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Purpose: Diabetes mellitus has been associated with increased dry eye disease (DED) and exacerbates DED's pathology. This preliminary short-term study aimed to evaluate the effects of 3% Diquafosol Sodium ophthalmic solution (DQS) on ocular surface inflammation and corneal nerve density in diabetic dry eye (DDE) patients. Methods: In this perspective, participants used 1 drop of 3% DQS (Diquas; Santen Pharmaceutical Co., Ltd., Osaka, Japan) 6 times daily for 8 weeks. Non-invasive tear breakup time (NITBUT), tear film lipid layer (TFLL), conjunctival hyperemia [redness score (RS)], corneoconjunctival staining (CFS), corneal sensitivity (CS), Meibomian gland quality (MGQ) and Meibomian gland expressibility (MGEx), corneal nerve fiber density (CNFD), and Standard Patient Evaluation Eye Dryness (SPEED) questionnaire were assessed at baseline, at weeks 4, and up to 8 weeks. Matrix metalloproteinase-9 (MMP-9) of tear samples was measured at baseline and weeks 8. Results: The mean age was 61.27 ± 11.68 years. At baseline NITBUT = 5.89 ± 2.81 s, tear meniscus height = 0.17 ± 0.05 mm, TFLL = 2.74 ± 0.51, CFS = 4.35 ± 0.68, CS = 53.83 ± 9.63 mm, MMP-9 = 49.10 ± 10.42 ng/mL, RS = 1.65 ± 0.44, MGEx = 1.85 ± 0.72, MGQ = 2.65 ± 0.50, CNFD = 20.36 ± 8.20 no./mm 2 , and SPEED = 12.62 ± 3.91. At week 4, significant improvements were found in all parameters except RS (1.59 ± 0.46, P  = 0.172) and CNFD (21.46 ± 8.41, P  = 0.163). Finally, at week 8, all parameters had significant improvements. Conclusion: Preliminary short-term findings suggest that treatment of DDE patients with DQS was found to be safe and efficacious in improving dry eye parameters. In addition, inflammatory marker and corneal nerve density were significantly improved. This study was registered with ClinicalTrials.gov (NCT05193331).

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

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., Competing Interests: G.R.B. and G.R.P. are coinventors on patent WO 2019/1736002 covering the composition of matter and use of EIDD-2749 and its analogs as an antiviral treatment. All other authors declare that they have no competing interests.

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.

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., Competing Interests: None

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.

Introduction: Diquafosol is a P2Y 2 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.

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.

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.

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.

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.

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., (© 2019 S. Karger AG, Basel.)

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-1β, 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-1β, 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-1β, 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-1β 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.

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.

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.

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.

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.

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.

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.

Aims: To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in patients with dry eye in China and Singapore., Methods: A total of 497 patients with dry eye (Schirmer's test, 5 mm; fluorescein and RB score, 3 points) from China and Singapore were randomised to receive either diquafosol ophthalmic solution (diquafosol) or sodium hyaluronate ophthalmic solution (HA) at 1:1 ratio. The fluorescein staining scores and rose bengal (RB) subjective symptom scores and tear film breakup time were evaluated before treatment and 2 and 4 weeks after start of treatment., Results: In the diquafosol group, changes in fluorescein and RB scores compared with baseline at week 4 or at the time of discontinuation were -2.1±1.5 and -2.5±2.0, respectively. Compared with the HA group, changes in fluorescein score were non-inferior and changes in RB score were superior (p=0.019). In addition, diquafosol and HA improved tear film breakup time by 1.046±1.797 and 0.832±1.775 s, respectively (no significant intergroup difference). Adverse event onset rates were 16.3% (40 of 246 subjects) and 10.0% (25 of 251 subjects) in the diquafosol group and HA group, respectively, with borderline significant intergroup differences (p=0.046), while adverse drug reaction incidence rates were 12.2% (30 of 246 subjects) and 6.0% (15 of 251 subjects), respectively (p=0.019). Only mild adverse drug reactions (>2%) in the form of eye discharge, itching or irritation were observed., Conclusions: Diquafosol improved fluorescein staining score in a manner similar to HA, and significantly improved RB score compared with HA., Trial Registration Number: NCT01101984., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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.

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.

Purpose: To investigate the short- and long-term effects of diquafosol ophthalmic solution on the optical quality of the eyes in patients with aqueous-deficient dry eye., Methods: Sixteen eyes in 16 patients with mild or moderate aqueous-deficient dry eye were treated with 3% diquafosol ophthalmic solution. Ocular higher-order aberrations (HOAs) were measured with a wavefront sensor before and at 15 min after diquafosol instillation at the baseline visit and at 4 weeks after treatment initiation. Dry eye symptoms, tear break-up time (BUT), corneal/conjunctival fluorescein staining and Schirmer's test were also evaluated before and after treatment with diquafosol., Results: Treatment with diquafosol ophthalmic solution significantly improved dry eye symptoms, corneal staining and BUT. Compared with mean total HOAs at baseline (0.180 ± 0.06 μm), those at 4 weeks after treatment significantly decreased (0.148 ± 0.039 μm; p = 0.035), whereas those 15 min after diquafosol instillation at the baseline visit did not change significantly (0.170 ± 0.049 μm; p = 0.279)., Conclusions: Although no significant change in HOAs was observed as a short-term effect of a single-drop instillation of diquafosol, long-term use of diquafosol to treat aqueous-deficient dry eye reduced HOAs as well as improved corneal epithelial damage and tear film stability., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to evaluate the treatment effect of diquafosol 3% with preservative-free sodium hyaluronate 0.1% eye drops in dry eye syndrome., Methods: In total, 150 patients with dry eye syndrome were divided randomly into 3 groups. Group 1 (50 patients) was treated 4 times daily with preserved sodium hyaluronate 0.1%, group 2 (50 patients) was treated 4 times daily with diquafosol 3%, and group 3 (50 patients) was treated 4 times daily with diquafosol 3% and preservative-free sodium hyaluronate 0.1% eye drops for 3 months. Ocular surface disease index (OSDI) score, tear film break-up time, Schirmer I test, corneal fluorescein staining, and impression cytology were evaluated., Results: There were significant improvements in the OSDI score, tear film break-up time, Schirmer I score, fluorescein and Rose Bengal staining, goblet cell density, and impression cytological findings in groups 2 and 3 compared with those for group 1 in patients with dry eye syndrome at 1, 2, and 3 months (P < 0.05). There were statistically significant improvements in the OSDI score (-8.48 ± 0.97, -5.69 ± 0.78; P = 0.02), fluorescein (-1.43 ± 0.21, -1.02 ± 0.18; P = 0.03), and Rose Bengal staining (-1.12 ± 0.26, -0.75 ± 0.12; P = 0.03), goblet cell density (89.65 ± 14.39, 70.36 ± 16.75; P = 0.03), and impression cytological findings (-0.53 ± 0.12, -0.34 ± 0.90; P = 0.01) in group 3 compared with those in group 2 at 3 months., Conclusions: Treatment with diquafosol 3% with preservative-free sodium hyaluronate 0.1% was more effective than diquafosol 3% monotherapy or treatment with preserved sodium hyaluronate 0.1% in dry eye syndrome. Preservative-free sodium hyaluronate 0.1% eye drops can increase the effect of diquafosol 3% in dry eye syndrome.

Purpose: To evaluate the effect of diquafosol tetrasodium (DQS) for the treatment of persistent dry eye after laser in situ keratomileusis (LASIK)., Setting: Miyata Eye Hospital, Miyazaki, Japan., Design: Noncomparative case series., Methods: This prospective study included 30 eyes of 15 patients in whom dry eye had persisted for over 12 months after LASIK, and the symptoms had not improved with artificial tears and sodium hyaluronate treatment. In addition, treatment with DQS 3% eye drops, 6 times a day, was performed for 12 weeks. Best-corrected visual acuity, tear secretion with the Schirmer test, tear break-up time, and fluorescein and lissamine green staining scores on the cornea and conjunctiva were examined before and at 1, 4, and 12 weeks after the addition. A subjective questionnaire of 14 symptoms was also assessed before and 12 weeks after treatment., Results: The fluorescein and lissamine green staining scores significantly improved over 12 weeks; however, the best-corrected visual acuity and tear secretion did not change. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort within the area of dryness improved after the additional DQS treatment., Conclusions: The DQS treatment improved the subjective and objective symptoms of persistent dry eye after LASIK. Increased mucin production because of the addition of DQS probably improved the tear film stability and reduced the symptoms of dry eye in patients who had persistent dry eye after LASIK.

Introduction: Dry eye is a multifactorial disease of the ocular surface causing ocular discomfort and visual impairment for the patient. A variety of topical and systemic drugs are available to treat dry eye. Conventional treatments are limited to tear supplementation or improvement of ocular surface inflammation by the use of corticosteroids or cyclosporine A. Treatment of severe dry eye associated with Sjögren's syndrome (SS) is even more challenging and is designed to improve the quality and quantity of tear fluid. Diquafosol tetrasodium , a P2Y2 purinergic receptor agonist, acts via a novel mechanism by activating P2Y2 receptors of the ocular surface., Areas Covered: The aim of this review is to summarize the pharmacokinetics, and pharmacological and clinical data of 3% diquafosol tetrasodium ophthalmic solution in patients with dry eye, particularly SS. The mechanisms of impaired ocular surface due to severe dry eye, as defined by the International Dry Eye Workshop, are analyzed., Expert Opinion: Diquafosol tetrasodium provides a novel mode of action in dry eye syndrome, including SS, by stimulating the quantity and quality of tear fluid secretion via various mechanisms. In clinical trials, 3% Diquafosol tetrasodium ophthalmic solution demonstrated a good safety profile and exhibited efficacy with clinical improvement of the ocular surface in dry eye including SS.

Aims: Peripheral neuropathy (PN) is a common condition whose incidence is approximately 8% in elderly persons. Neuropathic pain (NeP) has a significant incidence in the general population and affects more than half of all patients with PN. The pathophysiology of PN is characterized by lesions of myelin-producing Schwann cells in peripheral nerves. Regeneration/protection of the myelin sheath after a nerve lesion is a fundamental element of repair in PN. Nucleotides such as uridine monophosphate (UMP) have proven to be efficacious in treating the cause of the myelin sheath lesion in several experimental and clinical models. Our objective was to evaluate clinical improvement in patients with PN and NeP treated with a combination of UMP+folic acid+vitamin B12 (Keltican)., Patients and Methods: We performed an exploratory, open-label, multicenter, study of 212 patients followed for 2 months. Pain was assessed using the painDETECT questionnaire (PDQ)., Results: The intensity of the NeP assessed at the time of the consultation progressed favorably and decreased significantly (p<0.001) in all the types of PN included. The global score for pain assessed using PDQ decreased from 17.5 points to 8.8 points at the final evaluation (p<0.001). Nonsteroidal anti-inflammatory drugs were decreased/withdrawn in 77.4% of patients., Conclusions: The combination of UMP+folic acid+vitamin B12 is effective against NeP associated with PN. It leads to statistically significant reductions not only in the total PDQ score but also in the intensity of pain, number of areas affected, and pain radiation. Furthermore, it makes it possible to reduce the dosage of concomitant medication.

Purpose: To evaluate the possible advantages of combination therapy with diquafosol tetrasodium and sodium hyaluronate for dry eye after laser in situ keratomileusis (LASIK)., Design: Prospective randomized comparative trial., Methods: A total of 206 eyes of 105 patients who underwent LASIK were enrolled in this study. Patients were randomly assigned to 1 of 4 treatment groups according to the postoperative treatment: artificial tears, sodium hyaluronate, diquafosol tetrasodium, and a combination of hyaluronate and diquafosol. Questionnaire responses reflecting subjective dry eye symptoms, uncorrected and corrected visual acuity, functional visual acuity, manifest refraction, tear break-up time, fluorescein corneal staining, Schirmer test, and corneal sensitivity were examined before and 1 week and 1 month after LASIK., Results: Distance uncorrected visual acuity was significantly better in the combination group than in the hyaluronate group 1 week and 1 month after LASIK. Near uncorrected visual acuity was significantly better in the combination group than in the artificial tear and diquafosol groups 1 week and 1 month after LASIK. Distance functional visual acuity improved significantly only in the combination group 1 month after LASIK. The Schirmer value in the combination group was significantly higher than that in the hyaluronate group at 1 month after LASIK. Subjective dry eye symptoms in the combination group improved significantly compared with those in the other groups 1 week after surgery., Conclusions: Our results suggest that hyaluronate and diquafosol combination therapy is beneficial for early stabilization of visual performance and improvement of subjective dry eye symptoms in patients after LASIK., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the preliminary long-term efficacy of diquafosol ophthalmic solution for aqueous-deficient dry eye., Methods: Fifteen patients with mild-to-moderate aqueous-deficient dry eye were enrolled. After a washout period, the patients were treated with 3 % diquafosol ophthalmic solution for 6 months. We assessed 12 subjective dry eye symptoms, corneal and conjunctival staining with fluorescein, tear film break-up time (BUT), lower tear meniscus height measured with anterior-segment optical coherence tomography, Schirmer's testing, and adverse reactions at baseline and 1, 3, and 6 months after the start of treatment., Results: Treatment with diquafosol ophthalmic solution significantly improved dry eye symptoms, corneal staining, BUT, and tear meniscus height at 1 month and maintained the effectiveness for 6 months. Conjunctival staining significantly improved 3 and 6 months after treatment. No significant adverse reactions developed., Conclusions: Prolonged use of diquafosol ophthalmic solution for 6 months produced significant improvement both subjectively (dry eye symptom score) and objectively (ocular staining score and tear function tests) for aqueous-deficient dry eye.

Purpose: To investigate the effect of diquafosol tetrasodium on tear and visual function in short break-up time (sBUT) dry eye (DE)., Methods: This interventional nonrandomized comparative study involved 11 eyes in 11 patients with sBUT DE (symptom-positive sBUT group) and 13 eyes in 13 volunteers with BUT values ≤5 s without DE symptoms (symptom-negative sBUT group). Tear function was assessed by measuring BUT and Schirmer values. Serial measurements were made of visual acuities (using a functional visual acuity measurement system) and higher-order aberrations (using a wavefront sensor). The parameters were compared before and 1 month after diquafosol tetrasodium instillation. Any changes in symptomatology after administration were also recorded., Results: After diquafosol tetrasodium administration, BUT values tended to increase in the symptom-positive sBUT group (P=0.07) and significantly increased in the symptom-negative sBUT group (P<0.05). LogMAR functional, minimal, and maximal visual acuities and higher-order aberrations significantly decreased after diquafosol tetrasodium administration in the symptom-positive sBUT group (P<0.05), while there were no significant changes in these values in the symptom-negative sBUT group (P>0.05). Diquafosol tetrasodium administration provided relief of DE symptoms in 75% of patients in the symptom-positive sBUT group., Conclusions: Diquafosol tetrasodium appeared to improve tear film stability and visual function in sBUT DE.

Introduction: There has been rapid progress in our understanding of dry eye pathogenesis, as well as the development of improved diagnostic clinical tests. Various types of dry eye treatment drugs have been developed. This review summarizes the basic and clinical research carried out in the development of diquafosol for ophthalmic use., Results: Diquafosol is a dinucleotide, purinoreceptor P2Y(2) receptor agonist. Basic pharmacological studies have shown that it acts on P2Y(2) receptors at the ocular surface, to promote tear and mucin secretion via elevated intracellular Ca(2+) concentrations. Diquafosol also improves tear and mucin secretion in experimental dry eye models. Based on the results of laboratory experiments, the authors conducted a series of clinical studies in patients with dry eye disease. Diquafosol was effective in the treatment of dry eye disease at an optimal dose of 3% six times a day. In comparison to commercially available 0.1% sodium hyaluronate ophthalmic solution, 3% diquafosol ophthalmic solution showed non-inferiority in improving corneal fluorescein staining scores and superiority in improving keratoconjunctival Rose Bengal staining scores., Conclusions: Diquafosol ophthalmic solution has a novel mechanism of action that is characterized by its stimulatory effects on tear and mucin secretion. This drug has the potential to be effective in patients with tear film instability and short break-up time type of dry eye, which are essential factors in dry eye pathogenesis.

Among the most promising of the new therapies being developed for the treatment of Cystic Fibrosis (CF) are those targeted at increasing mucosal hydration on the surface of the airways. One of these therapies, P2Y(2) receptor agonists, bypasses the defective CFTR chloride channel, and activates an alternative chloride channel. This activation results in an increase in airway surface epithelial hydration, and through these actions and effects on cilia beat frequency, increases mucociliary clearance. The pharmacology of P2Y(2) agonists has been confirmed in several preclinical and clinical studies. Denufosol tetrasodium is a novel second-generation, metabolically stable, selective P2Y(2) receptor agonist currently in Phase 3 clinical development. In radiolabelled deposition studies of P2Y(2) agonists in healthy non-smokers and smokers, approximately 7mg of a 40-mg nebulizer (PARI LC Star) load was deposited in the lungs. In a pharmacokinetic study in healthy volunteers, very limited systemic exposure was observed when doses of 200mg of denufosol were nebulized. Thus, it appears that high concentrations of denufosol can be achieved in the airways with very low systemic absorption. Denufosol has been generally well-tolerated in healthy volunteers and patients with CF. The most common adverse events were in the respiratory system, with cough having the highest frequency. Doses of 20-60mg have been evaluated in Phase 2 trials of up to 28 days duration, and superiority relative to placebo on FEV1 has been observed in patients with relatively normal lung function (FEV1 greater than or equal to 75% of predicted). The first Phase 3 trial is a comparison of denufosol 60mg and placebo in 350 patients with CF with FEV1 at study entry greater than or equal to 75% of predicted.

Pyrimidine nucleotides, including UTP, UDP and UDP-glucose, are important signaling molecules which activate G protein-coupled membrane receptors (GPCRs) of the P2Y family. Four distinct pyrimidine nucleotide-sensitive P2Y receptor subtypes have been cloned, P2Y2, P2Y4, P2Y6 and P2Y14. P2Y2 and P2Y4 receptors are activated by UTP (the P2Y2, and the rat but not the human P2Y4 receptor are also activated by ATP), the P2Y6 receptor is activated by UDP, and the P2Y14 receptor by UDP-glucose. Furthermore, non-P2Y GPCRs, the cysteinylleukotriene receptors (CysLT1R and CysLT2R) have been described to be activated by UDP in addition to activation by cysteinylleukotrienes. While P2Y2, P2Y4, and P2Y6 receptor activation results in stimulation of phospholipase C, the P2Y14 receptor is coupled to inhibition of adenylate cyclase. Derivatives and analogs of the physiological nucleotides UTP, UDP and ATP have been synthesized and evaluated in order to obtain enzymatically stable, subtype-selective agonists. The P2Y2 receptor agonists diuridine tetraphosphate (diquafosol) and the uracil-cytosine dinucleotide denufosol are currently undergoing clinical trials for dry eye disease, retinal detachment disease, upper respiratory tract symptoms, and cystic fibrosis, respectively. The first antagonists for P2Y2 and P2Y6 receptors that appear to be selective versus other P2Y receptor subtypes have recently been described. Selective antagonists for P2Y4 and P2Y14 receptors are still lacking. Uracil nucleotide-sensitive P2Y receptor subtypes may constitute future targets for the treatment of certain cancer types, vascular diseases, inflammatory diseases, and immunomodulatory intervention. They have also been proposed to play a role in neurodegenerative diseases. This article is an updated version of "P2-Pyrimidinergic Receptors and Their Ligands" by C. E. Müller published in Curr. Pharm. Des. 2002, 8, 2353-2369.

The ophthalmic formulation of diquafosol tetrasodium (INS365), a P2Y2 receptor agonist, is targeted to treat dry eye disease through rehydration of the ocular surface. Existing pharmacological therapies for dry eye disease are limited, therefore, approval of this medication is anticipated. This review summarises key findings during development and in clinical trials including clinical effectiveness and safety. The relevance of P2Y2 receptor technology to dry eye disease and the disease process is discussed.

Inspire, in collaboration with Allergan and Santen, is developing an eye-drop formulation of diquafosol tetrasodium (INS-365), a second-generation uridine nucleotide analog P2Y, receptor agonist for the potential treatment of dry eye disease. In June 2003, Inspire submitted an NDA for the treatment of dry eye, and in July 2003 the FDA granted the NDA Priority Review status. FDA action is expected in December 2003, and in January 2003 launch was expected in the first half of 2004.

Diquafosol [INS 365, KPY 998, diquafosol tetrasodium, DE 089, INS 365 Respiratory, INS 365 Ophthalmic] is a mucolytic compound that stimulates mucociliary clearance and also hydrates the mucosal surface of the lung. It is an activator of the P2Y2 receptor, which appears to be a key regulator of mucociliary clearance. Unlike the earlier P2Y2 receptor agonists such as uridine 5'-triphosphate, diquafosol is very stable chemically and does not require refrigeration or special handling. This makes diquafosol suitable for the treatment of chronic conditions. Diquafosol was originally developed at the University of North Carolina in the US. In September 2003, the US FDA announced that it accepted Inspire Pharmaceuticals' NDA filing for diquafosol tetrasodium ophthalmic solution for the treatment of dry eye. Additionally, FDA has completed a preliminary review of the NDA and issued the Filing Review Letter stating that no potential filing review issues were found during the review period. Inspire Pharmaceuticals' NDA for diquafosol has been granted priority review status, with initial FDA action expected at a target of 6 months after NDA submission. The first launch of diquafosol could potentially occur in the first quarter of 2004. Previously in January 2002, preliminary results from one of the US trials (study 104) revealed that the primary efficacy objectives of the study were not met. Data were re-evaluated and resubmitted in March 2002. Inspire Pharmaceuticals received a milestone payment from Allergan, which was not dependent on the study outcome, following the completion of study 104 and the submission of these study data. Phase II trials of diquafosol for dry eye are being conducted in Japan by Santen Pharmaceuticals. Santen projects that the compound will be launched in Japan during 2008-9. Phase I trials are also being conducted in the UK. Diquafosol eye drops activate P2Y2 receptors on the surface of the eye and inner eyelids, enhancing the natural process of tear secretion. Stimulation of tear secretion with diquafosol causes the release of salt, water, mucin and other components of the tear film, resulting in hydration of the surface of the eye. As there are no approved pharmacological therapies for dry eye, diquafosol is a potential breakthrough treatment for this disorder.

There are many disorders of pyrimidine metabolism and those that involve an alteration in uridine metabolism have neurological and systemic effects, which provide insights into the biological activity of uridine and its analogues. Studies of the metabolism and actions of pyrimidines have uncovered a wealth of information on how these endogenous metabolites modulate cell physiology. In this article, the roles for the pyrimidine nucleoside uridine and its nucleotide derivatives in the regulation of a number of biological systems are examined and benefits of further studies are outlined. An understanding of how uridine and its nucleotides modulate such vastly complicated biological systems should ultimately lead to the development of new ways for modulating human physiology in both normal and diseased states. Likely targets for therapy include the respiratory, circulatory, reproductive, and nervous systems, and the treatment of cancer and HIV infection.

The antitumor activity of a nucleotide derivative, 5'-(1,2-dipalmitoyl-sn-glycero-3-phospho)-5-fluorouridine (TJ14026), was confirmed following both intraperitoneal and oral administration against a number of murine experimental tumor systems in vivo, which included Meth A fibrosarcoma, B16 melanoma, 5-fluorouracil (5-FU) resistant P388 leukemia, P815 mastocytoma and L5178Y-ML lymphoma. Successive i.p. injections of a small dose (10 mg/kg/d x 10) or intermittent i.p. injections of a larger dose (50 mg/kg/d x 3) were equally effective against the solid form of Meth A fibrosarcoma. Intraperitoneal injection of TJ14026 prolonged the life of mice with 5-FU resistant P388 leukemia. Oral administration of TJ14026 was also effective against P815 mastocytoma and L-5178Y-ML lymphoma in the liver, an P388 leukemia metastasized to the lymph nodes. Glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels were elevated in the serum of un-treated mice bearing P815 mastocytoma but not in mice treated with TJ14026.

The effects of the antimetabolites, cytarabine (Ara-C) and 5-fluorouridine 5'-monophosphate (FUMP), encapsulated in multivesicular liposomes on formation of vitreous fibroproliferative membranes in New Zealand white (NZW) rabbits were studied. In pharmacokinetic studies, the drug half-life in the vitreous cavity was 124 hr after intravitreal administration of 1.0 mg of FUMP in liposomes. By contrast, the drug half-life after a single injection in nonliposome-treated controls was only 4.5 hr. In a heterologous dermal fibroblast model of proliferative vitreoretinopathy (PVR), there was a 92% decrease in frequency of tractional retinal detachments in rabbits receiving a single intravitreal injection of liposome-encapsulated 0.1 mg of FUMP compared with controls receiving liposomes without drug. A dose of 1 mg of Ara-C in liposome-treated rabbits was associated with only a 46% reduction in tractional detachment compared with controls. Multivesicular liposome-encapsulated FUMP may be useful for inhibiting formation of fibroproliferative membranes in the vitreous after vitreoretinal surgery.

The effect of potassium orotate in a dose of 100 mg/kg and sodium uridine monophosphate (UMP) in doses of 25, 50 and 100 mg/kg on the development of adrenaline myocardiodystrophy was studied in experiments on white rats. Preliminary administration of these drugs increases the animals' resistance to the adrenaline-induced necrotic affection of the heart. It has been noted that the animals' survival increased and the cardiac muscle status improved (according to ECG readings, biochemical findings and relative heart weight). Administration of UMP in doses of 50 and 100 mg/kg exerted a more pronounced beneficial prophylactic effect as compared with potassium orotate.

A 1-beta-D-ribofuranosyl-5-fluorouracil-resistant clone, designated L5178Y/FUR, was established in this experiment. This is one of the colonies derived from a subculture which acquired resistance to 1-beta-D-ribofuranosyl-5-fluorouracil by passaging the L5178Y cells through four sucessive episodes of culture in Fischers' medium containing 1-beta-D-ribofuranosyl-5-fluorouracil; each analog treatment was followed by recovery intervals. In this subline, IC99 values for 1-beta-D-ribofuranosyl-5-fluorouracil was 0.57 muM, which was 24 times as great as in the parent line (0.0024 muM), and this subline showed a cross resistance to 5-fluorouracil. New alkylesters of 1-beta-D-ribofuranosyl-5-fluorouracil 5'-phosphate (FUMP-alkylesters) were synthesized and their antitumor activity was examined against 1-beta-D-5-fluorouracil-sensitive and -resistant L5178Y sublines. Only hexadecylester of 1-beta-D-ribofuranosyl-5-fluorouracil 5'-phosphate was effective, not only to 1-beta-D-ribofuranosyl-5-fluorouracil line but also to 1-beta-D-ribofuranolsyl-5-fluorouracil-resistant subline. Other compounds showed cross resistant in the 1-beta-D-ribofuranosyl-5-fluorouracil-resistant cells.