RU2376957C1 - Method of subretinal neovascular membrane treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, ophthalmology, and can be applied for treatment of subretinal neovascular membrane. For this purpose intravenously introduced is preparation "Photosens" 0.01-0.1 mg/kg of weight 10-20 hours before laser exposure. Laser exposure is realised on subretinal neovascular membrane with wave length corresponding to peak of absorption of photosensitiser with total light doze 300-500 J/cm² one time in 24-hours per course of 1-5 sessions. 48 hours after laser exposure medicine which blocks growth factor of vessel endothelium is introduced endovitreally one time.

EFFECT: method allows to obtain complete desolation of neogenic vessels net and prevent relapse of SNM growing in presence of maximal preservation of surrounding tissues, neuroepithelium and retinal pigment epithelium.

2 cl, 4 dwg, 2 ex

Description

The present invention relates to ophthalmology and is intended for the treatment of subretinal neovascular membrane.

The subretinal neovascular membrane (choroidal neovascularization, newly formed vessels of the choroid, CHM, CNF) is a frequent complication of fundus diseases and leads to a significant and persistent decrease in visual acuity, causing poor vision and disability of patients. SNM occurs in a large number of diseases: age-related macular degeneration, ocular histoplasmosis, pseudohistoplasmosis syndrome, complicated myopia, retinal angioid bands, and can also be a complication of laser coagulation of the retina and hyperthermia [Gurova I.V. The effectiveness of photodynamic therapy in the complex treatment of patients with subretinal neovascular membranes. Dis. c. m. 2007].

The selectivity of the lesion, the possibility of exposure to the endothelial cells of the newly formed vessels and the absence of a thermal effect detrimental to photoreceptors made it possible to recommend photodynamic therapy (PDT) for use in ophthalmology, in particular in the treatment of subretinal neovascular membranes. Despite the high cost, in many countries of the world until recently, PDT was the main method of treatment for some forms of heart failure. The possibility of the successful use of photosensitizers (PS) in widespread practice largely determines its properties, which depend on the distribution in the cell. In turn, the distribution depends on the physicochemical and biochemical properties of the drug. For example, hydrophilic PSs (chlorins, phthalocyanines) enter the cell through pinocytosis or endocytosis and, as a result of penetration, accumulate in lysosomes and endosomes. In turn, hydrophobic PSs, such as derivatives of hematoporfin and verteporfin (vizudin), are localized in mitochondria [E. Gragoudas, J. Miller, L. Zografos. Photodynamic therapy of ocular diseases. 2004].

1. The localization of FS in the cell determines the amount of damage and the mechanism of death. Localization in mitochondria leads to the rapid development of apoptosis and irreversible cell damage. Communication with the plasma membrane and lysosomes leads to cell death by the type of apoptosis and necrosis. The desire to “occupy” a large number of cellular organelles led to the synthesis and development of PS, which is based on a mixture of chemical compounds.

Then the photosensitized tissue is irradiated with a light source with a wavelength corresponding to the absorption spectrum of the photosensitizer, the PS molecule, having absorbed quantum radiation, passes into an excited triplet state and then enters into photochemical reactions.

Further, the reaction can proceed by two mechanisms.

A. - FS in a triplet state reacts with the substrate of the cell, after which the internal elements of the cell are oxidized.

B. - FS in a triplet state reacts with oxygen, giving it an active, singlet form of oxygen, which oxidizes the internal elements of the cell.

The main mechanism of cell death in PDT is lipid peroxidation, activated by reactive oxygen species in the PDT process.

Photodynamic therapy affects the newly formed vessels, inhibiting their growth, as a result of photodynamic occlusion, neovascularization starts and exudation on the fundus decreases, followed by stabilization or increased visual acuity.

To date, PDT with FS Visudin has been performed in more than 800 people (more than 1600 procedures), the follow-up period is more than 5 years. Encouraging treatment results were observed with PDT of subretinal neovascular membranes that developed against the background of complicated myopia and age-related macular degeneration (AMD) [Kertes, R.J. Verteporfin therapy of subfoveal minimally classic choroidal neovascularizaion in age-related macular degeneration: 2-year results of A randomized, clinical trial. // Ophthalmology. - 2006. - Vol.7, No. 1. - P.42-44]. Moreover, the younger the patient and the shorter the time for the formation of SIM, the better the result was obtained. In a group of patients with SNM against AMD, stabilization of the process was recorded in about 30% of cases, however, according to the authors, when prescribing PDT for this group of patients, it is necessary to limit indications for this treatment method (exclude subretinal neovascularization with a predominance of the fibrous component and the occult form of CIM) [ Rauber M., Binkle F., Kremp K., et al. Clincial experience of photodynamic therapy with Verteporfin. [Photodynamische therapic] 15 th Congress of the European Society of ophthalmology. - Berlin. - 2005 - p 2]. The long-term results of PDT with vizudine led to the following conclusions:

1. It is necessary to repeat PDT courses every 3-6 months.

2. The main complication of PDT with Visudine is atrophy of the pigment epithelium.

3. A positive result is the stabilization of visual functions within 3 lines /

4. In most cases, only stabilization of visual functions with selective visual enhancement is recorded in 13% of cases [Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization. // Am J. Ophthalmol. - 2001 .-- Vol.131. - P.541-560].

Let us examine in more detail the mechanisms of recurrence of SNM after PDT, in addition to the fact that there are endogenous mechanisms of disease progression - PDT itself in some cases against this background can lead to the release of inflammatory mediators. It happens as follows.

After photodynamic occlusion of the newly formed vessels, apoptosis and necrosis with perifocal inflammation develop in the affected area. LPO is less significant, since all reactions occur at the endothelial level, and vascular obliteration causes a cessation of oxygen supply and inhibits LPO.

So, inflammation and hypoxia lead to the release of HIF-1 (Hypoxia Inducible Factor), interleukin-1 and tumor necrosis factor, which at the transcriptional level stimulate the production of vascular endothelial growth factor, resulting in the stimulation of a new round of angiogenesis and the recurrence of SNM.

Thus, the need arose to develop complex therapy using anti-inflammatory therapy, inhibitors of vascular endothelial growth factor (VEGF, VEGF).

In recent years, three main drugs that suppress VEGF functions have been developed for use in ophthalmology:

1. Makugen. (Macugen, Pegantanib) - oligonucleotide, adapter with anti VEGF ₁₆₅ activity.

It is applied endovitreal at a dose of 0.3 mg; 1 time in 6 weeks; When conducting clinical trials of a drug, its effectiveness is almost equal to the effectiveness of photodynamic therapy (PDT), i.e. visual acuity decreases, but to a lesser extent than in the control group (placebo). [Eyetech Pharmaceuticals, Pfizer, Inc. Dermatologic and Ophthalmic Drugs Advisory Committee meeting. Pegaptanib sodium injection (Macugen). Available at: Accessed May 27, 2005].

2. Lucentis (Lucentis, ranibizumab, Genentech) - 49-kd fragment of an antibody with anti VEGF-A activity.

It is applied endovitreal at a dose of 0.5 mg (0.05 ml); 1 time in 4 weeks.

The international randomized clinical trials ANCHOR and MARINA were conducted to study the effectiveness of both monotherapy (PDT) and its combination with lucentis (PDT + Lucentis). After one year of observation, it was proved that the isolated use of PDT leads to a decrease in vision in 67.9% and an increase in visual acuity in 5.4% of cases. The combination of PDT + Lucentis can improve the result of treatment and significantly (more than 15 letters) increase visual acuity in 23.8% of cases. It has also been proven that combination therapy over 2 years can significantly reduce the number of PDT sessions [Miller JW, ASRS meeting, July 2005, Montreal].

3. Avastin (Bevacizumab, Genentech, Inc., South San Francisco, CA Genentech / Roche) - a recombinant humanized monoclonal antibody that blocks all forms of VEGF (VEGF ₁₁₀ , VEGF ₁₂₁ , VEGF ₁₄₅ , VEGF ₁₆₅ , VEGF ₁₈₃ , VEGF ₁₈₉ , and VEGF ₂₀₆ ). It is used endovitreal at a dose of 1.25 mg (0.05 ml); 1 time in 4 weeks.

The use of two treatment methods (PDT and anti-VEGF therapy) will reduce the number of PDT sessions and endovitreal interventions, reduce the frequency of iatrogenic complications, recurrence of CHM and significantly improve the patient's quality of life.

The closest analogue of the present invention is a method of the same purpose, including photodynamic therapy with the drug Vizudin and endovitreal administration of the drug Lucentis [Heier JS, Boyer DS, Ciulla TA, Ferrone PJ, Jumper JM, Gentile RC, Kotlovker D, Chung CY, Kim RY; FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Arch Ophthalmol. 2006 Nov; 124 (11): 1532-42].

According to the authors, in this 2-year, multicenter, randomized, study, patients received endovitreal ranibizumab (lucentis) (0.5 mg) monthly, photodynamic therapy with Visudine was performed 7 days before endovitreal administration of the drug and then was carried out every 3 months, according to necessary. Control was performed in patients without endovitreal administration of Lucentis. Within 12 months, 90.5% of the main group and 67.9% of patients from the control group experienced less vision loss of less than 15 characters. In conclusion, it was concluded that combination therapy is more effective than monotherapy. However, the method is not without drawbacks.

1. Frequent endovitreal administration of the drug can lead to serious complications. In this study, inflammatory reactions from the side of the eye developed in 11.4% of the cases, and endophthalmitis in 1.9%.

2. Recurrence of the subretinal neovascular membrane with a decrease in patient visual acuity.

3. The proposed method does not allow visual or television methods to monitor the effects of PDT on neovascularization during a session of photodynamic therapy, or this procedure is not performed due to the lack of equipment designed for recording and evaluating fluorescence. To evaluate the therapeutic effect, repeated angiography with fluorescein sodium or green indocyanin is required. If necessary, repeat the procedure requires repeated administration of the drug.

The objective of the invention was to develop a method of highly effective treatment of subretinal neovascular membranes with a minimal risk of complications.

The technical result of the invention is the complete desolation of the network of newly formed vessels and the absence of recurrent growth of the SNM in the presence of maximum safety of the surrounding tissues (neuroepithelium and retinal pigment epithelium).

The technical result is achieved through the use of the drug "Photosens" as a photosensitizer and the correspondingly selected regimen of laser exposure and the regimen of administration of the drug that blocks the growth factor of vascular endothelium. A phthalocyanine series preparation was used as a photosensitizer (PS), which is based on a mixture of sodium salts: tetra- and trisulfophthalocyanine hydroxyaluminium, which is determined in lysosomes, and disulfophthalocyanine hydroxyaluminium within the entire cytoplasm. Thus, after exposure to laser light, a uniform destruction of the entire cell occurs. This group of drugs has a high photodynamic effect and fluorescence upon excitation in the spectral range from 665-680 (photosens) to 730 (thiosens) nm. With the intravenous administration of FS in doses of 0.01-0.1 mg / kg body weight (the higher the SNM activity and the larger the area, the larger the dose of the drug administered), the drug is in the area of the pathological focus and fluoresces for 3-7 days. When laser mode: the total light dose of 300-500 J / cm ² once a day, for a course of 1-5 sessions. The irradiation mode is determined by the degree of pigmentation and the size of the SNM. The larger the size and pigmentation of the SNM, the higher the dose of laser exposure. With a decrease in the dose of the drug and laser irradiation, photothrombosis of the newly formed vessels does not occur, with an increase, damage to the surrounding tissues, such as retinal pigment epithelium and neuroepithelium, may develop [Gurova I.V. The effectiveness of photodynamic therapy in the complex treatment of patients with subretinal neovascular membranes. Dis. for a job. student from. K. honey n 2007]. And endovitreal administration of the drug is carried out 48 hours after the first laser exposure, since at that time, according to E. Gragoudas, J Miller, L Zografos Photodynamic therapy of ocular diseases. 2004. The maximum release of endothelial growth factor occurs. This approach avoids complications in the form of edema and photothrombosis of normal choriocapillaries and capillaries of the retina, edema and exudative detachment of the retina and choroid. Therefore, the control of the procedure is carried out by residual fluorescence, in the case of residual fluorescence of the subretinal neovascular membrane, additional irradiation can be carried out without repeated administration of the drug.

The method is as follows.

Phthalocyanine-based photosensitizer is slowly injected intravenously at doses of 0.01-0.1 mg / kg body weight 10-20 hours before photodynamic therapy. With the help of a laser spectroscopic complex for photodynamic therapy and fluorescence control, a CFM is diagnosed using the fluorescence picture of the fundus. Then, the SNM region is irradiated with laser radiation with a wavelength corresponding to the absorption peak of the photosensitizer with a total light dose of 300-500 J / cm ² , once a day, for a course of 1-5 sessions. After 48 hours, a drug blocking (production, receptors, growth factor itself) vascular endothelial growth factor is administered endovitreal. The control of the procedure is carried out by the residual fluorescence of the subretinal neovascular membrane. In case of its occurrence, additional irradiation is carried out with the above parameters for a week.

Example 1

Patient A. turned to the clinic with complaints of decreased visual acuity. During the examination, the visual acuity of the patient of the left eye was 0.1. When conducting fluorescence angiography of the fundus (FAGD) revealed an active subretinal neovascular membrane with pronounced subretinal hemorrhage, edema and extravasal release of fluorescein in the late phases (figure 1).

A phthalocyanine-type drug, Photosens, was slowly injected intravenously at a dose of 0.05 mg / kg of body weight of physiological saline diluted in 20 ml 12 hours before photodynamic therapy. Using a laser-spectroscopic complex for photodynamic therapy and fluorescence control, a fluorescence picture of the fundus was re-diagnosed with SNM with localization of the boundaries of the focus. Then, the SNM region was irradiated with laser radiation with a wavelength of 675 nm with a total light dose of 400 J / cm ² once a day. After 48 hours, the drug blocking vascular endothelial growth factor Avastin was administered at a dose of 1.25 mg (0.05 ml) endovitreal. The control of the procedure was carried out by the residual fluorescence of the subretinal neovascular membrane. Altogether, 4 irradiation sessions were carried out until the complete disappearance of SNM fluorescence. After 3 months, a control FAGD was performed - Fig.2. There is a resorption of hemorrhages and edema, desolation of the network of newly formed vessels. Visual acuity increased to 0.4. The patient is observed for 7 months, during the time of observation of the disease recurrence was not observed. Thus, a remission of the disease and an increase in the visual acuity of the patient are achieved.

Example 2

Patient B. went to the clinic with complaints of decreased visual acuity. On examination, the visual acuity of the patient in the right eye was 0.05. When conducting fluorescence fundus angiography (FAGD) revealed an active subretinal neovascular membrane with a slight subretinal hemorrhage, edema and extravasal output of fluorescein in the late phases (figure 3).

A phthalocyanine-type drug, Photosens, was slowly injected intravenously at a dose of 0.03 mg / kg of body weight of physiological saline diluted in 20 ml 12 hours before photodynamic therapy. With the help of a laser spectroscopic complex for photodynamic therapy and fluorescence control according to the fluorescence picture of the fundus, a repeated diagnosis of heart failure was performed with localization of the lesion boundaries. Then, the SIM region was irradiated with laser radiation with a wavelength of 675 nm with a total light dose of 300 J / cm ² once a day. After 48 hours, a drug blocking the vascular endothelial growth factor Avastin at a dose of 1.25 mg (0.05 ml) was administered endovitreal. The control of the procedure was carried out by the residual fluorescence of the subretinal neovascular membrane. Altogether, 2 irradiation sessions were carried out until the complete disappearance of SNM fluorescence. After 3 months, a control FAGD was performed - Fig. 4. There is a resorption of hemorrhages and edema, desolation of the network of newly formed vessels. Visual acuity increased to 0.6. The patient is observed for 12 months, during the time of observation of the disease recurrence was not observed.

Thus, our proposed method of treating a subretinal neovascular membrane is quite effective and safe for surrounding tissues and can be used in everyday ophthalmic practice.

Claims (2)

1. A method of treating a subretinal neovascular membrane, including photodynamic therapy with intravenous administration of a photosensitizer, laser exposure of a subretinal neovascular membrane with a wavelength corresponding to the absorption peak of the photosensitizer, and a single endovitreal administration of a drug that blocks the work of endothelial growth factor, characterized in that photosensitizer use the drug "Photosens", in doses of 0.01-0.1 mg / kg of body weight for 10-20 hours before the laser exposure, which is carried out stvlyayut with a total light dose of 300-500 J / cm ^2, once a day, for a course of 1-5 sessions, and 48 hours after laser exposure endovitrealno administered drug that blocks the action of vascular endothelial growth factor. 2. The method according to claim 1, characterized in that in the presence of residual fluorescence on the next day after endovitreal administration, the laser action is repeated with the same parameters.

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