Rebamipide has been noted to help with symptoms of dry eye disease but to date, I could not any data to say it is FDA approved nor find anyone selling this.
SLC
SLC
References:
1. https://iovs.arvojournals.org/article.aspx?articleid=2677081
Abstract
Purpose: The superoxide dismutase-1 knockout (Sod1−/−) mouse is an age-related dry eye mouse model. We evaluated the role of 2% rebamipide ophthalmic solution on the conjunctiva and ocular surface alterations in Sod1−/− mice.
Methods: Rebamipide eye drops (2%) were instilled in six 50-week-old male Sod1−/− mice and six C57BL/6 strain wild-type (WT) male mice four times a day for 2 weeks. Aqueous tear secretion quantity and tear film breakup time measurements as well as vital stainings were performed. Immunohistochemistry staining of the conjunctiva was performed using SAM pointed domain-containing ETS transcription factor (SPDEF), transglutaminase-1, and involucrin antibodies. Quantitative RT-PCR was carried out to study mRNA expression of the same markers.
Results: The mean tear quantities showed no significant changes in both mice strains after treatment (P = 0.24). The mean tear film breakup time (P = 0.003) and vital staining scores significantly improved in the Sod1−/− mice after treatment. Treatment with 2% rebamipide eye drops significantly decreased the corneal fluorescein (P = 0.0093) and Rose Bengal (P = 0.002) staining scores in the Sod1−/− mice. We showed a notable increase in SPDEF and a marked decrease in transglutaminase-1 and involucrin immunohistochemistry stainings, together with a significant increase in SPDEF (P = 0.0003) and a significant decline in transglutaminase-1 (P = 0.0072) and involucrin (P = 0.009) mRNA expression after treatment in the Sod1−/− mice.
Conclusions: Topical use of 2% rebamipide drops was observed to improve conjunctival epithelial differentiation and suppress keratinization in the Sod1−/− mice.
Wolters Kluwer — Medknow Publications
Efficacy of rebamipide 2% ophthalmic solution in the treatment of dry eyes
Saurabh Shrivastava, Priyanka Patkar, […], and Zahna Riaz
Associated Data
Abstract
AIM:
The aim of this study is to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes.
MATERIALS AND METHODS:
A prospective study was carried out on forty eyes of patients having signs and symptoms of dry eye. Two percent rebamipide ophthalmic solution was applied four times a day for a period of 4 weeks. Patients were evaluated on the basis of dry eye-related symptom score, tear film break-up time (TFBUT), tear meniscus height, fluorescein ocular surface staining score (FOSS), and the Schirmer’s test at the end of 2, 4, 6, and 12 weeks and their values were compared with the baseline.
RESULTS:
Significant improvement was noted in the mean dry eye-related symptom score, TBUT, and the FOSS values from the baseline at the end of 2, 4, 8, and 12 weeks. The values of tear meniscus height and Schirmer’s test were improved at the end of 8 weeks but were not statistically significant.
CONCLUSION:
Nearly 2% rebamipide ophthalmic solution provided relief in the symptoms of patients having dry eyes. It also prevented further ocular surface damage and aided in stabilizing the tear film.
Keywords: Dry eye, mucin secretagogue, rebamipide
Introduction
Dry eye disease was earlier defined as, the reduction of the aqueous phase of tear film. In 1995, the definition was modified to include medical and ocular diseases that reduce tear production and/or increase tear evaporation.[1] It causes damage to the interpalpebral ocular surface giving rise to the symptoms of ocular discomfort.
Literatures have recognized the various risk factors for the development of dry eye. These include female gender, hormonal changes, systemic autoimmune disease (most prominently Sjogren syndrome), decreased corneal sensation, refractive surgery, blinking abnormalities, drug effects, viral infections such as HIV, diabetes mellitus, Vitamin A deficiency, and graft-versus-host disease. In addition to the risk factors listed above, environmental, workplace stress (arid atmosphere, constant wind currents) or recreational stress (prolonged use of video display screens), and presence of contact lenses also add to the development of dry eye disease.[2]
The management of dry eyes continues to challenge the clinicians. Usually, the treatment is aimed at providing symptomatic relief. The choice of therapy for dry eye disease may be determined by the severity of the condition. In mild cases, artificial tears may be applied. In moderate cases, more frequent treatment will be required. Artificial tear eyedrops can also be supplemented with anti-inflammatory eyedrops, corticosteroids, topical or systemic omega 3 fatty acids, tetracycline, and autologous serum. In cases of severe dry eye, in addition to frequent instillation of unpreserved artificial tears, other tear conserving therapies are often required. These include occlusion of punctum and prevention of the evaporation of moisture from the eye with the use of room humidifiers, usage of tight-fitting goggles, moisture chamber spectacles, or tear feeding spectacles.[3,4] Hydrophilic bandage contact lenses are often used in cases of corneal ulceration or following corneal surgery.[4,5,6] Surgical modalities of treatment include the use of punctual plugs and tarsorrhaphy to reduce the exposed area of the cornea, thus reducing the evaporation of tears.
Rebamipide is a novel ophthalmic suspension which was initially used in treating gastric ulcers due to its mucin secretagogue activity. It is an amino acid analog of 2 (1H)-quinolinone. There have been very limited studies to see the effect of this new drug in cases with dry eye disease, and to the best of our knowledge, there is no study done till now in India. There is a poor correlation between the symptoms and signs of dry eye. Thus, it is particularly important to perform an assessment of efficacy using subjective measures (symptoms) as well as objective measures (signs). This study was done to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes using both subjective measures (symptoms) as well as objective measures (signs).
Materials and Methods
A prospective randomized study was carried out on twenty patients (forty eyes) over a period of 3 months, after taking permission from the ethics committee. An informed consent was taken from the patients prior to recruitment. All the therapeutic decisions were taken by the treating doctor. Patient confidentiality was maintained, and they had the right to opt out of the study at any point of time. A detailed history of disease and prior treatment was taken. We included patients above the age of 20 years who had mild-to-severe symptoms and/or Schirmer’s test value, without anesthesia of ≤10 mm/5 min; or tear film break-up time (TFBUT) ≤10 s; or fluorescein staining score of ≥4 (van Bijsterveld system) and Rose Bengal score of ≥4 were included in the study dry eye who were resistant to/not responding to the prototype dry eye treatment, namely, topical artificial tears, cyclosporine, and steroids (immunosuppressants). The following patients were excluded from the study as follows: (1) Patients with a systemic illness like Sjogren’s syndrome, (2) patients discontinuing the treatment, and (3) loss to follow-up cases.
All the patients were instructed to instill rebamipide 2% (Eyesec, Akumentis Healthcare Ltd.) eyedrop four times a day for a period of 12 weeks. These patients were asked to fill the dry eye symptom questionnaire which was developed by Schein et al.[7] It comprises of six questions based on six symptoms (dryness, gritty or sandy sensation, burning sensation, redness, crusting or discharge on the lashes, and having eyelids stuck shut in the morning). Patients were asked to grade the symptoms as under the categories of mild, moderate, and severe [Annexure 1].
The patients underwent routine ophthalmological examination which included visual acuity, slit lamp examination, Schirmer’s test (without anesthesia), tear film break up time (TBUT), corneal surface staining with fluorescein dye, and Rose Bengal stain. Tear production was measured by the Schirmer’s test. Schirmer’s test strip was placed over the lower lid margin into the tear lake at the junction of the middle and lateral one-third of the eye lids for 5 min. The strip was then removed, and the amount of wetting in millimeters was recorded as the Schirmer’s test score.
Tear film stability was estimated based on TBUT. A fluorescein-impregnated strip (Bell Pharma) wetted with nonpreservative saline solution was placed in the lower conjunctival sac. The examination was done under a slit lamp with the use of a cobalt blue filter. The time between the last blink and the appearance of the first black spot on the stained tear film was noted.
The ocular surface was examined by Fluorescein staining of the cornea (van Bijsterveld system) [Annexure 2]. A fluorescein impregnated strip wetted with nonpreservative saline solution was placed in the lower conjunctival sac of anesthetised eye. Corneal fluorescein staining was recorded in the temporal bulbar conjunctiva, nasal bulbar conjunctiva, and cornea and each graded on a scale of 0–3 points, with 0 being no stain, 1 indicating few separated spots of staining, 2 indicating many separated spots of staining, and 3 indicating confluent staining. The total score was from 0 to 9 points [Annexure 2].
Annexure 2
Fluorescein staining of the cornea : Van Bijsterveld system
Click here for additional data file.(463K, tif)
Rose Bengal staining was done to stain damaged conjunctival and corneal cells and thereby identifying damage to the eye. A Rose Bengal impregnated strip wetted with nonpreservative saline solution was placed in the inferior fornix of the anesthetized eye. The patient was asked to blink twice and measurement was done after approximately 3–5 min. Grading was done on a scale of 0–9 points, 0–3 being mild, 3–6 being moderate, and 6–9 being severe.
The eyedrop was instilled four times a day for a period of 12 weeks. Dry eye-related symptom score, tear film break-up time (TBUT), fluorescein ocular surface staining score (FOSS), Rose Bengal score, and Schirmer’s test without anesthesia were measured at the end of 1, 4, 8, and 12 weeks and their values were compared with baseline values which was taken as the control group. Efficacy was evaluated by comparing pretreatment/baseline score to posttreatment scores.
Statistical analysis
Data were entered in Microsoft Excel and analyzed using SPSS 24 Trial Version. We calculated the means and standard deviations and medians and interquartile ranges for continuous variables. We calculated the proportions for categorical variables. We used t-test for parametric data and Mann–Whitney test for nonparametric data. The proportions were compared using the Chi-square test or the Fischer’s exact test (for low expected cell counts). P < 0.05 was considered to be statistically significant.
Results
A total of 20 patients of age group of 20 years and above were enrolled in this study. A comprehensive summary of the test results is depicted in Figure 1. Patients who had severe symptoms showed a clinical as well as statistically significant improvement at the end of 12 weeks. There were 32.5% patients with severe symptoms at the start of the study, but there were none with severe symptoms at the end of 12 weeks (P < 0.01). However, in those with mild symptoms, there was no improvement. There were 27.5% cases with mild symptoms at the start of the study and at the end of 12 weeks. In those patients with moderate symptoms, there was an improvement. There were 40% cases at the start of the study whereas there were just 5% cases at the end of 12 weeks [Table 1 and Figure 2].
Symptoms score, TFBUT, Schirmer’s score, fluorescein ocular staining score and Rose Bengal score from baseline up to 12 weeks
Pre and post treatment values of symptoms and tests for dry eye
Symptoms score
Rose Bengal staining values did not show any significant change in the values at the end of 12 weeks. There were 75% cases with score between 0 and 3 at the beginning of the study as opposed to 92.5% cases at the end of 12 weeks. Cases with score between to 9 were 2.5% at the start and none at the end of 12 weeks [Table 1].
Fluorescein staining showed some improvement in values at the end of 12 weeks. 45% of cases with a high fluorescein score showed statistically significant decrease in score to 12.5% at the end of 12 weeks. This improvement was statistically significant (P < 0.01) [Table 1 and Figure 3].
Schirmer’s score value
Schirmer’s test scores did not show any improvement which was clinically or statistically significant. 92.5% patients had Schirmer’s score <10 mm which at the end of 12 weeks was seen in 82.5% patients. Thus, there was no significant improvement in the Schirmer’s values [Table 1 and Figure 4].
Fluorescein ocular staining score values
TFBUT scores showed minimal improvement at the end of 12 weeks. Nearly 90% patients had TFBUT <10 s which was 72.5% at the end of 12 weeks [Table 1].
Discussion
In 2007, the International Dry Eye Workshop updated the original definition and classified dry eye as, “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage of the ocular surface.” It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.[8,9] Rebamipide ophthalmic suspension (Eyesec) was recently approved for the treatment of dry eye in India. It was initially synthesized and developed by Otsuka Pharmaceutical Company, Limited (Tokyo, Japan). Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. Investigations have confirmed that rebamipide increases corneal and conjunctival mucin-like substances. Rebamipide upregulates the gene expression of MUC1, MUC4, and MUC16 which are expressed on the apical surface of the conjunctival and corneal epithelia.[10] Rebamipide also has anti-inflammatory properties. Rebamipide could suppress poly I: C-induced cytokine production and the expression of mRNAs for CXCL10, CXCL11, regulated on activation, normal T-cell expressed and secreted, monocyte chemotactic protein-1, and interleukin-6 (IL-6) in human conjunctival epithelial cells. Rebamipide inhibited IL-6 and IL-8 production induced by tumor necrosis factor alpha.[11] These findings suggested that the mechanism responsible for the inhibition was the inhibition of nuclear factor-κB activation. The tight junctions that exist between the corneal epithelial cells serve an important function as a barrier for deeper corneal tissue. Rebamipide ophthalmic solution has been shown to increase goblet cell count in normal rabbits as observed by impression cytology.[12] Studies show that it also helps in improving the tear status in patients having aqueous deficiency dry eyes.[13] Due to its ability to modify epithelial cell function, improve tear stability, and suppress inflammation in the absence of any known major side effects, rebamipide can also be used in treating other ocular surface disorders such as lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion.
In this observational case series study, we have evaluated the effect of 2% rebamipide ophthalmic suspension in patients with dry eye at baseline and at 2, 4, 8, and 12 weeks visit to elucidate the therapeutic effects of rebamipide ophthalmic suspension in clinical practice and shown relevant factors for the changes of subjective signs and objective symptoms of dry eye. There was statistically significant improvement in symptoms and fluorescein staining at the end of 12 weeks. There were 32.5% patients with severe symptoms at the start of the study; however, there were none with severe symptoms at the end of 12 weeks (P < 0.01). Forty-five percent of cases with a high fluorescein score showed statistically significant decrease in score to 12.5% at the end of 12 weeks (P < 0.01). TFBUT scores showed minimal improvement at the end of 12 weeks. However, there was no improvement in Schirmer’s score and Rose Bengal staining score. Kinoshita et al.[14] reported improvement of fluorescein corneal staining score, lissamine green conjunctival staining score and TFBUT. They found no significant difference for Schirmer’s score values. Another study by Igarashi et al.,[15] in which the ocular surface disease index questionnaire was used for evaluating the symptoms, showed significant improvement in symptoms in patients who were not showing improvement with the prototype treatment of artificial tears and immunosuppressants. This is in correlation to our study.
In India, artificial tears are the first-line agents and immunosuppressants (Cyclosporine A [CsA] and steroids) are the second-line agents. CsA is a fungal-derived peptide that has an anti-inflammatory and immunomodulatory mode of action. It inhibits T-cell activation and consequently inhibits the inflammatory cytokine production (selective inhibition of IL-I). In addition, CsA inhibits apoptosis by blocking the opening of the mitochondrial permeability transition pore (Matsuda and Koyasu 2000) and by increasing the density of conjunctival goblet cells.[16] However, CsA causes more stinging and irritation which was seen to be much less with rebamipide. Rebamipide has a multifactorial action, namely, anti-inflammatory, mucin secretagogue, tear film stability, and conjunctival healing, increasing the goblet cell counts. The only side effect observed was bitter taste or dysgeusia (10% patients). The most frequently observed adverse event in the Kinoshita et al. Phase III study was dysgeusia (bitter taste); but this was only observed in 9.7% of the 2% rebamipide group.[14] The only disadvantage is that rebamipide 2% is costly; therefore, rural population has to resort to cheaper alternatives. In addition, there can be poor patient compliance as it requires frequent instillation (four times a day) for a long duration. Since there is a poor correlation between the symptoms and signs of dry eye, it is particularly important to perform an assessment of efficacy using subjective measures (symptoms) as well as objective measures (signs).[17] In our study, 2% rebamipide four times a day significantly improves symptoms and fluorescein ocular staining score.
Conclusion
This study was done to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes using both subjective measures (symptoms) as well as objective measures (signs).
In our study, rebamipide 2% improved symptoms and signs (FOSS) in patients who were refractory to the conventional treatment (artificial tears and immunosuppressants, i.e., cyclosporine and steroids). Thus, it can be used as an alternative to the second-line agents in patients who are refractory to the existing line of treatment and improve the quality of life of such patients.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Article information
References
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Dove Press
Rebamipide ophthalmic suspension for the treatment of dry eye syndrome: a critical appraisal
Tomoyuki Kashima, Hirotaka Itakura, […], and Shoji Kishi
Abstract
Rebamipide was initially developed and approved for use in treating gastric ulcers and lesions associated with gastritis. Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. Investigations have confirmed that rebamipide increases corneal and conjunctival mucin-like substances along with improving corneal and conjunctival injury. Clinically, rebamipide ophthalmic suspensions can effectively treat tear deficiency and mucin-caused corneal epithelial damage, and can restore the microstructure responsible for tear stability. Topical rebamipide has also been shown to be effective in treating other ocular surface disorders such as lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion. Rebamipide’s ability to modify epithelial cell function, improve tear stability, and suppress inflammation in the absence of any known major side effects suggest that it may be a beneficial first drug of choice for severe dry eye treatment and other ocular surface disorders. This review summarizes the history and development of this innovative dry eye treatment from its initial use as an effective stomach medication to its current use in the treatment of dry eye in Japan.
Keywords: quinolinone derivative, tear deficiency, ocular surface disorder, mucin secretion, Mucosta
History
Rebamipide is a novel quinolinone derivative synthesized and developed by Otsuka Pharmaceutical Company, Limited (Tokyo, Japan) (Figure 1). After its initial discovery, it was used as an agent that promoted the healing of lesions in an experimental rat gastric ulcer model.1,2 Subsequently, in 1990, it was marketed as the Mucosta® tablet (Otsuka Pharmaceutical Company, Limited) for gastric ulcer therapy.3 Rebamipide has been shown to increase gastric endogenous prostaglandin E2 and I2, promote gastric epithelial mucin,1,4 behave as an oxygen free radical scavenger,5,6 and it has other anti-inflammatory actions.7–10 In addition to its use for the gastrointestinal mucosa, the biological effects of rebamipide, which include cytoprotection, wound healing, and anti-inflammatory properties, are known to be universal for a variety of tissues.10 In 1994, gastric mucosal lesions (erosion, hemorrhage, erythema, and edema) associated with gastritis were subsequently added to its indications.11 Since then, it has been widely used as a therapeutic agent for gastritis and gastric ulcers.12 The clinical effectiveness of rebamipide for the treatment of stomatitis;13 pulmonary,14 renal,15 and liver damage;16 colitis;17 and corneal protection18 has been demonstrated by both basic and clinical research.10 This drug also accelerated the healing of experimental gastric ulcers in Mongolian gerbils infected with Helicobacter pylori by improving cell kinetics, reducing apoptosis, and reducing inflammation.19
Structure of rebamipide.
After discovering that the pharmacological actions of rebamipide included increasing gastric mucus (mucin), its development for use as a dry eye medication began with investigations of its effect on the ocular surface mucin.1,4,20 In nonclinical studies, it was confirmed that rebamipide increased corneal and conjunctival mucin, and that it increased the conjunctival goblet cells in rabbits.21,22 The therapeutic effects of rebamipide are due to its ability to increase corneal and conjunctival mucin-like substances, and to improve corneal and conjunctival injury in vivo.18 It is known that rebamipide increases the mucin production in cultured conjunctival goblet cells23,24and in corneal epithelial cells.25 These reports additionally indicated that rebamipide increased the secretion of both membrane-associated and secreted-type mucins.
Clinical studies have shown that rebamipide has an improving effect not only on both corneal and conjunctivital epithelial damage, but also on subjective symptoms.26–28 Based on these results, rebamipide was launched in January 2012 for the treatment of dry eye in Japan (Mucosta ophthalmic suspension unit dose 2%). In this paper, we review the published data and current usage of this innovative drug developed from a preexisting effective stomach medication that essentially has few side effects.
Mechanism of action for gastric mucosa
The pharmacological action of rebamipide for gastric mucosal injury is roughly divided into an action related to the protection of the gastric mucosa, which promotes healing of the mucosal injury, and actions related to anti-inflammation and the suppression of free radicals.29–32
A dose-dependent increase in prostaglandin E2 in the gastric mucosa was observed for rebamipide when it was intraperitoneally administered to rats.1Rebamipide also increased the biosynthetic enzyme activity of the mucosal macromolecular glycoprotein and increased the amount of soluble gastric mucus in rats.33
In terms of the effect on free radicals, rebamipide was shown by electron spin resonance to scavenge hydroxyl radicals, which are very harmful reactive oxygen species that cause cell injury and lipid peroxidation.6 In rat neutrophils, rebamipide inhibits superoxide production induced by formyl-methionyl-leucyl-phenylalanine, a membrane receptor stimulator.34
The anti-inflammatory effects of rebamipide include a suppressive action on the infiltration of inflammatory cells into the gastric mucosa and on inflammatory cytokines.35 Rebamipide has been shown to inhibit increased interleukin (IL)-8 production induced by H. pylori irritation in cultured gastric cancer cells, which are derived from the gastric mucosa epithelium.36 In addition, rebamipide inhibited gastric mucosal injury and myeloperoxidase activity, which serves as an indicator of the infiltration of neutrophils across the gastric mucosa in an indomethacin-induced ulcer model.37,38 In an ischemia–reperfusion model, rebamipide inhibited mucosal injury and myeloperoxidase activity in the gastric mucosa.38These effects are related to the concentration of rebamipide in the gastric mucosa, which results from local penetration, as the blood levels and systemic distribution of rebamipide were shown to have little effect on its antioxidative and antineutrophilic activities.39
Therapeutic effect on gastric ulcers and gastritis
Rebamipide promoted the healing of a gastric mucosal injury in a rat acetic acid ulcer model.2 Recurrence of gastric mucosal injury was shown to be inhibited by the administration of rebamipide in the chronic ulcer model.40 When subjective and objective symptoms were examined in human subjects, the improvement rate for patients with marked or moderate improvement was found to be 76%.41 Follow-up of cases that were healed after the administration of rebamipide showed that there was a very low recurrence rate of a gastric mucosal injury of 6%.41An investigation of the efficacy of gastritis caused by non-steroidal anti-inflammatory drugs in healthy individuals demonstrated that rebamipide significantly inhibited gastric mucosal injury, erosion, and hemorrhage induced by indomethacin.42 Rebamipide has also been shown to contribute to the healing of artificial ulcers induced by endoscopic submucosal dissection for early-stage gastric cancer.43,44
Corneal and conjunctival mucin
Mucin on the ocular surface is divided into membrane-associated mucins (MUC1, MUC4, MUC16), which are expressed on the apical surface of the corneal and conjunctival epithelia, and the secreted-type mucin (MUC5AC), which is produced by conjunctival goblet cells and released into the tear fluid.21,45,46Membrane-associated mucins serve as a barrier by preventing contact with pathogens and foreign substances on the corneal surface. They also play an important role in improving the lubricating property of the corneal surface.45,46 The secreted-type mucin contributes to the stability of tear fluid by interacting with the membrane-associated mucin.45,46
With regard to its effect on membrane-associated mucin, rebamipide upregulates the gene expression of MUC1, MUC4, and MUC16, in addition to increasing the expression of protein in the cultured human corneal epithelial cells.47 For the secreted-type mucin, the amount of MUC5AC in the tear fluid has been shown to increase in an aqueous tear-deficient model following the instillation of a rebamipide ophthalmic suspension.22 Examination of the total mucin content in a rabbit eye model demonstrated that there was an increase in the corneal and conjunctival mucin content after the administration of a rebamipide ophthalmic solution.18
Rebamipide increased the secretion of both membrane-associated and secreted-type mucins through mucin production in the conjunctival goblet cells, and in the corneal epithelial cells.23–25Although the lack of a complete understanding of ocular mucin expression led to the elimination of mucin deficiency as a definitive entity in dry eye syndrome,46 the increase of secretory mucin by rebamipide is related to tear film stability through the enhancement of mucin expression,48 which might show another aspect of dry eye syndrome.
Conjunctival goblet cells
Secreted-type mucin is produced and secreted by conjunctival goblet cells. A decrease in the goblet cell number, which has been reported in dry eye patients, is thought to be one of the causes of the onset and exacerbation of dry eye.49 Investigations of the effect of rebamipide on the conjunctival goblet cell count using impression cytology found that a rebamipide ophthalmic suspension increased goblet cell count in normal rabbits (Figure 2).50
Effect of rebamipide on conjunctival goblet cells in rabbit.
Corneal and conjunctival epithelial damage
Based on the state of the tear fluid, dry eye is divided into an aqueous-deficient type and an evaporative type.51 In aqueous-deficient dry eye, the tear fluid supply from the lacrimal glands decreases and the tear exchange declines, leading to a deterioration in tear quality, such as high osmolality due to Sjögren’s syndrome.51 Evaporative dry eye, on the other hand, is caused by decreased tear stability due to various factors. One factor behind decreased tear stability is related to the decreased lubrication of the ocular surface caused by the decreased mucin secretion.52
The effect of a rebamipide ophthalmic suspension on corneal epithelial damage due to aqueous deficiency was investigated using a rat model in which the exorbital lacrimal glands were removed. The findings demonstrated that rebamipide significantly improved the corneal epithelial damage.53 Urashima et al18further examined the corneal and conjunctival epithelial damage in N-acetylcysteine-treated rabbit eyes, which causes a mucin deficiency condition on the ocular surface, and demonstrated that rebamipide significantly improved the corneal and conjunctival epithelial damage.
Microvilli on the corneal and conjunctival surface contribute to the stabilization of the tear fluid by serving as a scaffold for the localization of mucin. In dry eye patients, it has been reported that microvilli decrease and become irregular, with the decreases in tear stability occurring in conjunction with the microvilli decrease.54 A further study that investigated the effect of rebamipide on corneal and conjunctival microvilli found that rebamipide inhibited the microvilli damage in a N-acetylcysteine-treated rabbit model (Figure 3).55
Effect of rebamipide on microscopic structure in rabbit cornea after the application of N-acetylcysteine.
Overall, these findings suggest that a rebamipide ophthalmic suspension is not only effective for corneal epithelial damage due to tear deficiency and decreased mucin, but also for restoration of the corneal and conjunctival surface microstructure that contribute to the tear stability.
Inhibition of ocular surface inflammation
In 2007, the Dry Eye Workshop published a definition of dry eye that stated, “it is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface,” which emphasizes the inflammatory response.51 It is thought that the high osmolarity of the tear film is due to decreased tear secretion and increased tear evaporation. Thus, the net result is that the increased osmolarity causes inflammation of the ocular surface.
In a study using cultured human corneal epithelial cells,56 rebamipide inhibited IL-6 and IL-8 production induced by tumor necrosis factor alpha (TNF-α). These findings suggested that the mechanism responsible for the inhibition was the inhibition of NFκB activation. The tight junctions that exist between the corneal epithelial cells serve an important function as a barrier for deeper corneal tissue. A further study used electrical resistance and the expression of ZO-1, which is a tight junction protein, as indicators of the effect of rebamipide on the inflammatory cytokine-caused damage to tight junctions.51 The study results demonstrated that rebamipide had an inhibitory effect on TNF-α-induced decreased electrical resistance, in addition to having an inhibitory effect on decreased ZO-1 (occluding) expression. Furthermore, this study also found that a rebamipide ophthalmic suspension reversed the decrease in ZO-1 expression in the corneal epithelium in a rat dry eye model in vivo.53
Recently, Ueta et al57 reported that rebamipide significantly attenuated the production of inflammatory cytokines and downregulated the messenger ribonucleic acid level of these cytokines. This study showed that the infiltration of eosinophils was suppressed in a dose-dependent manner. Based on Rebamipide’s ability to modify epithelial cell functions, the authors suggested that this may open new strategies for treating human ocular surface inflammation, including allergic conjunctivitis and dry eye diseases.57
Rebamipide for clinical application
It has not been long since the rebamipide ophthalmic suspension was launched; however, several reports on its clinical application have been published.58–65 The study design and patient numbers adopted in those papers are different, and those characteristics were summarized in Table 1. We will introduce these reports in this section.
Comparison of the clinical reports introduced in this review
Rebamipide for dry eye syndrome
Randomized, double-masked, placebo-controlled, multicenter, and parallel-group clinical trials for rebamipide treatment of the human ocular surface are currently being conducted.58,57 Kinoshita et al58reported improvements of the fluorescein corneal staining score, lissamine green conjunctival staining score, and tear film break-up time score during their investigation of the rebamipide dose response, although they also found no significant difference for Schirmer’s test values between the rebamipide and placebo groups. The authors reported that dry eye-related ocular symptom scores and the patients’ overall treatment impression showed significant improvements in the 1% and 2% rebamipide groups. They confirmed the efficacy findings of their Phase II study results and demonstrated the superiority of 2% rebamipide to the 0.1% sodium hyaluronate.59Additionally, in a subsequent Phase III study that compared 2% rebamipide with 0.1% sodium hyaluronate, Kinoshita et al59 demonstrated that there were no adverse events with either 2% rebamipide or 0.1% sodium hyaluronate similar to those associated with the benzalkonium chloride preservative. However, the authors considered the advantage of the rebamipide ophthalmic suspension, in that it does not contain preservatives, which can cause destabilization of the tear film, disruption of the corneal epithelium, a decrease of the density of the goblet cells, conjunctival squamous metaplasia with apoptosis, and damage to the deeper ocular tissues. The most frequently observed adverse event for the rebamipide ophthalmic suspension in the Kinoshita et al59 Phase III study was dysgeusia (bitter taste); however, this was only observed in 9.7% of the 2% rebamipide group.
There is a poor correlation between the symptoms and signs of dry eye, as only 57% of symptomatic patients have been found to exhibit objective signs of dry eye. Thus, an assessment of efficacy using subjective measures (symptoms), as well as objective measures (signs), is particularly important to perform in patients with dry eye.
Koh et al60 reported finding significant increases in the tear film break-up time, and there were significant upward curves from the baseline in terms of the total corneal higher-order aberrations, coma-like aberrations, and spherical-like aberrations after the application of rebamipide (Figure 4). In addition, their study demonstrated that rebamipide improved tear stability, possibly leading to improved optical quality. Therefore, an assessment of optical quality and the evaluation of the mucin level can provide supportive evidence regarding the importance of mucin for the quality of vision in patients with dry eye. The authors reported in another study that a significant increase in higher-order aberrations and forward light scatter occurred 1 minute after the instillation of rebamipide suspension, which returned to the preinstillation level.61
Sequential post blink changes in corneal HOAs, representing the mean data from 26 eyes analyzed with a 4 mm diameter pupil. RMS is the difference between the measured wavefront and the reference wavefront that includes spheres and astigmatism. Reproduced …
Rebamipide for other ocular surface disorders
As we have previously discussed, the administration of topical rebamipide improves the ocular surface in dry eye. However, several previous studies have found that topical rebamipide was not only effective for dry eye patients, but also for other ocular surface disorders with or without dry eye, such as superficial limbic keratopathy (SLK), lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion.62–65
Takahashi et al62 reported that thyroid eye disease patients with SLK who received topical rebamipide all showed improvements in SLK, which showed the complete disappearance of SLK after treatment in 84.8% of patients. The authors concluded that topical rebamipide may be a first-line treatment in such patients.62
One study64 examined seven eyes in seven cases with mild lagophthalmos (three cases after eyelid surgery, two cases of incomplete facial nerve palsy, and two cases of senile ectropion); the fluorescein corneal staining score and tear break-up time were significantly improved, and the scores for the ocular symptoms, such as eye pain, dryness, blurred vision, and foreign body sensations, also significantly improved. These results were similar to those of the clinical studies conducted with the dry eye patients (Figure 5).58,59 In another study, topical rebamipide was also shown to be effective for corneal and conjunctival disorders in lid wiper epitheliopathy.63Although sodium hyaluronate and diquafosol are known to suppress inflammation, this study found that the antiinflammatory effect of rebamipide was greater than that of either of the drugs. Based on these findings, rebamipide eye drops were suggested as the first choice of treatment for patients with lid wiper epitheliopathy.63 In another case report,65 rebamipide was administered to Sjögren’s syndrome patients who had erosion in the inferior cornea after surgical punctual occlusion. After application, the corneal erosion gradually improved and completely disappeared at 4 weeks after administration, even though other existing drugs had not been able to previously treat the erosion.
Cornea of an 83-year-old female.
Conclusion
The rebamipide ophthalmic suspension was launched in January 2012 in Japan. Two years after this launch, published data have shown that this drug has been advantageous for the treatment of dry eye, as compared to other existing drugs currently being used, including lubricants. From our clinical experience of using this drug, the improvement of ocular surface conditions after its application is remarkable for the patients, especially in severe conditions. Overall, these findings confirm our belief that topical rebamipide may become the first drug of choice for some cases of dry eye syndrome. Moreover, we believe that this drug has a great potential to change the framework of treatment for ocular surface disorders in the future.
Footnotes
Disclosure
The authors report no conflicts of interest in this work.
Article information
Clin Ophthalmol. 2014; 8: 1003–1010.
Published online 2014 May 30. doi: 10.2147/OPTH.S40798
PMCID: PMC4051796
PMID: 24940041
This article has been cited by other articles in PMC.
Articles from Clinical Ophthalmology (Auckland, N.Z.) are provided here courtesy of Dove Press
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