Rebamipide Ophthalmic Solution Research Articles

Comparing two mucin secretagogues for the treatment of dry eye disease: a prospective randomized crossover trial

This study aimed to compare the clinical efficacy and investigate patients’ preferences for two mucin secretagogues in the treatment of dry eye disease (DED). Thirty patients with DED were randomly treated with either 3% diquafosol or 2% rebamipide ophthalmic solution for 4 weeks, followed by an additional 4-week treatment using the other eye drop after a 2-week washout period. Objective and subjective assessments, including the corneal and conjunctival staining score, tear breakup time (TBUT), Schirmer 1 test, tear osmolarity, tear matrix metalloproteinase-9 (MMP-9), lipid layer thickness (LLT) and ocular surface disease index (OSDI), were performed at baseline, 4 weeks, 6 weeks, and 10 weeks. Patient preferences were assessed based on four categories (comfort, efficacy, convenience, willingness to continue) using a questionnaire and the overall subjective satisfaction score for each drug was obtained at the end of the trial. In total, 28 eyes from 28 patients were included in the analysis. Both diquafosol and rebamipide significantly improved the OSDI (p = 0.033 and 0.034, respectively), TBUT (p < 0.001 and 0.026, respectively), and corneal (p < 0.001 and 0.001, respectively) and conjunctival (p = 0.017 and 0.042, respectively) staining after 4 weeks of treatment. An increase in Schirmer test scores was observed only after rebamipide treatment (p = 0.007). No significant changes were detected in tear osmolarity, MMP-9, and LLT following both treatments. The patients’ preference was slightly greater for diquafosol (46.4%) than rebamipide (36.7%), presumably due to rebamipide's bitter taste. The self-efficacy of both drugs and overall satisfaction scores were comparable. These findings indicate that two mucin secretagogues showed comparable effects in ameliorating symptoms and improving signs (TBUT, corneal and conjunctival staining) in patients with DED.

Benzalkonium Chloride-Induced Corneal Epithelial Injury in Rabbit Reduced by Rebamipide.

Purpose: We assessed the effect of rebamipide ophthalmic solution on corneal epithelial injury due to benzalkonium chloride (BAK) by fluorescein (FL) staining and corneal resistance (CR). Methods: After determining the absence of corneal epithelial damage by FL and CR, rebamipide ophthalmic solution (50 μL) was instilled five times, each interspaced by 5 min, into one eye of mature New Zealand white rabbits, and likewise physiological saline was instilled into the contralateral eye as the control. After 30 min, eyes were similarly treated with one of the following solutions: BAK solution 0.02%, latanoprost ophthalmic solution (0.02% BAK), or latanoprost ophthalmic solution without BAK. The presence of corneal epithelial damage was quantitated at 10, 30, and 60 min by CR after the last instillation. FL staining was also performed at 60 min after the last instillation. Results: CR ratios (%) at 60 min after the last instillation in rebamipide/BAK and rebamipide/latanoprost (0.02% BAK) groups were significantly increased by 18.3% and 25.6% compared with saline/BAK and saline/latanoprost (0.02% BAK) groups, respectively (P < 0.05). Findings by FL staining were consistent with those by CR; BAK and latanoprost with BAK groups were positive, and eyes with the most severe area and density of corneal epithelial damage (A2D2) were in the saline/BAK group. Conclusion: The rebamipide ophthalmic solution reduces the severity of corneal epithelial injury caused by BAK, an ophthalmic solution preservative.

A comparative study of rebamipide 2% and carboxy methylcellulose (CMC) 0.5% eye drop in patients with dry eyes: A randomized, hospital-based study

Aim: To compare the efficacy of 2% rebamipide and 0.5% Carboxy methylcellulose (CMC) eye drops in dry eye patients. Materials and Methods: A 100 dry eye patients were enlisted and screened. Patients were allotted randomly into 2 groups-(Group-A) 2% rebamipide or (Group-B) 0.5% Carboxy methylcellulose (CMC) ophthalmic solution, after screening and instilled as 1 drop in each eye four times a day, for about two months. The signs and symptoms were assessed -at baseline, 2, 4, and at 8-week visits. The objective signs were –“Schirmer test and Tear film break-up time” (TBUT) while subjective symptoms were dry eye related ocular symptoms (foreign body sensation, dryness, photophobia, eye pain, and blurred vision. Results: A compelling improvement was noticed in the Schirmer test and TBUT values after the treatment in the 2% rebamipide group. The patients on 2% rebamipide eye drop showed considerable improvement in dry eye related ocular symptoms, than the patients on 0.5% CMC eye drop (51% and 29% respectively) at 2 months. Conclusions: 2% rebamipide ophthalmic solution was more efficient in improving both the subjective symptoms and objective signs of dry eye in comparison to the CMC group in this 8-week study. These findings showed that 2% rebamipide is the more effective drug for dry eye. Keywords: Carboxy methylcellulose, Dry eye, Efficacy, Rebamipide.

The Effects of Rebamipide 2% Ophthalmic Solution Application on Murine Subbasal Corneal Nerves After Environmental Dry Eye Stress

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects.

Rebamipide ophthalmic solution modulates the ratio of Thelper cell 17/regulatory T cells in dry eye disease mice.

The aim of the present study was to confirm the effect of 2% rebamipide ophthalmic solution on a scopolamine-induced dry eye (DE) mouse model, and to investigate its effect on the ratio of T helper cell 17 (Th17)/regulatory T cell (Treg) numbers. C57BL/6 mice received subcutaneous injections of scopolamine and were exposed to a low-humidity environment in order to establish a DE model. Rebamipide eye drops (2%) administered four times daily for 2 weeks, significantly reduced the corneal staining scores and increased the tear film breakup time and tear production in the DE mice. Pathologically, the rebamipide restored the histological changes induced by DE in the cornea, conjunctiva and lacrimal gland. At a molecular level, it downregulated pro-inflammatory and upregulated anti-inflammatory cytokines in the conjunctiva and lacrimal gland. Furthermore, the increased Th17 and Treg levels were restored following treatment with rebamipide. In conclusion, the anti-inflammatory and Th17/Treg balance-preserving effects of rebamipide may contribute to the treatment of DE in mice.

The Effect of Rebamipide Ophthalmic Solution on Cytokine and Mucin Secretion in Culture of Conjunctival Epithelial Cells From the Cu, Zn-Superoxide Dismutase-1 (SOD-1) Knock-Down Mouse.

To evaluate the in vitro effects of 1-mM rebamipide ophthalmic solution on the expression of inflammatory cytokines and MUC5AC in Cu, Zn-superoxide dismutase-1 (SOD-1) knock-down conjunctival epithelium. Conjunctival epithelium from C57BL/6 wild-type mice was cultured and treated with rebamipide ophthalmic solution. Using cytometric bead array, we examined the levels of interleukin-(IL)-6, IL-10, IL-17, monocyte chemoattractant protein-1, interferon-γ (INF-γ), tumor necrosis factor, and IL-12p70 in the culture supernatants. The culture supernatants were obtained from the culture medium of nontreated or SOD-1 knock-down conjunctival epithelium using small interfering RNA (siRNA). In addition, ELISA was performed to ascertain the MUC5AC concentration in the culture medium. After rebamipide ophthalmic solution was applied, IL-6 concentration in the supernatants of conjunctival epithelial cells treated with and without siRNA showed a significant timewise decrease from 0 to 24 hr (963±42 to 0.07±0.05 pg/mL and 932±168 to 2.2±0.05 pg/mL, respectively) (P<0.001). Compared with baseline values, MUC5AC concentrations significantly increased 24 hr after rebamipide application to the conjunctival cultures-both with and without SOD-1 siRNA treatment (P<0.05 in both cases). Rebamipide seems to increase MUC5AC levels and suppress inflammation by decreasing IL-6 levels in mouse conjunctival epithelial cell cultures. SOD-1 siRNA-treated mouse conjunctival epithelial cell culture is a practical method for investigating changes in mucosa-associated mucins and proinflammatory cytokines in response to therapeutic interventions.

Severe Dry Eye With Combined Mechanisms is Involved in the Ocular Sequelae of SJS/TEN at the Chronic Stage.

Stevens-Johnson syndrome (SJS), and its more severe variant, toxic epidermal necrolysis (TEN), are life-threatening diseases of the skin and mucous membranes. After the acute-stage damage subsides, serious visual impairment and severe dry eye remains as ocular sequelae. At the acute stage, ocular complications occur in 77% of SJS/TEN patients. In cases with pseudomembranous formation and/or epithelial defects, the risk of ocular sequelae increases. Among 13 slit-lamp microscopy images that we obtained of SJS/TEN patients at the chronic stage, the loss of corneal epithelial stem cells and severe meibomian gland involvement were found to be the most common disorders. Severe dry eye in SJS includes three important mechanisms: (1) aqueous tear deficiency, (2) decreased wettability of corneal surface, and (3) increased evaporation. Dry eye severity in SJS patients is often underestimated when the meniscus is first observed, as the punctum is closed due to scarring or surgery. In SJS patients with severe dry eye, the dryness results in immense eye pain, and unstable tear film related to dry eye result in a change/loss of vision. For the treatment of dry eye in SJS, it is important to suppress chronic inflammation on the ocular surface, and 2% rebamipide ophthalmic solution reportedly helps to obtain ocular surface stabilization. Scleral contact lenses, as well as the newly developed limbal-rigid contact lenses, improve the patients' visual acuity and reduce symptoms related to severe dry eye. Further studies and new therapeutic methods are needed to more effectively treat dry eye in patients afflicted with SJS/TEN.

Efficacy of Rebamipide Instillation for Contact Lens Discomfort With Dry Eye.

Objective:To examine the effects of rebamipide ophthalmic solution on the symptoms, signs, and cytokine concentrations in tear fluid among soft contact lens (SCL) wearers with Dry eye disease (DED).Methods:From November 2015 to June 2017, this open-label, single-arm study examined 40 eyes of 20 SCL wearers with DED who had been using daily disposable SCLs for >3 months (mean age, 30.0±8.33 years; range, 20–47 years). Signs, symptoms, and cytokine concentrations were assessed before and 4 weeks after starting 2% rebamipide ophthalmic solution 4 times/day. Dry eye disease was diagnosed according to: compromised tear dynamics (Schirmer test ≤5 mm or tear break-up time (TBUT) ≤5 sec); ocular surface abnormalities (positive vital staining with fluorescein or lissamine green); and presence of symptoms. Touch thresholds using a Cochet-Bonnet anesthesiometer were also determined for the cornea and conjunctivae. Symptoms were assessed using the 12-item Ocular Surface Disease Index questionnaire. Concentrations of cytokines in tear fluid were measured.Results:Significant improvements in signs were seen for TBUT, surface abnormalities, and touch thresholds. Ocular Surface Disease Index scores likewise improved significantly in all the 12 items. Of the cytokines measured, only interleukin-1β, interleukin-8, and monocyte chemotactic protein-1 were found in ≥60% of tear samples, with no significant differences in concentrations before and after rebamipide use.Conclusions:Rebamipide significantly improved all signs and symptoms in patients with DED who wore daily disposable SCLs. Rebamipide is effective for DED treatment with SCL wear.

The Role of 2% Rebamipide Eye Drops Related to Conjunctival Differentiation in Superoxide Dismutase-1 (Sod1) Knockout Mice.

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. 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. 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. Topical use of 2% rebamipide drops was observed to improve conjunctival epithelial differentiation and suppress keratinization in the Sod1-/- mice.

Efficacy of rebamipide 2% ophthalmic solution in the treatment of dry eyes.

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.

Evaluation of Tear Meniscus Dynamics Using Anterior Segment Swept-Source Optical Coherence Tomography After Topical Solution Instillation for Dry Eye.

To investigate tear meniscus dynamics using anterior segment swept-source optical coherence tomography (SS-OCT) after the instillation of topical solutions for dry eye. Prospective, observational, cross-sectional study. Thirty-six healthy subjects (28 men and 8 women; mean age, 34.4 ± 6.7 years) were enrolled in this study. The lower tear meniscus height, tear meniscus area, and tear meniscus volume were assessed using anterior SS-OCT. After baseline measurements, 40 μL of 0.1% sodium hyaluronate, 0.3% sodium hyaluronate, 3% diquafosol ophthalmic solution, or 2% rebamipide ophthalmic solution was instilled in one eye of 10 subjects each, whereas 40 μL saline was instilled in the other eye. Tear meniscus measurements were obtained using SS-OCT at 30 seconds and 1, 3, 5, 10, 15, 20, and 30 minutes after instillation. The tear meniscus measurements showed a significant increase until 1, 3, 10, 10, and 3 minutes after the instillation of saline, 0.1% sodium hyaluronate, 0.3% sodium hyaluronate, 3% diquafosol, and 2% rebamipide, respectively, compared with the baseline levels (P < 0.05). Compared with those after saline instillation, the tear meniscus measurements were significantly higher until 30 seconds and 3, 30, and 15 minutes after the instillation of 0.1% sodium hyaluronate, 0.3% sodium hyaluronate, 3% diquafosol, and 2% rebamipide, respectively (P < 0.05). The instillation of ophthalmic solutions for the treatment of dry eye greatly increased tear meniscus measurements in healthy subjects. Thus, SS-OCT can be a practical tool for the quantitative evaluation of early-phase tear fluid dynamics.

Intravesical Application of Rebamipide Promotes Urothelial Healing in a Rat Cystitis Model

Rebamipide is used as a topical therapeutic agent for various organs. We examined the healing effects of intravesical rebamipide on damaged urothelium in a rat model of chemically induced cystitis. Hydrochloride was injected in the bladder of female Sprague Dawley® rats to induce cystitis. On days 1 and 4 rebamipide (1 or 10mM) or vehicle was administered in the bladder and maintained for 1 hour. Histopathology, urothelial permeability, cystometrogram and nociceptive behaviors were evaluated on day 7. Also, tissue rebamipide concentrations after the 1-hour bladder instillation were quantified using high performance liquid chromatography. Intravesically administered rebamipide permeated the bladder, particularly in hydrochloride treated rats, and the pharmacologically effective tissue dose remained for greater than 6 hours. Bladder histological evaluation revealed polymorphological inflammatory cell infiltration and decreased positive staining for uroplakin 3A in hydrochloride treated rats. Scanning electron microscopy showed damaged tight junctions in the hydrochloride group. Evans blue absorption in the bladder wall was increased in hydrochloride treated rats. These findings, which were associated with urothelial injury and increased permeability, were dependently suppressed by the rebamipide treatment dose. Cystometrogram demonstrated that the intercontraction interval was shorter in hydrochloride treated rats but prolonged by rebamipide. The increased nociceptive behaviors observed after intravesical resiniferatoxin administration werealso suppressed by rebamipide. Intravesical rebamipide accelerated the repair of damaged urothelium, protected urothelial barrier function and suppressed bladder overactivity and nociception.

The Effects of 2% Rebamipide Ophthalmic Solution on the Tear Functions and Ocular Surface of the Superoxide Dismutase-1 (Sod1) Knockout Mice

To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1(-/-)) mice. Two percent Rebamipide ophthalmic solution was applied to 40-week-old male Sod1(-/-) and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), in the conjunctiva to compare the results before and after rebamipide instillations. The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1(-/-) than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1(-/-) mice. The mean IL-6, IL-17, TNF-α, and IFN-γ levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout.

Resolution of persistent corneal erosion after administration of topical rebamipide

Rebamipide is an antiulcer agent used to treat gastric ulcer and gastritis. Biological effects of rebamipide include cytoprotection, wound healing, and anti-inflammatory properties that are known to be universal for a variety of tissues in addition to gastrointestinal mucosa. The therapeutic effects of rebamipide eye drops are due to its ability to increase corneal and conjunctival mucin-like substances and improve corneal and conjunctival injury in vivo. In this paper, we report a case of Sjögren’s syndrome with complete disappearance of corneal erosion after administration of rebamipide eye drops. This was observed even though corneal erosion had not improved for 6 months after punctal occlusion surgery. The patient was a 33-year-old female, diagnosed with Sjögren’s syndrome by a salivary gland biopsy. The corneal and conjunctival surfaces were filled with dense erosions, which did not improve with topical drugs. Punctal plugs were applied several times; however, the plugs were repeatedly shed. All four puncta of both eyelids were surgically occluded, and both corneal and conjunctival erosion was clearly improved. However, the erosion in the inferior cornea of both eyes had not improved for 6 months after surgery. We used the newly approved topical rebamipide for treatment of this patient. The corneal erosion gradually improved and completely disappeared 4 weeks after administration of the drug. Dry eye sensation disappeared at the same time. Both membrane-associated mucin and secreted mucin in the ocular surface are thought to be essential for maintenance of the tear film. Induction of mucin from ocular surface epithelium could be an effective treatment in cases of dry eye caused by mucin deficiency. Through its various mechanisms, rebamipide improves ocular surface conditions. To our knowledge, this is the first clinical case report using rebamipide ophthalmic solution. This drug may provide a novel approach to treat drying diseases of the eye.