RU2290973C1 - Method of curing subretinal neovascular membrane - Google Patents

Abstract

FIELD: ophthalmology.

SUBSTANCE: photodynamic therapy is performed due to intravenous injection of photo-sensitizer followed by radiation. As photo sensitizer the Photosense is used in dosage of 0,05-0,3 mkg/gram per weight. Laser radiation of membrane is carried out trans-papillary three days after Photosense was introduced. Membranes are radiated multiple at wavelength of 675 micron and power density of 80-200 mW/cm². Membranes are subject to radiation every 3-5 days without additional injection of Photosense. Two to ten procedures are taken in total.

EFFECT: reduced frequency of relapses of subretinal neovascular membranes; improved vision functions.

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Description

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

The subretinal neovascular membrane is a common complication of diseases such as age-related macular degeneration, myopia, pseudohistoplasmosis syndrome, and inflammatory diseases of the posterior segment of the eye. The reason for the formation of SNM has not been fully identified. According to many researchers, defects appear in the pigment epithelium, into which choroidal neoplasms begin to grow. As a result of this process, a conglomerate of fibrovascular tissue forms under the retina, which leads to hemorrhage and loss of vision.

The principles of drug therapy for SNM have not yet been formulated. Treatment with lutein (lutein complex) was based on the assumption that carotenoids (lutein [(3R, 3'R, 6'R) -beta, epsilon-Carotene-3,3'-diol] and zeaxanthin (3R, 3'R ) -beta, beta-Carotene-3,3'-diol) protect the retina from free radicals that accumulate during phototoxic reactions [Rapp Laurence M., Maple Seema S. Choi Jung H. "Outer Segment Membranes from Perifoveal and Peripheral Human Retina "// Investigative Ophthalmology and Visual Science. - 2000 - vol.41 - pp.1200-1209], however, drug treatment of LUT with lutein preparations did not give a significant effect.

A new direction in the treatment of SNM is the narrow proton medical bundle (12-15 Gy) and brachytherapy (applicators - palladium 103 used by Finger et all [Finger PT, Berson A, al. "Radiation therapy for subretinal neovascularization." // Ophthalmology. - 1996 - vol.103 - pp.878-889]. In 58% of cases, the process was stabilized, and in 42% of the vision continued to decline due to membrane activity, which indicates the inefficiency of the method. Thus, brachytherapy and AMP are also not effective .

The transition to a minimally invasive technique of endovitreal surgery highlighted the translocation surgery of the macula. This method of surgical treatment of CHM consists of translocation of 360 ° retinotomy [Pertile G, Claes C. "Macular translocation with 360 degree retinotomy for management of age-related macular degeneration with subfoveal choroidal neovascularization." // Am J Ophthalmol. - 2002 - vol.134 - pp.560-565]. However, in some cases, repeated operations were performed due to the development of proliferation. A wide range of complications has been identified. Among the complications of the method are noted: vitreoretinopathy, retinal folds in the macula, tears in the macula [Aisenbrey Sabine "Macular Translocation With 360 ° Retinotomy for Exudative Age-Related Macular Degeneration." // Arch Ophthalmol. - 2002 - vol. 120 - pp.451-459]. These complications do not allow recommending the method in widespread practice.

Another area in the treatment of chorioretinal dystrophies, including LUT, is the use of laser methods of treatment. In the 90s, krypton laser coagulation of SNM was used to destroy the membrane. The method is not widely used due to a sharp decrease in vision after laser intervention due to retinal damage and a decrease in the quality of life of patients. Argon laser coagulation was ineffective in eyes with a large area of SNM. Depletion of the neovascular zone occurred in a certain number of cases, and a decrease in visual acuity and a deterioration in the quality of life of the patient practically progressed [Macular Photocoagulation Study Group. Subfoveolar neovascular lesion in ARMD: guidelines for evaluation and treatment in the macular photocoagulation study. // Arch Ophthalmol. - 1991. - Vol. 109. - P.1242-1257].

The transpupillary thermotherapy (TTT) method is used in patients with latent SNM. We use a diode laser with a focal spot diameter in the plane of exposure from 3000 to 6000 μ and with an exposure of 60 seconds, the power varies from 600 to 1000 mW. In 71%, an increase in visual acuity was noted, in 29% - a decrease in visual acuity [Thach Alien B, MD; Jack O. "Large-Spot Size Transpupillary Thermotherapy for the Treatment of Occult Choroidal Neovascularization Associated With Age-Related Macular Degeneration." // Arch Ophthalmol. - 2003 - vol. 121 - pp.817-820]. However, the use of this method leads to the formation of coarse chorioretinal scars and a decrease in central vision and is not effective in the treatment of classical SNM. Thus, this method is used in a very narrow population of patients.

The theoretical justification for the use of photodynamic therapy (PDT) for SNM is the strict selectivity of radiation exposure to the pathological focus regardless of its location. PDT mechanisms are due to the ability of photosensitizers (PS), selectively accumulating in dividing cells, to generate singlet oxygen and other active radicals that have a cytotoxic effect when exposed to light with a wavelength corresponding to the peak absorption of PS [B. W. Henderson, Th. J. Dougherty. "Photodynamic therapy." // Eds. New York: Dekker. - 1992].

In addition, PDT induces photodynamic occlusion of newly formed vessels while preserving surrounding tissue [Schlötzer-Schrehardt U. Dose-related structural effects of photodynamic therapy on choroidal and retinal structures of human eyes. // Graefes Arch Clin Exp Ophthalmol. - 2002. - Vol. 240. - P.748-757]. The development was carried out simultaneously by several research groups in different countries of the world. Schmidt U. et al. In the experiment, selective occlusion of newly formed vessels was performed by means of PDT with SnET2 [Peyman, GA, Moshfeghi, DM, Moshfegbi, A, et al "Photodynamic therapy for choriocapillaris using tin ethyl etiopurpurin (SnET2)" // Ophthalmic Surg Lasers - 1997 - vol. 28 - pp. 409-417]. Schmidt U. and Hassan T. performed the same procedure with verteporfin (BPD) [Schmidt - Erfurth, U, Miller, JW, Sickenberg, M, et al. Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of a retreatments in a phase 1 and 2 study. // Arch Ophthalmol. - 1999 - vol.117 - pp.1177-1187]. Destruction of the newly formed vessels was noted with minimal damage to the layer of rods and cones, which could also take place as a result of the development of the SNM itself. Bruch's membrane remained intact.

The closest analogue of the present invention is a method of the same purpose, which is a photodynamic therapy using Vizudin (synonym: verteporfin) [Photodynamic Therapy Stady Group. Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-related Macular Degeneration With Verteporfin. // Arch.Ophthalmology. - 1999 - Vol.117 - P.1329-1345]. The method includes the introduction of the drug in an amount of 6 mg / m ² , irradiated transpillary diode laser with a power density of 500 mW / cm ² with an exposure of 83 seconds. The treatment is carried out in patients with a diameter of the SNM <5400 microns and visual acuity of 20 / 40-20 / 200. The criteria for the effectiveness of the treatment were indicators of visual acuity, hemorrhagic activity, and the state of newly formed vessels. During treatment, a significant improvement in all indicators was noted. However, after studying a large amount of clinical material, it was concluded that in more treated patients there is a relapse of SNM activity due to revascularization of SNM vessels obliterated after PDT.

The objective of the invention is to develop a more effective method for the treatment of CHM. To solve this problem, we have proposed a method of treating a subretinal neovascular membrane, which consists in conducting photodynamic therapy by intravenous administration of a photosensitizer followed by irradiation, and photosensitizer is used as a photosensitizer in a dose of 0.05-0.3 mg / kg body weight, and laser irradiation of the membrane is carried out transpupillary on the third day after the introduction of Photosens, upon reaching a therapeutic dose of a photosensitizer in the membrane at a wavelength of 675 nm and a power density of 80-200 mW / cm ² , many multiple, while irradiation can be repeated every 3-5 days, and the number of sessions brought from 2 to 10.

The technical result of the invention is the occlusion of newly formed vessels in the SNM with subsequent suppression of the "activity" of the SNM itself.

The technical result is achieved through the use of PDT photosensitizer "Photosens" and fractional or fractional irradiation of the surface of the SNM in a certain mode.

With a single administration of Photosens at a dose of 0.05 to 0.3 mg / kg body weight, the therapeutic concentration in the tissues of the human eyeball lasts from an average of 3 to 6 weeks. Subsequent laser irradiation at a wavelength of 675 nm initiates photothrombosis of the newly formed vessels of the choroid, which contributes to a decrease in SNM activity with subsequent dosed scarring while maintaining the functional activity of the retina. The minimum power density sufficient to initiate photodynamic phenomena is 80 mW / cm ² , when exposed to SNM with a power density of more than 200 mW / cm ^2, we found that in most cases retinal edema develops. The diameter of the light spot is from 1100 microns to 6400 mm and is selected according to well-known rules [Photodynamic Therapy Stady Group. Photodynamic Therapy of Subfoveal Choroidal Neovascularization in Age-related Macular Degeneration With Verteporfin. // Arch.Ophthalmology. - 1999 - Vol. 117. - P.1329-1345]. This indicator is determined by several points. First, the minimum membrane size at the time of diagnosis, as a rule, reaches 100 microns. Further, when conducting radiation exposure with fixation on the SNM, it is necessary to take into account rotator movements of the eye, which normally reach 500 microns in different directions. Therefore, when irradiating, it is necessary to take the diameter of the light spot, which would overlap the SNM on all sides by 500 microns. Then, during rotator eye movements, during PDT, the SNM will not periodically leave the irradiation zone and the PDT session will be complete: the SNM will receive the entire calculated dose.

To completely obliterate the vessels of the SNM, irradiation can be repeated every 3-5 days, for a total of 2-10 sessions.

Photosens "consists of a mixture of sodium salts of sulfonated phthalocyanine hydroxyaluminium in distilled water containing a disubstituted product and a trisubstituted product, the remainder is a tetrasubstituted product with an average degree of sulfonation of 3.0 + 0.2 (RF Patent 2220722 A 61 K 31/409/2004 g) The substance "Photosens", used for the preparation of a medicinal injection form of the drug, is a sodium salt of sulfonated phthalocyanine hydroxyaluminium and is a synthetic second-generation PS for PD and PDT malignant x tumors. The substance "Photosens" is a macrocyclic compound with a closed chromophore, readily soluble in water due to the presence of sulfo groups in the molecule. It has an intense absorption band in the red region of the spectrum with a maximum at 675 nm. The second, less intense band, is located at 350 nm.

As it turned out, Photosens essentially has the ability to persist for a long time in the SNM, while its concentration of SNM is kept at the therapeutic level. This allows you to reduce a single light dose, that is, by irradiating fractionally small doses in 2-10 sessions for several weeks (3-6).

This technique allows you to prevent the development of retinal edema, which can occur when irradiated with a high power density simultaneously. When fractional irradiation of the entire surface of the membrane with the capture of healthy tissue minimizes the possibility of leaving the active sections of the membrane, both in length and in depth. It is impossible to do this in one session, since the true dimensions of the neovascular membrane can sometimes not be determined because part of it can be covered with blood or exudate. However, after several sessions, developing photothromboses in the SNM eliminate edema, hemorrhages are partially resolved, and the exudate is resorbed, exposure of those parts of the SNM that were previously hidden. As they are exposed, we add the number of radiation sessions, including them in the irradiation zone, thereby increasing the effectiveness of photodynamic therapy.

The method is as follows. The photosensitizer “Photosens” is administered intravenously at a dose of 0.05 to 0.3 mg / kg of body weight, which is selected individually, depending on the duration of the disease, the thickness of the SNM and the degree of pigmentation of the fundus. The longer the disease and the thicker the SNM, the greater the dose of the drug administered. Over the next period, the concentration of the drug in the tissues is determined using the LESA-01 Biospek spectroscopic complex in order to clarify the presence of therapeutic concentration in the SNM [Loschenov VB, Stratonnikov AA, Volkova AI, Prokhorov AM Portable spectroscopic system for fluorescence tumor diagnosis and control of photodynamic therapy. // Russian Chemical Journal. - 1998. - T.KHP. - N.5. - S.50-53.]. Photosens fluorescence is recorded on the fundus in the fundus tissues using a device developed on the basis of the SchL-GZ slit lamp (ZOMZ OJSC). The lamp was additionally equipped with a video channel, including color and highly sensitive black and white video cameras, and a personal computer for processing and displaying video information, as well as a laser and an optical adapter that focuses (using an additional Goldman lens) the laser radiation to the fundus. On the 3rd day, when the contrast gradient between the SNM and surrounding tissues becomes maximum (the amount of the drug in the retinal vessels and healthy choroid is less than in the SNM zone) and the photosens level reaches the therapeutic level, photodynamic therapy is performed. In this case, the therapeutic level is determined by the ratio of tissue fluorescence and the standard sample with a known therapeutic concentration. The pupil of the patient is expanded with mydriatics to the maximum size. Using a 3-mirror Goldman lens, the SNM zone is irradiated at a wavelength of 675 nm and a power density of 80 to 200 mW / cm ² . The specific dose of radiation is chosen depending on the state of the retina (edema, racemose changes), the thickness of the SNM and the degree of pigmentation of the fundus. The greater the swelling, the lower the dose. Over the next time, irradiation is repeated every 3-5 days, for a total of 2-10 sessions, depending on the severity of retinal edema, the area and depth of the SNM. The deeper the SNM lies and the more pronounced the edema, the more sessions are used. In this case, laser irradiation of the membrane is carried out transpupillary.

Example 1. Patient G., 68 years old, was admitted to the hospital with complaints of decreased vision, distortion of objects, the appearance of a dark spot in front of the left eye in the last month.

When examining visual acuity OD-1.0, OS-0.2.

Ophthalmoscopic and angiographic picture presented in Fig.№1. The diagnosis was made: Age-related macular degeneration, subretinal neovascular membrane of the left eye.

Given the short period of the disease, the small size of the membrane, the patient was administered Photosens at a dose of 0.1 mg / kg of body weight.

On day 3, the concentration of the drug in the tissues of the eye was comparable with the therapeutic.

Conducted PDT. The power density was 100 mW / cm ² . After the first session, perifocal retinal edema formed, which was resorbed on the 2nd day, after which the radiation session with the same parameters was repeated. In all, 4 sessions were conducted. Reached photothrombosis of newly formed vessels with their subsequent obliteration.

Visual acuity increased, and amounted to OS-0.7. On the ophthalmoscopic and angiographic picture (see figure 2), there is a decrease in SNM activity and resorption of hemorrhage.

Example 2. Patient N., 36 years old, was admitted to the hospital with complaints of decreased vision, distortion and bifurcation of objects, the appearance of spots in front of both eyes over the past 3 months.

On examination, the visual acuity of OD-0.3 with correction was 18.0 D, OS-0.2 with correction was 15.0 D.

The clinical and angiographic picture corresponds to the subretinal neovascular membrane in the active phase in both eyes.

A PDT with a power density of 100 mW / cm ² with photosensitivity was performed. The latter is introduced at a dose of 0.05 mg / kg of body weight. Multiplicity of sessions brought to 7. Sessions were carried out every other day.

A month after the treatment, visual acuity increased to 0.6 in the right eye and to 0.8 with the previous myopic correction in the left eye. The above complaints ceased.

At the fundus, desolation of the newly formed vessels, leveling of edema and resorption of hemorrhage were angiographically observed.

With a follow-up of up to 8 months, the process stabilized.

Thus, our proposed method of treating a subretinal neovascular membrane is more effective than its analogues. Using the proposed method allows to achieve remission of the disease with complete occlusion of the newly formed vessels of the choroid.

Claims (3)

1. A method of treating a subretinal neovascular membrane (SNM), which consists in conducting photodynamic therapy by intravenous administration of a photosensitizer followed by transpupillary laser irradiation of the SNM, characterized in that Photosens is used as a photosensitizer in a dose of 0.05-0.3 mg / kg weight, and irradiation is carried out on the third day after the introduction of Photosens upon reaching a therapeutic dose of a photosensitizer in the membrane at a wavelength of 675 nm and a power density of 80-200 mW / cm ² , irradiated repeatedly. 2. The method according to claim 1, characterized in that the irradiation is repeated every 3-5 days. 3. The method according to claim 1, characterized in that the number of sessions varies from 2 to 10.

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