RU2612810C2 - Nsaids application in excimer laser corneal surgery - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to non-steroidal anti-inflammatory drugs application in excimer laser corneal surgery. Stroma ablation is performed after de-epithelized cornea staining with 0.1-1.0% isotonic solution of rose bengal with additional postoperative corneal UV protection by means of sunglasses. This creates a shielding effect for secondary transformed UV radiation (emerging during ablation) penetration in the deeper layers adjacent to the ablation zone. Appointment of corneal sunglasses protection to block external UV rays in the postoperative period contributes as well.

EFFECT: prevention of additional phototoxic products formation from NSAIDs.

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Description

The invention relates to medicine, and more particularly to ophthalmology, and for the use of non-steroidal anti-inflammatory drugs (NSAIDs) in excimer laser corneal surgery.

It is known that NSAIDs are used in excimer laser surgery of the cornea by instilling them into the conjunctival cavity, before and after photorefractive surgery [2, 3]. The positive effect of the use of NSAIDs is due to the fact that they reduce the pain symptom, excessive aseptic inflammatory and regenerative reactions in response to stromal ablation. This is why NSAIDs are recommended for use in excimer laser corneal surgery for photorefractive and phototherapeutic corneal ablation. This applies to correction for ametropia, medical and optical reconstructive operations for various pathology of the cornea. However, the well-known fact of increasing the photosensitivity of tissues to light and, above all, to UV radiation is missed when there are a number of drugs in them, in particular NSAIDs [4]. Along with an increase in photosensitivity, the development of a phototoxic damaging effect is also possible. Such conditions are created when exposed to ultraviolet radiation on tissues containing NSAIDs. So, during corneal ablation with excimer laser radiation with a wavelength of 193 nm, part of it is transformed into longer waves in the range of 310-330 nm, which penetrate much deeper than the ablated layer of the cornea. Moreover, during ablation, secondary UV radiation initiates the cascade fluorescence of collagenous stromal proteins, visible to the eye. The effect on the NSAIDs of secondary UV radiation and guiding fluorescence leads to the destruction of the drug with the additional formation of oxide radicals and other phototoxic products that have a damaging effect on keratocytes and collagen structures of the stroma. In all cases, the larger the volume of corneal tissue undergoes ablation and the higher the concentration of NSAIDs in it, the higher the likelihood of a phototoxic effect of varying severity. After the operation, with continued general and local use of NSAIDs, an increased sensitivity of the cornea to external UV radiation develops. It can also affect the course of postoperative aseptic inflammatory and regenerative reactions and the final optical-refractive result.

A known method (method) for the prevention or reduction of photosensitive and / or phototoxic reactions to medications (Method for preventing or reducing photosensitivity and / or phototoxicity reactions to medications, patent US 5668134 A) [1]. The essence of the proposed method is to take medications that cause an increase in photosensitivity or phototoxicity at a certain time of the day, when there is minimal light load. However, this method cannot be used to reduce the effect of phototoxicity in excimer laser ablation of corneal stroma saturated with NSAIDs. In addition, this method cannot be applied in the postoperative period, since local installation of NSAIDs is carried out in the daytime.

The essence of the new technical solution in the proposed method for the use of NSAIDs in excimer laser surgery of the cornea is to perform stromal ablation after staining of the depithelized cornea with 0.1-1.0% isotonic solution of pink Bengal with additional postoperative UV protection of the cornea with glasses. This method can be applied with various methods of saturation of stroma of the cornea of NSAIDs. In this case, general, local and combined methods of using NSAIDs before and after excimer laser surgery on the cornea can be used. The general procedure involves oral, intramuscular or intravenous routes of administration of the drug. With topical use of NSAIDs, various techniques are also possible: an epibulbar drip or aerosol method, a subconjunctival or parabulbar technique for their administration.

The specified technical result is achieved by the fact that before ablation, the surface layers of the corneal stroma are stained with Bengal pink. This creates a screening effect for the penetration of the transformed radiation into deeper layers adjacent to the ablation zone. Thus, the formation of additional phototoxic products from NSAIDs is prevented under the influence of secondary radiation that occurs during ablation. It is known that phototoxic products have a damaging effect on corneal keratocytes and provoke an excessive aseptic inflammatory response to excimer laser ablation.

Studies have shown that when an epibulbar drip or aerosol (using an ultrasonic nebulizer) is applied to a de-epithelized cornea, 0.1-1.0% of an isotonic solution of Bengal pink is stained to a depth of 100 microns and this does not affect the rate of ablation. After one minute or more at a minimum concentration of 0.1% and a maximum concentration of 1.0%, the color does not differ in intensity of the red color tone. The latter indicates that the minimum time for saturation of the surface layers of the corneal stroma to a depth of 100 μm is one minute. In clinical practice, there are restrictions on the depth of ablation of the corneal stroma, and most often it is carried out within 100 microns of its surface layers. In cases of a larger volume of ablation, staged (re) staining of the cornea with Bengal pink can be carried out.

Depending on the specific type of photorefractive or phototherapeutic operation using excimer laser radiation, various options for implementing the proposed ablation method are possible. So, with the transepithelial technology of photorefractive and phototherapeutic keratectomy, the epithelialization and saturation of the stroma of the cornea of NSAIDs is first performed, then Bengal pink is stained, and only then excimer laser ablation is performed.

In order to prevent the development of photosensitive and / or phototoxic reactions after surgery, regardless of the general, local or combined use of NSAIDs, protection from external UV radiation is also necessary. For this, ordinary sunglasses can be used, as well as glasses with polarizing or photochromic glasses that completely block ultraviolet radiation.

The half-life of most NSAIDs does not exceed 20 hours, which means that after forty hours the drug is completely absent in the blood plasma. This fact indicates the advisability of continuing the UV spectacle protection of the cornea for at least two days after the cessation of the use of the drug (NSAIDs), regardless of the method of its use. However, as clinical observations have shown, it is advisable to use UV spectacle photoprotection for a longer period. The duration of this period is determined by the stabilization of visual and optical refractive results, regardless of the duration of NSAID use.

A key element of the mechanism of action of NSAIDs is the inhibition of prostaglandin synthesis through inhibition of the activity of cyclooxygenases (COX1 and COX2). It is COX1 and COX2 that is the main enzyme involved in the metabolism of arachidonic acid, which is formed during any damage to the phospholipid elements of cell membranes, regardless of the etiological factor. Under the influence of the COX metabolism enzyme and lipoxygenase (LOG), arachidonic acid is involved in the formation of mediators of prostaglandin inflammation (cyclic endoperoxides, prostaglandins (PG), thromboxane, leukotrienes, etc.).

In turn, prostaglandins are the main active factors in the mechanism of inflammation, the onset of pain and fever. They are mediators that cause local vasodilation, edema, exudation, white blood cell migration, as well as an increase in the sensitivity of the vascular wall to inflammatory mediators of histamine and serotonin.

In addition to pronounced anti-inflammatory activity, NSAIDs also have significant analgesic potential. This leads to a decrease in inflammation in the lesion area and a decrease in the migration of leukocytes to the focus of inflammation. In addition, NSAIDs have a positive effect on the balance of cytokines. The main mechanism of action of NSAIDs is to suppress the synthesis of prostaglandins (PG), which are important mediators of pain and inflammation.

Recently, a new molecular mechanism of action of NSAIDs has been discovered, the essence of which is to suppress the activation of nuclear transcription factor (Kappa factor, NF-kB) in cells. Moreover, the activation of the nuclear transcription factor occurs under the influence of UV radiation, oxide radicals and various pro-inflammatory cytokines. All these provoking factors occur during excimer laser surgery of the cornea.

The cytoprotective effect of NSAIDs before surgery is associated with their inhibitory effect on the nuclear transcription factor and its transition from the cell cytoplasm to the nucleus. This, ultimately, prevents the stimulation of keratocytes already at the stage of excimer laser ablation and their transition to the active form of keratoblasts. All this reduces the response regenerative response to photorefractive ablation. The nuclear transcription factor is involved in the regulation of the expression of various genes in keratoblasts of the corneal stroma, the transformed active forms of which are called myofibroblasts.

It is known that in cells, the nuclear factor Kappa is contained in the cytoplasm and, under the influence of various stimulating factors, passes into the nucleus. Accordingly, in most keratocytes not stimulated by secondary UV radiation, this factor is stored in the cytoplasm, and after stimulation it moves to the nucleus, binding to a specific kB receptor of the target gene region. It is the UV-induced nuclear translocation NF-kB that is involved in the regulation of the expression of various genes in myofibroblasts (keratoblasts) of the corneal stroma and their excessive activation. Such activation can lead to an excessive regenerative response to excimer laser ablation of the corneal stroma and cause recurrent myopization or the development of subepithelial fibroplasia after photorefractive or phototherapeutic corneal surgery.

In studies on cell cultures of human fibroblasts, it was found that if UV exposure is applied to fibroblasts previously incubated with NSAIDs, but placed in solution without NSAIDs, then the phototoxic effect is not observed. At the same time, irradiation of fibroblasts incubated with NSAIDs in solution with NSAIDs caused a phototoxic effect, which depended on the concentration of the drug and the total dose of UV exposure [5]. These studies showed that the phototoxic effect on fibroblasts is exerted by products formed upon exposure to UV radiation on NSAIDs in solution. These studies make it possible to understand why the occurrence of a photoxic effect on cell structures during UV irradiation of tissue containing NSAIDs is possible. In this case, the concentration of NSAIDs in the stroma of the cornea and the total dose of UV radiation are of great importance. As shown by clinical observations of patients instilling NSAIDs in the postoperative period, they themselves find a way out by resorting to wearing sunglasses on the street.

One of the known groups of drugs that affect the activity of nuclear factor Kappa (NF-κB) are NSAIDs. They are able to inhibit IKK, preventing IκB phosphorylation. Thus, the pathway of activation of the nuclear factor Kappa is blocked.

Nuclear (nuclear) factor κB (kappa B - “kappa-bi”; NF-κB) is one of the main transcription factors responsible for adaptive cell responses. It represents a family of cytoplasmic proteins that, upon stimulation, move to a free state, moving to the nucleus, where they are active, binding to the promoter regions of more than 100 genes (according to other sources, more than 300) responsible for inductive homeostasis. NF-kB plays an important role in cell proliferation, apoptosis, inflammatory and autoimmune reactions, as it regulates the expression of genes involved in these processes. It is a heterodimeric complex of Rel family proteins, which are inactive in most resting cells and are in the cytoplasm in complex with specific inhibitory proteins IκB (inhibitors of kappa B), the family of which includes IκBα, IκBβ, IκBγ / p105, IκBδ / p100, IκBε and factor-3 B cell lymphoma (Bcl-3). NF-κB mediates an inflammatory and immune response, a response to viral infections, cell division and the regulation of apoptosis. It can be involved in both anti- and pro-apoptotic signal.

The method is illustrated by the following examples.

Example 1. Patient K., 28 years old. Diagnosis: moderate myopia, complex myopic astigmatism in both eyes. Visual acuity before surgery: right eye 0.03 s corr. sph (-) 4,50 D, cyl (-) 2,00 D ax 178 ° = 0,8; left eye 0.03 s corr. cyl (-) 4.00 D, cyl (-) 1.75 ax 180 ° = 0.9, binocular 0.9.

An operation of transepithelial PRK in both eyes. An hour before surgery, 1 tablet (8 mg) of xefocam was given. After epibulbar anesthesia and removal of the epithelium by laser radiation, a 0.1% isotonic solution of Bengal pink was instilled, photorefractive ablation was performed a minute later and a soft contact lens was applied. On the left eye, photorefractive ablation was performed without staining of the epithelialized cornea with Bengal pink. The pain symptom was minimal during the first night, by the end of the first day there was only a slight sensation of a foreign body in the right eye and moderate in the left. Tearing and photophobia did not exceed 1 point on the right and 2 points on the left eye when assessed on a 4-point scale. There was a slight pericorneal injection on the right and moderate on the left eye. A light test showed more pronounced photophobia in the left eye, where Bengal pink staining was not used before ablation. Complete epithelization of the ablation zone in the right eye occurred after 36 hours and after 48 hours in the left eye.

The contact lens was removed after two days in both eyes. After epithelialization, a standard decreasing dexamethasone instillation regimen was prescribed. Xefocam ingestion of 8 mg twice a day was continued for another 2 days after the operation with eye protection from external UV radiation with sunglasses, and after two days the wearing of sunglasses was canceled. Two weeks after the operation, the cornea of the right eye is transparent, and mild subepithelial fibroplasia was detected on the left eye (1 point on a five-point rating scale). Subepithelial fibroplasia in the left eye was reversible and completely disappeared 2 months after surgery. A year after the operation, the cornea in both eyes is transparent, visual acuity of 0.9 in both eyes, binocular 1.0. Refraction on the right eye sph (-) 0.00 D, cyl (-) 0.50 D ax 172 °, on the left eye (+) 0.25, cyl (-) 0.50 ax 178 °.

Example 2. Patient Ns, 30 years. Diagnosis: High myopia, anisometropic, complex myopic astigmatism in both eyes. Visual acuity before surgery: right eye 0.02 s corr. sph (-) 8,250 D x cyl (-) 2,00 D ax 169 ° = 0.7; left eye 0.02 s corr. sph (-) 7.00 D x cyl (-) 1.75 D ax 174 ° = 0.8, binocular 0.8.

Transepithelial PRK operation on both eyes. On the right eye, after epibulbar anesthesia and removal of the epithelium by laser radiation, the stroma was saturated with a prepared ex tempore 0.1% isotonic solution of lornoxicam. Saturation was carried out for three minutes by means of an ultrasonic nebulizer. After that, staining of the cornea with 1.0% solution of pink Bengal was performed and photorefractive ablation was performed in a minute. On the left eye, after saturation of the cornea with a prepared ex tempore 0.1% isotonic solution of lornoxicam, Bengal pink was not stained. Upon completion of ablation, a contact lens was applied on both eyes. The pain symptom was minimal, and by the end of the first day there was only a slight sensation of a foreign body in the right eye and moderate in the left. There was a slight pericorneal injection on the right and moderate on the left eye with a mild injection of the vessels of the bulbar conjunctiva. Tearing and photophobia did not exceed 1 point on the right and 2 points on the left eye when assessed on a 4-point scale. During the light test, there was very weak photophobia on the right and moderate photophobia on the left eye, where it was not used before ablation with Bengal pink staining. Complete epithelialization of the ablation zone occurred after 48 hours in both eyes. Two weeks after surgery, mild subepithelial fibroplasia was noted on the left eye (1 point on a five-point scale). Subepithelial fibroplasia was reversible and completely disappeared 3 months after surgery. After a year, the cornea in both eyes is transparent, visual acuity of 0.9 in both eyes, binocular 1.0. Refraction on the right eye sph (-) 0.25 D, cyl (-) 0.50 D ax 168 °, on the left eye (-) 0.25 cyl (-) 0.750 ax 174 °.

Example 3. Patient K-va, 24 years old. Diagnosis: High myopia, anisometropic, complex myopic astigmatism in both eyes. Visual acuity before surgery: right eye 0.03 s corr. sph (-) 6,750 D x cyl (-) 2,00 D ax 171 ° = 0.8; left eye 0.02 s corr. sph (-) 7.50 D x cyl (-) 1.75 D ax 170 ° = 0.8, binocular 0.9.

FemtoLASIK operation was performed on both eyes. An hour before surgery, 1 tablet (8 mg) of xefocam. On the left eye, after raising the corneal flap, the stroma was stained with 0.1% Bengal pink solution and refractive ablation was performed a minute later. A day after the operation, photophobia and a light injection of the vessels of the bulbar conjunctiva in the left eye were detected during the light test. Recommended for two days wearing sunglasses. At the control examination on the third day, photophobia and vascular injection of the bulbar conjunctiva in the left eye disappeared. A week after surgery, visual acuity of 0.9 in both eyes, binocular 1.0. Refraction on the right eye sph (-) 0.25 D, cyl (-) 0.50 D ax 169 °, on the left eye (-) 0.50 cyl (-) 0.750 ax 172 °.

Information sources

1. Patent US 5668134 A. Method for preventing or reducing photosensitivity and / or phototoxicity reactions to medications.

2. Ioshin I.E., Khachatryan G.T., Artamonova A.V., Molchanova E.A. Nonsteroidal anti-inflammatory drugs in the correction of the postoperative period in refractive surgery. Cataract and refractive surgery. - 2013. - No. 3. - S. 24-30.

3. Chekhova T.A. New aspects of the use of NSAIDs in the practice of an ophthalmologist. Russian Ophthalmology Online, 2013, October-December, No. 12.

. Photosensitivity to selected topical nonsteroidal anti-inflammatory drugs preparations - a review of literature data and author's own experience. Centr Eur J Immunol., 2011; 36 (3): 197-203.4. Jenerowicz D., Jakubowicz O., Polanska A., Sadowska-Przytocka A., Danczak-Pazdrowska A.,

. Photosensitivity to selected topical nonsteroidal anti-inflammatory drugs preparations - a review of literature data and author's own experience. Centr Eur J Immunol., 2011; 36 (3): 197-203.

5. Bracchitta G., Catalfo A., Martineau S., Sage E., De Guidi G., Girard P.M. Investigation of the phototoxicity and cytotoxicity of naproxen, a nonsteroidal anti-inflammatory drug, in human fibroblasts. Photochem Photobiol Sci. 2013 May; 12 (5): 911-22.

Claims (1)

A method of photoprotection of the cornea using non-steroidal anti-inflammatory drugs (NSAIDs) in excimer laser surgery, which consists in performing ablation at least 1 minute after staining the depithelized cornea with a 0.1-1.0% solution of pink Bengal followed by postoperative UV protection of the cornea with glasses for not less than two days after stopping the use of NSAIDs.