Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Figure 14-4 Artificial tear insert (Lacrisert).

may decrease. Measurements in human subjects indicate that the insert prolongs TBUT. It is uncertain, however, whether this effect lasts longer than with tear substitutes applied as drops. The insert produces a tear film that is clinically thicker than normal and that appears to retain fluid within it.

The device is generally comfortable and well accepted by many patients, but its use does have certain disadvantages. Some patients have problems with discomfort (foreign body sensation) or expulsion of the Lacrisert.The insert can be wetted with saline before insertion to improve comfort, but this can make even more difficult the insert’s placement into the lower cul-de-sac, which requires a moderate amount of dexterity. Supplementation with artificial tears after insertion may improve comfort. The most common patient complaint is blurred vision associated with the intense release of polymer during the first 4 to 6 hours after instillation, from a thickened tear film. Adding such fluid as drops of NaCl 0.9% or artificial tear solution can reduce the tear film viscosity and minimize the visual complaints. As the insert dissolves it releases debris that can blur vision and cause irritation.

Most patients with mild signs and symptoms of dry eye do not experience improvement with use of the insert, as compared with the use of conventional tear solutions. Because some tear secretion is necessary to dissolve the Lacrisert, KCS patients with low basal tear secretion may not benefit from or tolerate its use.

Autologous Serum

Serum has been proposed as a source of tear replacement in severe dry eye. Autologous serum application to dry eye was reported as early as 1984. Tears contain several essential growth factors important in regulating the proliferation and maturation process of the epithelium; these same growth factors are present in serum. Improved ocular surface staining has been reported in patients using serum diluted in saline. Tsubota et al. demonstarated the use of serum eyedrops in Sjögren

patients resulted in significant increase in mucin expression and a beneficial effect on rose bengal staining. The main drawbacks of serum solutions are time-consuming preparation, short storage (refrigerated) time, and handling difficulties in patients with transmissible diseases.

Tear Conservation

Tear conservation may be achieved through techniques that reduce evaporation or obstruct tear outflow. Evaporation can be minimized by use of nonmedicated ophthalmic ointment and control of environmental factors. Shielded goggles, moisture chambers, and room humidifiers are helpful for some patients. Drafts, wind, smoke, air conditioning and heating systems, and fans can aggravate dry eye conditions by increasing evaporation. Obstruction of the lacrimal drainage system can be achieved through surgical methods, cautery or laser procedures, or punctal plugs. In severe cases tarsorrhaphy may be indicated. Tear conservation techniques are indicated with aqueous-deficient dry eye but may help other forms of dry eye as well. For such techniques to be effective, at least some aqueous secretion must be present unless tear supplementation also occurs.

Ointments

Nonmedicated ointments are indicated for moderate to severe dry eye, especially with lagophthalmos, persistent inferior corneal stippling, or severe epithelial compromise. Esters of fatty acids with long-chain alcohols, such as petrolatum, mineral oil, lanolin, and lanolin alcohols, serve as lubricants and create a lipid layer, retarding evaporation. Although these preparations (Table 14-2) melt at the temperature of the ocular tissue and disperse with the tear fluid, they appear to be retained longer than other ophthalmic vehicles. Because of their molecular

Table 14-2

Selected Nonmedicated Ophthalmic Ointments

size, petrolatum and mineral oil are not as easily removed by the lacrimal drainage system by blinking. Another significant factor appears to be the physiochemical relationship between the components of the ointment and the cornea. The precorneal tear film and the ointment bases both have nonpolar components, allowing adsorption of the oil bases to the cornea.

Patient acceptance of ointment preparations is highly variable. Because ointments are insoluble in water and do not mix readily with the tear film, they can reduce TBUT and blur vision.They are not generally recommended for daytime use in patients with aqueous-deficient dry eyes. Limiting the use of ointments to the evening or at bedtime avoids the visual effects. Ointment preparations generally are nonirritating to ocular tissue. In addition, ointment vehicles currently used do not appear to interfere with corneal or conjunctival wound healing. Ointment use, however, should be avoided in eyes with impending corneal perforations, deep or flap-like corneal abrasions, or severe corneal lacerations because of the possibility of ointment entrapment.

Lacrimal Occlusive Devices

Occlusion of the lacrimal drainage system has been used to preserve existing tears since electrocautery of the canaliculi was first advocated in 1936. Punctal plugs were introduced in 1974 to block tear drainage and thereby prolong the action of natural tears as well as artificial tear preparations. Absorbable inserts made with hydroxypropyl cellulose, polydioxanone, collagen, or gelatin and permanent ones made with silicone, thermodynamic acrylic polymer, or hydrogel material are available. Permanent punctual occlusion can also be achieved through thermal methods (cautery, diathermy, or laser) that destroy or shrink canaliculi walls.

The two most common types of plugs currently in use are collagen and silicone (Table 14-3). The water-soluble collagen rods are temporary, dissolving 4 to 7 days after insertion. Silicone plugs are more permanent but can be removed when necessary.

Temporary collagen implants come in a variety of sizes (diameters) to ensure as close a fit as possible.The plug is grasped with a jeweler’s forceps and, with the aid of magnification, placed halfway into the punctal opening (Figure 14-5). It then is nudged until flush with the punctum and is further advanced into the horizontal canaliculus.Topical anesthetics may be used to minimize eyelid reaction, but the procedure can be performed without anesthesia. The aqueous environment of the canaliculus causes the collagen implant to swell, impeding tear flow by as much as 60% to 80%. Degradation time of implants is unpredictable, because they have been reported to block tear drainage from 3 days to 2 weeks. Plugs made from synthetic materials such as polydioxane and PCL are also promoted as absorbable, but last considerably longer—up to 5 or 6 months. These provide a possible treatment option for temporary dry eye

Table 14-3

Selected Punctal Plugs

conditions, such as frequently experienced after refractive surgery.

Silicone plugs are inserted into either the punctum or the canaliculus, depending on the plug design. They are also available in a range of sizes (diameters) and shapes (designs). Some come with their own applicator (insertion device).The inferior drainage system is plugged most often, because it has a greater responsibility for tear drainage and is more accessible than the superior branch.The procedure by which silicone plugs are placed may require topical anesthesia and dilation of the punctal opening.

Figure 14-5 Insertion of collagen plug. (Courtesy Leo Semes.)

Figure 14-6 Inserted punctal plug. (Courtesy Leo Semes.)

In some cases insertion can be difficult or the plug can be expelled, especially if the patient rubs the eyelid. Spontaneous extrusion of plug appears to be the most common complication, with replacement plugs having an even lower retention rate than the initial plugs. Some studies show no significant difference in retention between upper and lower plugs, but others found plugs placed in the upper puncta were more prone to be lost than those in the lower lid. If reversal of occlusion is desired, lacrimal (intracanalicular) plugs, inserted into the horizontal canaliculus, can be removed through saline irrigation. Punctal plugs have heads that sit outside the punctum to impede migration and aid in removal (Figure 14-6).

Other materials are also available for patients deemed suitable for more permanent occlusion. “Form Fit” intracanalicular plugs (OASIS) are made of hydrogel material that once inserted into the vertical canaliculus and exposed to tears expands to form a gelatinous plug. The SmartPLUG (Medennium) also expands into a gelatinous plug after insertion into the canaliculus. Instead of hydration, body temperature conforms the thermodynamic acrylic polymer to the puncta.

Lacrimal occlusion can benefit patients who have symptoms of dryness or other ocular abnormalities that topical therapy alone does not resolve. The procedures are indicated in moderately severe to severe dry eye patients to prevent drainage and thereby conserve natural tears as well as instilled tear substitutes, reducing the frequency of application. Lacrimal occlusion also can improve contact lens tolerance in mild dry eye cases. Various studies have demonstrated that plugs may increase the aqueous tear component of the tear film, decrease corneal and conjunctival staining, and improve patient symptoms. Tear osmolarity decreases, probably due to increased tear volume.

Although rare, punctal occlusion can lead to epiphora, rupture of the punctal ring, pruritus, or canaliculitis. Pyogenic granulomas, in response to the presence of silicone plugs, have also been reported in a few patients.

Tearing with mucopurulent discharge, secondary to chronic dacryocystitis, is a contraindication to the use of lacrimal plugs.

Although punctal occlusion decreases dry eye symptoms in many patients, others may actually experience increased irritation. After occlusion, ocular surface sensation may diminish and reduced tear turnover can result from a decline in tear production and/or tear drainage. As tear clearance decreases, the concentration of proinflammatory cytokines increases in the tear film, exacerbating ocular surface desensitization. This affects the neural feedback loop between the ocular surface and lacrimal gland, leading to decreased tear production and, consequently, further inflammation and irritation.

Tear Stimulation

If some secretory parts of the lacrimal gland remain functional, stimulation to enhance tear production may be possible. Secretagogues or lacrimomimetics, such as cholinergic agents (carbachol, bethanecol, pilocarpine) and mucolytics (bromhexine and ambroxol), have been used to stimulate lacrimal glands, but none of these agents is in general use in the United States for the treatment of dry eye. P2Y2 nucleotide receptor agonists are also being investigated as topical secretagogues. Reducing ocular surface inflammation, through anti-inflammatories, immodulation or other means, may also stimulate tear production.

Pilocarpine

Pilocarpine is a parasympathomimetic agent with a muscarinic secretagogue effect. Pilocarpine HCl (Salagen) has been used orally in the treatment of xerostomia secondary to radiation for head and neck cancer and in Sjögren’s syndrome. It decreases symptoms of dry mouth and may also improve eye, skin, nose, and vaginal dryness. Subjective improvement in dry eye symptoms has been reported in investigations of oral pilocarpine for the treatment of KCS in Sjögren’s syndrome. Objectively, oral pilocarpine increases tear volume and flow, although nausea and sweating can be present. Topically applied pilocarpine shows no effect on stimulation of accessory lacrimal glands in rabbits.

Bromhexine

Bromhexine hydrochloride (Bisolvan) is a bronchial mucolytic agent and secretagogue that may have a stimulating effect on tear secretion. Oral bromhexine and its derivative ambroxol have equivocal results in clinical trials and are associated with side effects of nausea, sweating, and rashes.

Diquafosol

P2Y2 receptors are present in the epithelial cells of the ocular surface and stimulation of them by ATP increases mucin-like glycoprotein secretions in conjunctival

goblet cells.Activation of the receptors also stimulates the fluid pump mechanism of the accessory lacrimal glands, increasing water flow through cells and tear production. Some studies also suggest that receptor is present in meibomian glands and could control lipid composition. Therefore P2Y2 receptor agonists potentially have an effect on all three layers of the tear film.

Diquafosol tetrasodium 2% (diuridine tetraphosphate) is a potent and selective P2Y2 purinergic receptor agonist. In several clinical trials it was efficacious in improving corneal and conjunctival staining and Schirmer test values as well as providing some symptomatic benefit for dry eye patients. Phase II and III studies are completed, and a New Drug Application was submitted by Inspire Pharmaceuticals to the U.S. Food and Drug Administration in 2003.An amendment to the New Drug Application was filed in 2005, after the completion of two additional phase III trials.

Diquafosol is highly water-soluble dinucleatide, stable at room temperature. It does not appear to be systemically absorbed and is rapidly metabolized on the surface of the eye to naturally occurring compounds. It is well tolerated with localized side effects (burning/stinging). It is administered four times a day as an unpreserved, sterile, aqueous drop.

Inflammation Control

Chronic dry eye is the result of an underlying cytokine and receptor-mediated inflammatory process that affects the ocular surface and lacrimal gland, leading to decreased tear production or altered tear film contents. Hormonal, anti-inflammatory, or immunomodulatory agents may be able to suppress the inflammation and normalize the neural reflex between the ocular surface and lacrimal glands.

Hormone Therapy. When androgen levels decrease with age, certain autoimmune diseases (i.e., Sjögren’s syndrome) or menopause, a stimulus such as an infection or dry environment can activate T cells, causing an inflammatory immune response on the ocular surface and/or lacrimal gland. Two studies showed that hormones are important contributors to the lacrimal gland’s maintenance of function and resistance of immune insult. Others have reported androgens regulate meibomian gland function and promote the formation of tear film’s lipid layer. Therefore hormone insufficiency may contribute to meibomian gland dysfunction, tear film instability, and evaporative dry eye. Systemic androgen therapy suppresses the inflammation and stimulates the function of the lacrimal gland in mice, further suggesting topical androgen might be an effective therapy for dry eye. Topical androgen drops for the treatment of dry eye are currently being studied.

Corticosteroids. Studies have shown unpreserved topical corticosteroids (i.e., methylprednisone or loteprednol

etabonate) can improve the severity of KCS symptoms and decrease levels of ocular surface inflammation and cytokines. However, they can have potential unwanted side effects such as ocular hypertension, glaucoma, cataracts, and secondary infections. Therefore topical corticosteroid use in dry eye should be limited to short periods (less than 2 weeks) and for symptoms that are severe and refractory to other treatments.

Cyclosporine. Cyclosporine (cyclosporin A) is used principally in autoimmune disease and to prevent rejection after organ/tissue transplantation, but it has also been used systemically to treat the ocular manifestations of autoimmune disease and endogenous uveitis. Topical cyclosporine was approved by the U.S. Food and Drug Administration in December 2002 and released in 2003 as Restasis (Allergan) to reduce the inflammatory response on the ocular surface and in the lacrimal gland in patients with dry eye. A decrease in inflammation contributes to an improvement in the ocular surface epithelial integrity and sensitivity. The neural signals to the lacrimal gland are increased by enhanced ocular surface sensitivity.

Cyclosporin is an immodulator that inhibits activation of T cells by cytokines and other agents of inflammation. Studies show conjunctival levels of activated lymphocytes, immune activation markers, and the inflammatory cytokine interleukin-6 significantly decreased after 6 months of treatment with topical 0.05% cyclosporin. The density of conjunctival goblet cells was significantly greater after the same treatment in Sjögren’s and nonSjögren’s KCS patients. There have also been reports of successful treatment of meibomian gland dysfunction with cyclosporin.

A 6-week crossover study compared cyclosporine 1% ophthalmic ointment with a placebo and reported improvement in ocular surface staining, patient symptoms, and Schirmer’s test results with cyclosporine. Cyclosporin A ophthalmic emulsions in 0.05%, 0.1%, 0.2%, and 0.4% concentrations were studied by another group. Used twice a day for 12 weeks in moderate to severe dry eye, all concentrations showed significant improvement in rose bengal staining, superficial punctate keratitis, and subjective symptoms. Although no clear dose–response relationship was noted, the 0.1% solution produced the most consistent objective and subjective endpoints and the 0.05% solution produced the most consistent improvements in patient symptoms. Another study compared 0.05% and 0.1% cyclosporin with the vehicle alone in moderate to severe dry eye in patients with and without Sjögren’s.After 6 months of twice daily use, both cyclosporin emulsions resulted in significantly greater improvements than the vehicle in corneal staining and Schirmer’s test values, whereas the 0.05% emulsion showed significantly more improvement than the vehicle in subjective parameters of blurred vision and use of lubricating eyedrops.This study found improvement only

in Schirmer’s tests obtained with anesthesia. The lack of improvement in tests obtained without anesthesia suggests cyclosporin affects baseline tearing and not reflexive tearing.

Restasis is a 0.05% emulsion of cyclosporin with a vehicle of glycerin, castor oil, polysorbate 80, carmoner 1342, purified water, and sodium hydroxide. (The vehicle is marketed separately as Refresh Endura.) It is preservative free and white opaque to slightly translucent in color. The most common adverse effects are mild burning and stinging; topical cyclosporin appears to have minimal systemic absorption. It is used twice daily, and patients can expect results after 3 to 6 months of treatment.

Fatty Acids. Some essential fatty acids, which cannot be produced by the body, are natural modulators of inflammatory activity. Omega-3 fatty acids are present in oily fish, such as tuna, mackerel, salmon, sardines, and herring; they are also found in flaxseed oil. Sources for omega-6 fatty acids include beef, dairy products, and vegetable cooking oils and shortenings.

N-3 fatty acids contain eicosapentaenoic acid and docosahexaenoic acid and are metabolized to eicosanoids, hormone-like lipids involved in inflammation control. Oral omega-3 fatty acids can enhance meibomian gland function, resulting in a more stable tear film and reduction in evaporative tear loss. Some suggest n-3 fatty acids may also affect tear production by reducing inflammation of the lacrimal gland and ocular surface. N-6 fatty acids are converted to arachidonic acid, which promotes inflammation; eicosapentaenoic acid and docosahexaenoic acid may inhibit this conversion. TheraTears Nutrition (Advanced Vision Research), a capsule-form supplement containing flaxseed oil (1,000 mg), eicosapentaenoic acid (400 mg), and docosahexaenoic acid (300 mg), is promoted to treat OSD by decreasing inflammation and enhancing lipid and aqueous production.

It was recently reported that women with a higher intake of n-3 fatty acids tend to have a lower risk of dry eye, based on information gathered from a questionnaire on dietary habits. A completed questionnaire was received from over 32,000 subjects in the Women’s Health Study. A high dietary intake ratio of n-6 to n-3 fatty acids was associated with a greater prevalence in dry eye. Although the questionnaire results suggest intake of n-3 fatty acids and the ratio of their consumption to n-6 fatty acids can affect the amount of inflammatory activity in the body, there has been no systematic study to establish the role of fatty acids in the treatment of dry eye.

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Yokoi N, Komuro A, Nishida K, Kinoshita S. Effectiveness of hyaluronan on corneal epithelial barrier function in dry eye. Br J Ophthalmol 1997;81:533–536.

Osmotherapy was introduced to ocular therapeutics in 1904 with the use of oral hypertonic saline to reduce elevated intraocular pressure.Topical ocular use of hyperosmotic agents has been proven clinically useful in the treatment of corneal edema, particularly when the cause is endothelial dysfunction.

The following discussion considers the pharmacologic properties of hyperosmotic agents available for topical use. Chapter 26 discusses the clinical uses of topical osmotherapy in the management of conditions characterized by corneal edema.

CORNEAL EDEMA

A variety of clinical situations can give rise to corneal edema (Box 15-1). Because the endothelium is the main structure involved in maintaining normal corneal deturgescence, it plays a role in stromal hydration and compensates for the driving force of intraocular pressure. Also, the active transport system involved in the movement of water and electrolytes from the cornea to the aqueous humor must be maintained to prevent fluid retention. Endothelial failure, a frequent cause of corneal edema, can occur due to defects in the transport system or stromal compression resulting from elevation of intraocular pressure, which can induce water movement toward the epithelium.

Whenever swelling takes place, transparency is lost in the region where the edema occurs. Because the corneal epithelium and tear film constitute the most anterior optical surface of the eye, epithelial edema can exert a major detrimental influence on vision because it induces anterior irregular astigmatism.

It is clinically useful to consider corneal edema as epithelial, stromal, or a combination of both. In general, epithelial edema is more responsive to topical hyperosmotic therapy.

TOPICAL HYPEROSMOTIC AGENTS

Topical hyperosmotic agents can be useful in dehydrating edematous corneas. The clinical objective of topical

osmotherapy is to increase the tonicity of the tear film and thereby enhance the rate of movement of fluid from the cornea. All the currently available hyperosmotic preparations are hyperosmolar to the ocular tissue fluid. When applied to the ocular surface, water is drawn from the cornea to the more highly osmotic tear film and is eliminated through the usual tear flow mechanisms. Patients with minimal to moderate epithelial edema often achieve subjective comfort and improved vision with use of these agents.

Various agents can reduce corneal edema,including corn syrup, glucose, gum cellulose, sodium chloride, and glycerin. Only a few of these have proved clinically useful and acceptable to most patients. Sodium chloride and glycerin (Table 15-1) are the preferred agents in clinical practice.

Sodium Chloride

Pharmacology

Sodium chloride is a component of all body fluids, including tears. A solution of 0.9% is approximately isotonic with tears. Of the various concentrations tested, 2% to 5% formulations have proven effective, with an irritation level acceptable to most patients. Studies comparing various hyperosmotic agents in human subjects have confirmed the usefulness of hypertonic sodium chloride in the treatment of corneal edema. Use of 5% sodium chloride in ointment form can be effective in reducing corneal thickness and in improving vision.The maximum reduction in corneal thickness occurs 3 to 4 hours after instillation of the ointment (Figure 15-1).

Despite their apparent efficacy, the usefulness of sodium chloride solutions in the treatment of edematous corneas with a traumatized epithelium appears to be limited. The intact corneal epithelium exhibits limited permeability to inorganic ions. In the absence of an intact epithelium the cornea imbibes salt solutions, which reduces the osmotic effect. In the management of corneal edema associated with traumatized epithelium, hypertonic saline solutions may be of limited value due to their increased ability to penetrate the epithelial barrier.

280 CHAPTER 15 Antiedema Drugs

Box 15-1 Causes of Corneal Edema

Endothelial

Birth trauma

Congential hereditary corneal dystrophy

Fuchs’ dystrophy

Keratoconus and hydrops

Mechanical trauma

Surgical trauma

Inflammation

Increased intraocular pressure

Acute angle-closure glaucoma

Chronic glaucoma

Adapted from Boruchoff SA. Clinical causes of corneal edema. Int Ophthalmol Clin 1968;8:581–600.

Clinical Uses

Sodium chloride is useful for reducing corneal edema of various etiologies, including bullous keratopathy. Generally, one to two drops are instilled in the eye every 3 to 4 hours. Sodium chloride ointment requires less frequent instillation and is generally reserved for nighttime use.

Sodium chloride is commercially available in 2% and 5% solutions and as 5% ointment (see Table 15-1). In clinical practice, the 5% concentration appears to be somewhat more effective.

The way in which hyperosmotic preparations are administered may affect the clinical results. Because vision is usually worse on arising, several instillations during the first waking hours can prove helpful. On hot dry days, eyes may require less medication, because tear film evaporation is enhanced.

Side Effects

Whereas isotonic saline (0.9% sodium chloride) is nontoxic to the cornea and conjunctiva, sodium chloride, especially at the 5% concentration, can cause discomfort on instillation. Stinging, burning, and irritation are common complaints, but patients generally tolerate the therapy, especially if vision is improved. Epistaxis has been associated with use of 2% sodium chloride solution. The solution formulation should not be used if it changes color or becomes cloudy.

Glycerin (Glycerol)

Pharmacology

Glycerin is a clear, colorless, syrupy liquid with a sweet taste. It is miscible with both water and alcohol. In contact with water, glycerin absorbs water and thereby exerts an osmotic effect. When placed on the eye, its hygroscopic action clears the haze of corneal epithelial edema. Because the molecules mix readily with water, the osmolality of the applied solution decreases rapidly as water is imbibed from the cornea, and the clinical effect is transient.

Clinical Uses

Topical application of glycerin in concentrations from 50% to 100% results in a significant reduction of corneal edema within 1 to 2 minutes. Because application to the eye is painful, a topical anesthetic must be instilled before use. It is useful in ophthalmoscopic and gonioscopic examination of the eye in acute angle-closure glaucoma, bullous keratopathy, and Fuchs’ endothelial dystrophy.

Because its action is transient and application to the eye painful, glycerin is used primarily for diagnostic purposes.

Time (min)

Figure 15-1 Percent reduction in corneal thickness after application of 5% sodium chloride ointment (triangles = central; unfilled circles = nasal; filled circles = temporal). (Modified from the American Journal of Ophthalmology 1971;71:847–853. Copyright The Ophthalmic Publishing Company.)

In acute angle-closure glaucoma, additional glycerin may be used as the gonioscopic bonding solution to prolong the hyperosmotic effect during gonioscopy.

Side Effects

When applied topically to the eye without prior instillation of an anesthetic, glycerin causes significant stinging and burning. Reflex tearing follows, and dilation of conjunctival vessels may occur.These effects are transient, and no significant toxic effects occur with short-term use.

Glycerin is classified as Pregnancy Category C, and it is unknown whether it is excreted in breast milk. Safety for use in children has not been established.

Glucose

Pharmacology

Glucose solutions ranging from 30% to 50% have been used topically on the eye to treat corneal edema. The dehydrating action of a 30-minute glucose bath eliminates corneal epithelial edema and reduces corneal thickness. The effect lasts 3 to 4 hours.

Clinical Uses

The clinical effectiveness of 40% glucose is comparable with that of 5% sodium chloride. Because it is difficult to maintain sterility of the solution unless a preservative is added, a commercial preparation containing 40% glucose may often contain preservatives and is available in ointment formulation (see Table 15-1).

Side Effects

After topical application glucose exhibits a low degree of irritation and in the 30% to 50% concentrations is nontoxic to the eye. However, some transient stinging and irritation of the conjunctiva may occur after instillation.

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