RU2367387C1 - Therapy of early cataract - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to ophthalmology, and aims at treatment of early cataract. A neutral bath of low-molecular peptide fraction that is prepared of acidic protein fraction of muscle extract of mammal lenses fractionated in 100% ammonium sulphate (Vilenzin) is instilled in conjunctival cavity. Instillations are carried out at 9, 12 and 17 o'clock, 2 drops in both eyes twice every 5 minutes within course 2-6 months every 10 days after 30 days.

EFFECT: method provides partial resorption and prevents progression of cataract.

2 ex

Description

The present invention relates to ophthalmology and is intended for the treatment of initial cataract.

Cataract is one of the most common causes of decreased vision, while the number of patients with age-related, complicated and traumatic cataracts increases every year. Currently, the radical surgical method dominates the treatment of cataracts [Kopaeva V.G. // Eye diseases: Textbook / Ed. V.G. Kopaeva. - M .: Medicine, 2002. - S.245-268]. Moreover, for the most part, the patient’s subjective discomfort is already an indication for it, even if the visual acuity with correction reaches 0.8-0.9. Therapeutic treatment has faded into the background. There is still no medicine whose effect could be compared to surgery. Therefore, the search for drugs that can provide an acceptable therapeutic effect continues.

Conventionally, they can be divided into three large groups.

1. Inorganic salts.

2. Organic compounds.

3. Synthetic preparations.

Violation of protein synthesis and their breakdown, violation of tissue respiration, vitamin deficiency - all this necessitated the use of macroergic compounds in the treatment of combined drops - "vicin", "vitiodurool", amino compounds - "taurine", "cysteine", glutathione, aminoguanidine [ Zhang W., Chen C. A study on the prevention of selenite cataract with taurine // Zhonghua. Yan. Ke. Za. Zhi. - 1998. - V.34, No. 3. - P.208-210]. The latter, in addition to the construction function, contributes to the inactivation of Ca-dependent proteases.

Free thiol groups, EDTA are able to prevent the action of quinones and heavy metals [David L.L., Shearer T.R. Calcium-activated proteolysis in the during selenite cataractogenesis // Invest Ophtalmol Vis Sci. - 1984. - V.25, No. 11. - P.1275-1283] on the lens proteins. An example of this is cysteine. Synthetic preparations “quinax” and “catalin” have the same effect; in addition, they are able to inhibit LPO processes. The antioxidant effect is also inherent in N-acetylcarnazine [Chasovnikova L.V. Formazyuk V.E., Sergienko V.I., Boldyrev A.A., Severin S.E. The antioxidative properties of carnosine and other drugs // Biochem. Int. - 1990. - V.20, No. 6. - P.1097-1103].

Natural Antioxidants: Vitamins C, E [Simsek M., Naziroglu M., Erding A. Moderate exercise with a dietary vitamin C and E combination protects against streptozotocin-induced oxidative damage to the kidney and lens in pregnant rats // Exp.Clin. Endocrinol. Diabetes. - 2005. - V.113, No. 1. - P.53-59], chimes, venorutin, taurine, curcumin and other substances can block peroxidation and be effective in the treatment of senile, diabetic, radiation cataracts. Although some authors consider their therapeutic effect insufficient, for example with diabetic cataracts, because there are no mechanisms aimed at blocking the enzyme aldose reductase.

Deciphering one of the main pathogenetic links of diabetic cataract has led to the use of aldose reductase inhibitors as anti-cataracts. This is quercetin [Mears A.V., Fransworth P.N. Diminished sugar cataractogenesis by quercetin // Exp. Eye Res. - 1979. - Vol. 28, No. 6. - P.709-716] and other drugs. The mechanism of their action is associated with the blocking of this enzyme and the inability to utilize glucose in the sugar alcohol sorbitol, which, in turn, changes the osmotic balance in the lens, which leads to clouding of the lens.

Attempts have been made to incorporate lens proteins into anti-cataract agents to activate the immune response and subsequent clouding lysis [Shropshire R.F., Ginsberg J.R., Jacobi M. Theonsurgical treatment of cataract // Science. - 1952. - V.116, No. 3011. - P.276-278]. They did not receive further distribution.

Used in the treatment of NSAIDs (aspirin, paracetamol, ibuprofen). The effect of their action is explained by the ability to prevent protein aggregation by stabilizing the crystalline charge, as well as the ability to inhibit aldose reductase and prevent the accumulation of sorbitol in diabetic cataract [Harding J.J. Pharmacological treatment strategies in age-related cataracts // Drugs. Aging. - 1992. - V.2, No. 4. - P.287-300]. There is evidence of antioxidant function of aspirin.

Summarizing the above data, we can conclude that most known anticataract drugs act on the lens either by the principle of "replacement therapy", that is, there is a deficiency of a substance or trace element and it is replenished, or as an antioxidant. There are no medications that act purposefully on the reparative department of the lens. Therefore, it seems interesting to develop and study tools that affect the regeneration processes in the lens.

Prevention and treatment of the initial form of the cataract in the crystalline lens is an urgent problem, since surgical treatment is not always possible and indicated, and people with initial forms of cataract need to maintain a high and high-quality vision, which is especially important among the working part of patients, as well as for older people whose activity limited.

Thus, the search for medicines continues and goes in different directions.

Under the influence of free radicals, a structural disorganization of the membranes of the lens fibers occurs, protein aggregation due to the oxidation of methionine and cysteine residues (disulfide binding) [Truscott RJW, Augestenyn R.C. Oxidative changes in human lens proteins during senile nuclear cataract formation // Biochem. Boiphys. Acta. - 1977. - Vol. 492, No. 1. - R. 43-53]. When exposed to ultraviolet radiation in the wavelength range of 280-400 nm, photochemical oxidation of aromatic amino acids occurs, primarily tryptophan, leading to covalent binding of proteins and promoting their aggregation (non-disulfide binding) [Finley EL, Busman M., Dillon J., Crouch RK, Schey KL Identification of photooxidation sites in bovine alpha-crystallin // Photochem. Photobiol. - 1997. - V.66, No. 5. - P.635-641]. The last type of protein binding includes processes in which Ca ²⁺ ions are involved. The latter initiate the work of proteases, causing the destruction of many functionally significant proteins. It was shown that regardless of the causes of cataracts during the development of this pathology, the level of calcium in the lens increases several times, and increasing it by four times leads to a two-fold decrease in the activity of K ⁺ -Na ⁺ - dependent ATPase [Tang D., Borchman D. , Yappert MC, Vrensen GFJM, Rast V. Influence of age, diabetes, and cataract on calcium, lipid-calcium, and protein-calcium relationships in human lenses // IOVS. - 2003. - V.44, No. 5. - P.2059-2066]. The result of the development of these processes is a violation of the electrolyte balance and a change in the osmotic status of the lens, a violation of protein synthesis, transport of various substances through the membranes, including nutrients, a decrease in the level of cyclic nucleotide monophosphates and a violation of regulatory transduction processes [Highthower KR, Hind D. Cytotoxic effects of calcium on sodium-potassium transport in the mammalian lens // Curr. Eye Res. - 1982-1983. - V.2, No. 4. - P.239-246].

During cataractogenesis, a modification of the lipid composition occurs: the cholesterol content increases, but the amount of unsaturated fatty acids and phospholipids decreases. A decrease in the total amount of protein in the lens due to a decrease in its synthesis, activation of proteolysis was also noted, but at the same time, there is a decrease in the level of glutathione and other antioxidants - vitamins E, C, carotenes [Pozdnyak N.I. The role of metabolic disorders of the lens in the pathogenesis of age-related cataracts and the rationale for the principles of conservative treatment: Dis .... Dr. med. sciences. - Minsk, 1989. - P.17-23].

Thus, the key role in the pathogenesis of cataract formation is assigned to lipid peroxidation and disruption of Ca ^{+ 2-} mediated processes (disruption of homeostasis of Ca ^{+ 2} ions). A known method of treating cataracts (RU 2071316, priority from 08/05/93), comprising the use of eye drops based on the carnosine peptide (dipeptide beta-alanyl-L-histidine).

However, this method does not provide sufficient effectiveness in the treatment of cataracts, since it acts only as an antioxidant. The closest analogue of the invention is a method of the same purpose, including the use of eye drops based on polysulfate azapentacene Quinax. This drug is a reducing agent of SH-groups of directed action. However, when using this method, the optical density decreases only in the posterior capsular layers, and in the nuclear layers, on the contrary, the optical density increases within 36 months, which aggravates the nuclear cataract process, and also requires a long course of treatment (up to 1.5 years).

The objective of the invention is to create an effective method of treating initial cataracts.

The technical result of the invention is partial resorption and prevention of cataract progression. The technical result is achieved by restoring the structure of the lens fibers and intracellular proteins of the lens using a solution of a low molecular weight fraction of peptides obtained from vertebral lenses in a certain mode.

A substance is known that has an anti-cataract effect (RU 2315607, January 21, 2008), which is a solution of regulatory peptides that trigger a cascade of reactions, while entering the lens through tissue fluid, they activate metabolic processes in the lens epithelium, which in turn leads to restoration the ordered structure of the lens fibers and intracellular crystalline proteins. Use a neutral solution of a low molecular weight fraction of pepids obtained from the fraction of acidic proteins isolated by fractionation in a 100% solution of ammonium sulfate, tissue extract of vertebral lenses (Vilenzin) in the form of instillations into the conjunctival cavity at 9, 12 and 17 hours, 2 drops in both eyes 2 times with an interval of 5 minutes with a course of 2-6 months with an interval of 10 days every 30 days, which has an excellent mechanism of action based on the activation of metabolic processes in the lens epithelium, as well as on restoration disordered conformation of the molecules of intracellular proteins and crystallins makrostrutury location lens fibers. The corresponding regimen of instillation with an interval of 5 minutes is selected, since the first time when instillation, a significant amount of the drug is washed out with the tear formed, and when the instillation is repeated, the substance penetrates into the tissue fluid. Breaks every 30 days should be done so that the metabolic processes in the lens are not always in a state of active stimulation and so that the body itself can, after starting the drug, continue to maintain a high metabolic rate without inhibiting the activation of its own metabolic processes by the feedback mechanism. The selected time of day for instillation corresponds to the highest activity of metabolic processes in the lens and, accordingly, to the best therapeutic effect of the drug at a given time of day. We use endogenous peptides (Vilenzin), isolated from the lenses of the eyes of vertebrates. These peptides are characterized by the following properties: high calcium-binding activity; resistance to chemical and physical factors; they act in ultra-low doses (SMD) corresponding to 10 ^-12 -10 ^-15 mg / ml; the secondary structure of these peptides is characterized by a predominant content of β-structures and a statistical coil. A study of the physicochemical properties of the lens peptides demonstrated the ability of their molecules in aqueous solutions to participate in the formation of stable nanoparticles. In our opinion, these data allow us to raise the question of the relationship between such a peculiar state in solutions of these lens peptides and their manifestation of biological activity in SMD. In this aspect, it should be noted that many substances upon transition to the state of nanosized particles begin to exhibit new unique properties. These peptides are localized in the intercellular space of the capsular epithelium, which plays a fundamental role in the homeostasis of this eye structure, in particular, is responsible for the processes of fiber formation in the lens. The capsule epithelium is a cellular source of regeneration in the lens. it is here that the processes of cell proliferation and differentiation are most intense. The results obtained in the study of the localization of endogenous peptides in the lens, indicate the possibility of their participation in these processes. This assumption was fully confirmed in the study of the specific biological activity of the lens peptides, in which their protective property was demonstrated.

In order to study the specific activity of the lens peptides, experimental models of in vitro and in vivo cataractogenesis were used, which differ in the mechanism of development of the pathological process and reflect the most common types of cataracts in humans: traumatic, some forms of senile cataract, diabetic, etc. An experimental model of cataractogenesis was first developed. in vitro, which is based on the mechanism of electrolyte imbalance in the lens of vertebrate animals - an analogue of diabetic human cataract a sheep. In experimental vitro and in vivo vertebrate cataractogenesis models, lens peptides were studied and it was shown for the first time that they inhibit the development of cataracts in SMD, which are based on disruption of Ca ^{+ 2} -dependent enzyme systems and peroxidation systems lipids. In addition, the protective effect of the lens peptides on the development of osmotic cataract caused by the violation of ionic homeostasis in the lens was shown. This experimental model, in our opinion, may reflect some stages of the pathogenetic development of diabetic cataract in humans.

The in vivo traumatic cataract model demonstrated the ability of peptides to inhibit the development of inflammatory processes in the tissues of the eye, as well as to prevent the formation of complete cataract. The experimentally established fact of the absence of the biological effect of the lens peptides on the model of radiation cataract indicates, in our opinion, its ability to participate in regulatory processes that control the operation of the main enzyme systems of the lens, but do not affect the recovery processes in the chromosome apparatus of cells. These data contribute to a more specific understanding of the mechanism underlying the biological action of the lens peptides, which fine-tune the processes of organ-tissue homeostasis.

For these Vilenzin peptides, a complete absence of acute and chronic toxicity, immunotoxicity, teratogenicity and allergenicity, the absence of any adverse adverse reactions from individual tissues of the eye and the body as a whole was shown. Based on the data obtained in the study of the lens peptides and the new ophthalmic drug "Vilenzin", developed on its basis, it can be assumed that this drug may occupy a certain niche among anti-cataract drugs.

Unlike carnosine and quinax - drugs of unidirectional action, the drug "Vilenzin" has a multidirectional effect, exhibiting both antioxidant properties and is a reducing agent for SH-groups, and, most importantly, affects the lens epithelium.

The method is as follows. A neutral solution of a low molecular weight fraction of peptides obtained from a fraction of acidic proteins isolated by fractionation in a 100% solution of ammonium sulfate, tissue extract of vertebral lenses (Vilenzin) is instilled into the conjunctival cavity in the form of instillations into the conjunctival cavity at 9, 12 and 17 hours, 2 drops in both eyes 2 times with an interval of 5 minutes, a course lasting 2-6 months with a break of 10 days every 30 days, which has an excellent mechanism of action based on the activation of metabolic processes in the lens epithelium As well as the restoration of conformation ordering of molecules of intracellular proteins and crystallins makrostrutury location lens fibers.

A method of treating initial cataract is characterized by the following examples.

Example 1

Patient B., 45 years old. Diagnosis. Initial cortical cataract, myopic astigmatism in both eyes. Complaints of decreased vision in the last 8 years, instilled vitamin drops, no effect was observed. Visual acuity before treatment:

right eye = 0.09 sph. - 5.0 ^D cy1-1.5 ^D a × 175 ° = 0.7;

left eye = 0.35c-0.5 ^D cy1-1.5 ^D a × 30 ° = 0.9-1.0.

The course of treatment with Vilenzin was prescribed according to the following scheme: the drug was instilled into the conjunctival cavity at 9, 12 and 17 hours, 2 drops in both eyes 2 times with an interval of 5 minutes with a course of 3 months with a break of 10 days every 30 days

Three months later, a decrease in opacities in the cortical layers of the lens (according to biomicroscopy), as well as the density of the lens substance (according to U3-Dopplerography from 85 cu to 69 cu), an improvement in visualization of details of the fundus (according to photographic registration) were revealed on the fundus camera).

Visual acuity after treatment:

right eye = 0.1 sph. - 3.0 ^D cy1-1.0 ^D a × 175 ° = 0.8;

left eye = 0.4 s cy1-1.5 ^D a × 30 ° = l, 0.

Thus, when using the drug "Vilenzin" the patient showed an improvement in subjective and objective indicators of vision, which indicates partial resorption of cataracts and an improvement in the function of the lenses.

Example 2

Patient N., 30 years old. He received a contusion injury to his right eye with a cork from champagne. 3 months after the injury noted a decrease in vision. Diagnosis: initial traumatic cataract of the right eye, weak myopia of both eyes. Indicators before treatment:

right eye = 0.15 sph. - 2.5 ^D = 0.85;

left eye = 0.2 sph. - 2.5 ^D = 0.9-1.0.

Clinically, traumatic mydriasis, opacities in the anterior cortical layers and anterior lens capsule are detected in the right eye. The patient was treated with Vilenzin drug for 4 months according to the scheme: the drug was instilled into the conjunctival cavity at 9, 12 and 17 hours, 2 drops in both eyes 2 times with an interval of 5 minutes with a course of 4 months with a break of 10 times every 30 days . After treatment, the patient subjectively notes an improvement in vision, the disappearance of the "veil" in front of the eye. Biomicroscopy reveals gentle “cloud-like” opacities in the cortical layers along the periphery, the anterior lens capsule is transparent. According to dopplerography, the density of the anterior lens capsule is 87 cu, which is the norm; density of cortical layers - 6 cu at a rate of 1-4 cu Visual acuity of the right eye with correction = 0.9-1.0.

Thus, the drug "Vilenzin" has an anti-cataract effect, which is expressed in a decrease in the density of the lens substance, as well as the area of turbidity; its use leads to a corresponding decrease in the degree of myopia and lens astigmatism. The drug used prevents the progression of cataracts, especially traumatic genesis, causes partial or complete resorption of opacities in the layers of the lens.

Claims (1)

A method of treating initial cataract, characterized in that a neutral solution of a low molecular weight fraction of peptides obtained from a fraction of acidic proteins of a tissue extract of vertebral lenses isolated by fractionation in a 100% solution of ammonium sulfate (Vilenzin) is instilled into the conjunctival cavity at 9, 12 and 17 hours 2 drops in both eyes 2 times with an interval of 5 minutes with a course lasting 2-6 months with a break of 10 days every 30 days.