Mucins, which play important roles on the ocular surface in wettability, lubrication, and barrier function, are classified into two categories: secreted mucins and membrane-associated mucins. The most important secreted mucin on the ocular surface is MUC5AC, which is secreted by the conjunctival goblet cells. In the human conjunctiva, goblet cells are present in higher concentrations in the fornix, inferior nasal bulbar, and the lid wiper on the lid margin. The number of conjunctival goblet cells and MUC5AC expression/secretion are decreased in a patient with dry eye. In Japan, drugs that stimulate mucin secretion or increase the number of conjunctival goblet cells are commercially available. A P2Y₂ receptor, diquafosol, stimulates tear fluid secretion from conjunctival epithelial cells and promotes mucin secretion from conjunctival goblet cells. Rebamipide was marketed originally as an oral therapeutic drug to treat gastritis in Japan. Topical rebamipide increases numbers of goblet cells in the bulbar conjunctiva and the lid wiper area of palpebral conjunctiva. Many researchers have reported decreases in the ocular surface mucin expression including MUC5AC secreted by goblet cells in patients with dry eye. However, it is unknown whether changes in mucin expression on the ocular surface cause or result from dry eye. Further study is needed to determine the true mechanism of dry eye disease.

This study aimed to investigate the actual use of eye drops for dry eye disease (DED), the reasons for instillation behavior, and the relationship between instillation behavior and subjective symptoms. This web-based cross-sectional study collected data on instillation behavior, medication instruction, reasons for instillation behavior, and subjective symptoms. In total, 2645 participants were enrolled. The proportion of participants who instilled at the frequency specified in the package insert (the specified frequency) was 10.2%. The most common reason for not instilling at the prescribed frequency was as-needed instillation to alleviate subjective symptoms, and 61.3% of participants instilled when feeling symptoms. The improvement in the subjective symptoms score was significantly greater in the group that regularly instilled at the specified frequency than the other group (p = 0.0027), and patients in the other group were younger and had a higher rate of contact lens use and over-the-counter eye drops use. In conclusion, most participants did not instill the DED eye drops at the specified frequency to alleviate symptoms. In order to obtain the appropriate effect of eye drops, ophthalmologists need to impress upon patients the importance of regular instillation at the frequency specified in the package insert, while taking into account patient characteristics.

Introduction DE-089C is a newly developed long-acting formulation of diquafosol ophthalmic solution with less frequent administration (three times daily) than the currently approved and clinically used diquafosol ophthalmic solution (six times daily), hereinafter referred to as DQS. DE-089C is desirable for achieving better patient adherence in clinical practice for dry eye therapy. The objective of this study was to confirm the efficacy and safety of DE-089C in patients with dry eye compared to placebo. Methods This randomized, multicenter, double-masked, placebo-controlled, parallel-group phase 3 study was conducted in Japan. Patients with aqueous-deficient dry eye satisfying Schirmer’s test I results ≤ 5 mm/5 min were included. A total of 337 patients with dry eye were randomized in an equal ratio to treatment with DE-089C or placebo ophthalmic solution, three times daily for 4 weeks. The primary endpoint for efficacy was change in fluorescein corneal staining score from baseline to week 4. The incidence of adverse drug reactions was investigated for safety evaluation. Results The background characteristics of patients in the two groups were similar. Primary endpoint of change in fluorescein corneal staining score at week 4 in the DE-089C group was significantly improved compared with the placebo group (least squares mean difference − 0.51, 95% CI − 0.754 to − 0.269, P < 0.0001). The secondary endpoint of the Lissamine green conjunctival staining score was also significantly improved in the DE-089C group compared to that in the placebo group, while other secondary endpoints were not achieved in this study. Commonly (incidence ≥ 1%) reported adverse drug reactions in the DE-089C group were eye irritation (3.6%) and eye discharge (1.8%) with mild severity, and the incidences of these two events were not higher than those in previous clinical studies on DQS. Conclusion The efficacy and safety of DE-089C administered three times daily at half the dosage of DQS in patients with dry eye were confirmed in this study. Trial Registration Japan Pharmaceutical Information Center ID, JapicCTI-205177.

Purpose: To investigate the short-term effects of 2 new secretagogue eye drops for dry eye, 3% diquafosol tetrasodium ophthalmic solution (diquafosol) and 2% rebamipide ophthalmic suspension (rebamipide), on the concentration of mucin 5AC (MUC5AC) in rabbit tear fluid and conjunctival goblet cells. Methods: One dose of artificial tears, diquafosol or rebamipide, was instilled into 8 eyes of Japanese white rabbits. MUC5AC concentration in the tear fluid was examined using the enzyme-linked immunosorbent assay 15 min after instillation and compared with 8 untreated controls. Impression cytology was performed to measure the number of periodic acid Schiff (PAS)-positive cells and the ratio of the PAS-positive area using image analysis software. Statistical comparison was performed using ANOVA with post hoc analysis with the Tukey's test. Results: After 15 min, only diquafosol significantly ( P ≤ 0.01) increased the MUC5AC level in the tear fluid. Although no drug affected the number of PAS-positive cells, the ratio of the PAS-positive area decreased significantly ( P ≤ 0.01) only in the diquafosol group. Conclusions: These data indicated that more PAS-positive MUC5AC was released into the tear fluid from the goblet cells by diquafosol than by rebamipide. There is a difference in the induction pattern of MUC5AC into the tears from the goblet cells between these eye drops.

Purpose: To investigate the correlation between the changes in the ocular surface temperature (OST) and tear film stability over soft contact lenses (SCLs). Methods: We enrolled 20 eyes of 20 normal SCL wearers (20 men; 24.4 ± 4.1 years). We used four different daily disposable SCLs: one silicone hydrogel lens (delefilcon A) and three hydrogel lenses (etafilcon A with polyvinylpyrrolidone [PVP], etafilcon A, and polymacon). OST was measured every second during 10 seconds without blinking. We defined the difference in the OST from 0 to 10 seconds as ΔOST. To evaluate tear film stability, we measured noninvasive tear break-up time (NIBUT) and tear interference patterns on the contact lenses (TIPCL) using tear film interferometry. The parameters were measured before and 15 minutes after wearing each SCL. Results: ΔOST was correlated significantly with NIBUT without (r = 0.411, P < 0.01) and with SCL (r = 0.642, P < 0.01). TIPCL grade was correlated significantly with ΔOST over SCLs (r = −0.636, P < 0.01). ΔOST was significantly smaller with silicone hydrogel delefilcon A than hydrogel etafilcon A and polymacon lenses (P < 0.05 and P < 0.01, respectively). Delefilcon A and etafilcon A with PVP lenses had significantly smaller NIBUT than etafilcon A (P < 0.05 for both comparisons). TIPCL grade of delefilcon A lens was significantly smaller than those of etafilcon A and polymacon (P < 0.01 for both comparisons). Conclusions: The changes in OST over SCLs are related to tear film stability. Measurements of OST can be used to evaluate tear film stability for SCL wearers.

Purpose: Dry eye–induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye–induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α₂δ–1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye–induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α₂δ–1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α₂δ–1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye–induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α₂δ–1 subunit. Here, we showed that pregabalin is effective for treating dry eye–induced ocular neuropathic pain even after chronic pain has been established.