Effects of a Long-Acting Diquafosol Ophthalmic Solution on the Ocular Surface, Tolerability, and Usability in Dry Eye Disease.

INTRODUCTION: This study aimed to investigate the tolerability of high-viscosity diquafosol tetrasodium (DQS) ophthalmic solution (DIQUAS LX; DQSLX) and examine its usability and effect on clinical findings in patients with dry eye disease (DED). METHODS: This interventional retrospective study included 66 eyes of 66 patients with DED who switched from conventional DQS to DQSLX ophthalmic solution. Tear function assessments (tear film breakup time [BUT], keratoconjunctival vital staining [VS] score), evaluations of DED symptom relief, and a four-item usability questionnaire ("comfort upon instillation," "irritation upon instillation," "eye mucus discharge," "convenience of instillation frequency") assessed using a visual analog scale from 0 (worst) to 10 (best) were administered 4 weeks after switching to DQSLX. Factors associated with drug tolerability were assessed using multiple regression analysis. RESULTS: The symptoms improved by 64.2% after switching to DQSLX. The BUT value, VS score, and the questionnaire items "comfort upon instillation" and "convenience of instillation frequency" were significantly improved after switching to DQSLX. DQSLX tolerability was reported as acceptable in 56 (84.8%) and unacceptable in 10 (15.2%) patients. Overall, DQSLX tolerability was significantly associated with "comfort upon instillation" and "convenience of instillation frequency" and tended to be associated with a VS score ≥ 1. DQSLX tolerability depended on symptom and VS score improvements and absence of excessive "eye mucus discharge" in patients with a VS score ≥ 1 (39 patients), but on "comfort upon instillation" and absence of excessive "eye mucus discharge" in patients with a VS score = 0 (27 patients). CONCLUSION: The high-viscosity DQSLX ophthalmic solution was generally considered acceptable in the study population. However, drug tolerability seemingly differed between patients with DED with and without epithelial damage. The former were affected by improvements in symptoms and clinical findings, whereas the latter were affected by comfort upon instillation. TRIAL REGISTRATION: University Hospital Medical Information Network identifier, UMIN000051390.

Modeling Heartland virus disease in mice and therapeutic intervention with 4'-fluorouridine.

Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.

Comparison of matrix metallopeptidase-9 expression following cyclosporine and diquafosol treatment in dry eye.

PURPOSE: We sought to evaluate the expression of matrix metalloproteinase-9 (MMP-9) in dry eyes treated with 0.05% cyclosporin A and 3.0% diquafosol tetrasodium. METHODS: One-hundred ninety-five eyes of 195 patients with dry eye were divided into three groups as follows: group 1, cyclosporin group (n = 69); group 2, diquafosol group (n = 59); and group 3, artificial tears eyes (n = 67). All eyes were treated and followed up for three months. Schirmer I Test, corneal staining, tear-film break-up time (TBUT), and tear-film MMP-9 content were measured at three months and compared between groups. The expression of MMP-9 was confirmed using a point-of-care test device (InflammaDry®; RPS Diagnostics, Sarasota, FL, USA) and graded as zero to four points. RESULTS: At the third month, MMP-9 expression was lower in group 1 as compared with in groups 2 and 3 (p = 0.020 and 0.006, respectively). The mean MMP-9 grade according to point-of-care testing was also lower in group 1 than in groups 2 or 3 (p = 0.002 and 0.038, respectively). MMP-9 showed a correlation with corneal staining in both groups 1 and 2 (all p < 0.001) and with Schirmer I Test and TBUT in group 1 (p = 0.018 and 0.015, respectively). CONCLUSIONS: MMP-9 expression and grade were lower after treatment with cyclosporin than after treatment with diquafosol in the dry eye disease. Anti-inflammatory treatment can decrease ocular MMP-9 levels in dry eye disease.

MMP-9 expression and grade were lower after treatment with cyclosporin than after treatment with diquafosol in the dry eye disease. Anti-inflammatory treatment can decrease ocular MMP-9 levels in dry eye disease.

Safety and efficacy of topical diquafosol for the treatment of dry eye disease: An updated meta-analysis of randomized controlled trials.

Dry eye disease (DED) is a common multi-factorial disease that is characterized by tear film instability. Diquafosol tetrasodium (DQS), an ophthalmic solution, has been shown to be beneficial in the treatment of DED. The goal of this study was to provide an update on the safety and efficacy of topical 3% DQS in treating DED patients. A thorough search for all the published randomized controlled trials (RCTs) up to March 31, 2022 in CENTRAL, PubMed, Scopus, and Google Scholar databases was performed. Data were reported as standardized mean difference (SMD) with 95% confidence interval (CI). Modified Jadad scale was used for sensitivity analysis. Funnel plot and Egger's regression test assessed the publication bias. Fourteen RCTs evaluating the safety and efficacy of topical 3% DQS treatment in DED patients were included. Eight included RCTs reported data on the DED after cataract surgery. Overall findings suggest that 3% DQS treatment in DED patients was associated with significantly better improvement at 4 weeks in tear breakup time, Schirmer test, fluorescein staining scores, and Rose Bengal staining score as compared to patients treated with others eye drops including artificial tears or 01% sodium hyaluronate. However, no significant difference in ocular surface disease index was observed. Our findings suggest that 3% DQS treatment is safer and had a superior efficacy compared to artificial tears or sodium hyaluronate for treating DED in general and DED after cataract surgery.

Impact of Diquafosol Ophthalmic Solution on Tear Film and Dry Eye Symptom in Type 2 Diabetic Dry Eye: A Pilot Study.

Purpose: Diquafosol ophthalmic solution (DQS) stimulates P2Y2 receptors on the ocular surface, which enhances mucin secretion from goblet cells. Therefore, tear film stability and hydration of the ocular surface can be achieved independent from lacrimal gland function. Methods: This prospective, open-label pilot study included 60 eyes of 30 diabetic patients diagnosed with dry eye disease (DED) and were randomly assigned to either DQS (n = 30 eyes) or hyaluronate (HA) group (n = 30 eyes). Participants in the DQS group received 3% diquafosol ophthalmic solution, whereas HA group received 0.1% sodium HA preservative-free artificial tears. The dosage for both drugs was 1 drop, 6 times per day for 4 weeks. Tear film lipid layer (TFLL), noninvasive breakup time (NITBUT), corneoconjunctival staining (CS) score, meibomian gland (MG), conjunctival hyperemia [redness score (RS)], ocular surface disease index (OSDI) was assessed and compared at baseline, day 14, and day 28. Results: Comparing baseline and day 28 measurements revealed that both groups found significant improvements in NITBUT, CS, MG quality, MG expressibility, and OSDI scores significantly (P < 0.05), in addition TFLL improvements were only found in the DQS group. At day 28, the magnitude of change in mean NITBUT was 1.74 (DQS) versus 0.31 (HA), 1.16 (DQS) versus 0.37 (HA) point grade reduction in corneoconjunctival staining score and 9.80 (DQS) versus 4.80 (HA) point grade in mean OSDI score. Conclusion: Three percent diquafosol ophthalmic solution treatment demonstrated the ability to improve the tear film dry eye parameters and clinically reduced sign and symptoms of DED in diabetic dry eye patients. Clinical Trials.gov ID: NCT04980144.

Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study.

INTRODUCTION: Diquafosol is a P2Y2 receptor agonist that has been shown to be effective in the treatment of dry eye disease (DED) in short-term studies; however, its long-term safety and effectiveness have not been evaluated in a real-world setting. METHODS: This prospective, multicentre, open-label observational study was conducted in patients with DED over 12 months. Safety endpoints included the incidence of adverse drug reactions (ADRs) and serious ADRs. Effectiveness endpoints included change from baseline in keratoconjunctival staining score, tear film break-up time (BUT) and Dry Eye-related Quality of Life Score (DEQS). RESULTS: A total of 580 patients were included, most of whom were female (82.9%). The proportion of patients who completed 12 months of observation was 55.0%, the most common reason for discontinuation was patient decision (54.6%). The incidence of ADRs was 10.7% and was highest during the first month of treatment (5.5%); no serious ADRs were reported. Compared with baseline, significant improvements in all effectiveness outcomes, including keratoconjunctival fluorescein staining score, BUT and DEQS summary score, were observed at each evaluation during the treatment period (p < 0.001). CONCLUSION: The present, real-world study showed that diquafosol 3.0% ophthalmic solution was well tolerated and effective in the long-term treatment of DED.

Effects of Preservative-free 3% Diquafosol in Patients with Pre-existing Dry Eye Disease after Cataract Surgery: A Randomized Clinical Trial.

Dry eye disease (DED) after cataract surgery has become a critical concern, and various therapeutic options have been developed. Recently, preservative-free diquafosol ophthalmic solution has been introduced; however, its therapeutic effect on DED after cataract surgery has not been reported. We investigated the efficacy of preservative-free diquafosol in patients with pre-existing DED after cataract surgery. We divided subjects who were diagnosed with DED and scheduled to undergo cataract surgery, into 3 groups (preservative-free diquafosol, group 1; preservative-containing diquafosol, group 2; preservative-free hyaluronate, group 3), and each eye drops was administered 6 times daily after surgery. Tear break up time (TBUT), Ocular Surface Disease Index (OSDI), corneal staining score, lid margin abnormality, and meibum quality improved over time in group 1. Groups 1 and 2 had significantly superior TBUT, meibomian gland dysfunction grade, and meibomian gland expressibility throughout the study period than group 3. Meibum quality of group 1 was significantly better than group 2 at 1 and 3 months after surgery. Preservative-free diquafosol showed better efficacy in treating DED after cataract surgery than preservative-containing diquafosol or preservative-free hyaluronate. Preservative-free diquafosol may serve as a reliable option for the management of patients with pre-existing DED after phacoemulsification.

Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial.

BACKGROUND: This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). METHODS: This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. RESULTS: At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by - 6.60 for CN and - 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by - 13.03 ± 19.63 for CN and - 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. CONCLUSIONS: The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. TRIAL REGISTRATION: KCT0002180 , retrospectively registered on 23 December 2016.

Tear film lipid layer increase after diquafosol instillation in dry eye patients with meibomian gland dysfunction: a randomized clinical study.

Diquafosol promotes secretion of tear fluid and mucin at the ocular surface and is administered for treatment of dry eye (DE). Tear film lipid layer is secreted from meibomian glands and stabilizes the tear film. We recently showed that diquafosol administration increased lipid layer thickness (LLT) for up to 60 min in normal human eyes. We here evaluated tear film lipid layer in DE patients (n = 47) with meibomian gland dysfunction (MGD) before as well as 30, 60, and 90 min after diquafosol administration. One drop of artificial tears or one drop of diquafosol was applied randomly to the eyes of each patient. Diquafosol significantly increased LLT at 30 (P < 0.001) and 60 (P = 0.042) min and noninvasive tear film breakup time for at least 90 min (P < 0.001 at each assessment point). Artificial tears had no such effect. Diquafosol significantly improved the tear interferometric pattern compared with artificial tears (P < 0.001 at each assessment point). A single topical administration of diquafosol thus improved LLT and tear film stability in DE patients with MGD, suggesting that diquafosol is a potential treatment not only for aqueous-deficient DE but also for evaporative DE associated with MGD.

The Protective Effect of a Topical Mucin Secretagogue on Ocular Surface Damage Induced by Airborne Carbon Black Exposure.

Purpose: Exposure to airborne particulate matter can induce ocular surface damage and inflammation. We evaluated the effects of a topical mucin secretagogue on the mitigation of ocular surface damage induced by exposure to airborne carbon black (CB). Methods: Sprague-Dawley rats were exposed to ambient CB for 2 hours twice daily for 5 days. Corneal staining score and tear lactic dehydrogenase (LDH) activity were measured to evaluate ocular surface damage. Serum immunoglobulin (Ig) G and IgE levels and the sizes of cervical lymph nodes were also measured. The expressions of interleukin (IL)-4, IL-17, and interferon (IFN)-γ were measured by Western blot analysis. Diquafosol tetrasodium was instilled six times a day for 5 days, and the extent of ocular surface damage was evaluated. Results: After exposure to airborne CB, the median corneal staining score and LDH activity were significantly increased. Serum IgG and IgE levels and the sizes of cervical lymph nodes were also significantly increased. Additionally, the expression of IL-4 and IFN-γ was elevated in the anterior segment of the eyeball. Furthermore, the expression of IL-4, IL-17, and IFN-γ was elevated in the cervical lymph nodes. When exposed to airborne black carbon, topical diquafosol tetrasodium significantly increased tear MUC5AC concentration and decreased tear LDH activity. Conclusions: Exposure to airborne CB induced ocular surface damage and increased proinflammatory cytokines in the eyes and cervical lymph nodes. Topical mucin secretagogues seem to have a protective effect on the ocular surface against exposure to airborne particulate matters.

Efficacy and Safety of Topical 3% Diquafosol Ophthalmic Solution for the Treatment of Multifactorial Dry Eye Disease: Meta-Analysis of Randomized Clinical Trials.

PURPOSE: A meta-analysis was performed to evaluate the safety and efficacy of topical 3% diquafosol in treating patients with dry eye disease (DED). METHODS: Nine qualified randomized controlled trials incorporating 1,467 patients were included. Two of the reviewers selected the studies and independently assessed the risk of bias. The outcome measures were Schirmer score, tear film break-up time (TFBUT), rose bengal staining score, and corneal fluorescein staining score. To confirm the effect of diquafosol on dryness after cataract surgery, we performed a subgroup analysis according to the presence or absence of surgery. RESULTS: We observed statistically significant improvements in scores on the Schirmer test (weighted mean difference 0.74 mm at 4 weeks; 95% CI: 0.24-1.24; I2 = 0%), fluorescein stain, rose bengal stain, and TFBUT after treatment with diquafosol compared with the group using other eye drops. As a result of the subgroup analysis of DED after cataract surgery, diquafosol was found to be more effective than the other eye drops with regard to TFBUT and rose bengal staining. CONCLUSIONS: Topical diquafosol could be an effective treatment for DED, and also for DED after cataract surgery. Further randomized controlled trials with larger sample sizes for the different clinical types of DED are warranted to determine the efficacy and limitations of diquafosol for these different clinical types of DED.

Diquafosol Sodium Inhibits Apoptosis and Inflammation of Corneal Epithelial Cells Via Activation of Erk1/2 and RSK: In Vitro and In Vivo Dry Eye Model.

Purpose: To evaluate the effect of diquafosol on corneal epithelium in a dry eye model using Transwell culture and a scopolamine-induced dry eye rat model. Methods: Desiccation stress induced in an in vitro dry eye model using human corneal epithelial cells was used, and the cells were incubated with or without diquafosol media diluted at 1:100. Reactive oxygen species (ROS) generation was measured using 2',7'-dichlorofluorescein diacetate (DCFH-DA). Apoptosis was analyzed, and levels of phosphorylated Erk1/2, phosphorylated p90RSK, phosphorylated Akt, IκB-α, and NF-κB-p65 were determined. Levels of IL-1ß, TNF-α, IL-6, IL-8, and GM-CSF were quantified. To investigate the in vivo effects of diquafosol, we induced dry eye in Wistar rats using scopolamine hydrobromide. The rats were divided into three groups: control, dry eye, and dry eye diquafosol; topical DIQUAS was applied four times daily for 28 days. We used immunohistochemistry to detect the levels of phosphorylated Erk1/2, phosphorylated p90RSK, and IL-1ß, and used the TUNEL assay in corneal tissue. Results: The distribution of highly fluorescent dichlorofluorescein and the proportion of annexin V- and PI-positive cells decreased in the diquafosol medium. Diquafosol increased the levels of phospho-Erk1/2, phospho-90RSK, phospho-Akt, and IκB-α, whereas it significantly decreased the levels of NF-κB-p65, IL-1ß, and TNF-α. In vivo, apoptosis was enhanced in dry eye group. This response was markedly reduced and the level of phosphorylated p90RSK and phosphorylated ERK1/2 were upregulated and IL-1ß was downregulated by DIQUAS. Conclusions: Diquafosol treatment reduced intracellular ROS levels, apoptosis, and inflammation, all of which were increased in the dry eye model through desiccation.

Effects of Diquafosol Ophthalmic Solution on Quality of Life in Dry Eye Assessed Using the Dry Eye-Related Quality-of-Life Score Questionnaire: Effectiveness in Patients While Reading and Using Visual Display Terminals.

PURPOSE: Diquafosol ophthalmic solution improves objective findings in the ocular surface and subjective symptoms in patients with dry eye. The Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire was developed to assess dry eye symptoms and their effects on quality of life. However, because little research using the DEQS has been reported, we evaluated the effects of diquafosol ophthalmic solution on ocular surface findings and quality of life using the DEQS in patients with dry eye. METHODS: Sixty-three patients with dry eye were assigned to the control group (artificial tears) or diquafosol group. Both groups instilled 1 drop of the solution in both eyes 6 times daily and were evaluated after 2 weeks; the diquafosol group also was instructed to be examined at 1 and 3 months. We evaluated the subjective symptoms using the DEQS, fluorescein staining score, tear film breakup time (BUT), Schirmer testing, and lower tear meniscus height with anterior-segment optical coherence tomography. RESULTS: In the diquafosol group, the fluorescein staining score, BUT, tear meniscus height, and DEQS scores improved significantly compared with before treatment in contrast to the control group. Furthermore, in the diquafosol group, the staining score and BUT improved significantly compared with the control group. Analysis of each DEQS item indicated that diquafosol ophthalmic solution relieved foreign body sensation and problems when reading and using visual display terminals compared with the control group. CONCLUSIONS: Diquafosol ophthalmic solution was effective in patients with dry eye, especially those with foreign body sensation and problems when reading and using visual display terminals.

A Clinic-based Survey of Clinical Characteristics and Practice Pattern of Dry Eye in Japan.

INTRODUCTION: The aim of this study was to investigate the clinical characteristics and practice pattern of patients with dry eye disease (DED) in eye clinics across Japan. METHODS: A multi-center, cross-sectional study was conducted among patients with DED who visited eye clinics in Japan. Subjective symptoms, patient's background, ocular surface features, and tear function were evaluated. Main outcome measures were tear break-up time (TBUT), Schirmer I value, kerato-conjunctival staining score, and dry eye symptom questionnaire score. RESULTS: Initially, 463 subjects were enrolled, and 449 cases (63 male and 386 female; mean age, 62.6 ± 15.7 years) were included in the final analysis. Overall, 94.9% of patients had a shortened TBUT (≤5 s), and 54.6% had an aqueous tear deficiency (Schirmer I value ≤5 mm). The most prevalent subtype of dry eye was aqueous-deficient dry eye, which was present in 35.0% of all patients, followed by short-BUT-type dry eye, which was seen in 26.7%. CONCLUSION: The two most common DED subtypes were aqueous-deficient and short-BUT-type dry eye. Shortened TBUT is the most common feature of dry eye, regardless of subtype. The current treatment choice mainly consisted of hyaluronic acid, two novel mucin secretagogues, diquafosol and rebamipide, and steroidal eye drops. TRIAL REGISTRATION: University Hospital Medical Information Network: UMIN (registries no. UMIN 000015890). FUNDING: Japan Dry Eye Society, Tokyo, Japan, and Santen Pharmaceutical Co., Ltd., Osaka, Japan.

The Efficacy of Diquafosol Ophthalmic Solution in Non-Sjögren and Sjögren Syndrome Dry Eye Patients Unresponsive to Artificial Tear.

PURPOSE: This study evaluates the efficacy of 3% diquafosol tetrasodium ophthalmic solution in Sjögren's syndrome (SS) and non-SS dry eye patients unresponsive to conventional artificial tear. METHODS: This retrospective study included 38 dry eye patients (11 with SS and 27 with non-SS) who were treated with 3% diquafosol due to lack of response to artificial tear treatment for more than 3 months. Signs such as tear film break-up time (TBUT), Schirmer-I test, and total ocular staining score (OSS), which consisted of corneal OSS and conjunctival OSS, were evaluated at baseline and the first visit after treatment. Symptoms were quantified using visual analog scale (VAS) and ocular surface disease index (OSDI) scores. Changes of parameters after treatment in all the patients and differences of changes in SS and non-SS were evaluated. RESULTS: In total population, total OSS and corneal OSS improved average 6 weeks after diquafosol treatment (all P < 0.05, paired t-test), although conjunctival OSS had no improvement. TBUT increased after treatment (P = 0.036), while Schirmer-I test, OSDI, and VAS showed no improvement. With respect to comparisons, total and corneal OSS improved in non-SS patients and TBUT improved in SS patients (all P < 0.05). CONCLUSIONS: Three percent diquafosol tetrasodium treatment could be considered as an additive or substitute treatment when artificial tear treatment is insufficient, as it improved OSS and TBUT. This study also demonstrated that diquafosol treatment is beneficial for TBUT improvement in SS, while it is beneficial for OSS improvement in non-SS dry eye patients.

Diquafosol sodium ophthalmic solution for the treatment of dry eye: clinical evaluation and biochemical analysis of tear composition.

PURPOSE: To evaluate the clinical efficacy of 3% diquafosol sodium ophthalmic solution for dry eye, and to analyze the concentration of tear proteins and mucin-like substances after the treatment. METHODS: Fifty eyes of 25 patients with dry eye syndrome were prospectively enrolled. The patients were treated with diquafosol solution at a dose of 1 drop in each eye 6 times daily for 4 weeks. The parameters of clinical efficacy were tear osmolarity, tear breakup time (BUT), fluorescein staining scores for the cornea and conjunctiva, Schirmer test values, and subjective symptoms evaluated using the ocular surface disease index (OSDI). Tears collected with Schirmer test strips were analyzed by high-performance liquid chromatography, and the concentrations of the total protein and the 4 major tear proteins, namely, secretory IgA, lactoferrin, lipocalin-1, lysozyme, and N-acetyl-neuraminic acid (Neu5Ac), were measured. Neu5Ac is a major sialic acid, a marker of secretory mucins. RESULTS: The BUT, keratoconjunctival staining scores, and Schirmer test values were improved with statistical significance after the treatment with diquafosol solution, while changes in the other parameters, including tear osmolarity, corneal staining scores, and OSDI scores were not significant. The Neu5Ac concentration was significantly increased, which was not accompanied by changes in tear proteins. CONCLUSIONS: Topical application of diquafosol significantly improved the clinical parameters of the BUT, keratoconjunctival staining scores, and Schirmer test values and was accompanied by increased sialic acid content in the tears of patients with dry eye.

Three percent diquafosol ophthalmic solution as an additional therapy to existing artificial tears with steroids for dry-eye patients with Sjögren's syndrome.

PURPOSE: To investigate the long-term results of 3% diquafosol ophthalmic solution as an alternative therapy to existing ophthalmic solutions, including topical immunosuppression, for the treatment of dry eye in patients with Sjögren's syndrome. METHODS: This study involved 14 female dry-eye patients (mean age: 62.4 years) with Sjögren's syndrome who insufficiently responded to their current therapy. In all patients, 3% diquafosol ophthalmic solution was administered six times daily for 12 months in substitution for artificial tears and sodium hyaluronate ophthalmic solution. Their use of corticosteroid eye drops remained unchanged from that prior to the treatment with diquafosol sodium. The subjective symptoms assessed, and ocular signs including tear meniscus radius and the tear film breakup time, and ocular-surface epithelial damage score were examined at 1, 2, 3, 4, 5, 6, 9, and 12 months after initiating treatment. RESULTS: Among the subjective symptoms, significant improvement was obtained in dryness at 2 months post treatment, in eye fatigue at 1, 2, 3, 4, and 12 months post treatment, and in pain at 1, 2, 6, and 12 months post treatment. Difficulty in opening the eye, foreign body sensation, and redness were also significantly ameliorated at various time-points. The tear meniscus radius and the tear film breakup time were significantly improved throughout the observation period, and the corneal epithelial staining scores were significantly decreased at 3 months post treatment. CONCLUSIONS: In dry-eye patients with Sjögren's syndrome, treatment with 3% diquafosol ophthalmic solution improved both symptoms and signs, and that effectiveness was maintained for 12 months.

Comparison of Topical Cyclosporine and Diquafosol Treatment in Dry Eye.

PURPOSE: To compare the treatment effects of topical cyclosporine A (CsA) and diquafosol sodium (DQS) for the treatment of moderate to severe dry eye disease (DED). METHODS: This prospective, nonrandomized, comparative study involved 60 eyes of 60 patients with moderate to severe DED who were treated with topical CsA 0.05% (group 1, 31 patients) or DQS 3% (group 2, 29 patients) in addition to artificial tears for 3 months. Before treatment, and at 1 and 3 months after treatment, the Ocular Surface Disease Index, tear breakup time, Schirmer score, tear clearance rate, and corneal and conjunctival staining scores were compared. RESULTS: Significant improvements in Ocular Surface Disease Index score, tear clearance rate, and corneal staining score were observed 1 month after treatment in group 2 (p = 0.014, p = 0.002, and p < 0.001, respectively), when compared with group 1. However, no significant differences were observed between the two groups 3 months after treatment (p > 0.05). Tear breakup times were significantly higher in group 2 compared with group 1 for the duration of the study (p < 0.001). Three months after treatment, Schirmer score was significantly higher and conjunctival staining score was significantly lower in group 1 compared with group 2 (p < 0.001). CONCLUSIONS: Both topical CsA 0.05% and DQS 3% are effective in patients with moderate to severe DED. However, the timing and degree of therapeutic effects on tear film and ocular surface parameters, as well as symptoms, can be different between the two treatments.

Diquafosol ophthalmic solution 3 %: a review of its use in dry eye.

Diquafosol ophthalmic solution 3 % (Diquas(®)) is a P2Y2 receptor agonist that promotes tear fluid and mucin secretion and is currently approved in Japan and South Korea for the treatment of dry eye. In randomized, double-blind, multicentre trials in patients with dry eye, significantly greater improvements in fluorescein and rose bengal staining scores were seen with diquafosol ophthalmic solution 3 % than with placebo, and diquafosol ophthalmic solution 3 % was noninferior to sodium hyaluronate ophthalmic solution 0.1 % in terms of the improvement in the fluorescein staining score and more effective than sodium hyaluronate ophthalmic solution 0.1 % in terms of the improvement in the rose bengal staining score. The efficacy of diquafosol ophthalmic solution 3 % in the treatment of dry eye was maintained in the longer term, with improvements also seen in subjective dry eye symptoms, and was also shown in a real-world setting. Diquafosol ophthalmic solution 3 % also demonstrated efficacy in various specific dry eye disorders, including aqueous-deficient dry eye, short tear film break-up time dry eye, obstructive meibomian gland dysfunction, dry eye following laser in situ keratomileusis surgery and dry eye following cataract surgery, as well as in contact lens wearers and visual display terminal users. Diquafosol ophthalmic solution 3 % was generally well tolerated in patients with dry eye, with eye irritation the most commonly reported adverse event. In conclusion, diquafosol ophthalmic solution 3 % is a useful option for the treatment of dry eye.

Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

PURPOSE: Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)-related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. CASE REPORTS: Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. CONCLUSIONS: Long-term treatment with topical rebamipide and diquafosol can improve dry eye in patients with cGVHD or OCP-like disease.