables producing an antiangiogenic binding VEGF-A165 with Kd less than 10-7 M protein, which inhibits binding VEGF-A165 to VEGFR-2.

12 cl, 4 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention represents a composition for preventing and treating allergic conjunctivitis and keratoconjunctivitis, containing cromoglicic acid, boric acid and water-soluble polymers specified in a group of: carbomer, hypromellose, macrogol and polyvinylpyrrolidone with the components of the composition taken in specific relations, g in 1 ml of the mixture.

EFFECT: invention provides the better reduction of the inflammatory process and symptoms of the disease; there are also ensured ease of use with a smaller frequency of administration, prolonged action and no side effects.

5 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and aims at treating dry eye syndrome, for contact lens disinfection and remoistening. A sterile water-based ophthalmic composition contains poly(ethylene oxide)-poly(butylene oxide) block copolymer of formula (EO)m(BO)n and galactomannan. Herewith, m has an average value of 45, and n has an average value of 9 to 18. Said galactomannan represents guar or its derivative. Besides, presented are a method for treating dry eye syndrome and a method for disinfecting a contact lens with using the above composition. The other embodiment discloses a method for delivering a pharmaceutical agent into the eyes involving the local administration of a formulation containing one or more pharmaceutically active agents and the above composition into the eyes.

EFFECT: using the group of inventions enables ensuring the more effective application of the above composition by providing the additional stability of a lachrymal film of the composition.

19 cl, 6 tbl, 29 dwg, 3 ex

FIELD: physics.

SUBSTANCE: mechanism (100, 200, 310) of positioning of high-intensity focused ultrasound for positioning of radiator (292, 304) of high-intensity focused ultrasound. Note here that said mechanism comprises positioning plate (108, 308) to house radiator of high-intensity focused ultrasound, mechanism support (174) to accommodate positioning mechanism and multiple rods (110, 112, 114, 116, 118, 120, 210, 212, 214, 216, 218, 220). Note here that every rod has first and second ends. Note here that first end of every rod make a separate ball joint (122, 124, 126, 128, 130, 132, 222, 224, 226, 228, 230, 232) with positioning plate. Note here that multiple linear drives (146, 148, 150, 246, 248, 250, 252, 254) are mounted at mechanism support. Note also that every linear drive comprises drive unit (164, 166, 168, 264, 266, 268, 270, 272). Note here that second end of every rod make a separate ball joint (134, 136, 138, 140, 142, 144, 234, 236, 238, 240, 242, 244) with one of drive units.

EFFECT: development of mechanism of positioning of high-intensity focused ultrasound.

13 cl, 12 dwg

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