RU2714193C1 - Method of treating inflammatory or dystrophic eye diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to ophthalmology, and can be used for treating inflammatory or dystrophic eye diseases. For this purpose, in 2–4 weeks after the anti-inflammatory or anti-dystrophy therapy, the autologous thrombocyte lysate is injected 0.6–0.8 ml sub-conjunctivally or 0.8–1.0 ml paravequatorially, with course of 4–6 injections, with interval of 48–72 hours.

EFFECT: method provides accelerating natural mechanisms of tissue regeneration, reducing a recurrence rate of the disease, preventing complications, improving visual functions due to the anti-inflammatory, anti-edema and reparative action of the therapy.

3 cl, 10 dwg, 5 ex

Description

The invention relates to medicine and can be used in ophthalmology for the treatment of inflammatory and degenerative eye diseases.

Inflammatory eye diseases include keratitis, keratoconjunctivitis, uveitis and other diseases. Uveitis is an inflammatory process in the eye and is accompanied by a decrease in visual function. One reason for low vision for uveitis is cystic macular edema. Persistent macular edema can lead to irreversible destruction of the connections between retinal neurons, which results in permanent loss of vision; transient edema of the macula is often resolved favorably, with the restoration of visual acuity.

Dystrophic diseases of the eye include dystrophy of the cornea, choroid, retina and atrophy of the optic nerve.

Dystrophic diseases of the retina and choroid are characterized by a violation in the area of the retinal pigment epithelium, photoreceptors, Bruch's membrane, or the choriocapillary layer of the choroid.

Atrophy of the optic nerve is accompanied by a violation of the papillomacular or axial bundles of nerve fibers.

Dystrophic diseases of the cornea are accompanied by a violation in the epithelium and anterior border membrane, stroma or posterior border membrane and endothelium of the cornea.

There are various methods of treating inflammatory and degenerative eye diseases based on the use of antibiotics, mydriatics, corticosteroids, proteolytic enzymes, as well as keratoplastic, retino- and neuroprotective agents.

Known, for example, is a method of treating inflammatory eye diseases by topically administering to a patient an eprosartan preparation in the form of eye drops or ointment (patent RU 2423127 C2, publ. 07/10/2011). The invention provides the treatment of diseases such as corneal ulcer, keratitis, conjunctivitis, point surface superficial keratitis, dry keratoconjunctivitis, superior limbic keratoconjunctivitis or filamentous keratitis.

A known method of treating deep stromal keratitis, including the use of specific antiviral and / or antibacterial drugs, non-steroidal anti-inflammatory and anti-allergic drugs, as well as keratoprotectors. Additionally, 0.5 ml of a cell suspension containing autologous mononuclear cells (AM) is injected into the stroma of the cornea of the patient’s eye around the pathological focus. The suspension is introduced immediately after its preparation. To do this, AM is isolated from heparinized blood of a patient by density gradient fractionation on a ficoll-verographin separation solution with a ratio of the gradient volumes and the suspension to be separated 1: 3-1: 4, at 2000 rpm, at room temperature for 15 minutes. Then 1.0 ml of isotonic sodium chloride solution is added and the resulting suspension is again centrifuged for 7 minutes at 1500 rpm. Next, the resulting cell suspension is placed in a sterile vial with the addition of 3.0 ml of isotonic sodium chloride solution and used to introduce into the stroma of the cornea. In the process of treatment, the procedure is repeated 1-2 times with an interval of 4-6 days, depending on the severity of the disease and the dynamics of the clinical picture (patent RU 2440801 C1, publ. 01.27.2012)

A known method of treating uveitis by conducting complex drug therapy. From the third day of treatment, exchange plasmapheresis is additionally carried out by exfusion of 700 ml of blood, followed by centrifugation at 3700 rpm at a temperature of 20 ° C for 10 min and removal of the supernatant plasma. The remaining cell mass is resuspended in 100 ml of physiological saline. Then, 120 cm ^{3 of an} ozone-oxygen mixture with an ozone concentration of 10,000 μg / L is introduced into containers with a cell mass. The resulting ozonated cell mass is reinfused intravenously at a rate of 30 drops per minute. The course of plasmapheresis consists of 5 sessions, which are carried out at intervals of 3 days (patent RU 2336849 C1, publ. 27.10.2008).

Closest to the claimed method of the prototype, is a method of complex treatment of endogenous uveitis, accompanied by macular edema. To do this, alternately on the side of the affected eye carry out pterygopalatine and behind-the-ear injections of drugs and carry out ultraviolet irradiation of blood. Pterygopalatine injections are carried out by introducing autoplasma enriched with platelets in a dose of 3-5 ml with a course of 3-4 injections with an interval of 72-96 hours. Behind-the-ear injections are performed by administering a drug mixture containing dalargin 1 mg, lidocaine 40 mg, mexidol 50 mg, hemase 5000 ME. The course of treatment is 6-7 injections daily. Additionally, intravenous administration of an ozonized physiological solution with an ozone concentration of 400-800 μg / l, a volume of 150-200 ml, at a rate of 30-40 drops per minute, a course of 6-7 injections, daily is carried out. The method provides a stable long-term clinical result (patent RU 2635083 C1, publ. 01.11.2017).

The disadvantages of this method are the complexity, complexity and duration, as well as limited functionality, since it is intended only for the treatment of endogenous uveitis, accompanied by macular edema.

The objective of the invention is to simplify the method, expand its functionality and increase the effectiveness of treatment.

Effect: simplify the method, expand its functionality and increase the effectiveness of treatment.

The proposed method is as follows.

Prior to treatment, an eye disease is diagnosed and a biomicrophthalmoscopic examination is performed (assessment of the condition of the conjunctiva, cornea, choroid, retina, optic nerve).

2-4 weeks after the standard anti-inflammatory or anti-dystrophic therapy, the patient is injected into the affected eye with an autologous platelet lysate (ALT) subconjunctively at a dose of 0.6-0.8 ml or para-equatorially at a dose of 0.8-1.0 ml, course 4 -6 injections, with an interval after each injection of 48-72 hours.

Subconjunctival administration of ALT is as follows. ALT is thawed at room temperature for 10-15 minutes. Then install (instill) 1 drop of proxymethacaine (alkaine) in the affected eye twice with an interval of 1 minute. After 3-5 minutes, an ALT injection is performed: the patient looks up, the conjunctiva is punctured in the lower-outer quadrant and 0.6-0.8 ml of ALT is injected.

Paraequatorial administration of ALT is as follows. ALT is thawed at room temperature for 10-15 minutes. The patient looks up and to the nose. The skin is treated in the area of the external corner of the affected eye with 70% ethyl alcohol, the lower-outer edge of the orbit is visualized (found) with a finger and the needle is injected parallel to the lower wall of the orbit to a depth of 1 cm with the subsequent administration of 0.8-1.0 ml ALT. For injection use a syringe with a volume of 1.0 ml with a fixed needle with a diameter of 29-30 G.

Characteristic ALT. Platelets contain the following growth factors: IGF (insulin-like growth factor), PDGF (platelet-derived growth factor), EGF (epidermal growth factor), FGF (fibroblast growth factor), TGF-β (transforming growth factor), PDEGF (platelet-derived growth factor endothelial cells), VEGF (growth factor of vascular endothelium), PLGF-1 / -2 (placental growth factors).

Thus, the main mechanism of ALT action is the ability to influence the mitogenic and chemotactic activity of retinal glia cells and retinal pigment epithelium. In addition, ALT affects the restoration of metabolic processes, improved microcirculation, normalization of tissue respiration, and activation of local immunity. The above-mentioned mechanisms of ALT action allow, together with traditional anti-inflammatory or anti-dystrophic therapy, to improve visual functions, as well as accelerate the natural mechanisms of tissue regeneration, reduce the frequency of recurrence of uveitis and prevent the development of complications.

Obtaining an autologous platelet lysate (pHPL) is as follows: in 6-8 specialized tubes with the commercial name Plasmolifting containing heparin and a unique gel, a 9 ml blood sample is taken, the tubes are placed in a centrifuge and centrifuged for 6-7 minutes at 3700- 3800 rpm During rotation in a centrifuge, blood is divided into two main fractions - an erythrocyte-leukocyte clot and a blood plasma containing platelets (platelet autoplasma). Then, with a syringe (10.0–20.0 ml), the supernatant containing autoplasma enriched with platelets located in the upper part of the tube above the separation gel is taken from one tube into a single tube (15.0–50.0 ml) and centrifuged again within 12-15 minutes at 3500-3600 rpm., at which a maximum platelet concentration of at least 1 × 106 cells / ml is achieved, the excess of acellular plasma is removed. From a platelet-rich autoplasma, a lysate is prepared by lysing the platelet membrane. Autologous plasma platelets are lysed by freezing twice in liquid nitrogen (-196 ° C) and quickly thawing in a water bath (+ 60 ° C). The resulting autologous platelet lysate (pHPL) is filtered through a filter (0.22 nm) and stored until use at -20 ° C.

The defining hallmarks of the proposed method, compared with the prototype, are:

- as a medicine, an autologous platelet lysate is injected into the affected eye in a patient, in an experimentally selected optimal dose of 0.6-1.0 ml, depending on the severity of the disease and the route of administration, which allows to simplify the method and increase its effectiveness;

- autologous platelet lysate is administered subconjunctively at a dose of 0.6-0.8 ml or paraequatorially at a dose of 0.8-1.0 ml, a course of 4-6 injections, with an interval after each injection of 48-72 hours, which allows to expand the functionality ways and increase the effectiveness of treatment.

The method is illustrated by the following examples of specific performance.

Example 1

Patient S., 59 years old, was admitted to the Novosibirsk branch of the IRTC “Eye Microsurgery” with a diagnosis of dystrophy of the basement membrane of the epithelium, recurrent erosion of the cornea of both eyes.

The first episode of the disease is October 2014, a course of keratoplastic therapy at the place of residence. The last exacerbation was October 2018, manifested by complaints of severe photophobia, lacrimation, and decreased vision.

Before treatment, Visus OD / OS = 0.05 / 0.3 s corr. IOP - 19 mmHg

The anterior segment of both eyes: the conjunctiva is pale pink, on the cornea are land-shaped changes in the epithelium, erosion. When viewed in a slit lamp in a cobalt filter after instillation of a 1% solution of sodium fluorescein, defects in the epithelium are stained with green, as shown in the overview photo of the cornea (Fig. 1). Moisture of the anterior chamber is transparent, deeper sections without pathology.

The patient underwent keratoplastic therapy in a clinic.

2 weeks after therapy, the treatment was carried out by the claimed method: the patient, when looking up, punctured the conjunctiva in the lower outer quadrant and injected into the right eye an autologous platelet lysate in a dose of 0.6 ml with a course of 6 injections with an interval of 48 hours. Similarly, an autologous platelet lysate was injected subconjunctively into the left eye at a dose of 0.6 ml with a course of 6 injections with an interval of 48 hours.

After treatment, Visus OD / OS = 0.4 / 0.5 s corr. IOP - 18 mmHg

There is a significant reduction in photophobia and discomfort in both eyes.

Anterior segment: complete corneal epithelization (when viewed in a slit lamp in a cobalt filter after instillation of a 1% solution of sodium fluorescein, epithelial defects were not observed) (Fig. 2). Deep-lying departments without pathology.

The result of the treatment was a subjective improvement of the eye condition (reduction of discomfort), objective improvement of visual functions (increase in visual acuity OD by 0.35; OS by 0.2), complete epithelialization of the cornea (absence of epithelial defects upon examination in a slit lamp in a cobalt filter after instillation of a 1% sodium fluorescein solution).

Example 2

Patient S., 59 years old, was admitted to the Novosibirsk branch of the IRTC “Eye Microsurgery” with a diagnosis of stromal herpetic keratitis of the right eye.

The first episode of the disease is December 2016, anti-inflammatory courses of residence. Last exacerbation in January 2018, PCR smear from the cornea for the herpes simplex virus is positive.

Before treatment, Visus OD = 0.05 s corr. IOP - 18 mmHg

Anterior segment of the eye: the conjunctiva is pale pink, on the cornea in the lower sections for 4-6 hours a cone-shaped infiltrate with fuzzy borders, capturing the epithelium and stroma, around the corneal opacities. When viewed in a slit lamp in a cobalt filter after instillation of a 1% solution of sodium fluorescein, an epithelial defect stained with green is visible, which is shown in the overview photo of the cornea (Fig. 3). The moisture of the front camera is transparent. The posterior synechiae of the iris is absent. The lens is the remains of the pigment on the front capsule, turbidity in the core. The vitreous body is transparent, the fundus without pathology.

The left eye is intact.

The patient underwent a course of antiviral, keratoplastic therapy in a clinic. Maintenance therapy: Valaciclovir (Valtrex) 500 mg orally 1 r / d.

2 weeks after therapy, the treatment was carried out by the claimed method. An autologous platelet lysate was thawed at room temperature for 10-15 minutes. In the right eye, twice with an interval of 1 minute, 1 drop of proxymethacaine (alkaine) was installed. After 3-5 minutes, a subconjunctival injection of 0.8 ml of autologous platelet lysate was performed in the lower outer quadrant. The course of treatment was 4 injections with an interval of 72 hours.

After treatment, Visus OD = 0.15 s corr. IOP 17 - mm Hg

Anterior segment of the eye: conjunctiva pale pink, complete epithelialization of the cornea (Fig. 4), in the lower sections of the cornea clouding. The moisture of the front camera is transparent. Departmental departments without dynamics.

The result of the treatment was a subjective improvement in the condition of the eyes, an objective improvement in visual functions (an increase in visual acuity by 0.1), complete epithelialization of the cornea (absence of epithelial defects when examined in a slit lamp in a cobalt filter after instillation of a 1% sodium fluorescein solution).

Example 3

Patient V., 38 years old, was admitted to the Novosibirsk branch of the IRTC “Eye Microsurgery” with a diagnosis of hereditary Stargardt macular degeneration in both eyes.

The first episode of the disease since 1990, treatment courses at the place of residence, since January 2006, courses of retinoprotective therapy 2 times a year at the place of residence and in the clinic. A sharp deterioration in visual acuity since December 2011 from 0.4 to 0.03 s corr. Last deterioration since September 2018

Before treatment, Visus OD / OS = 0.01 / 0.01 s corr. IOP - 18 mmHg

The total field of view according to spheroperimetry OD / OS = 415/420, absolute central scotomas (Fig. 5).

Anterior segment of both eyes without pathology. On the fundus of the optic nerve disc, monotonous, clear boundaries. In a rounded macula, a dystrophic lesion, atrophy sites of retinal pigment epithelium and pigment accumulation (according to the OST of the macula, the profile of the macular region is irregular, the thickness of the outer layers of the retina decreases, the areas of atrophy of the pigment epithelium, destruction of the outer segments of the photoreceptors).

The patient underwent a course of retinoprotective therapy in a clinic.

1 month after therapy, the treatment was carried out by the claimed method. A paraequatorial patient was administered 0.8 ml of autologous platelet lysate with a course of 6 injections (in each eye) at an interval of 72 hours in both eyes. The technique of paraequatorial administration of the lysate: the patient looks up to the nose. The skin is treated in the outer corner of the affected eye with 70% ethanol, palpation of the lower outer edge of the orbit and the needle stick parallel to the bottom wall of the orbit to a depth of 1 cm, followed by the introduction of an autologous platelet lysate.

After treatment, Visus OD / OS = 0.03 / 0.03 s corr. IOP - 17 mmHg

The total field of view according to spheroperimetry OD / OS = 420/430, the decrease in the area of cattle (Fig. 6).

Front, rear segment without dynamics.

After 3 months after the introduction of an autologous platelet lysate Visus OD / OS = 0.03 / 0.03 s corr. IOP - 16 mmHg

The result of the therapy was subjective improvement (increasing the clarity of vision), objective improvement of visual functions according to visometry (increasing visual acuity by 0.02 / 0.02) and spheroperimetry (increasing the total field of view by 5/10 degrees), stabilization of visual indicators by for 3 months

Example 4

Patient N., 37 years old, was admitted to the Novosibirsk branch of the IRTC “Eye Microsurgery” with a diagnosis of tapetoretinal abiotrophy, a mixed form of both eyes.

The first episode of the disease since 1991, treatment courses at the place of residence, since February 2004 courses of retinoprotective therapy 2 times a year at the place of residence and in the clinic. A sharp deterioration in visual acuity since December 2012 from 0.1 to 0.05 s corr., A narrowing of peripheral vision, hemeralopia was noted. Last deterioration since September 2018

Before treatment, Visus OD / OS = 0.05 / 0.05 s corr. IOP - 18 mmHg

The total field of view according to spheroperimetry OD / OS = 370/240, absolute central scotomas (Fig. 7).

Anterior segment of both eyes without pathology. The fundus of the eye: the optic nerve disc is pale, the borders are clear, the arteries are narrowed, on the middle periphery there is a pigment of the type “bone bodies”, the atrophy zone of the retinal pigment epithelium, dystrophic changes in the posterior pole (according to the OCT of the macula the profile of the macular region is flattened, pronounced destruction of the pigment epithelium, areas of atrophy, destruction of the outer segments of the photoreceptors).

The patient underwent a course of retinoprotective therapy in a clinic.

1 month after therapy, an autologous platelet lysate was administered paraequatorially at a dose of 1.0 ml in both eyes with a course of 4 injections with an interval of 48 hours.

After treatment, Visus OD / OS = 0.06 / 0.06 s corr. IOP - 17 mmHg

The total field of view according to spherical perimetry OD / OS = 400/365, the decrease in the area of cattle (Fig. 8).

Front, rear segment without dynamics.

After 3 months after the introduction of an autologous platelet lysate Visus OD / OS = 0.06 / 0.06 s corr. IOP - 16 mmHg

The result of the treatment was subjective improvement (increasing the clarity of vision), objective improvement of visual functions according to visometry (increasing visual acuity by 0.01 / 0.01) and spherometry (increasing the total field of view by 30/125 degrees), stabilization of visual indicators by for 3 months

Example 5

Patient E., 28 years old, was admitted to the Novosibirsk branch of the IRTC “Eye Microsurgery” with a diagnosis of chronic sluggish generalized uveitis of the right eye.

The first episode of the disease is May 2017, anti-inflammatory courses of residence. Last exacerbation September 2018

Prior to treatment, Visus OD = 0.65 IOP - 18 mmHg.

Anterior segment of the eye: no injection, on the endothelium of the cornea along the Türk-Erlich line, isolated precipitates, the moisture of the anterior chamber is transparent, the posterior synechia of the iris is absent. The lens is transparent. In the vitreous body, an inflammatory reaction (according to the B-scan of inclusion of medium echo density), in the lower parts of the retina on the far periphery there are sporadic inflammatory foci, cystic macular edema. The left eye is intact.

The retina thickness in fovea is 448 μm (Fig. 9), cystic retinal changes in the form of middle cysts.

According to microperimetry, the retinal photosensitivity in fovea is 21.7 dB.

The patient underwent anti-inflammatory treatment, after treatment, a decrease in inflammatory phenomena in the tissues of the eye was noted, however, macular edema persisted. Maintenance therapy: installations of 0.1% dexamethasone, nepaphenac in the right eye for 1 month.

2 weeks after therapy, an autologous platelet lysate was injected paraequatorially into the right eye at a dose of 0.9 ml with a course of 5 injections with an interval of 72 hours.

After treatment, Visus OD = 1.0 IOP - 17 mm Hg

The retina thickness in fovea is 276 μm (Fig. 10), the absence of cystic cavities, the complete restoration of the profile of the macular region.

According to microperimetry, the retinal photosensitivity in fovea is 25.2 dB.

Anterior segment without pathology. In the vitreous body, a significant decrease in turbidity (according to the B-scan, single inclusions of medium echo density). Resorption of inflammatory changes on the far periphery of the retina, macula without pathology.

The result of the therapy was subjective and objective improvement of visual functions, resorption of precipitates on the cornea, resorption of opacities in the vitreous body, restoration of the foveolar cavity profile according to OCT, disappearance of cystic changes, decrease in retinal thickness in fovea by 172 μm, increase in retinal photosensitivity by 3 in , 5 dB.

The proposed method allows to increase the effectiveness of treatment due to the anti-inflammatory, decongestant and reparative effects of the used ALT, which is accompanied by an improvement in the maximum corrected visual acuity, an increase in the total field of view in patients, and stabilization of the process for several months.

Claims (3)

1. A method of treating inflammatory or dystrophic diseases of the eyes, including anti-inflammatory therapy and injection of autologous blood into the affected eye, characterized in that the patient is injected 0.6-0 into the affected eye 2-4 weeks after anti-inflammatory or anti-dystrophic therapy, 8 ml of autologous platelet lysate subconjunctival or 0.8-1.0 ml paraequatorially, with a course of 4-6 injections, with an interval of 48-72 hours. 2. The method according to p. 1, characterized in that when subconjunctival administration of the drug to the patient, when looking up, puncture the conjunctiva in the lower-outer quadrant and inject 0.6-0.8 ml of autologous platelet lysate. 3. The method according to p. 1, characterized in that when paraequatorial administration of the drug in a patient, when looking up to the nose, the lower outer edge of the orbit is visualized and the needle is injected parallel to the lower wall of the orbit to a depth of 1 cm with the subsequent introduction of 0.8- 1.0 ml autologous platelet lysate.

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