RU2161982C1 - Tetrapeptide stimulating eye retina function, pharmacological agent based on thereof and method of its using - Google Patents

Abstract

FIELD: medicine, ophthalmology. SUBSTANCE: invention relates to design of preparations used for treatment of ophthalmic diseases. Invention proposes: tetrapeptide alanyl-glutamyl-asparagyl-glycine of the general formula Ala-Glu-Asp-Gly as an agent showing capability to stimulate function of eye retina; pharmacological agent containing effective amount of tetrapeptide Ala-Glu-Asp-Gly or its salts by amino-group (acetate, hydrochloride, oxalate) or by carboxyl-groups (metal salts of sodium, potassium, calcium, lithium, zinc, magnesium and organic and inorganic cations - ammonium, triethyl-ammonium) as an active component; method of treatment of patients with diseases and pathological states accompanying with disorder of function of eye retina involving prophylactic and/or curative administration to patient the pharmacological agent in the doses 0.01-1000 mcg/kg of body mass, for at least once per a day for period that is necessary for therapeutic effect attainment. EFFECT: low doses of biologically active compound provide therapeutic effect. 12 cl, 9 tbl, 10 ex

Description

 The invention relates to medicine and relates to the use in ophthalmology of a synthesized tetrapeptide for the treatment of eye diseases by stimulating the function of the retina of the eye.

The following groups of pharmacological drugs are known for diseases associated with impaired function of the retina of the eye: vasodilators (nicotinic acid, nigexin, no-spa, nikoshpan, theophylline, aminophylline, compliment, sodium nitrate); agents that improve the condition of the vascular wall and microcirculation (prodectin, trental); anticoagulants (heparin); biogenic stimulants (aloe, peat, placental blood, FiBS, vitreous humor, peloid distillate, antireticular cytotoxic serum); ATP; vitamin preparations (vitamins A, E, B ₁ , B ₆ , C); detoxification drugs (unitiol); nucleic acid preparations (dronuclide, enkad, sodium nucleinate) [1,2].

 However, due to the non-specificity of therapy with these drugs, their therapeutic effect, as a rule, is short-term and unstable, in addition, these drugs have pronounced side effects [3].

 The use of peptide drugs for the treatment of eye diseases is known. In particular, it is known a tool used in ophthalmology and restores the function of the retina of the eye [4]. This preparation is a complex of low molecular weight polypeptides obtained from the retina of animals by extraction with a 3% solution of acetic acid with the addition of zinc chloride and treatment of the supernatant with acetone.

 It should be noted that this method of production of a medicinal substance has some disadvantages, which include limited reserves of the source of organic raw materials, the complexity and energy intensity of production.

 The invention is aimed at obtaining a new biologically active compound of peptide nature, which has the property of stimulating the function of the retina of the eye, which can be obtained in large-scale production with minimal cost.

 The essence of the invention consists in the use of the tetrapeptide Ala-Glu-Asp-Gly, or its salts (hereinafter the tetrapeptide), as a means having the ability to stimulate the function of the retina of the eye, with the aim of a long-term and lasting improvement of visual functions.

 The tetrapeptide is obtained by the classical method of peptide synthesis in solution [5].

 According to the invention, the tetrapeptide alanyl-glutamyl-asparagil-glycine with the following amino acid sequence: Ala-Glu-Asp-Gly, exhibits a new biological activity, which consists in the ability to stimulate the function of the retina of the eye.

 According to the invention, a pharmacological agent having the ability to stimulate the function of the retina of the eye contains, as an active principle, an effective amount of a tetrapeptide of the formula Alanyl-Glutamyl-Asparagil-Glycine (Ala-Glu-Asp-Gly) or its salts.

 According to the invention, a pharmacological agent having the ability to stimulate the function of the retina of the eye may contain salts at the amino group (acetate, hydrochloride, oxalate), or at carboxy groups (metal salts of sodium, potassium, calcium, lithium, zinc, magnesium, and organic and inorganic cations - ammonium, triethylammonium).

 According to the invention, the pharmacological agent is intended for parenteral, parabulbar, retrobulbar, subconjunctival, local use, as well as in the form of ocular instillations, skin application and physiotherapeutic effects in any dosage form or composition, as the only medication or in combination with other drugs .

 The term "pharmacological agent" used in this application means the use of a dosage form suitable for the route of administration and containing a tetrapeptide or its salt, which may find prophylactic and / or therapeutic use in medicine as an agent that stimulates the function of the retina of the eye.

 The term "effective amount" used in this application means the use of the amount of active principle, which, in accordance with its quantitative indicators of activity and toxicity, as well as on the basis of specialist knowledge should be effective in this dosage form.

 According to the invention, a method of treating diseases and pathological conditions includes the prophylactic or therapeutic administration to a patient of the claimed pharmacological agent in doses from 0.01 to 1000 μg / kg of body weight at least once a day for a period necessary to achieve a therapeutic effect depending on the nature of the course pathological process.

 According to the invention, the tetrapeptide is active when administered in doses of 0.01 μg / kg body weight, although lower doses may be used depending on the nature of the pathological process.

 The invention is illustrated by an example of the synthesis of a tetrapeptide of the formula alanyl-glutamyl-asparagil-glycine (Ala-Glu-Asp-Gly) (example 1), examples that clearly demonstrate the revealed new properties of the studied drug in experimental models (examples 2, 3, 4, 5), as well as examples of the results of the clinical use of a pharmacological agent in a limited group of patients, demonstrating its pharmacological properties and confirming the possibility of achieving a preventive and / or therapeutic effect (examples 6, 7, 8, 9, 10).

EXAMPLE 1
Synthesis of a tetrapeptide of the formula Alanyl-Glutamyl-Asparagil-Glycine (Ala-Glu-Asp-Gly)
1) BOC-Glu (OBzl) -Asp (OBzl) -OH (I), N-tert. Butyloxycarbonyl- (γ-benzyl) glutamyl-β benzyl) aspartate.

N-tert-butyloxycarbonyl- (γ-benzyl) glutamic acid N-oxysuccinimide ester BOC-Glu (OBzl) -OSu 4.34 g (0.0100 mol) is dissolved in 20 ml of dimethylformamide, triethylamine 1.72 ml (0, 0125 mol) and β-benzyl aspartate 2.80 g (0.0125 mol). Stirred at room temperature for 24 hours. The product is planted 0.5 N. a solution of sulfuric acid (150 ml), extracted into ethyl acetate (3x30 ml), washed with 0.5 N. sulfuric acid solution (2x20 ml), water, 5% sodium bicarbonate solution (1x20 ml), water, 0.5 n. sulfuric acid solution (2x20 ml), water and dried over anhydrous sodium sulfate. Ethyl acetate was filtered, evaporated in vacuo at 40 ^o C, the residue was dried in vacuo over P ₂ O ₅ . An oil of 5.68 g (≈100%) is obtained. R _f = 0.42 (benzene-acetone 2: 1, PTCX-P-B-UV Sorbfil plates, CTX-1VE silica gel 8-12 μm, UV manifestation and chlorine / benzidine).

 2) TFA · H-Glu (OBzl) -Asp (OBzl) -OH (II), trifluoroacetate (γ-benzyl) -glutamyl- (β-benzyl) aspartate.

N-tert. butyloxycarbonyl- (γ-benzyl) glutamyl- (β-benzyl) aspartate (I) 5.68 g (≈0.01 mol) is dissolved in 20 ml of a mixture of dichloromethane-trifluoroacetic acid (3: 1). After 2 hours, the solvent was evaporated in vacuo at 40 ^° C., the evaporation was repeated with a new portion of dichloromethane (2x10 ml), the residue was dried in vacuo over NaOH. An oil of 5.80 g (≈100%) is obtained. R _f = 0.63 (n-butanol-pyridine-acetic acid-water, 15: 10: 3: 12).

 3) Z-Ala-Glu (OBzl) -Asp (OBzl) -OH (III), N-carbobenzoxyalanyl- (γ-benzyl) -glutamyl- (β-benzyl) aspartate.

Trifluoroacetate (γ-benzyl) glutamyl- (β-benzyl) aspartate (II) 5.65 g (0.01 mol) is dissolved in 10 ml of dimethylformamide, triethylamine 2.80 ml (0.02 mol) and N-oxysuccinimide ether are added N-carbobenzoxyalanine 4.14 g (0.013 mol). The mixture was stirred for 24 hours at room temperature. The product is planted 0.5 N. a solution of sulfuric acid (150 ml), extracted into ethyl acetate (3x30 ml), washed with 0.5 N. sulfuric acid solution (2x20 ml), water, 5% sodium bicarbonate solution (1x20 ml), water, 0.5 n. sulfuric acid solution (2x20 ml), water and dried over anhydrous sodium sulfate. Ethyl acetate was filtered, evaporated in vacuo at 40 ^o C, the residue was crystallized in ethyl acetate / hexane. The product is filtered off and dried in vacuo over P ₂ O ₅ . Yield 4.10 g (66%). T _pl. = 154 ^o C. R _f = 0.48 (benzene-acetone, 1: 1), R _f = 0.72 (n-butanol-pyridine-acetic acid-water, 15: 10: 3: 12).

 4) Z-Ala-Glu (OBzl) -Asp (OBzl) -Gly-OBzl (III), N-carbobenzoxyalanyl- (γ-benzyl) glutamyl- (β-benzyl) aspartylglycine benzyl ester.

TosOH · H-Gly-OBzl, glycine benzyl ester tosylate 1.01 g (3 mmol) is suspended in 15 ml of tetrahydrofuran and triethylamine 0.4 ml (3 mmol) is added with stirring, then after 5 min. N-carbobenzoxyalanyl- (γ-benzyl) glutamyl- (β-benzyl) aspartate (III) 1.28 g (2 mmol), N-hydroxybenzotriazole 0.27 g (2 mmol) and cool the mixture to 0 ^o C. Then a solution of N, N'-dicyclohexylcarbodiimide, 0.42 g (2 mmol) in 5 ml of tetrahydrofuran, cooled to 0 ^° C, is added, the mixture is stirred at this temperature for 2 hours and allowed to stir at room temperature overnight. The dicyclohexylurea precipitate was filtered off, the solvent was evaporated in vacuo, the residue was dissolved in 30 ml of ethyl acetate, and the solution was washed with 1 N hydrochloric acid solution, water, 5% sodium bicarbonate solution, water, 1 N. hydrochloric acid solution, water and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the product was crystallized in ethyl acetate / hexane. Yield 1.30 g (82%). T _pl. = 146-148 ^o C. R _f = 0.75 (benzene-acetone, 2: 1).

 5) H-Ala-Glu-Asp-Gly-OH (IV), alanyl-glutamyl-aspartyl-glycine.

N-carbobenzoxyalanyl- (γ-benzyl) glutamyl- (β-benzyl) aspartylglycine (III) benzyl ester 1.25 g was hydrogenated in a methanol-water-acetic acid (3: 1: 1) system over a Pd / C catalyst. Monitoring the completeness of the release in TLC systems benzene-acetone (2: 1) and acetonitrile-acetic acid-water (5: 1: 3). At the end of the reaction, the catalyst was filtered off, the filtrate was evaporated in vacuo and the residue was crystallized in a water / methanol system. The product is dried in vacuo over KOH. Yield 520 mg (95%). R _f = 0.73 (acetonitrile-acetic acid-water, 5: 1: 3). For purification, 390 mg of the preparation was dissolved in 4 ml of 0.01% trifluoroacetic acid and subjected to high performance liquid chromatography on a 50 x 250 mm reverse phase column of Diasorb-130-C16T, 7 mkm. Chromatograph Beckman System Gold, 126 Solvent Module, 168 Diode Array Detector Module. Chromatography conditions A: 0.1% TFA; B: 50% MeCN / 0.1% TFA, gradient B 0 ---> 5% in 80 min. Sample volume 5 ml, detection at 215 nm, scanning 190-600 nm, flow rate 10 ml / min. A fraction of 54.0-66.0 minutes was taken. The solvent was evaporated in vacuo at a temperature not exceeding 40 ^o C, evaporation was repeated (5 times) with 10 ml of 10% acetic acid solution. The residue was finally dissolved in 20 ml of deionized water and lyophilized. Received 290 mg of a purified preparation in the form of an odorless white amorphous powder.

The obtained peptide in the form of acetate is converted into the free form by treatment with IRA anion exchange resin or similar in (OH ^- ) form. Then, salts are obtained by the amino group, adding the equivalent of the corresponding acid (hydrochloric or oxalic). The resulting aqueous solution is lyophilized and analyzed as a finished product.

To obtain the corresponding salts of the carboxyl groups, the calculated amount of an aqueous hydroxide solution of the corresponding metal (NaOH, KOH, Zn (OH) ₂ , LiOH, Ca (OH) ₂ , Mg (OH) ₂ , NH ₄ OH) is added to the free tetrapeptide. To obtain a triethylammonium salt, the treatment is carried out in a similar manner using triethylamine as the base.

 The content of the basic substance was determined by HPLC on a Supelco LC-18-DB column 4.6x250 mm, gard. LC-18-DB. A: 0.1% TFA; B: 50% MeCN / 0.1% TFA; grad B 0 ---> 20% in 20 minutes. Flow rate 1 ml / min. Detection at 220 nm, scanning 190-600 nm, sample 20 microns. The content of the main substance is 98.45%.

Determination of amino acid composition is carried out on the analyzer after 6 hours of hydrolysis in 6 N. HCl at 125 ^o C 24 hours. The amino acid content: Glu: Asp: Ala: Gly is 1.02: 1.00: 1.01: 1.00, respectively.

 An injectable pharmaceutical preparation containing a tetrapeptide as an active principle is prepared as follows. The peptide obtained by the method described above is dissolved in 0.9% isotonic sodium chloride solution. The contents of one vial is 1 ml of a solution with a tetrapeptide concentration of 10 μg / ml.

 An experimental study of the tetrapeptide revealed its pharmacological effects not previously known, such as stimulation of visual functions and a decrease in destructive processes in the retina during its toxic dystrophy, prevention of the development of toxic dystrophy of the retina, prevention of the development of abiotrophic changes and improvement of visual function during hereditary retinal abiotrophy, acceleration of light restoration sensitivity of the retina after visual maladaptation.

EXAMPLE 2
The effect of the treatment course of the tetrapeptide on the function and morphology of the retina in toxic dystrophy.

 2.1. The effect of the treatment course of the tetrapeptide on the parameters of the electroretinogram in toxic rabbit retinal dystrophy.

 The possible therapeutic effect of the tetrapeptide on the retina was studied under conditions of its experimental dystrophy in the eyes of 15 sexually mature chinchilla rabbits weighing 2.5-3.5 kg. Experimental toxic retinal dystrophy was created by intravenous administration of a 4% solution of monoiodoacetic acid (hereinafter - MYUK) in doses of 15 mg / kg (severe degree of retinal damage) and 5 mg / kg (moderate degree of retinal damage). The degree of damage to the retina was evaluated by the level of its bioelectric activity, determined by the method of electroretinography (ERG). ERG was recorded under conditions of adaptation to darkness before the introduction of monoiodoacetic acid (initial values), as well as 20 minutes, 5, 10, 15, and 35 days after its introduction. Animals of the experimental group throughout the experiment received daily single intramuscular injections of the tetrapeptide at a dose of 1 μg / kg, starting from 3 days after the introduction of monoiodoacetic acid. Animals of the control group received appropriate injections of sterile saline.

 The results of the study of the bioelectric activity of the retina of rabbits of the experimental and control groups are presented below in table 1.

 As can be seen, the amplitude of the wave "in" ERG already 20 minutes after the introduction of monoiodoacetic acid amounted to 4% of the initial values for severe lesions and 40% of the initial values for moderate degree of damage to the retina.

 The use of tetrapeptide leads to a significant increase in the wave "in" of the ERG compared with the control. So, with moderate severity of retinal damage, the therapeutic effect of the tetrapeptide is detected already on the 15th day of observation, reaching its maximum by 35 days. The amplitude of the wave "in" ERG in experimental animals during this period reaches 85% of the background level and almost 2 times exceeds that in the control group. The positive effect of the tetrapeptide is also observed in the case of severe damage to the retina. If in the control group after the introduction of monoiodoacetic acid (15 mg / kg), ERG was practically not recorded during the entire observation period in all animals, then in the experimental group, against the background of tetrapeptide administration, the wave "b" was recorded in 50% of the animals, and by 35 days of the study the amplitude of the wave "in" ERG was 18% of the initial level. As the data in the table show, another confirmation of the positive effect of the tetrapeptide on the function of the damaged retina is the stabilization of the wave amplitude "in" ERG at the initial stage of development of dystrophy in the experimental group, while in the control group there was a steady decrease in wave amplitude "in" ERG in subsequent 5-10 days after injection of monoiodoacetic acid.

 Thus, the obtained results indicate that the claimed tetrapeptide stimulates the function of the damaged retina in toxic degenerative diseases of the retina caused by a toxic agent.

 2.2. The effect of the treatment course of the tetrapeptide on retinal morphology in rabbit toxic retinal degeneration.

 The action that stimulates the function of the retina was studied under the action of a tetrapeptide on the retina under the conditions of its experimental dystrophy in the eyes of 15 mature chinchilla rabbits weighing 2-3 kg. Experimental toxic retinal dystrophy was created by intravenous administration of a 3% potassium iodide solution at a dose of 30 mg / kg. Animals of the experimental group (10 rabbits) received daily single intramuscular injections of the tetrapeptide at a dose of 0.3 μg / kg for 7 days, starting from 10 days after the administration of the toxic agent. Animals of the control group received appropriate injections of sterile saline. A daily ophthalmoscopic examination was performed, as well as a histological examination of the eyes at various times after the administration of potassium iodide.

 1 hour after the administration of the toxic agent, there was an edema of the optic disc and retina, more pronounced on the periphery. Histologically, on the 2nd day after the introduction of potassium iodide, it was revealed that the retina is sharply swollen, the layers are loosened, there is a significant accumulation of fluid in the regions of neurons I and III, and the blood vessels of the iris are full. On the 7th day, the appearance of amorphous foci of a grayish-black color along the periphery of the fundus was observed ophthalmoscopically. Subsequently, retinal edema of the retina of the eye persisted, and accumulation of pigment cells located closer to the corner of the eye was observed on the periphery of the retina. In the ciliary body, fusion of the processes with each other with the formation of "cavernous lacunae" was found.

 Histologically, 5 days after the end of the course of treatment in the control (untreated) animals, moderate retinal edema persisted and amorphous foci were observed along the periphery of the retina. When ophthalmoscopy in rabbits treated with tetrapeptide revealed a decrease in retinal edema, a decrease in the size of amorphous foci. This was confirmed by the data of a histological study conducted 5 days after the end of the tetrapeptide treatment: retinal edema was not detected in the experimental animals, the remaining foci were smaller in comparison with the control.

 Thus, the results of the study indicate that the tetrapeptide introduced against the background of developing dystrophic changes in the retina caused by a toxic agent reduces the severity of destructive changes, prevents the further development of the pathological process and contributes to the normalization of retinal structures. This property of the tetrapeptide suggests its high therapeutic value in diseases accompanied by dysfunction of the retina, in particular with secondary chorioretinal dystrophies, retinopathies of various origins, vascular retinal disorders, macular degenerations and peripheral degenerations of the retina, retinal detachment and defects, and chemical and physical retinal lesions factors, other chorioretinal disorders.

EXAMPLE 3
The influence of the preventive course of tetrapeptide on the morphology of the retina in toxic dystrophy.

 The possible prophylactic effect of the tetrapeptide on the development of experimental retinal dystrophy in the eyes of 12 sexually mature chinchilla rabbits weighing 2-3 kg was investigated. Animals of the experimental group received daily single intramuscular injections of the tetrapeptide at a dose of 0.3 μg / kg for 30 days. Animals of the control group received appropriate injections of sterile saline. After injections were completed, experimental toxic retinal degeneration was simulated in animals by intravenous administration of a 3% potassium iodide solution at a dose of 30 mg / kg. Subsequently, a daily ophthalmoscopic examination was performed for 2 weeks, as well as a histological examination of the eyes for various periods after the administration of potassium iodide.

 In control animals, after administration of potassium iodide, ophthalmoscopically and histologically determined pronounced edema of the retina and optic disc, the formation of amorphous foci along the periphery of the retina. In contrast to the control, in animals that received prophylactic injections of the tetrapeptide, ophthalmoscopic edema of the optic disc and the appearance of amorphous foci on the retina were not detected. When histological examination of the retina of animals of the experimental group of pathological changes were not detected.

 Thus, the results of the study indicate that the tetrapeptide, administered within 1 month before the onset of the toxic agent, has a pronounced protective effect and prevents the development of toxic retinal dystrophy. This property of the tetrapeptide suggests its high prophylactic value in diseases accompanied by dysfunction of the retina, in particular with secondary chorioretinal dystrophies, retinopathies of various origins, vascular retinal disorders, macular degenerations and peripheral degenerations of the retina, retinal detachment and defects, chemical and physical retinal lesions factors, other chorioretinal disorders.

EXAMPLE 4
The use of tetrapeptide for hereditary retinal degeneration in CAMBELL rats.

 The effect of the tetrapeptide on the retina function of 19 Campbell rats, characterized by the development of hereditary retinal degeneration, was investigated. Retinal pigment atrophy in Campbell rats begins to develop 17-20 days after birth and leads to complete blindness of the animals by the end of the 2nd month after birth. The animals of the experimental group (10 rats) received daily single intramuscular injections of the tetrapeptide at a dose of 1 μg / kg throughout the study period, starting from the 17th day after birth. Animals of the control group (9 rats) received appropriate injections of sterile saline.

Retinal function in animals of both groups was evaluated by electroretinogram (ERG), recorded on the 30th and 47th day after birth. All animals were kept under natural light. Before recording the ERG, rats were adapted to dark for 2 hours. The ERG was removed under nembutal anesthesia using a wick electrode touching the moistened cornea. The pupil was dilated with 1% atropine solution, the cornea was anesthetized with 0.25% dicain solution. A white diffuser was used as a photostimulus. Light flashes of 100 ms duration were used; the maximum stimulus brightness was 5 · 10 ⁴ nt. The stimulation frequency was varied from single to 34 pulses per second. The criterion for evaluating the effectiveness of the tetrapeptide was a change in the wave amplitude "in" of the ERG at various frequencies of reproduction of the photostimulation rhythm.

 ERG indices in animals of both groups on the 30th day after birth are presented below in table 2.

 As can be seen, in rats treated with the tetrapeptide, the wave amplitude "in" of the ERG on the 30th day was significantly higher compared to the control, and this difference is observed over the entire range of stimulus frequencies. In addition, in control rats at a frequency of 34 cps it was not possible to induce the corresponding waves of ERG, which indicates a decrease in the functionality of the retinal receptor elements to reproduce the stimulation rhythm. In contrast, in animals treated with the tetrapeptide, this ability to reproduce the rhythm of stimulation was maintained. It should be noted that it was not possible to identify significant differences in the fundus pattern in the animals of the studied groups, however, the behavioral reaction of the rats in the control group indicated a decrease in visual function.

 ERG indices in animals of both groups on the 47th day after birth are presented below in table 3.

 As on the 30th day, the amplitude of the wave "in" ERG in rats treated with the tetrapeptide is significantly higher compared to the control over the entire range of stimulus frequencies. When analyzing the dynamics of ERG in control animals, a decrease in the amplitude of wave "B" by 50-80% compared with the 30th day, while in animals treated with tetrapeptide, this decrease compared with the 30th day was only 15- 20%. In addition, in control animals with a pulse frequency of 24 per minute or more, the retinal receptor elements did not reproduce the stimulation rhythm, and in rats receiving the tetrapeptide, the ability to reproduce the rhythm was maintained at all levels of photostimulation frequency.

 On the fundus of rats in the control group, signs of abiotrophic changes in the retina were observed during these periods; the severity of these changes in the experimental group was significantly less. Sharp differences were found in the behavioral reaction. Thus, in rats of the control group, in contrast to experimental animals, signs of a sharp drop in visual function were observed.

 Thus, the study shows the high effectiveness of the tetrapeptide in preventing the development and treatment of retinal abiotrophy of hereditary origin. This property of retiline suggests its high therapeutic and prophylactic value in diseases such as hereditary retinal degeneration and congenital malformations of the eye, accompanied by impaired retinal function.

EXAMPLE 5
The effect of the tetrapeptide on the rate of restoration of light sensitivity of the retina after the maladaptive photostimulus.

 The effect of the tetrapeptide on the speed of restoration of the light sensitivity of the retina by wave "in" electroretinograms (ERG) after disadaptive flashes of light was studied. In 18 rabbits weighing 3-4 kg after presentation of a maladaptive photostimulus, ERG was recorded (control), then the studied tetrapeptide was administered once intramuscularly at a dose of 1 μg / kg. After dark adaptation and subsequent repeated exposure to a maladaptive photostimulus, ERG was again recorded. The results of the study are presented in table 4.

 As can be seen, the tetrapeptide significantly accelerates the restoration of the retinal light sensitivity at the initial stage of visual maladaptation, which is manifested in significantly higher values of the wave amplitude "in" of the ERG in comparison with the control.

 Thus, the data obtained indicate that the tetrapeptide accelerates the restoration of the retinal light sensitivity after visual maladaptation. In this regard, we can conclude that the claimed drug is effective in the treatment and prevention of retinal diseases, as well as other diseases and pathological conditions, which alone or through their complications lead to a decrease in retinal function and may be accompanied by visual disturbances such as visual field disturbances , violation of color perception, hemeralopia, etc.

 The new properties of the tetrapeptide preparation revealed as a result of an experimental study make it possible to consider its therapeutic and prophylactic use to stimulate retinal functions in a number of diseases and pathological conditions accompanied by a dysfunction of the retina of the eye. The list of diseases and pathological conditions is given in accordance with the international classification of diseases (ICD-9-CM, Washington, 1989).

360 Lesions of the eyeball
360.0 Purulent endophthalmitis
360.00 Purulent endophthalmitis (unclassified otherwise)
360.01 Acute endophthalmitis
360.02 Panophthalmitus
360.03 Chronic endophthalmitis
360.04 Vitreal abscess
360.1 Other endophthalmitis
360.11 Sympathetic Waves
360.12 Panuevit
360.13 Parasitic endophthalmitis (otherwise unclassified)
360.19 Others
Phacoanaphylactic endophthalmin
360.2 Degenerative lesions of the eyeball
360.20 Degenerative damage to the eyeball (otherwise unclassified)
360.21 Progressive high (degenerative) myopia
Malignant myopia
360.23 Siderosis
360.24 Other metalloses
Chalcosis
360.29 Others
361 Detachment and retinal defects
361.0 Retinal detachment with retinal defect
Regmatogenous retinal detachment
361.00 Retinal detachment with retinal defect (unclassified otherwise)
361.01 Fresh detachment, partial, with a single defect
361.02 Fresh detachment, partial, with multiple defects
361.03 Fresh detachment, partial, with a giant gap
361.04 Fresh detachment, partial, with retinal dialysis
Dialysis (juvenile) of the retina (with detachment)
361.05 Fresh detachment, total or subtotal
361.06 Old detachment, partial
Limited old retinal detachment
361.07 Old detachment, total or subtotal
361.1 Retinoschisis and retinal cysts
361.10 Retinoschisis (otherwise unclassified)
361.11 Flat retinoschisis
361.12 Bullous retinoschisis
361.13 Primary retinal cysts
361.14 Secondary retinal cysts
361.19 others
Retinal Pseudocyst
361.2 Serous retinal detachment
Retinal detachment without retinal defect
361.3 Defects of the retina without detachment
361.30 Retinal defect (unclassified otherwise)
Retinal Gap (s) (Unclassified otherwise)
361.31 Rounded retinal opening without detachment
361.32 Horseshoe retinal tear without detachment
Retinal Gap
361.33 Multiple retinal defects without detachment
361.8 Other forms of retinal detachment
361.81 Traction retinal detachment
Traction detachment with vitreoretinal organization
361.89 Others
361.9 Unclassified retinal detachment
362 Other retinal lesions
362.0 Diabetic retinopathy
Also: Diabetes with ophthalmic manifestations (250.5)
362.01 Background diabetic retinopathy
Diabetic Retinal Microaneurysms
Diabetic retinopathy (otherwise unclassified)
362.02 Proliferative diabetic retinopathy
362.1 Other secondary retinopathies and vascular retinal disorders
362.10 Secondary retinopathy, nonspecific
362.11 Hypertensive retinopathy
362.12 Exudative retinopathy
Coates Syndrome
362.13 Changing the appearance of blood vessels
Retinal vessel thickening
Retinal Atherosclerosis (440.8)
362.14 Retinal microaneurysms (not elsewhere classified)
362.15 Retinal telangiectasia
362.16 Retinal neovascularization (otherwise unclassified)
Neovascularization:
chloride
subretinal
362.17 Other intraretinal microvascular disorders
Retinal varicose veins
362.18 Retinal vasculitis
Ills disease
Retinal:
arteritis
endarteritis
Retinal:
perivasculitis
phlebitis
362.2 Other proliferative retinopathies
362.21 Retrollent fibroplasia
362.29 Other non-diabetic proliferative retinopathies
362.3 Occlusion of retinal vessels
362.30 Occlusion of retinal vessels (unclassified otherwise)
362.31 Occlusion of the central retinal artery
362.32 Occlusion of an artery branch
362.33 Partial arterial occlusion
Hollenhrost Plaque
Retinal microembolism
362.34 Transient arterial occlusion
Transient Blindness (ammaurosis fugax)
362.35 Occlusion of the central retinal vein
362.36 Venous branch occlusion
362.37 Venous congestion
Retinal Vein Occlusion:
initial
partial
362.4 Detachment of retinal layers
362.40 Detachment of the retinal layer (otherwise unclassified)
362.41 Central serous retinopathy
362.42 Serous detachment of retinal pigment epithelium
Exudative detachment of retinal pigment epithelium
362.43 Hemorrhagic detachment of retinal pigment epithelium
362.5 Degeneration of the macula and posterior pole
362.50 Senile macular degeneration (unclassified otherwise)
362.51 Non-exudative senile macular degeneration
Senile macular degeneration:
atrophic
dry
362.52 Exudative senile macular degeneration
Kunt-Unius Degeneration
Senile macular degeneration:
disciform
wet
362.53 Cystic macular degeneration
362.54 Macular cyst, indentation or pseudo-indentation
362.55 Toxic maculopathy
362.56 Macular folding
Preretinal fibrosis
362.57 Druze (degenerative)
362.6 Peripheral retinal degeneration
362.60 Peripheral retinal degeneration (otherwise unclassified)
362.61 Degeneration of the type of "cobblestone pavement"
362.62 Microcystic degeneration
Blessig's Cysts
Kisty Ivanova
362.63 lattice degeneration
Retinal degeneration
362.64 Secondary pigmentary degeneration
Pigmented pseudoretinitis
362.65 Secondary vitreoretinal degeneration
362.7 Hereditary retinal dystrophies
362.70 Hereditary retinal dystrophy (not elsewhere classified)
362.71 Retinal dystrophy in systemic or cerebroretinal lipidoses
Indication of underlying disease, for example:
Cerebroretinal lipidoses (330.1)
Systemic lipidoses (272.7)
362.72 Retinal dystrophy in other systemic disorders and syndromes
Indication of underlying disease, for example:
Bessen-Kornzweig syndrome (272.5)
Refsum disease (356.3)
362.73 Vitreoretinal dystrophies
Youthful Retinoschisis
362.74 Retinal pigment dystrophy
White-point retinal dystrophy
Retinitis pigmentosa
362.75 Other dystrophies with primary damage to the sensory layer of the retina
Progressive dystrophy of cones (rods)
Stargardt disease
362.76 Dystrophy with primary lesion of retinal pigment epithelium
Yellow spotted fundus
Vitelliform dystrophy
362.77 Dystrophy with primary lesion of Bruch's membrane
Dystrophy:
hyaline
pseudo-inflammatory foveal
Inherited Druze
362.8 Other Retinal Disorders
362.81 Retinal hemorrhage
Hemorrhage:
preretinal
retinal (deep, superficial)
subretinal
362.82 Exudates and deposits in the retina
362.83 Retinal edema
cotton stains
retinal edema (focal) (macular)
(peripheral)
362.84 Retinal Ischemia
362.85 Defects of the nerve fibrous bundles of the retina
362.89 Unclassified retinal disorder
363 Chorioretinal inflammation, scars and other disorders of the choroid
363.0 Focal chorioretinitis and focal retinochoroiditis
363.00 Focal chorioretinitis (otherwise unclassified)
Focal:
choroiditis or chorioretinitis
retinitis or retinochoroiditis
363.01 Focal choroiditis and chorioretinitis, juxtapapillary
363.03 Focal choroiditis and chorioretinitis of the posterior pole of the eye of another location
363.04 Focal choroiditis and chorioretinitis, peripheral
363.05 Focal retinitis and retinochorioiditis, juxtapapillary
Neuroretinitis
363.06 Focal retinitis and retinochoroiditis, macular or paramacular
363.07 Focal retinitis and retinochorioiditis of the posterior pole of the eye of another location
363.08 Focal retinitis and retinochorioiditis, peripheral
363.1 Disseminated chorioretinitis and disseminated retinochorioiditis
363.10 Disseminated chorioretinitis (otherwise unclassified)
Disseminated:
choroiditis or chorioretinitis
retinitis or retinochoroiditis
363.11 Disseminated choroiditis and chorioretinitis, posterior pole
363.12 Disseminated choroiditis and chorioretinitis, peripheral
363.13 Disseminated choroiditis and generalized chorioretinitis
Indication of underlying disease, for example:
tuberculosis (017.3)
363.14 Disseminated retinitis and retinochorioiditis, metastatic
363.15 Disseminated retinitis and retinochorioiditis, retinitis pigmentosa
Acute posterior multifocal placoid pigmented epithelium
363.2 Other forms and unclassified forms of chorioretinitis and retinochoroiditis
363.20 Chorioretinitis, unclassified
Choroiditis (Unclassified otherwise)
Retinitis (Unclassified otherwise)
Uveitis, posterior (unclassified otherwise)
363.21 Parsplanit
Rear cyclite
363.22 Harada's disease
363.3 Chorioretinal scars
Scar (anti-inflammatory) (post-surgical) (post-traumatic):
choroid
retina
363.30 Chorioretinal scar, unclassified
363.31 Radiation retinopathy
363.32 Other macular scars
363.33 Other scars of the posterior pole
363.34 Peripheral scars
363.35 Disseminated scars
363.4 Choroid degeneration
363.40 Choroid degeneration, unclassified
Choroid sclerosis
363.41 Senile atrophy of the choroid
363.42 Diffuse secondary atrophy of the choroid
363.43 Angioid choroid bands
363.5 Hereditary choroidal dystrophies
Hereditary choroidal atrophy:
partial (capillaries)
total (all vessels)
363.50 Hereditary choroidal dystrophy or atrophy, not classified
363.51 Paropapillary dystrophy of the choroid, partial
363.52 Total periapillary dystrophy of the choroid, total
Choroid Helicoid Dystrophy
363.53 Central dystrophy of the choroid, partial
Choroidal dystrophy:
central areolar
annular
363.54 Central dystrophy of the choroid, total
Choroidal dystrophy:
central spiral
creeping
363.55 Chorioderma
363.56 Other diffuse or generalized dystrophies, partial
Diffuse choroid sclerosis
363.57 Other diffuse or generalized dystrophies, total
Generalized spiral atrophy of the choroid
363.6 Choroidal hemorrhages and tears
363.61 Choroidal hemorrhage, unclassified
363.62 Expulsive choroidal hemorrhage
363.63 Choroidal gap
363.7 Choroid Detachment
363.70 Choroid detachment, unclassified
363.71 Serous detachment of the choroid
363.72 Hemorrhagic detachment of the choroid
363.8 Other Choroid Disorders
363.9 Unclassified choroid disorder
366 Cataract
366.3 Secondary cataract for eye diseases
366.34 Cataract in degenerative disorders
Sunflower cataract
With an indication of the underlying disease, for example:
retinal pigment dystrophy
368 Visual impairment
368.4 Visual field defects
368.40 Defect of visual fields, unclassified
368.41 Scotoma involving the central region
Scotoma:
central
centrocecal
paracentral
368.42 Scototomy involving the blind spot
Paracecal scotoma
Extended:
angioscotoma
blind spot
368.43 Sector and arc defects
Scotoma:
arcuate
Bierrum
Seidel
368.44 Other limited visual field defects
Scotoma:
annular
otherwise unclassified
Visual field defect
peripheral
nasal step
368.5 Deficits of color vision
Color blindness
368.51 Protan defect
Protanomaly
Protanopia
368.52 Deitan defect
Deuteranomaly
Deuteranopia
368.53 Tritan defect
Tritanomaly
Tritanopia
368.54 Achromatopsia
monochromatism (rod) (conical)
368.55 Acquired color vision deficits
368.59 Other color vision deficits 368.6 Night blindness
Hemeralopia
Nictalopia
368.60 Night blindness, unclassified
368.61 Congenital night blindness
Inherited night blindness
Oguchi's disease
368.62 Acquired night blindness
368.63 Disturbed dark adaptation curve
Broken threshold of rods or cones
Slow adaptation of rods or cones
368.69 Other types of night blindness
377 Lesions of the optic nerve and optic tract
377.0 Edema of the optic nerve, unclassified
377.01 Edema of the optic nerve associated with increased intracranial pressure
377.02 Edema of the optic nerve associated with reduced intraocular pressure
377.03 Edema of the optic nerve associated with retinal disorder
377.04 Kennedy Syndrome
377.1 Atrophy of the optic nerve
377.10 Atrophy of the optic nerve, unclassified
377.11 Primary atrophy of the optic nerve
377.12 Post-tail inflammatory atrophy of the optic nerve
377.13 Atrophy of the optic nerve associated with retinal dystrophies
377.14 Glaucomatous atrophy of the optic disc
377.15 Partial atrophy of the optic nerve
Temporary pallor of the optic disc
377.16 Hereditary atrophy of the optic nerve
Atrophy of the optic nerve:
dominant hereditary
Lebera
377.2 Other lesions of the optic disc
377.21 Druze optic disc
377.22 Crater-like recesses of the optic disc
377.23 Coloboma of the optic disc
377.24 pseudo-edema of the optic nipple
377.3 Optic neuritis
377.30 Optic neuritis, unclassified
377.31 Papillitis
377.32 Retrobulbar neuritis (acute)
377.33 Trophic optic neuropathy
377.34 Toxic optic neuropathy
Toxic Amblyopia
377.39 Others
377.4 Other disorders of the optic nerve
377.41 Ischemic optic neuropathy
377.42 Hemorrhage in the sheath of the optic nerve
377.49 Others
Optic nerve compression
743 Congenital malformations of the eye
743.5 Congenital malformations of the posterior segment
743.53 Congenital chorioretinal degeneration
743.54 Congenital folds and cysts of the posterior segment
743.55 Congenital macular changes
743.56 Other congenital retinal changes
743.57 Classified abnormalities of the optic disc
Optic nerve coloboma (congenital)
743.58 Vascular abnormalities
Congenital retinal aneurysm
743.59 Others
794 Non-specific results of functional studies not in accordance with the norm
794.1 Peripheral nervous system and sensory organs
794.11 Violations detected during functional studies of the retina
Violations on the electroretinogram (ERG)
794.12 Disorders in the electrooculogram (EOG)
794.13 Violations of visually induced potential
The following are examples of clinical trials of the claimed drug on a limited number of patients. Studies of the therapeutic efficacy of the claimed drug in diseases of the retina convincingly demonstrated the high clinical efficacy of this drug. The above examples of the results of a clinical study of the claimed drug indicate its high therapeutic value and confirm the possibility of its use as a means of stimulating the function of the retina of the eye.

 EXAMPLE 6

 The use of tetrapeptide for other lesions of the retina [362] on the example of degeneration of the macula and the posterior pole [362.5].

 6.1. The tetrapeptide was used in 56 patients (112 eyes) with central involutional chorioretinal dystrophy (non-exudative senile macular degeneration [362.51] and disciform senile macular degeneration [362.52].

 The age of patients ranged from 48 to 79 years.

 The drug was administered parabulbarly or intramuscularly at 10.0 μg once daily for 10 days. The control group consisted of 24 patients (48 eyes) with a similar disease who received traditional treatment in such cases (tissue, vitamin, vasodilator therapy) according to the established scheme.

 The clinical picture in the patients (pre-form stage, non-exudative form, predominant changes in retinal pigment epithelium) was characterized by the disappearance of macular reflexes, the presence of mottling, drusen, dystrophic foci in the macular region. In some cases, destruction of the pigment epithelium and mottling in the posterior pole of the eye were observed. In patients with a dysformiform stage of dystrophy, pronounced changes in the pigment epithelium in the macula, cicatricial changes, sub- and preretinal fibrosis were detected. In 90% of cases, sclerosis of retinal vessels was recorded. Visual function was reduced in all patients. During fluorescence angiography, typical signs of this pathology were revealed (luminescence of drusen; bright fluorescent spots - areas of leakage of blood plasma elements through Bruch's membrane and defects of the pigment epithelium; brightly luminous hemorrhages against a dark background, indicating the presence of subretinal neovascularization). An electrophysiological study of the retina showed a decrease in activity and an increase in latency of I and II neurons in the macula.

 The use of tetrapeptide contributed to an increase in visual function. Visual acuity increased in 82.1% of cases, in 17.9% - remained unchanged, and in no case was its decrease recorded. The number of registered positive or relative cattle decreased by 68%, there was an expansion of the peripheral boundaries of the field of view along various meridians from 5 to 10 degrees. The results of fluorescence angiography indicated a decrease in dye perspiration in all cases.

 Table 5 presents the data obtained with a local ERG electroretinographic study of the retina before and after treatment.

 As can be seen, injections of tetrapeptide led to an increase in activity and a decrease in the latency time of I and II neurons in the macula according to the results of local ERG. The persistence of clinical improvement in patients who received the course of the tetrapeptide preparation remained in 79.4% of cases for six months and in 20.6% for a year or more.

 In the control group, a positive clinical result was obtained only in 39.6% of cases, in addition, in 28.5% of cases, the progression of the pathological process was recorded (decreased visual acuity, the appearance of new cattle in the central field of vision, worsened results of fluorescence angiography, electrophysiological studies retina, the appearance of hemorrhages in the fundus).

 6.2. Patient I., 70 years old. Amblyopia on the left eye since childhood. Diagnosed with dry sclerotic macular degeneration (non-exudative senile macular degeneration [362.51]) in both eyes was made five years ago. Twice a year, she received a course of conservative therapy in the leading medical institutions of the city, but visual function continued to decline.

 On examination: the visual acuity of the right eye of 0.25 is not corrected, the visual acuity of the left eye of 0.06 with a sphere of + 6.0 diopters = 0.25 is not corrected. The peripheral boundaries of the field of vision in both eyes are concentrically narrowed. In the field of view of the right eye, 3 relative central scotomas are determined, for the left eye - 2. During biomicroscopy of the lens of both eyes in the cortical layers, beginning turbidity is detected. When ophthalmoscopy of the fundus of both eyes revealed dystrophic foci in the macula. Moderately severe retinal angiosclerosis. Optic nerve disc and visible periphery without pathological changes. An electrophysiological study of the retina revealed a decrease in I neuron activity in both eyes and an increase in latency time in the right eye in the macula.

 A course of parabulbar injections of tetrapeptide in both eyes was carried out at 10 μg daily once for 10 days.

 After the 4th injection of the drug, the patient began to notice a subjective improvement (a clearer image, increased visual performance). By the end of the course, visual acuity increased by 0.3 in the right eye and by 0.15 with correction in the left. The peripheral boundaries of the field of view along the different meridians expanded by 5–13 degrees. In the field of view of the right eye, the scotomas disappeared completely, and the left one was left alone. According to the electrophysiological study of the retina, a significant increase in the activity of neuron I in the macula in both eyes was recorded.

 Dynamic observation for 6 months showed stabilization of the pathological process.

 6.3. Patient L., 49 years old, turned to an ophthalmologist due to visual impairment in both eyes and the appearance of spots in front of his right eye. A decrease in visual acuity and the appearance of cattle in the field of vision was noted a year ago.

Diagnosis: maculopathy in both eyes (degeneration of the macula and posterior pole [362.5])
On examination: visual acuity of the right eye of 0.4, left - 0.85. In the field of view of the right eye, two absolute central scotomas are defined. In biomicroscopy, optical media are transparent. With ophthalmoscopy of the fundus of the right eye in the macula, a small defect with perifocal edema and small dystrophic foci is determined paramacularly. The course and caliber of the vessels is not changed. Optic nerve disc and visible periphery without pathological changes. With ophthalmoscopy of the left eye, the fuzziness of the macular reflex is determined. The course and caliber of the vessels is not changed. Optic disc and visible periphery without pathological changes. According to the electrophysiological study of the retina, a change in the activity of I neuron in the macula on the right is noted, the remaining indicators are at the upper limit of the norm.

 A course of parabulbar injections of tetrapeptide in both eyes was carried out at 10 μg daily once for 10 days.

 After the second injection, the patient began to note that the scotomas had decreased in size and brightened. Daily, the patient recorded the dynamics of the sizes of cattle on the Amsler grid. From the first days of treatment, the patient noted subjective positive visual sensations, which went along with an increase in visual acuity. By the end of the course with the tetrapeptide preparation, visual acuity in both eyes reached 1.0. Only one scotoma remained in the field of view of the right eye, which significantly decreased in size and brightened. With ophthalmoscopy of the fundus of the right eye, macular edema completely disappeared, the macular reflex in the left eye became more clear. In an electrophysiological study of the retina, all indicators were within normal limits.

 Thus, the use of the preparation of the claimed tetrapeptide is an effective method for the treatment of central dystrophic processes (degeneration of the macula and posterior pole [362.5]).

 EXAMPLE 7

 The use of tetrapeptide in progressive high (degenerative) myopia [360.20].

 7.1. The tetrapeptide was used in patients with high myopia and changes in the fundus. The main group consisted of 39 patients (78 eyes) suffering from myopic disease. The age of patients ranged from 19 to 43 years. The tetrapeptide preparation was administered parabulbularly or intramuscularly at a dose of 10.0 μg once daily for 10 days.

 The control group consisted of 16 patients (32 eyes) with a similar clinical picture and receiving the trophic therapy adopted in these cases.

 The clinical picture in all patients was characterized by dystrophic changes in all membranes of the eye and environments, but primarily in the retina. An ophthalmoscopy revealed the following: myopic cone in the optic nerve head, true scleral staphylomas, dystrophically altered areas of the retina, retinal breaks, and sections of retinal detachment. The results of electroretinography (ERG) of the retina testified to a decrease in activity and an increase in the latency time of I and II neurons in the total ERG.

 All patients receiving the tetrapeptide noted a subjective increase in visual functions - the image became clearer, brighter, the flies disappeared in the field of view, and visual performance increased. In addition, there was an improvement in the temporal parameters of the visual sequential image caused by color stress.

 Table 6 presents the data obtained with total retinal ERG before and after treatment.

 The research results show that after the course of treatment with the tetrapeptide preparation, an increase in activity and a decrease in the latency time of I and II neurons in the total ERG occur. The data obtained also indicate an improvement in the processes of metabolism in the retina and an increase in the conductivity of pulses between neurons of the visual analyzer. It should be noted that the regular use of the claimed drug prevented the appearance of dystrophically altered areas of the retina, tears or its detachment.

 In patients of the control group, the course of trophic therapy in most cases did not give any positive dynamics in the clinical picture.

 7.2. Patient P., 28 years old. Myopia since childhood. In 1983, sclerotherapy was performed on both eyes, but myopia continued to progress. In February 1997, laser coagulation (LC) of valvular ruptures of the retina in both eyes was performed. Diagnosis: progressive high (degenerative) myopia of both eyes [360.20].

 On examination: complaints of rapid fatigability, decreased visual performance and metamorphopsies in the field of vision of both eyes. Visual acuity of the right eye is 0.03 with a sphere of 15.0 diopters = 0.3; left eye - 0.03 with a sphere - 15.0 diopters = 0.2. With biomicroscopy, the destruction of the vitreous body of both eyes is determined. On the fundus of the right eye: optic nerve disc with a grayish tint, staphyloma. The vessels are moderately narrowed. Redistribution of pigment throughout the fundus. At the 11th hour, the valve rupture is delimited by the LC. At the fundus of the left eye, the changes are similar to the right, however, the retinal valve rupture, delimited by LC, is located at 2 o’clock. ERG results indicated a decrease in the activity of neuron I, an increase in latency time of neuron II on both sides, and a sharp decrease in the amplitude activity of neuron II on the left.

 A course of parabulbar injections of tetrapeptide in both eyes was carried out at 10 μg daily once for 10 days.

 The patient began to observe subjective positive visual sensations after 4 injections of the drug. By the end of the course, complaints of metamorphopsies in the field of view of both eyes were completely gone, and visual performance increased significantly. Visual acuity remained the same, but the brightness and contrast of the image increased. ERG data indicated an increase in amplitude activity and a decrease in latency time of I and II neurons on both sides.

 EXAMPLE 8

 The use of tetrapeptide in other lesions of the retina [362] on the example of hereditary central tapetoretinal abiotrophy of the retina such as Stargardt, Best and Franceschitti.

 8.1. The tetrapeptide was used in 36 patients (72 eyes) aged 18-49 years with hereditary central tapetoretinal abiotrophies of the Stargardt type [362.75], Besta (vitelliform dystrophy [362.76] and Franceschetti (yellow-spotted fundus [362.76]), The drug was administered tetrapeptide 10.0 mcg once daily for 10 days.

 The control group consisted of 20 patients (40 eyes) with tapetoretinal abiotrophy who received traditional therapy.

In 32 eyes with hereditary central tapetoretinal abiotrophies such as Stargardt, Best, and Franceschetti, in the initial and developed stages with parabulbar administration of tetrapeptide, a pronounced positive effect was observed. An increase in visual acuity by 0.1-0.35, an expansion of the peripheral boundaries of the visual field along different meridians by 10 ^o or more, and disappearance in the central field of vision by cattle were noted. We also observed positive dynamics in color perception (blue discernment), a significant decrease in destructive changes in pigment epithelium on fluorescence angiograms, and positive dynamics in ERG indices.

In a far-reaching stage of hereditary central tapetoretinal abiotrophy (40 eyes), a positive clinical effect was also observed in the treatment with tetrapeptide: an increase in visual acuity to 0.1, an expansion of the peripheral borders of the visual field along different meridians from 5 ^o and above, a decrease in central cattle field of vision, positive dynamics in color perception and indicators of ERG.

 In control patients receiving traditional treatment methods, a pronounced positive result was noted only in 20% of cases.

 Thus, the use of the claimed tetrapeptide is an effective method for the treatment of hereditary central tapetoretinal abiotrophies such as Stargardt, Best and Franceschetti.

 EXAMPLE 9

 The use of tetrapeptide in patients with retinitis pigmentosa [362.74].

 The tetrapeptide was used in 32 patients (64 eyes) aged 18-69 years with retinal pigment peripheral abiotrophy (retinitis pigmentosa [362.74]). The tetrapeptide was used in the form of parabulbar injections of 10.0 μg once daily for 10 days.

 The control group consisted of 25 patients (50 eyes) with retinitis pigmentosa treated with traditional methods (vasodilators, angioprotectors, anti-sclerotic drugs, vitamin and tissue therapy).

 Before treatment, patients with the control and experimental groups observed changes characteristic of pigmentary peripheral abiotrophy: decreased visual acuity, visual field boundaries (narrowing of peripheral visual field borders, presence of paracentral cattle in the visual field), color perception disorders, impaired dark adaptation, change in ophthalmoscopic picture fundus (fundus pigmentation, characteristic "waxy" staining of the optic nerve), violation of electrophysiological parameters (decrease in amplitudes wave "in" electroretinogram and svetotemnovogo Arden ratio). Already in the first week of treatment with the preparation of the claimed tetrapeptide, an improvement in visual functions was observed in 75.0% of patients in the main group. By the end of the course of treatment, 90.6% of patients noted subjective positive visual sensations, which were confirmed by ophthalmological examination. First of all, visual acuity increased, there was an expansion of the peripheral boundaries of the visual fields, as well as a decrease or disappearance of paracentral cattle.

 Table 7 presents the results of studies of electrophysiological indicators.

 As can be seen, in all patients of the main group there was an increase in the amplitude of the "in" wave of the electroretinogram and the Arden light coefficient, which indicates a positive effect of the tetrapeptide on the retina of the eyes of patients with retinitis pigmentosa. In the control group, a positive clinical effect was obtained only in 24% of cases.

 Thus, the study showed that the claimed tetrapeptide has a stimulating effect on the visual function of the eye in patients with retinitis pigmentosa and, therefore, is a highly effective treatment.

 EXAMPLE 10

 The use of tetrapeptide in diabetic retinopathy [361.0].

 10.1. The tetrapeptide was used in 52 patients (104 eyes) aged 21-69 years with diabetic retinopathy [362.0]. The drug was administered parabulbarly at 10.0 μg once daily for 10 days. The control group consisted of 21 people who received standard therapy in such cases (vasodilator drugs, angioprotectors). All patients were diagnosed with diabetic retinopathy (DR) at various stages.

 Table 8 presents the change in visual acuity indicators in patients with diabetic retinopathy before and after the course of treatment with the drug.

As a rule, under the influence of the tetrapeptide, visual acuity first changed. After several injections, patients noted subjective positive visual sensations, which went along with an improvement in visual function. Increased visual acuity tended to increase with the passage of treatment. From table 8 it is seen that in 49.1% of cases, visual acuity at the end of treatment reached its maximum value - 0.9-1.0. This is 21.2% more than before treatment. In 21.1% of cases, visual acuity indicators ranged from 0.0 to 0.1 and in 29.8% of cases from 0.2 to 0.8. In the control group, under the influence of traditional therapy, an increase in visual acuity to the maximum values of 0.9 - 1.0 occurred only in 9.6% of cases, which is two times less than in the main group. Changes in visual acuity under the influence of the drug were uneven at various stages of diabetic retinopathy (DR). Persons with early stages of the disease were more susceptible to treatment and gave a faster and more stable increase in visual acuity by an average of 0.2-0.4. So, with the non-proliferative stage of DR, visual acuity reached a maximum value of -1.0 in 68.7% of cases. With the transition of the disease to more severe stages (preproliferative, proliferative), visual acuity in a smaller percentage of cases (28.9%) reached 1.0, which was associated with the presence of severe complications (complicated or secondary cataracts, gross proliferative changes, hemophthalmus). In this regard, visual acuity in these groups increased only by hundredths or 0.1-0.2. In all patients who had, before treatment with tetrapeptide, a narrowing of the visual field due to the combination of DR with angiosclerosis, it was possible to expand the peripheral boundaries of the visual field in various meridians by 5-15 ^o . An improvement in the ophthalmoscopic fundus picture was observed in the vast majority of patients. So, in 81.3% of cases, partial or complete resorption of hemo- and plasmorrhages was observed. In the remaining 18.7% of cases, there were no significant changes in the ophthalmoscopic picture due to the presence of severe complications. Nevertheless, in all patients receiving the tetrapeptide, there was a clear tendency to resorption of hemorrhages and exudates.

 According to the fundus fluorescence angiography (FAGD), after the course of treatment with the tetrapeptide preparation, a decrease in the sweating of the dye from the vessels, a decrease in the number of microaneurysms in the central and paracentral areas of the fundus were revealed. Table 9 shows some indicators of carbohydrate metabolism in patients with diabetic retinopathy before and after treatment with the claimed agent.

It can be seen that, as a result of the treatment, all patients significantly decreased their sugar level, glycated hemoglobin. Normalization of the immune status has occurred. We noted a significant increase in the number of T cells with the CD 3 phenotype (T cells) from 51.3 ± 0.5% to 65.3 ± 0.1%, immunoregulatory index
CD4 / CD8 to 1.86 ± 0.04 due to an increase in CD8 from 16.9 ± 0.8 to 21.3 ± 0.5%. In addition, in 90% of patients with GB, a steady decrease in blood pressure was achieved.

 In the control group, only in 22.5% of cases there was an increase in visual functions, and the increase in visual acuity did not exceed 0.15. In other cases (77.5%), visual acuity either did not change or decreased. There was no significant expansion of the peripheral boundaries of the visual field after conventional treatment. In the ophthalmoscopic picture of the fundus, there was also no significant dynamics. Only in 21.4% of cases, there was a tendency to resorption of minor hemorrhages. In 69.1% of cases, the ophthalmoscopic picture remained unchanged, and in 9.5% it worsened (new hemorrhages and plasmorrhages appeared). According to the FAGD, there were no significant changes after treatment. Patients in the control group showed a certain tendency in lowering blood sugar levels and normalizing immunological parameters, however, we did not obtain reliable data. No significant changes in blood pressure were also recorded.

 10.2. Patient S., 20 years old. Type I diabetes since 10 years (since 1987). Heredity burdened - diabetes in the father. Eye manifestations of diabetes have been identified since January 1996. Every six months, against the background of general therapy, the patient received a course of taufon parabulbar - no improvement was noted. The question was raised about laser coagulation of the retina.

 Diagnosis: proliferative stage of diabetic retinopathy in both eyes.

 Maculopathy of both eyes.

 On examination: visual acuity of the right eye = 0.5, visual acuity of the left eye 0.2 sphere + 1.5 diopters = 0.2 Optical media are transparent. Intraocular pressure is normal. On the fundus: the optic disc is pink in color with a grayish tint, neovascularization on the temporal side (more on the left eye). The veins are dilated, convoluted. Along the vessels there are many small hemorrhages. In the macula, several “solid” exudates, hemorrhages, are ophthalmoscopically. On the left eye, the number of retinal hemorrhages is much greater.

The results of determining the level of sugar and acetone in daily urine:
I portion 750 ml, specific gravity 1020, acetone "-", sugar - 2.4%
II portion 600 ml, specific gravity 1022, acetone “-”, sugar - 5.6%
III portion of 500 ml, specific gravity 1025, acetone “-”, sugar - 5.4%.

Blood sugar test results:
9.00-17.7 mmol / l
11.00-12.9 mmol / l
13.00 -13.8 mmol / l
A course of parabulbar injections of the tetrapeptide preparation in both eyes was carried out in 10 μg daily once for 10 days.

 On examination: visual acuity of the right eye = 1.0, visual acuity of the left eye = 0.2 sphere + 1.5 diopters = 0.6 On the fundus: the right eye is a pink optic disk with clear contours. Retinal hemorrhages along the vessels completely resolved, the amount of “solid” exudates in the macula decreased significantly. On the left eye - remained single hemorrhages.

The results of determining the level of sugar and acetone in daily urine:
I portion 100 ml, specific gravity 1022, acetone "-", sugar - 2.0%
II portion 150 ml, specific gravity 1011, acetone "-", sugar - 0.4%
III portion 250 ml, specific gravity 1014, acetone "-", sugar - 0.2%
Results determination of blood sugar.

9.00-15.7 mmol / l
11.00-12.3 mmol / l
13.00-7.4 mmol / l
Under the action of the claimed tetrapeptide, visual acuity significantly increased (especially in the right eye), the number of hemo- and plasmorrhages significantly decreased (in the right eye - completely resolved). According to clinical and laboratory data, there is a tendency to lower blood sugar levels, although they have not reached the normal level. After the course of treatment, the patient himself began to feel better, more efficient.

 Unfortunately, fluorescence angiography (FAGD) of the retina was not performed due to an unfavorable allergic history. However, neither allergic nor adverse reactions after the use of tetrapeptide in the patient were detected.

 10.3 Patient J., 59 years old. Type II diabetes since 1992. Eye manifestations of diabetes have been identified since late August 1997.

 Diagnosis: Preproliferative stage of diabetic retinopathy in both eyes.

 On examination: visual acuity of the right eye = 0.5, visual acuity of the left eye = 0.9. Optical media are transparent. Intraocular pressure is normal. In the fundus: optic nerve head disk of satisfactory nutrition, with clear boundaries. Arteries are moderately narrowed. The veins are dilated, convoluted. Along the vessels there are many retinal hemorrhages and plasmorrhages (more on the left eye). On the right eye - preretinal hemorrhage 2/3 of the diameter of the optic disc (DD).

 FAGD data: abundant perspiration of the dye from the vessels, many microaneurysms in the central and paracentral regions of the fundus.

Blood Sugar - 8.9 mmol / L
Glycosylated hemoglobin - 8.25%
A course of parabulbar injections of the tetrapeptide preparation in both eyes was carried out in 10 μg daily once for 10 days.

 On examination: visual acuity of the right eye = 0.8, visual acuity of the left eye = 1.0. Optical media are transparent. Intraocular pressure is normal. In the fundus: optic nerve head disk of satisfactory nutrition, with clear boundaries. Vessels - no change. The number of hemorrhages and plasmorrhages significantly decreased. Preretinal hemorrhage in the right eye completely resolved.

 FAGD data: in comparison with the results of FAGD from 10 / XII - 97, a significant decrease in the sweating of the dye from retinal vessels, a decrease in the number of microaneurysms, was revealed.

Blood Sugar - 5.47 mmol / L
Glycolized hemoglobin - 6.1% (2 months after the course of peptide bioregulators).

 Under the influence of the tetrapeptide, visual acuity significantly increased (especially in the right eye). The number of hemorrhages and plasmorrhages decreased, preretinal hemorrhage in the right eye completely resolved. FAGD results significantly improved. The level of sugar and glycosylated hemoglobin in the blood decreased. The patient notes an improvement in well-being.

 Thus, as a result of therapy with the use of tetrapeptide, 96.5% of patients achieved clinical improvement to varying degrees. In addition to increasing visual functions (increasing visual acuity, expanding visual fields, improving the results of fluorescence angiography and an ophthalmoscopic fundus picture), the claimed tetrapeptide helps to improve the somatic status of patients with DR (normalization of the immune status, glycated hemoglobin, blood sugar, lowering blood pressure in hypertensive patients, improvement of well-being).

Sources of information
1. Therapeutic ophthalmology. Ed. M.L. Krasnova, N.B. Shulpina.- M .: Medicine, 1985, p. 33, 340, 358.

 2. Katsnelson L.A., Forofonova T.I., Bunin A.Ya. Vascular diseases of the eyes.- M .: Medicine, 1990, p. 249-256.

 3. Mashkovsky M.D. Medicines - M .: Medicine, 1988, v. 1, p. 450, 456-457, 461; t. 2, p. 6,181.

 4. RF patent N 2073518, MKI A 61 K 35/44, 1993.

 5. Yakubke H.-D. and Eskite X. Amino acids, peptides, proteins: Per. with him. - M.: Mir, 1985 .-- 456 p.

Claims (12)

 1. The tetrapeptide alanyl-glutamyl-asparagil-glycine of the general formula Ala-Glu-Asp-Gly, which has the ability to stimulate the function of the retina of the eye.  2. Pharmacological agent that stimulates the function of the retina of the eye, containing an active principle and a pharmaceutically acceptable carrier, characterized in that the active principle contains an effective amount of Ala-Glu-Asp-Gly tetrapeptide or its salts.  3. The tool according to claim 2, characterized in that it contains salts of an amino group selected from acetate, hydrochloride, oxalate.  4. The tool according to claim 2, characterized in that it contains salts of carboxylic acid groups selected from sodium, potassium, calcium, lithium, zinc, magnesium or organic and inorganic cations, selected from ammonium, triethylammonium.  5. The tool according to p. 2, characterized in that its dosage form is intended for parenteral administration.  6. The tool according to p. 2, characterized in that its dosage form is intended for parabulbar administration.  7. The tool according to p. 2, characterized in that its dosage form is intended for retrobulbar administration.  8. The tool according to p. 2, characterized in that its dosage form is intended for subconjunctival administration.  9. The tool according to p. 2, characterized in that its dosage form is intended for local administration.  10. The tool according to p. 2, characterized in that its dosage form is intended for administration in the form of ophthalmic instillations, skin applications with physiotherapeutic influences.  11. A method of treating diseases and pathological conditions accompanied by a dysfunction of the retina of the eye, which consists in administering to the patient a pharmacological agent containing an effective amount of an Ala-Glu-Asp-Gly tetrapeptide or its salts by an amino group selected from acetate, hydrochloride, oxalate or its salts for carboxyl groups selected from salts of sodium, potassium, calcium, lithium, zinc, magnesium, as well as organic and inorganic cations, selected from ammonium, triethylammonium in a dose of from 0.01 to 1000 μg / kg body weight at least once a day during a period necessary for attaining the therapeutic effect.  12. The method according to claim 11, characterized in that the agent is administered to the patient parenterally, parabulbarno, retrobulbar, subconjunctival or topically, including ocular instillations, cutaneous applications, physiotherapeutic effects.

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