RU2489146C1 - Method of treating "dry" form of age-related macular degeneration - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular opthalmology, and may be used for treating the patients with a "dry" form of age-related macular degeneration. That is combined with using lutein-containing antioxidants and carotenoids for one year every 2-3 months. Fenofibrate (Tricor 145) is additionally used for a period of time long enough to normalise a lipid profile and to maintain the above values at the attained level. Vitrum vision forte and nutrof total are used as the above lutein-containing antioxidants and carotenoids.

EFFECT: invention provides arresting the progression of the "dry" form of age-related macular degeneration.

2 cl, 1 ex

Description

The present invention relates to ophthalmology and is intended for the treatment of patients with a “dry” form of age-related macular degeneration (AMD). According to statistics, the “dry” form of AMD is found in 90% of cases, the “wet” form - in 10%. The “dry” form of AMD is characterized by the two-sided process and chronic slow progression from slight in the early stages to low vision and blindness in the late stages of the disease, for this reason the disease takes third place among the causes of blindness in the second half of life after glaucoma and diabetic retinopathy.

Research in this area is highly relevant given the loss of general disability due to AMD by persons of working age. In this category of patients, lipid metabolism disorders lead to a sharp imbalance in the oxidative processes of the vascular system of the body (oxidative stress), causing damage to both large vessels and the smallest. This category includes microvessels that feed the photoreceptors in the macular region. Numerous studies confirm that the primary influence on the development of AMD is atherosclerotic changes in the vessels of the choriocapillary layer of the eyeball. Ophthalmoscopic changes in dry AMD are manifested in the form of drusen and various degrees of destruction of the retinal pigment epithelium in the macula.

Considering that at AMD, atherosclerotic changes occur at the level of the smallest and smallest vessels of the body, the drugs used in the treatment of this disease should also be appropriate for their purpose and affect the improvement of the state of the microvascular system of the eye. Therefore, this category of patients without fail should simultaneously with treatment by an ophthalmologist be monitored by a physician or cardiologist in order to strictly compensate for blood pressure and also control and normalize lipid profile indicators.

State of the art

In the treatment of the “dry” form of AMD, the effectiveness of drugs has not yet been confirmed by multicenter, randomized, placebo-controlled studies. Therefore, in the overwhelming majority of domestic hospitals in patients with “dry” forms of AMD, the effectiveness of parenteral administration of drugs has not yet been confirmed. Mandatory is the appointment of vasoprotectors, nootropics, vitamins, coenzymes and retinoprotectors (sermion, phosphaden, cytoflavin, cytochrome C, cavinton). These drugs practically do not affect the process on the fundus, causing, perhaps, only some positive temporary effect on the general condition of patients. In recent years, in the treatment of patients with “dry” forms of AMD, peptide bioregulators have been used (retinolamine for topical use and cortexin for intramuscular use). Retinolamine is a complex of low molecular weight polypeptides with a molecular weight of from 1000 to 10,000 daltons, sufficient to pass through the blood-ophthalmic barrier. One of the disadvantages of the drug is a sharp pain with subconjunctival and parabulbar administration. The drug is used for numerous eye diseases of the retina and optic nerve, however, no hopes have been placed on obtaining a stable therapeutic effect with any disease. Cortexin in patients with “dry” forms of AMD is used as a means of correcting the functional state of the central nervous system, improving intellectual functions and a psycho-emotional state, as well as having antioxidant activity (Boyko E.V., Zhuravleva L.V., Sosnovsky CB Methodical recommendations - “Age-related macular degeneration” (risk factors, classification, diagnosis, prevention, treatment). 2010). Thus, the effect of this drug has a somewhat indirect function, without directly affecting the disease process.

More focused on the pathological processes that occur in the macular region with the "dry" form of AMD are the use of drugs that provide antioxidant defense of the body. The main recognized antioxidants today are: vitamin C (ascorbic acid), vitamin E (dl-alpha tocopherol acetate), vitamin zinc (zinc oxide), vitamin B ₂ (riboflavin), selenium (selenium chelating amino acid complex), rutin, extract blueberries. However, these drugs are essentially a favorable basis, which is included in a given dose in the composition of these vitamin complexes. The main components of these drugs are carotenoids (lutein and zeaxanthin), which have a positive effect on the state of macular pigments. The protective mechanism of carotenoids is based on their ability to absorb light (especially the short-wave spectrum) and on their increased antioxidant activity, which slows down the damaging photo-oxidative processes directly in the central region of the retina. Clinical studies have confirmed that long-term administration of complexes including carotenoids ensures the delivery of lutein and zeaxanthin directly to the macular region; therefore, the quality of drugs is currently evaluated depending on the quantitative content of zeaxanthin, and, in particular, lutein.

In recent years, many lutein-containing drugs of domestic and foreign production have appeared.

The closest analogue of the present invention is a method of the same purpose, involving the oral use of Nutrof total (Bausch & Lomb), which, along with antioxidants and carotenoids (lutein 10 mg, zeaxanthin 2 mg), includes the anticholesterol drug OMEGA-3. covering at the recommended dose - 1 tablet per day 50% of the daily needs needed by an adult (P. A. Bezdetko // Ways to optimize the prevention and treatment of age-related macular degeneration. // - Health of Ukraine, No. 23-24, Dec April 2008, S.74-75.)

Recently, much attention has been paid to the positive pharmacological effect of OMEGA-3 PUFAs (polyunsaturated fatty acids) on the pigment epithelium and vascular endothelium. Reliable clinical studies of AREDS 2 (Age-Related Eye Disease Study Group) (2007-2009) consisted in the use of a combination of lutein 10 mg and zeaxanthin 2 mg with the inclusion of OMEGA-3 (polyunsaturated fatty acids - 1 g of docosahexaenoic acid and eicosapentaenoic acid) in patients with a "dry" form of AMD. The results of this study allowed us to conclude that the risk of an early form of AMD is lower in people with a higher level of OMEGA-3 (PUFA) intake compared with those who did not use them or used them in smaller quantities. With the recommended intake of the drug from 1 to 3 months, cases of stabilization and suspension of the process of progression of the "dry" form of AMD are described. Numerous clinical studies have shown that OMEGA-3 polyunsaturated fatty acids are the basis of a healthy diet to support the functioning of the heart and positively affect the reduction of low-density lipoproteins, normalize the ratio of cholesterol and triglycerides in the blood. OMEGA-3 polyunsaturated fatty acids inhibit the processes of thrombosis, ensure the maintenance of the body’s immune status, normalize cerebral circulation, increasing the stability of cerebral vessels during hypoxia and a drop in blood pressure. Eicosapentaenoic acid and docosahexaenoic acid are important representatives of a number of OMEGA-3 polyunsaturated fatty acids. The drug prevents the deposition of cholesterol in the walls of blood vessels, protects cells, protects the heart from damage associated with a deficiency of magnesium or a lack of oxygen. However, to date, there is no evidence base regarding the specific effect of OMEGA-3 on microvessels and their blood flow. OMEGA-3 also does not have the property of “building up" high density lipoproteins, which is very important not only with respect to the atherogenic defense of the vascular system, but also with respect to microvascular protection.

Almost the majority of patients with a “dry” form of AMD suffer from vascular diseases (hypertension, coronary heart disease), and some patients with AMD develop on the background of type 2 diabetes mellitus. When examining the lipid spectrum in these patients, violations of this type of metabolism with an increased atherogenicity coefficient are almost always detected, which is associated with the threat of serious vascular catastrophes (heart attacks, strokes, thromboses). On the other hand, Nutrof Total, which includes OMEGA-3, is used for a limited time (1-3 months) with the subsequent replacement of lutein-containing drugs or a pause in the appointment of drugs of this type. However, this category of patients needs constant microvascular antilipid protection against the background of periodic intake of antioxidants and carotenoids.

The technical result of the invention is to ensure the suspension of the progression of the "dry" form of AMD.

The technical result is achieved due to the complete microvascular antilipid protection while taking lutein-containing antioxidants and carotenoids of oral use of fenofibrate (Traicor 145) for a period of time sufficient to normalize the lipid profile and maintain these indicators at the achieved level. Lutein-containing drugs are prescribed in repeated courses for 2-3 months with interruptions for 1-2 months.

The lipid profile, as is known, reflects the values of the cholesterol profile: these are indicators of total cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL), very low density lipoproteins (VLDL). The relationship of these indicators is very important, as they reflect the coefficient of atherogenicity - a threat to the development of vascular catastrophes in the body.

Pathogenetically targeted treatment is anticholesterol, which provides microvascular protection, and antioxidant, which positively affects damaging photo-oxidative processes directly in the central region of the retina.

The proposed method of treating the “dry” form of AMD is significantly different from the analogue in that it provides complete long-term microvascular protection of the patient due to a significant decrease in the lipid profile and alignment of their relationships. So Tricor 145, unlike OMEGA-3, is able to “increase” HDL, which plays a big role in achieving a patient-safe atherogenic coefficient. This effect is achieved by the long-term administration of the drug Tricor 145 with monthly monitoring of the patient’s blood lipid profile. Unlike OMEGA-3, the positive effect of Tricor on the cholesterol profile of patients manifests itself after 3-4 weeks and, usually, the performance of several fractions simultaneously improves.

Tricor 145 belongs to the class of fibroic derivatives of fibroic acid, used since the late 50s in the treatment of vascular diseases, accompanied by an increase in cholesterol and its fractions (coronary heart disease). However, it later turned out that these drugs thoroughly provide microvascular protection and only partially affect atherosclerotic changes in large vessels in coronary artery disease. Currently used fenofibrate (Tricor 145) is already a 3rd generation drug and at the moment it is the most studied, safe and proven use in domestic and foreign clinical practice. The drug appeared in Russia in September 2008. It is currently supplied by Abbott Products in the form of a special form of nanoparticles obtained by the Nano Cristall technology in the Irish city of Cork. Currently, this is the only drug obtained in this way that provides: 1. minimum doses when taken; 2. maximum bioavailability; 3. maximum safety; 4. complete absorption from the gastrointestinal tract; 5. independence from food intake; 6. taking 1 tablet per day at any time of the day; 7. the absence of the need for special selection of doses of the drug. Tricor is prescribed in a single dosage of 145 mg once a day for all patients, regardless of age, duration of the disease and the severity of complications. It was investigated that Tricor is well tolerated by patients, which is confirmed by the great clinical experience of its use abroad, where it is taken by more than 36 million patients with diabetic retinopathy.

The mechanism of action of fenofibrate - Tricorr 145 is explained by its ability to stimulate a specific fraction of alpha receptors, which in the liver cells are responsible for lipid metabolism. These receptors play a dominant role in the intracellular regulation of transfer and transcription of DNA genomes responsible for lipid metabolism and inflammatory cytokines. The activation of the receptors occurs as a result of their binding to Tricor 145 through complex biochemical processes leading to the excitation of the lipase enzyme system. This process is accompanied by a decrease in triglyceride concentration, normalization of particle sizes of low density lipoproteins (LDL) - from small, dense and atherogenic to larger, floating and less atherogenic particles, an increase in high density lipoproteins (HDL), which is manifested in total by a decrease in the atherogenicity of the blood lipid spectrum .

In addition, Tricor 145 has a non-lipid pleiotropic effect, which explains the positive effect of Tricor 145 on the patient’s retina with a “dry” form of macular degeneration in a normal lipid profile. This effect not only helps to slow the progression of microvascular retinal changes, its positive effect also extends to the progression of atherosclerosis and cardiovascular events in this category of patients.

In clinical trials, we selected the regimen of the use of the drug Tricor 145 against the background of periodic doses of lutein-containing antioxidants in patients with a “dry” form of macular degeneration. The most optimal regimen was selected, the aim of which was to: 1. Bring the patient’s lipid metabolism studies to normal or close to the physiological norm and maintain at this level in order to eliminate the main pathogenetic cause of the disease. 2. To improve metabolic functions in the body as a whole while taking broad-spectrum antioxidants that are part of lutein-containing drugs in order to prevent antioxidant stress in the vascular system and in the retina. 3. Slow down or completely suspend the progression of the "dry" form of AMD using a complex of the above drugs.

The method is as follows.

Treicor 145 therapy is prescribed after examining the fundus of the patient, obtaining the results of the lipid profile, as well as computed tomography data. The drug is prescribed 1 tablet. 1 time per day for continuous use. At the same time as Traicor 145, a lutein-containing antioxidant drug is prescribed (mainly with the largest amount of lutein in its composition). Currently, these drugs are Vitrum Vision Fort and Nutrof Total. These drugs are prescribed with a break of 2-3 months throughout the year. Vitrum vision fort and nutroph total are somewhat different in composition, so their perception by patients is also different. Depending on their individual preferences, patients report that some of the drugs seems more effective to them. This drug is recommended for them to take. Every 3 months, a study of the patient’s lipid profile is performed, as well as visual functions are examined.

Example: Patient A., 62 years old. Age-related macular degeneration (AMD) is the “dry” form of both eyes. Concomitant: Coronary heart disease. Hypertonic disease. Complaints about the gradual (within 2 years) decrease in vision of both eyes, the “blur” of the image in the center, which interferes with reading. I applied to the institute on 02/09/2011. Before that, I was observed in the clinic at the place of residence, where I was treated mainly with vasodilating and nootropic drugs (Cavinton, Afobazole, Sermion) locally with a combination of hard and soft friends - emoxypine installations.

Visual acuity of the right eye = 0.3 s + 2.0D = 0.3-0.4; Visual acuity of the left eye = 0.4 s + 2.5D = 0.6. Amsler test is negative - no distortion. In the study of perimetry, pathology was not detected. According to OCT (optical coherent perimetry), the presence of drusen is indicated by the wave-like contour of the pigment epithelium layer. At the same time, the epithelium retains its thickness; no changes in photoreceptors have been detected.

The retina is thinned, the optical density of the underlying tissues is increased. In connection with coronary heart disease, the study of phage was not performed. The fundus of both eyes is almost identical with ophthalmobiomicroscopy: The optic disc is pink, the borders are clear, the veins are slightly dilated, stagnant, the arteries are convoluted, their walls are tightened, sclerotized. The symptom of Salus 1-11 is noted, which indicates the hypertonic nature of vascular lesions. In the macular and paramacular zones of both eyes, many friends are hard and soft, partially draining.

The patient was recommended: 1. Control and compensation of blood pressure. 2. The study of the lipid profile, which revealed a significant significant increase in the values of total cholesterol (up to 6.9 with refrain values of 3.1-5.2) and low density lipoproteins (up to 4.56 with refrain values of 1.5-3.50), the remaining lipid profile was at the upper limit of normal. The patient was prescribed: 1. Tricor 145, 1 tablet 1 time per day. Duration of admission is not less than 8 months. 2. Vitrum Vision Fort for 1 tab. 2 times a day orally for a year, with an interval of 2-3 months.

After 3 months: visual acuity and condition of the fundus without negative dynamics, however, the patient notes an improvement in visual comfort, a feeling of “blurring” of the image in the center when reading appears much less often. OCT data without negative dynamics. Blood pressure is normalized with regular use of antihypertensive drugs. In the study of lipidograms - a decrease in the levels of total cholesterol to 4.8 and low density lipoproteins to 3.2. The use of Traicor 145 continued, 1 tablet 1 time per day. Reception of Vitrum Vision Fort is resumed after 2 months.

After 3 months, with subsequent observation, visual acuity: right eye = 0.3 s + 2.0D = 0.4. Visual acuity of the left eye = 0.4 s + 2.5D = 0.5-0.6. The feeling of “blurring” the image in the center disappeared completely.

An examination of the fundus showed a slight restoration of caliber and a decrease in vein tension, and the state of arteries at the same level. The number of drusen has not increased, there is no calcification, there is no increase in the number of confluent drusen, which indicates the absence of negative dynamics. OCT without deterioration. When studying a lipid profile, total cholesterol = 4.2, low density lipoproteins at a level of 2.4. It is recommended to continue taking TRICOR 145 as before. It is recommended to repeat the course of taking Vitrum Vision Fort for 3 months.

After the next 3 months (with a total follow-up period = 12 months). Visual acuity of the right eye = 0.3-0.4 s + 2.0D = 0.4-0.5. Visual acuity of the left eye = 0.4 s + 2.5D = 0.5-0.6. Reading comfort increased, blurring did not resume. Blood pressure remains compensated by taking antihypertensive drugs. In the fundus, in comparison with the previous examination, there is no negative dynamics. Lipid profile: total cholesterol = 4.0; low density lipoproteins at a level of 2.2. Other indicators of the lipid profile are also at the level of reference values. Since the patient noted that while taking Traicor, her general condition significantly improved with some improvement in visual functions, she was asked to continue taking Traicor 145 against the background of periodic courses of taking Vitrum Vision Fort.

The proposed method of treatment, including the appointment of Tricorr 145 and lutein-containing antioxidants, has so far been used in 26 patients with a “dry” form of AMD, in all cases a positive result was obtained, in no case was the progression of the disease with significant follow-up periods, in any patient no side effects or complications were detected.

Thus, the proposed method of treating the “dry” form of AMD can improve the quality of life of patients against the background of stabilization or some improvement not only in visual functions, but also in general condition, and to avoid serious vascular catastrophes that occur when the blood lipid profile is disturbed.

Claims (2)

1. A method of treating patients with a “dry” form of age-related macular degeneration, including oral use of lutein-containing antioxidants and carotenoids, characterized in that they are used for a year with an interval of 2-3 months and additionally use fenofibrate for a time sufficient to normalize the lipid profile and maintaining these indicators at the achieved level. 2. The method according to claim 1, characterized in that Vitrum Vision Fort or Nutrof Total are used as lutein-containing antioxidants and carotenoids.